3904T1.doc

1 FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH MEETING OF THE DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY COMMITTEE 8:35 a.m. Monday, November 4, 2002 Versailles Ballroom Holiday Inn - Bethesda 8120 Wisconsin Avenue Bethesda, Maryland

2 ATTENDEES COMMITTEE MEMBERS: ROBERT S. STERN, M.D., Chairman Professor of Dermatology Beth Israel Deaconess Medical Center 330 Brookline Avenue Boston, Massachusetts 02215 KAREN M. TEMPLETON-SOMERS, Ph.D. Acting Executive Secretary Advisors and Consultants Staff Center for Drug Evaluation and Research Food and Drug Administration 5630 Fishers Lane, HFD-21 Rockville, Maryland 20857 ELIZABETH A. ABEL, M.D. Dermatology 2660 Grant Road, Suite D Mountain View, California 94040 ROBERT KATZ, M.D. Dermatology 11510 Old Georgetown Road Rockville, Maryland 20852 LLOYD E. KING, JR., M.D., Ph.D. Professor of Medicine, Dermatology Division Vanderbilt University 1301 22nd Avenue North 3900 TVC (The Vanderbilt Clinic) Nashville, Tennessee 37232-5227 PAULA KNUDSON, Consumer Representative Executive Coordinator for IRB Research and Academic Affairs The University of Texas Houston Health Science Center 1133 John Freeman Boulevard Jesse Johnes Library, Room 322 Houston, Texas 77030

3 ATTENDEES (Continued) COMMITTEE MEMBERS: (Continued) R. TODD PLOTT, M.D. Acting Industry Representative (non-voting) Vice President, Clinical Research Medicis Pharmaceutical Company 8125 N. Hayden Road Scottsdale, Arizona 85258 SHARON S. RAIMER, M.D. Professor and Chairman Department of Dermatology University of Texas Medical Branch Galveston, Texas 77550-0783 KATHLEEN Y. SAWADA, M.D. Dermatologist U.S. Naval Reserve Medical Corps Alpine Dermatology Associates P-LLC 1785 Kipling Street Lakewood, Colorado 80215 MING T. TAN, Ph.D. Professor of Biostatistics Room N9E36 University of Maryland Greenbaum Cancer Center 22 S. Greene Street Baltimore, Maryland 21201 CONSULTANTS: (voting) WILMA F. BERGFELD, M.D. Head of Clinical Research Department of Dermatology Cleveland Clinic Foundation 9500 Euclid Avenue, Room A61 Cleveland, Ohio 44195-5001 S. JAMES KILPATRICK, JR., Ph.D. Professor of Biostatistics Medical College of Virginia Virginia Commonwealth University 1101 East Marshall Street Sanger Hall, Room B-1-039-A Richmond, Virginia 23298-0032

4 ATTENDEES (Continued) CONSULTANTS: (voting) (continued) THOMAS R. TEN HAVE, Ph.D. Department of Biostatistics and Clinical Epidemiology University of Pennsylvania School of Medicine 607 Blockley Hall 423 Guardian Drive Philadelphia, Pennsylvania 19104-6021 GUEST SPEAKERS: (non-voting) ALBERT KLIGMAN, M.D. University of Pennsylvania Department of Dermatology 226 Clinical Research Building 415 Curie Boulevard Philadelphia, Pennsylvania 19104 HAROLD LEHMANN, M.D. Division of Health Sciences Informatics 2024 East Monument Street, 1-201 Baltimore, Maryland 21287-0007 JAMES J. LEYDEN, M.D. Professor of Dermatology University of Pennsylvania 2nd Floor Rhoads Pavilion 3400 Spruce Street Philadelphia, Pennsylvania 19104 PETER E. POCHI, M.D. Emeritus Professor of Dermatology Boston University 715 Albany Street, J-205 Boston, Massachusetts 02118 ALAN R. SHALITA, M.D. Chair, Department of Dermatology State University of New York Downstate Medical Center 450 Clarkson Avenue Brooklyn, New York 11203

5 ATTENDEES (Continued) FOOD AND DRUG ADMINISTRATION STAFF: MOHAMED ALOSH, Ph.D. JONCA BULL, M.D. BRENDA CARR, M.D. MARKHAM C. LUKE, M.D., Ph.D. JOSEPH PORRES, M.D., Ph.D. JONATHAN WILKIN, M.D. ALSO PRESENT: JOANNE M. FRASER, Ph.D.

6 C O N T E N T S AGENDA ITEM PAGE INTRODUCTION OF THE COMMITTEE 9 CONFLICT OF INTEREST STATEMENT by Dr. Karen Templeton-Somers 11 OPEN PUBLIC HEARING PRESENTATIONS by Dr. Joanne Fraser 14 INTRODUCTION by Dr. Jonathan Wilkin 23 OVERVIEW by Dr. Wilma Bergfeld 26 EVIDENCE OF EFFECTIVENESS OF ACNE PRODUCTS by Dr. Jonathan Wilkin 40 FDA PERSPECTIVE ON GLOBAL EVALUATION by Dr. Brenda Carr 51 QUESTIONS TO THE SPEAKERS 56 THE AMERICAN ACADEMY OF DERMATOLOGY CONSENSUS CONFERENCE REPORT ON ACNE CLASSIFICATION by Dr. Peter Pochi 77 PHYSICIANS' GLOBAL SEVERITY SCALE: WHAT CONSTITUTES SUCCESS AND THE UTILITY OF AN INFLAMMATORY ONLY SCALE by Dr. James Leyden 91 CONSIDERATIONS ON SUCCESS CRITERIA IN ACNE TRIALS by Dr. Alan Shalita 106 PROBLEMS WITH LESION COUNTS AND WHY THEY ARE STILL USEFUL by Dr. Albert Kligman 114 QUESTIONS TO THE SPEAKERS 129 STATISTICAL ANALYSES OF ACNE CLINICAL TRIAL DATA - PART ONE by Dr. Mohammed Alosh 152 QUESTIONS TO THE SPEAKER 180

7 C O N T E N T S (Continued) AGENDA ITEM PAGE STATISTICAL ANALYSES OF ACNE CLINICAL TRIAL DATA - PART TWO by Dr. Mohammed Alosh 197 QUESTIONS TO THE SPEAKER 210 COMBINATION TOPICAL PRODUCTS FOR THE TREATMENT OF ACNE VULGARIS by Dr. Markham Luke 216 LABELING FOR EFFICACY: THE CLINICAL STUDIES SECTION by Dr. Joseph Porres 219 QUESTIONS TO THE SPEAKERS 223 ACNE THERAPY: A METHODOLOGIC REVIEW by Dr. Harold Lehmann 232 QUESTIONS TO THE SPEAKER 245 COMMITTEE DISCUSSION 252

8 1 P R O C E E D I N G S 2 (8:35 a.m.) 3 DR. STERN: Good morning, everyone. I'm Robert 4 Stern. I'm chair of the advisory committee for dermatology 5 to the Food and Drug Administration. 6 Today and tomorrow morning, we'll be working with 7 everyone here to try to come up with the advice concerning 8 six areas, as listed on questions, to help the FDA in its 9 production of a draft guidance document on evaluating therapies 10 for mild to moderate acne. So our purpose here is really to 11 see how therapies for this class of acne are currently measured, 12 learn about that, think about how which ones work well and 13 poorly, and try to come up with suggestions about what are 14 the best ways so that we can understand which agents are in 15 fact effective, and then also how information about how 16 effective and in what types of acne they're effective can be 17 best transmitted to practitioners for drugs that are 18 subsequently approved for this indication. So that's what 19 we're trying to do. 20 I'm looking forward to it because acne is one of 21 my interests, but certainly not my core interest, and I'm hoping 22 to learn a lot today from our very august and learned speakers. 23 And I'd like to start with going around the room, 24 starting on my left, if everyone would introduce themselves 25 and tell me and the audience a little bit about where they're

9 1 from and what their background is. 2 DR. PLOTT: My name is Todd Plott. I'm from 3 Medicis Pharmaceutical Company in Scottsdale, Arizona. I'm 4 the Vice President of Clinical Research and Regulatory Affairs. 5 I am the Industry Representative to the committee. 6 DR. ABEL: I'm Elizabeth Abel, Clinical Professor 7 of Dermatology at Stanford University Medical School, and I'm 8 in the private practice of dermatology in Mountain View. 9 DR. TEN HAVE: Tom Ten Have. I'm Professor of 10 Biostatistics in the Department of Biostatistics and 11 Epidemiology at the University of Pennsylvania. My 12 collaborative experience has been more in the areas of 13 psychiatry and disparities research focusing on clinical 14 trials and issues regarding dropout and noncompliance, 15 nonadherence. This is a new experience for me. I am also 16 hopefully going to learn a lot here today. Thank you. 17 DR. KING: I'm Lloyd King. I am Professor of 18 Dermatology at Vanderbilt University, and I'm a member of this 19 FDA board. 20 DR. KILPATRICK: Jim Kilpatrick, biostatistics, 21 Medical College of Virginia, Virginia Commonwealth University. 22 I'm known as the joker of the pack, and so I'm neither learned 23 nor august. 24 (Laughter.) 25 MS. KNUDSON: That's a hard act to follow. I'm

10 1 Paula Knudson, and I'm an IRB administrator at the University 2 of Texas in Houston. And I've learned a lot already just by 3 reading the material that was sent. It was fascinating. 4 DR. SAWADA: And I'm Kathleen Sawada. I'm from 5 Lakewood, Colorado. I am a practicing dermatologist in 6 private practice, and I am also a recent graduate -- or I like 7 to think recent -- of the Medical College of Virginia. 8 DR. TEMPLETON-SOMERS: Karen Templeton-Somers, 9 acting Executive Secretary to the committee, FDA. 10 DR. BERGFELD: I'm Wilma Bergfeld from the 11 Departments of Dermatology and Pathology at the Cleveland 12 Clinic, and I'm acting as a consultant to this advisory 13 committee, and I've been previously on it for many years. 14 DR. TAN: I'm Ming Tan. I'm a practicing 15 biostatistician and a professor of biostatistics at the 16 University of Maryland School of Medicine. I've been with 17 the committee for several years. 18 DR. RAIMER: I'm Sharon Raimer. I'm Professor 19 of Dermatology at the University of Texas in Galveston and 20 also a member of the committee. 21 DR. KATZ: I'm Robert Katz. I'm a practicing 22 dermatologist here in Rockville, Maryland, Clinical Assistant 23 Professor of Dermatology at Georgetown, and a consultant at 24 Walter Reed Army Hospital. 25 DR. CARR: I'm Brenda Carr. I'm a medical officer

11 1 in the Division of Dermatologic and Dental Drug Products, FDA. 2 DR. WILKIN: Jonathan Wilkin. I'm Director of 3 the Division of Dermatologic and Dental Drug Products, FDA. 4 DR. BULL: Good morning. Jonca Bull. I'm the 5 Director of the Office of Drug Evaluation V. 6 DR. TEMPLETON-SOMERS: The following 7 announcement addresses the issue of conflict of interest with 8 respect to this meeting and is made a part of the record to 9 preclude even the appearance of such at this meeting. 10 Since the topics to be discussed at the meeting 11 will not have a unique impact on any particular product or 12 firm, but rather may have widespread implications with respect 13 to an entire class of products, all committee participants 14 have been screened for interests in products indicated for 15 use in the treatment of acne vulgaris and their sponsors. 16 In accordance with 18 U.S.C. 208(b)(3), Dr. Thomas 17 Ten Have and Dr. Robert Stern have been granted particular 18 matter of general applicability waivers which permit them to 19 participate fully in the matters at issue. 20 A copy of the waiver statements may be obtained 21 by submitting a written request to the agency's Freedom of 22 Information Office, room 12A-30 of the Parklawn Building. 23 Because general topics impact so many 24 institutions, it is not prudent to recite all potential 25 conflicts of interest as they apply to each member and

12 1 consultant. 2 FDA acknowledges that there may be potential 3 conflicts of interest, but because of the general nature of 4 the discussion before the committee, these potential conflicts 5 are mitigated. 6 With respect to FDA's invited guest speakers, 7 there are reported interests that we believe should be made 8 public to allow the participants to objectively evaluate their 9 comments. 10 Dr. Albert Kligman is a consultant and scientific 11 advisor for Allergan, Dermik Laboratories, and Medicis 12 Pharmaceutical, and receives $10,000 annually from each 13 company for his services. He also owns stock in each firm. 14 Dr. Peter Pochi owns stock in Pfizer. 15 Dr. James Leyden has participated in clinical 16 trials, served on advisory boards, given lectures, served as 17 a consultant, and received research grants from Bertek 18 Pharmaceuticals, Dermik Laboratories, Pharmacia and Upjohn, 19 Galderma, Medicis Pharmaceutical, Lederle Laboratories, 20 Oclassen, and Ortho Dermatologic. 21 Lastly, Dr. Alan Shalita owns stock in Johnson 22 & Johnson, Medicis Pharmaceutical, and Allergan. In addition, 23 he is a researcher, consultant, and scientific advisory for 24 Allergan, Medicis Pharmaceutical, and Stiefel. He is also 25 a consultant and scientific advisor for Dermik Laboratories

13 1 and a researcher for Johnson & Johnson. Lastly, he lectures 2 for Galderma, Dermik Laboratories, Medicis Pharmaceutical, 3 and Allergan. 4 We would also like to note for the record that 5 Dr. R. Todd Plott is participating in this meeting as a 6 non-voting acting industry representative, employed by Medicis 7 Pharmaceutical Company. Medicis Pharmaceutical is one of the 8 many firms which could be impacted by the committee's 9 discussions. 10 In the event that the discussions involve any other 11 products or firms not already on the agenda for which FDA 12 participants have a financial interest, the participants' 13 involvement and their exclusion will be noted for the record. 14 With respect to all other participants, we ask 15 in the interest of fairness that they address any current or 16 previous financial involvement with any firm whose product 17 they may wish to comment upon. 18 Thank you. 19 DR. STERN: We'll begin this morning with the open 20 public hearing. Dr. Fraser from Stiefel Research Institute. 21 DR. FRASER: Dr. Stern, members of the committee, 22 FDA representatives, and invited guests, good morning. My 23 name is Joanne Fraser. I'm the Director of Research at Stiefel 24 Research Institute which is the research arm for Stiefel 25 Laboratories.

14 1 This presentation concerns the use of acne lesion 2 counts in clinical trials. 3 Acne vulgaris is characterized by the presence 4 of papules, pustules, open and closed comedones, nodules, and 5 cysts. In clinical trials, investigators are asked to count 6 inflammatory lesions and non-inflammatory lesions. A total 7 lesion count is then calculated as the sum of the two. Total 8 lesions is used in an attempt to represent the patient's overall 9 acne condition. 10 In this presentation, I hope to convince you that 11 the variable, total lesions, is not useful in assessing the 12 efficacy of acne products and can lead to misconceptions about 13 efficacy. 14 In determining the treatment for a patient with 15 acne vulgaris, the types of lesions present is an important 16 factor. There are specific drug products to treat 17 inflammatory and non-inflammatory lesions, and there are some 18 agents that affect both. These lesions are physiologically 19 different and respond to drugs differently. 20 Currently the requirements for an approval for 21 a drug product for the indication of acne vulgaris are that 22 a significant difference from control be shown for two out 23 of three lesion types, inflammatory, non-inflammatory, and 24 total, and global severity. So where the circles are 25 intersecting represents meeting the requirement of two out

15 1 of three. 2 If a product is only active for the treatment of 3 one type of lesion, then the only requirement for approval 4 should be for that lesion type, plus global. There is a concern 5 that the patient's overall acne should look better as a result 6 of treatment, and therefore if the total lesion count improves, 7 there's some assurance of the overall effect. But global 8 severity could be used to address this concern. Using total 9 lesions for this purpose adds no information about the efficacy 10 of the product and can lead to misconceptions about efficacy. 11 This was a study of a combination product. The 12 results of the combination, each of the single agent controls 13 and vehicle are shown for inflammatory lesions, 14 non-inflammatory lesions, and total lesions. The use of total 15 lesions has no advantage over the separate analysis of 16 inflammatory and non-inflammatory lesions. In many cases, 17 the percent reduction of total lesions is essentially the 18 average of the percent reductions of non-inflammatory and 19 inflammatory lesion counts. 20 This slide shows hypothetical data for two 21 subjects. The first subject has more non-inflammatory lesions 22 and the second subject has more inflammatory lesions. The 23 percent reductions for inflammatory and non-inflammatory are 24 the same for each subject, 60 and 20. For subject 1, percent 25 reduction for total lesions, 30, is similar to the

16 1 non-inflammatory lesion percent reduction, 20, the more 2 numerous lesion type. For subject 2, total is closer to the 3 inflammatory percent reduction, the more numerous lesion type. 4 In a study of subjects similar to subject 1, a large reduction 5 in inflammatory lesions is canceled out in the total lesion 6 percent reduction because of the small change in 7 non-inflammatory lesions. 8 This slide shows two subjects from one of our 9 clinical trials. The entry criteria was at least 25 10 inflammatory lesions and 12 non-inflammatory lesions. In a 11 subject with both inflammatory and non-inflammatory lesions, 12 non-inflammatory lesions are usually more numerous. In our 13 clinical trials, approximately two-thirds of subjects have 14 had more non-inflammatory than inflammatory lesions despite 15 similar entry criteria. For these subjects, the percent 16 reduction of total lesion count is similar to the percent 17 reduction for non-inflammatory lesions, the more numerous 18 lesion type. For subject 2, substantial efficacy for 19 inflammatory lesions was canceled out in the total lesion 20 variable because of no efficacy in non-inflammatory lesions. 21 Applying the rule of two out of three, a product with results 22 like for subject 2 would not be approvable even though it has 23 substantial efficacy toward inflammatory lesions. The 24 product with results like subject 1 might be approvable for 25 acne vulgaris with only modest efficacy for inflammatory

17 1 lesions. 2 This slide shows two more subjects. The first 3 subject has more inflammatory lesions than non-inflammatory 4 lesions. The same is true, that the percent reduction for 5 total lesions is similar to the lesion type count that is more 6 numerous. Subject 2 has approximately equal numbers of 7 inflammatory and non-inflammatory lesions, with substantial 8 efficacy for inflammatory and modest efficacy for 9 non-inflammatory. Percent reduction for total lesions is 10 approximately the average. The exact average is 59. 11 This is data from a recently approved product. 12 All three lesion types were significantly different from the 13 vehicle control for percent reduction. The total lesion count 14 data adds no information about the efficacy of the product. 15 This product was approved for the treatment of acne vulgaris. 16 This is data from the first of two studies from 17 a recently approved product. In this study, all three lesion 18 types were significantly different from vehicle control. 19 Again, the total lesion count data adds no information about 20 the efficacy of the product. 21 This is the data from the second study for this 22 product. In this study only inflammatory and total lesion 23 counts were significantly different from the vehicle control. 24 The use of the total lesion count data masks the lack of 25 efficacy for non-inflammatory lesions. This product was

18 1 approved for the treatment of acne vulgaris because it met 2 the two out of three lesions requirement and global for both 3 studies. Perhaps this product would have been more accurately 4 labeled for treatment of inflammatory acne based on these 5 studies. 6 This data is included in the package insert which 7 is then available for the clinician to decide for themselves 8 how best to use this product, but regardless of the indication, 9 it seems useful to include all the data on the labeling. But 10 again, total lesion data does not add any real information. 11 Two products were recently approved, both 12 containing the same active ingredients at the same 13 concentration. Product A was approved for inflammatory acne, 14 and product B was approved for acne vulgaris in general. 15 Five studies were completed for product A and two 16 studies were completed for product B. Here are the percent 17 reductions in inflammatory lesions for each product. They 18 are quite similar in the effect on inflammatory lesions. And 19 here are the percent reductions in non-inflammatory lesions 20 for each product. Again, the results are quite similar. And 21 here are the percent reductions for total lesions. Again, 22 very similar. 23 As these products were combination products, the 24 control of interest and challenge to find a statistical 25 difference was the comparison to the benzoyl peroxide alone

19 1 control. For product A, three of five studies showed a 2 significant difference compared to BPO, and for product B, 3 both studies showed a significant difference for inflammatory 4 lesions. 5 This is the difference for the non-inflammatory 6 lesions. Neither product is more effective than benzoyl 7 peroxide for the treatment of non-inflammatory lesions. The 8 labeling for product A, which was approved for the treatment 9 of inflammatory lesions only, has a statement that the product 10 is not more effective than benzoyl peroxide for the treatment 11 of non-inflammatory lesions. The labeling for product B does 12 not include the same statement. 13 And the reason product B was approved for acne 14 vulgaris is the differences for total lesions compared to 15 benzoyl peroxide. The differences are significant in both 16 studies for product B and in only two of five studies for product 17 A. The results of the total lesions has masked the lack of 18 effect of product B for non-inflammatory lesions compared to 19 benzoyl peroxide. 20 The data in the previous slides were for the 21 comparison to benzoyl peroxide control since those were 22 combination products, but both products have substantial 23 efficacy compared to vehicle for inflammatory lesions and for 24 non-inflammatory lesions. 25 In summary, product A was approved for

20 1 inflammatory acne only. It did not meet the two out of three 2 requirement when compared to benzoyl peroxide. An exception 3 was made for the indication of inflammatory acne. Product 4 B met the two out of three rule with inflammatory and total 5 when compared to benzoyl peroxide and so was approved for the 6 indication, acne vulgaris. Both products were effective 7 against both types of lesions compared to vehicle or 8 clindamycin. 9 The labeling for product A includes percent 10 reduction results for inflammatory lesions and the statement 11 that the product is not more effective than benzoyl peroxide 12 for the treatment of non-inflammatory lesions. The labeling 13 for product B includes the percent reductions for all three 14 lesion types. There is no statement about product B not being 15 more effective than benzoyl peroxide for the treatment of 16 non-inflammatory lesions. And the difference in labeling for 17 these two products with essentially identical activity is due 18 to the results of the derived variable, total lesions. Use 19 of the variable, total lesions, has masked the lack of 20 effectiveness of product B for non-inflammatory lesions 21 compared to benzoyl peroxide. 22 In conclusion, we need the option of three target 23 lesions for products to treat acne, inflammatory, 24 non-inflammatory, and acne vulgaris when a product is effective 25 for both. And I hope I've convinced you that total lesions

21 1 is not a useful variable in assessing the efficacy of an acne 2 product. 3 Thank you. 4 DR. STERN: Could I just ask you one question? 5 DR. FRASER: Sure. 6 DR. STERN: Or two questions. One is, are you 7 then saying that you're advocating that products, when they 8 go to phase III, there should be an advance hypothesis that 9 we will prove efficacy for inflammatory acne or 10 non-inflammatory acne or both, and if it's for both, is it 11 going to be that unless you get it for both, the product is 12 not approved? Or are you advocating that if you say we want 13 to do this for both and it only makes criteria by one, that 14 in fact, since you put forward three hypotheses, that there 15 be some correction, some change in the requirements of the 16 p value for multiple comparisons? 17 So those are sort of two related questions. The 18 first is, do you just pick one of the three indications and 19 you've got to go with that to the end, meet the criteria 20 statistically? The second, if you're going to allow a 21 fall-back by another criteria other than the one you put 22 forward, how are you going to correct for the multiple 23 comparison problem? 24 DR. FRASER: Right. I believe that's correct 25 that if you set your hypothesis just for one lesion type when

22 1 you're going into the study, that would be the best way to 2 do it, but if you want the option of either one, you're going 3 to have to adjust for that statistically. 4 DR. STERN: Any other questions from the 5 committee? 6 DR. KILPATRICK: Thank you, sir. 7 It seems very obvious to me that since total equals 8 inflammatory plus non-inflammatory, total depends on these 9 two. Therefore, from a purely statistical point of view, you 10 can only have two of these three things, whatever they are. 11 So it was a given to me, before you started, that you use 12 either inflammatory or non-inflammatory because total is the 13 sum of the two. I mean, it's so obvious. 14 DR. FRASER: Right. 15 DR. KILPATRICK: So I don't know what the fuss 16 is about. But Dr. Stern asked the difficult question. 17 DR. TEN HAVE: Isn't there also a multiple 18 comparisons problem with the current approach, if you're 19 choosing two out of three? 20 DR. FRASER: Right. Currently there's no 21 statistical adjustment for the multiple -- 22 DR. TEN HAVE: Comparisons problem with the 23 current -- 24 DR. FRASER: Right. 25 DR. STERN: Thank you very much.

23 1 Is there anyone else who would like to comment 2 during the open public hearing? 3 (No response.) 4 DR. STERN: Seeing no one who wishes to do so, 5 we will go on to Dr. Jonathan Wilkin who will give an 6 introduction to why we're here today and tomorrow. 7 DR. WILKIN: Well, we are here today because there 8 are over 50 million people in the United States with acne and 9 many of these are adolescents and young adults. The burden 10 of acne, especially in this population, the physical, the 11 psychological, the quality of life issues, impels the public 12 health need for safe and effective products for acne. 13 What we're asking the committee to consider today 14 and tomorrow is how should we look at the evidence for 15 effectiveness of these products in a way that we can craft 16 this into a guidance document so that industry and academics 17 and the regulatory folks at FDA can all be working from the 18 same page. 19 To help the committee in thinking about the six 20 questions, which I should say are actually essay questions, 21 not yes or no questions, we have multiple speakers. We've 22 asked Dr. Bergfeld who, as she mentioned, is an alumna of DODAC, 23 to give an overview of acne, and the dermatologists always 24 gain something from her insights, but especially helpful I 25 think will be for the statisticians and others on the committee

24 1 who might need an acne 101 so that they know what the different 2 lesion types are. 3 I'll follow up with sort of an historical view 4 of how FDA has viewed the two primary efficacy endpoints of 5 lesion counts and global and also give some work that I did 6 before I came to FDA which actually looks at the relationship 7 between acne counts and global. 8 And then the speakers who follow immediately will 9 be primarily talking about the global severity scale, Dr. Carr, 10 Dr. Pochi, and then Dr. Leyden, Dr. Shalita, and Dr. Kligman 11 will be talking about severity scales but also lesion counts 12 and what their views are. 13 One of the important aspects of all of this is 14 not just what the primary efficacy endpoints might be but how 15 do we analyze the data, what are the statistical methodological 16 issues, and Dr. Alosh will be presenting that. 17 Dr. Luke will speak to some of the interesting 18 aspects of combination topical products and how we look at 19 efficacy. 20 And then we will end up the FDA's portion with 21 Dr. Porres describing what kind of information gets crafted 22 into the package insert which describes efficacy outcomes, 23 and we'll be asking the committee for suggestions on how we 24 might improve that to better convey to the clinician and to 25 the patient and to improve the patient-clinician communication

25 1 on what might the expectations be for acne therapy. 2 Then finally this afternoon Dr. Lehmann, who has 3 conducted research under a contract to the Agency for Health 4 Care Research and Quality, which is a sister organization in 5 our Department of Health and Human Services, will have some 6 thoughts on how to get some useful information out of acne 7 trials that might even be in addition to what we're going to 8 talk about earlier in the day. 9 And then we're looking to tomorrow to actually 10 have the questions deliberated. 11 DR. STERN: Thank you very much. 12 Now I'm very pleased to have Wilma Bergfeld speak 13 to us about acne. 14 DR. BERGFELD: Thank you very much. I'm 15 delighted to be back at the FDA. I always love coming back. 16 This is a very important committee activity. 17 What I've been asked to do is to paint a picture 18 of acne today and perhaps reflect a little bit about what was 19 going on yesterday. 20 It's important to realize that acne represents 21 4 percent of all dermatological disease and it, as you heard, 22 involves a population group that is very large, basically 50 23 million. This represents the demographics of acne, mainly 24 a disease of youth, as you can see here in the white, 12- to 25 24-year-olds representing 40 million plus, whereas 25- to

26 1 35-year-olds, about 3.5 or 3.8 million, and a very large growing 2 group is the adult group which is usually women 35 to 44 years 3 of age. 4 Now, you heard from Jonathan Wilkin that it is 5 very important that we address acne, being a major disease 6 for us in dermatology and as a health issue, but also it's 7 very important because of the psychological and economic 8 impact. There have been numerous studies done over the last 9 20 years that display that those who have moderate to severe 10 acne greatly suffer in their life, psychologically as well 11 as economically. You will note here that they have reduced 12 self-esteem, confidence, and body image, which then reflects 13 in their ability to perform, to reach the essence of their 14 life and their desires for success, but it also limits their 15 lifestyles, their interpersonal relationships, and 16 interestingly enough, has been noted to reduce their 17 employment. They're more unemployable. And certainly adults 18 are more affected than the young, but all are affected. 19 Now, the problem that we see today in dermatology 20 is that there's a growing desire for the patient, the parents 21 of the patient to reach dermatologists, and there's a growing 22 need for more dermatologists to be in practice. And this is 23 reflected by patient preference as well as the growing addition 24 of dermatologists to a variety of HMOs and other medical groups. 25 And patients now have great access to dermatologists through

27 1 a variety of a different health care programs. So we are seeing 2 that acne is one of our number one diseases to treat. We are 3 seeing a growing population that's affected, one that is 4 growing in its age as well, and also the fact that we do not 5 have a great enough work force to take care of these patients. 6 What we know about acne. Again, here is another 7 graph or table demonstrating it is a major disease for 8 dermatologists, but there are other physicians who care for 9 the disease, but the dermatologists are the key caretakers. 10 Now, the acne classification is rather classic. 11 comedones, which is blackheads, papulopustules, which are 12 erythematous papules and pustules, and then cysts. And the 13 dermatologists have classically defined these as being mild, 14 moderate, and severe and also include the sites of involvement, 15 which are usually face and trunk and occasionally arms and 16 buttock. 17 I'd like to show you a number of pictures of mild 18 to moderate acne and then end with some very serious forms 19 of acne. This is a comedonal acne in an African American black 20 young athlete showing both blackheads, comedones, as well as 21 inflammatory papules. 22 A caucasian with comedones and milia which are 23 closed comedones, whiteheads, around the mouth, cheeks with 24 cheek scarring. 25 An Indian young woman demonstrating a number of

28 1 features, namely hirsutism as well as acne, with inflammatory 2 papules and scars on the cheek. 3 A little less well demonstrated here, but a lot 4 of inflammatory lesions on the cheek and around the chin. 5 A male demonstrating the inflammatory form of acne 6 and the classic distribution on cheeks and chin. 7 A cystic form of acne in a little bit older 8 individual who has excoriated these lesions. 9 And a more severe form which is the erosive 10 pustular form which is a very serious disorder for us. 11 Now we know that acne affects almost all age groups 12 and it certainly has been noted in the neonate. Usually they 13 are comedones and they're non-scarring. In the young infant, 14 especially the male infant, we can see papulopustular lesions. 15 These do leave scarring, and the teenage acne usually is face 16 and trunk and is male dominant and it can induce scarring. 17 And now the adult acne which is mainly in females, but males 18 do also have this, and this is a late onset usually or it can 19 be chronic from teenage through their mid-years up to about 20 60. 21 Now, it's important when a dermatologist or a 22 physician sees a patient with acne, that they take the 23 appropriate history. There's no doubt that it's familial. 24 We do see it run in families. It's important for us to examine 25 the patient and ask some very pertinent questions around family

29 1 history, as well as androgen excess and diabetes. 2 As you've already heard, we do do lesion typing 3 as well as location of lesions, and we do grade these acne 4 patients. This then evolves into developing therapeutic 5 options, which are discussed with the patient, along with the 6 adverse events that might occur, as well as the expectation, 7 and the therapy is then given. 8 Now, the therapy is aimed at a variety of different 9 areas of the acne pathogenesis, namely getting rid of the 10 blackheads and whiteheads which are thought to be the primary 11 lesions, especially what we call the microcomedones, getting 12 rid of the microorganisms that live in these lesions, getting 13 rid of the inflammation. And a group of these, at least 14 one-third of these patients, especially the female, have 15 androgen excess, and they have androgen stimulation of the 16 sebaceous gland which then induces or exaggerates the acne. 17 And certainly external irritants can either worsen the acne 18 or, in some instances, can actually induce acne. 19 Now, if we look specifically at how we do this 20 and why we do this, we want to get right of the P. acnes because 21 it produces inflammatory lipids, which are fatty acids, which 22 then release cytokines. We want to get rid of the inflammation 23 because there is a cascade of cytokines which then ends up 24 with tissue destruction. We attempt to get rid of the 25 keratinizing defects which are in the hair follicle canal way

30 1 plugging the follicle, thus inducing the blackhead, the 2 micro-blackhead. And we also want to reduce the size and 3 function of the sebaceous gland from putting out its oil, or 4 sebum. And we certainly want to reduce, when present, the 5 hormonal influence on the oil gland, the sebaceous gland, and 6 in doing so, we can improve the acne. So as you can see, when 7 we look at all these various targets, we may be using multiple 8 therapies to achieve this end. 9 So what might we use for the blackheads, 10 whiteheads, or even milia, which are the closed blackheads? 11 We would use a variety of agents, the retinoids being the 12 leading ones usually used topically. They can reduce the size 13 and the function of the oil gland, reduce the microorganisms, 14 reduce the inflammation. Benzoyl peroxide can be used as well, 15 which has similar effects in reducing the organism. And there 16 are a number of other acids, both fruit acids, natural acids, 17 that can be used for similar purposes. 18 When we're looking at inflammatory acne with 19 papules and pustules, however, we're looking at using more, 20 I guess, important drugs in some aspects in the fact that 21 they're mostly antibiotics and they may also include the use 22 of oral Accutane. But for antimicrobial, we can use the 23 benzoyl peroxide agents because they certainly do have some 24 activity in that area, as well as some of the natural topical 25 acids, but we do use commonly topical antibiotics in the form

31 1 of erythromycin and clindamycin, and we also use oral 2 antibiotics in the form of minocycline, tetracycline, and more 3 recently zithromycin. 4 We use, as I said, oral and topical retinoids. 5 We also use, in very severe forms, 6 anti-inflammatory agents which would include corticosteroids 7 in the very, very severe forms of this disease. 8 We do also use anti-androgens to reduce the 9 testosterone or androgen effect on the oil gland, and these 10 would fall into groups such as estrogens in the female, 11 spironolactone, and flutamide. Mainly those are used in the 12 female. 13 We also identify in this group, especially the 14 female, an androgen excess syndrome related to insulin 15 resistance, and this leads us into other therapies such as 16 metformin. 17 And we can also use vitamins and minerals for some 18 of their anti-inflammatory as well as anti-androgen activity. 19 Now, the tretinoin effects. I'd just like to go 20 over them because they are so broad and affect many of the 21 targets that we need to hit. We can reduce the scaling that 22 occurs in the hair follicle which plugs it up. We can alter 23 the microorganisms by reducing them. We can resolve the early 24 comedones and the microcomedones, the milia, with these 25 particular agents. We can prevent new lesions, and we can

32 1 enhance, which is very important, penetration of other drugs. 2 Now, here is the list of the topical retinoids 3 that we do have available to us, and as you can see, there 4 are numerous ones and they come in all concentrations and 5 vehicles, all of which assist us in treating topically these 6 microcomedones and comedones. 7 Now, when we look at their efficacy, using two 8 different ones -- not to discuss their comparison, but using 9 two different ones -- adapalene and also Retin A, we can see 10 that we can get greater than 50 percent reduction of lesions, 11 which is very important. You can see that some are better 12 at inflammatory and some are better at non-inflammatory, but 13 the bottom line is that they reduce greater than 50 percent 14 the inflammatory and non-inflammatory lesions. 15 But we also have a problem with topical retinoids 16 in the fact that they are irritants, and we have had a hard 17 time reducing the irritancy of these because over time, using 18 these two same drugs, we can see that the irritation is about 19 the same. And irritation, as I mentioned, is, one, painful 20 but also it can induce more acne. 21 Using some of the natural acids -- and this happens 22 to be one, dicarboxylic acid -- we can also have some effect 23 on bacteria anti-inflammatory activities, as well as reducing 24 keratinization. So we have other options other than the 25 tretinoins, but the tretinoins have been our base therapy.

33 1 As I mentioned, antimicrobial therapy would 2 include benzoyl peroxide. It is a potent bactericidal agent. 3 We also use it as an agent that kills all in my practice. 4 And you can use it up to 10 percent, and it can reduce blackheads 5 and also papules and pustules. It reduces the infectious agent 6 P. acnes, but it also can induce irritation to the skin. And 7 that reflects in dryness and pain, scaling. We use topical 8 antibiotics, again erythromycin, clindamycin, specifically 9 for the same reasons, and oral antibiotics. 10 This is a study done very early by Kligman, and 11 this demonstrates the activity of benzoyl peroxide on P. acnes 12 in red, reducing it basically 60 percent plus, as well as the 13 fatty acids which are produced by the sebaceous gland. So 14 it is an effective therapy too. 15 Now, one of the problems that we've had and, in 16 fact, discussed here at the FDA is the bacterial resistance 17 to some of the antibacterial agents that we use in dermatology, 18 and this is a growing problem for us today in practice because 19 we are having more patients present to us who fail to respond 20 to what we consider our basic regimens and this is something 21 that we're striving to overcome. 22 Now, I wanted to touch very briefly on androgen 23 activity because the circulating, as well as the androgens 24 present in the tissue and the target organ, namely the sebaceous 25 gland and the hair follicle, do stimulate acne. We know that

34 1 the sebaceous gland in particular has androgen receptors. 2 So using anti-androgen therapy selectively in both males and 3 females can be exceedingly helpful, especially in the more 4 resistant forms of acne. 5 Now, there have been some studies, and the classic 6 studies have been looking at circulating androgens. And one 7 done by Lucky in the 1980s demonstrated that females with very 8 persistent papulopustular acne had elevations of free and total 9 testosterone and less commonly elevated DHEAS, which is an 10 adrenal androgen. 11 This followed a study done by Ortho regarding the 12 Ortho Tri-Cyclen that's used in acne in females, and this was 13 a study in 250 female acne patients with moderate acne. What 14 it demonstrated was that 83 percent versus the control which 15 had 63 percent improvement -- that 83 percent improvement of 16 acne was seen in this study. When measuring circulating 17 androgens, it was noted that the testosterone levels were 18 reduced. As I just previously mentioned, these testosterone 19 levels are elevated in some of these acne females. And there 20 was also an increase in sex-binding hormone which is important 21 because it binds the testosterone. 22 At the Cleveland Clinic, we too have studied 23 androgens and androgen excess presentation, one being acne. 24 And we noted that it was common for us to have elevations 25 of total and free testosterone, as well as the adrenal androgen.

35 1 And the reason for pointing this out at this time is that 2 testosterone can be made by either the ovaries or the adrenal 3 gland, and the birth control pills would affect mainly a 4 suppression of the ovarian testosterone. However, if the acne 5 was stemming from the adrenal gland, one would have to suppress 6 the adrenal gland as well. 7 So, hormonal therapy is generally reserved only 8 for females, and we use a variety of therapies, namely the 9 low dose birth control pills. We can use anti-androgens in 10 the form of spironolactone, and we can use corticosteroids, 11 especially if the adrenal gland is involved. We also have 12 the opportunity in selected patients of using Accutane. It 13 is more commonly used today in males than females for this 14 form of acne. And we also would be using anti-inflammatories 15 because this is an inflammatory disease and one needs to also 16 address that. 17 So when we look at the therapeutic options that 18 we have in acne, one has to address the fact that we are after 19 multiple targets that induce the final lesion. So we have 20 a number of agents that fall under getting rid of the blackhead 21 or the whitehead, or the milia, the closed comedone, and these 22 include the retinoids, benzoyl peroxide, sulfur, and some of 23 the natural acids. 24 We have a number of agents that we have available 25 to reduce sebum, or oil production by the oil gland, namely

36 1 the retinoids, the anti-androgens, the low dose birth control 2 pills, and we could add corticosteroids here. 3 We have agents to reduce the main organism that 4 produces acne. At least in our belief it produces acne. And 5 there are a variety of topical and oral antibiotics, the 6 retinoids, benzoyl peroxide. 7 And the inflammation can also be reduced by oral 8 antibiotics and retinoids. 9 Now, what we are looking at today is the fact that 10 because of the bacterial resistance, we are looking towards 11 what are the effects of combining benzoyl peroxide with a number 12 of antibiotics, and they seem to be very good. In fact, not 13 only are they combined with oral antibiotics, but also zinc. 14 So this is the future for us in dermatology, at least in the 15 topicals, because of bacterial resistance. There is very 16 little resistance to benzoyl peroxide, in fact, none to date, 17 but there is resistance to erythromycin and the 18 tetracycline-like products. So combining them, we then get 19 rid of our resistance. 20 Now, what is important to us in dermatology is 21 the fact that no one gets better with one or two prescriptions, 22 go off, and come back never again. We need to see these 23 patients again and they need to understand what's going on 24 with their disease, why they have it, and why we are giving 25 certain medications.

37 1 They also need to know what the time frames are 2 for improvement, and certainly we never promise anyone any 3 marked improvement under a couple of months. 4 And they need to know that their therapies might 5 be changed on each visit depending on what their clinical 6 response is and what their skin irritation is. So each time 7 a patient returns, their therapy is reevaluated. 8 We also need to have patient compliance. 9 Now, patient compliance is important because most 10 patient, if you give them a load of prescriptions aimed at 11 a variety of these targets, will not do any of it or do too 12 much of it. So it is an active agreement that the physician 13 dermatologist has to have with the patient as to what they 14 will do and what you want them to do, and somehow you have 15 to mesh these choices so that there is something active being 16 given to this patient to improve their acne. 17 It's important for physicians, as well as parents, 18 to remember that no one can remember more than three things. 19 So you need to write down instruction, or greater than that, 20 we need to have patient educational materials for both the 21 parent as well as the young person, and we need to provide 22 written instructions for our patients. 23 Now, what I see as the acne treatment pitfalls 24 is not just the diagnosis, not just establishing the therapies, 25 but if the visit is too quick and the educational piece is

38 1 not given, as well as the instructions, and the compliance 2 pledged. I also see a problem in over-treatment. When there 3 is too much skin pain and irritation from the therapies, the 4 patient is not compliant. And then we have the problem of 5 giving therapies that are non-compliant with the lifestyle 6 of the patient. 7 So what does the patient do? He gets irritated 8 if he overwashes, too many medical facials, too many 9 medications, lack of education, and fear of the therapies. 10 And certainly there are patients who want to get better with 11 no therapy. 12 So we the dermatologists, specifically the 13 dermatologists, have a real medical problem that faces us with 14 acne. This is not just a superficial disease and a cosmetic 15 problem, but this is a profound disease that needs attention. 16 And as you can see, it has many aspects of both diagnosis 17 and therapy, follow-up, compliance, and safety. 18 So thank you. 19 DR. STERN: Thank you very much, Wilma. 20 Our next speaker will be Dr. Wilkin who will speak 21 to us about evidence of effectiveness of acne products. 22 DR. WILKIN: Many years ago I participated in an 23 acne trial as an investigators, counted lesions, and I noticed 24 that at the end of the trial, that the lesion counts by 25 themselves didn't seem to actually be as meaningful as what

39 1 the global looked like or what the patients felt they had 2 accomplished in the trial. Their sense of how better their 3 acne got actually seemed to me to be related to the global 4 and not directly, at least all the time, to the difference 5 in lesion counts. 6 So I thought about this for over a decade, and 7 it seemed like a paradox, at least to me. How could you have 8 a system that inherently had a lot more information in it -- that 9 is, all these different lesion counts and very precise, very 10 unbiased, very accurate -- how could that really not have as 11 much clinically meaningful information as just the simple 0 12 to 4-plus subjective ordinal scale, sort of an estimate? 13 Now, acne is too complex to ask the question about 14 how this would happen with all the different kinds of lesions. 15 So I chose a model. And a model, when you're going 16 to look for mathematical relationships, is the system that 17 has the relevant properties, but only those properties, and 18 everything else has been removed. So it's an oversimplified 19 model. It doesn't have many of the things that we look at 20 when we're looking at acne severity like halos of erythema 21 around the inflammatory lesions. It doesn't have the 22 different size kinds of lesions. It doesn't have elevation. 23 So that's why you'll see acne in quotes because 24 what I chose to do is to have acne lesions literally painted 25 on faces of human models who didn't have acne so that I could

40 1 characterize the relationship between the actual number of 2 these painted-on lesions and the perceived severity of the 3 acne lesions. Since again, there was no variation in the size 4 and morphology of the lesions, what really is perceived 5 severity is judged numerosity. How numerous did the lesions 6 appear? 7 So to do this, we recruited 33 research subjects 8 who were the evaluators. They came into a dark room and looked 9 at kodachromes of two models, and the models had lesions painted 10 on their face for acne severity. The two models had up to 11 200 of these acne lesions painted on their face by a 12 professional theatrical cosmetic artist. And then the 13 research subjects, the observers, looked at these kodachromes 14 and scored on a 10 centimeter linear horizontal visual analogue 15 scale what they thought was the acne severity. And the visual 16 analogue scale was scored by digimatic calipers which are quite 17 precise. 18 This is the visual analogue scale. You can see 19 here where if this were one of the research subjects marking 20 it, they would have marked a 35-millimeter deflection from 21 clear, and so that would be one-third as bad as the acne could 22 be. 23 So this is the basic paradigm of the study. The 24 input is the actual number of the lesions that have been painted 25 on by the theatrical cosmetic artist. The test subjects are

41 1 the human subjects that came in and looked at the kodachromes. 2 And then their mind processed it, and then they wrote on a 3 horizontal linear visual analogue scale. They made a mark 4 which was the judged numerosity, if you will, of the acne. 5 This was the first model they looked at. This 6 was stated as clear. 7 And this was stated as bad as can be. It was 8 intended that there would be only 100 lesions, but it turned 9 out the cosmetic artist was not majoring in mathematics and 10 there are actually 101 if you count them all. 11 I'll only show a couple. I won't show you all 12 48 slides. 13 This is nine. If you look at it, you can actually 14 count that. 15 Next is 49. 16 Now, for the committee, there's going to be a quiz 17 after this. So I'll show you the anchors at the beginning. 18 This is clear. This is as bad as can be, which is in this 19 case 200. This is 50, 100, 20. Okay. Here's your unknown. 20 How many think there is less than 150 lesions here? How about 21 more than 150 lesions? 22 (A show of hands.) 23 DR. WILKIN: Actually there are 120. So there 24 is a nonlinearity. 25 What we have here, the output is judged numerosity,

42 1 and so it is the millimeters of deflection on the horizontal 2 visual analogue scale, again, of judged numerosity. The input 3 is the actual number of lesions painted on the face. So you 4 can see we've got two series. The blue line is the subject 5 that had from 0 to 200, and the yellow line is the subject 6 that had 0 to 101. 7 What we're showing on this slide is input, which 8 is the actual number of lesions painted on the face and seen 9 on the kodachromes, given as a fraction of the maximum input 10 so that we can bring the 101 and the 200 into the same kind 11 of scale. And then judged numerosity is likewise presented 12 as millimeters of deflection from clear or 0, represented as 13 a fraction of the maximum judged numerosity, or as bad as it 14 can be. 15 What we've done on this slide is we've added some 16 very fine lines. Those I think at the table may be able to 17 see these. So we've broken up this curvilinear relationship 18 into three segments, and I would just point out that in this 19 segment, you can see that for every increase in lesion count, 20 you actually get twice as much impact on judged numerosity. 21 If one is up in the range above one-half maximal lesion count 22 that is painted on the face of the subjects, then in that range 23 you get only half of the judged numerosity for each increased 24 number of lesions at the upper end. 25 Now, the one thing that's been added to this slide

43 1 is that the output domain, judged numerosity, has been broken 2 up into an ordinal scale so that this would be 4 plus, 3 plus, 3 2 plus, 1 plus, and 0. What you can see is that for the maximum 4 number of lesions painted on the face, if you reduce that in 5 half, that is appreciated by the human subjects who were judging 6 numerosity as a drop in one grade, so from, say, 100 lesions 7 to 50 lesions. That's a drop from a grade 4 to a grade 3. 8 If you go from 50 lesions to 25 lesions, which is another half 9 drop, then that's going from a grade 3 to a grade 2. And if 10 you go from 25 lesions to about 10 lesions, that's again 11 approximately a drop in half, and one drops another rank on 12 the ordinal scale. 13 So what I believe this to be is that the ordinal 14 scale is actually an empiric attempt at a ratio scale, and 15 we know that that is sort of the psychometric wiring of the 16 human mind. That's what happens with decibels when one is 17 considering loudness. It's not really a linear function. 18 It's a logarithmic function. When one goes down 10 decibels, 19 you're reducing loudness literally by 90 percent. 20 Likewise stellar magnitude. You go out at night. 21 You look up at the constellations. You see first magnitude 22 stars the brightest and so on down to sixth magnitude. It's 23 not equal differences in terms of the photon energy coming 24 in the starlight. It's actually a ratio function. 25 So, I think this is the way people look at acne

44 1 lesion severity, at least the part of judged numerosity, in 2 a manner that is a cognate of stellar magnitude and the decibel 3 system. 4 Having said that the psychometric model provides 5 a curvilinear relationship between the more clinically 6 relevant acne global severity scale and the more precise acne 7 lesion counts, I would like to come back and again emphasize 8 the disclaimer I gave at the beginning. I've stripped away 9 an awful lot of the reality of acne. I've taken away the 10 difference in size, the many different kinds of lesions. 11 Certainly inflammatory lesions have more of an impact on judged 12 severity than non-inflammatory lesions. Some have that 13 erythema halo. So again, I'm not offering this as a very simple 14 way of looking at real acne, but I think this relationship, 15 nonetheless, exists. It's probably too complex to ever 16 convert acne lesions per se into a global, and Dr. Alosh will 17 mention that later. 18 Now, I did this about three years before coming 19 to FDA. Once I came to FDA, I learned from the people who 20 were already at FDA, in the usual oral tradition, how they 21 had looked at acne lesions. I learned this from the clinicians 22 and the statisticians that were on the team. 23 So I'm describing actually what was happening 24 before 1994 when the division was created, and as my colleagues 25 at FDA know, I refer to that as the paleo-regulatory era.

45 1 I can't really give all of the discussions that happened at 2 that time, but it is clear that the folks at FDA and industry 3 were using lesion counts which was total plus either 4 inflammatory or non-inflammatory, and also an investigator's 5 global assessment, which early on sometimes wasn't 6 dichotomized into a success and non-success, but more 7 frequently later on was dichotomized into a success and 8 non-success. 9 Over time the total became, I think, changed to 10 two out of three, that is, the total, the inflammatory, and 11 the non-inflammatory, because it was thought that if you won 12 with two out of three, one of them was going to be total. 13 It would be pretty hard to win on inflammatory and 14 non-inflammatory and not win on total. 15 What I learned from the statisticians and 16 clinicians of '94 and '95 is that they viewed the lesion counts 17 to be more accurate, more objective, harder data, if you will, 18 I think was the line. The investigator's global was imprecise, 19 subjective, might vary among investigators, especially with 20 some of the less morphologically defined global scales. 21 And then over the last decade, we've seen a lot 22 of differences in the NDAs that have come in. We've seen very 23 different baseline lesion counts from one study to another, 24 even within the same sponsor's package. We've seen different 25 lesion count analyses. Dr. Alosh will be talking about this.

46 1 We've seen absolute change studied in some, percent change, 2 a whole variety of transformed values, and then also a lot 3 of different global investigator scales. 4 So we'd like to have one consistent way where we 5 can approach the evidence for effectiveness for these acne 6 products, that is, the mild to moderate kind of acne vulgaris 7 products. 8 And our first question to the committee will be, 9 should the current success criteria using co-primary endpoints 10 be retained? Of course, that's not meant really to be a simple 11 yes or no because if the answer is no, we'd like an essay 12 question telling us how to fix it and which parts we need to 13 preserve. 14 How should lesion counts be analyzed? 15 What investigators' global severity scale should 16 be used? At what level should it be dichotomized? 17 I really cannot recall any sponsor initially 18 coming in saying that they wanted only inflammatory lesions 19 or non-inflammatory lesions of acne as their indication. All 20 of the applications that I've seen, sponsors have come in saying 21 that they want the indication of mild to moderate acne vulgaris 22 as monotherapy. I think Dr. Bergfeld indicated that while 23 dermatologists may focus on different lesion types, it's not 24 clear that non-dermatologists actually make a distinction 25 between inflammatory and non-inflammatory.

47 1 So I think that's going to be one of the questions 2 that we need to work with, and that is, should acne lesion 3 types, inflammatory or non-inflammatory, be medically 4 acceptable indications? I think there are two products out 5 there right now that actually have this. Maybe there is a 6 third. But is it something we want to continue that practice? 7 What we can do is we can always craft into the 8 package insert outcome measures for both lesion types so that 9 a more elite kind of dermatologic practice that wants to use 10 a particular, say, topical for a particular lesion type can 11 still find that information in the package insert. But again, 12 the question is going to be, do you want something less than 13 acne? Do you want lesion types as an indication? 14 Number five, should lesion counts be assessed at 15 multiple time points late in the study and averaged to increase 16 power? What we know and what Dr. Kligman has actually written 17 about is that acne lesions, inflammatory and non-inflammatory, 18 surprisingly fluctuate in size and appearance and even number 19 in very short periods of time. 20 So one of the ways to reduce intra-subject 21 variability and hence increase the power is to go out to that 22 time in an acne study when you're on that horizontal asymptote 23 of efficacy, which may be 8 to 12 weeks, and instead of just 24 capturing one lesion count or one global assessment, do these 25 assessments at, say, week 8, week 9, week 10, and week 12,

48 1 and then take the average, and by doing that, you can 2 substantially reduce the intra-subject variability. You can 3 increase the power. 4 The other side of that, though, is that you can 5 drive some very impressive p values within some very small 6 lesion count deltas. But that will be one of the questions 7 for the committee. 8 Then how should the efficacy outcomes of clinical 9 trials be portrayed in the package insert to be maximally 10 effective in communicating, especially so that physicians can 11 communicate with patients? And we'll be presenting some 12 information on that later today and, again, hope to hear from 13 the committee on that point as well. 14 Then as Dr. Stern mentioned, the ultimate goal 15 is a guidance document on the evidence for effectiveness for 16 products for mild to moderate acne vulgaris. What we hope 17 to gain over the next two days is the pieces of information 18 that we can put together to craft a draft guidance document, 19 which then would be published. We would get some comments 20 back, and that would get us going in the process. 21 Thank you. 22 DR. STERN: Thank you very much. 23 We'll be having questions after our next speaker, 24 Dr. Carr, who will talk with us about the FDA perspective on 25 global evaluation. Thank you, Dr. Carr.

49 1 DR. CARR: Again, I'll be speaking on the FDA 2 perspective on the global evaluation in facial acne. 3 I'm going to begin by describing some challenges 4 associated with the design of a global evaluation scale, move 5 on to discuss benefits of a standard scale, then discuss 6 proposed attributes of a scale, and close by giving examples 7 of scales that have been proposed for use to the agency. 8 A number of different scales have been published 9 in the literature and a number of different scales have been 10 proposed by sponsors for use at the agency. It begs the 11 question, what is it about acne that makes it so difficult 12 to design a scale that's universally accepted? 13 The American Academy of Dermatology convened a 14 consensus conference in 1990 which considered acne 15 classification, and one of the conclusions was that the 16 difficulties in large part related to the pleomorphic nature 17 of acne pertaining to the mixture of lesion types, inflammatory 18 and non-inflammatory, the variability in the clinical 19 presentation of those lesions, how they can vary, particularly 20 inflammatory lesions, in size, the papules, the pustules, the 21 cysts, and how they can vary with regard to the extent of 22 inflammation associated with the lesions. Also, there's 23 variability in how the lesions evolve over time. 24 Additionally, there's no consensus as to what 25 should be assessed in the global evaluation of acne. Some

50 1 consider that only inflammatory lesions should be considered. 2 Some consider that nonfacial sites should also be factored 3 into the global evaluation. 4 The potential benefits of a standard scale would 5 include that for clinicians it could serve as an objective 6 basis for treatment choices, as well as assessment of treatment 7 responses. In the investigational setting, a standard scale 8 could potentially increase consistency across centers as to 9 enrollment of subjects who more closely fit the enrollment 10 criteria as well as increasing consistency of assessments of 11 study treatment response. And for clinicians and 12 investigators, a standard scale could serve as a common system 13 to aid in the interpretation of clinical trial results. 14 Now, the proposed attributes of a scale would 15 include that it have a limited number of levels -- we'd suggest 16 no more than five or six -- that each of the levels be described 17 sufficiently so that intra-observer and inter-observer 18 variability is minimized; that the scale include levels which 19 indicate the clear state and the almost clear state because 20 these are the most clinically meaningful treatment outcomes; 21 that it be of a static design so that the assessment reflects 22 the clinical picture at a particular time point; and that the 23 scale have a high degree of correlation with lesion counts. 24 I'm going to give some examples of a few scales 25 that have been referenced in applications that have come to

51 1 the agency and make a couple of comments about each of the 2 scales. 3 The first one is the Leeds scale, sometimes 4 referred to as the Cunliffe scale. And it's presented as a 5 10-grade scale where grade 0 represents no acne and grade 10 6 the most severe acne. But it actually is a 26-point scale 7 because with this scale, grades 0 to 2 are subdivided so that 8 there are nine possible grade assignments between grades 0 9 to 2. Similarly grades 2 to 10 are subdivided by increments, 10 making for a total possibility of 17 grades. So this makes 11 for a possibility of 26 grades on this scale, and a case could 12 be made that that's a bit cumbersome. 13 Additionally, the only two levels that have word 14 descriptors on this scale are the grades 0 and 10. So this 15 scale would be considered to be perhaps lacking in definitions. 16 The Cook scale presents five definitions. 17 However, it's a 9-point scale because with use of this scale, 18 investigators can assign grades to points that aren't 19 identified on the scale. So investigators can assign grades 20 of 1, 3, 5, and 7, and that makes for a problem, or potentially 21 so, because those levels aren't defined which means assignment 22 to those levels is completely arbitrary. 23 Additionally, if we look at some of the 24 definitions, we see that there's no level that represents the 25 clear state. Grade 0 permits for some lesions, albeit few

52 1 lesions, but lesions nonetheless. And then if we step down 2 to grade 4, we see that it begins by being described as being 3 between grades 2 and 6. So it's considered that perhaps 4 reworking of some of the definitions might make this scale 5 more useful. 6 Now, this is another proposed scale and this is 7 an example of a dynamic scale. The problem with dynamic scales 8 is that their memory-dependent requiring that investigators 9 have some recollection of the baseline status of a subject 10 in order to make the assessment. Additionally, there are no 11 clinical descriptors given to any of these levels, so it's 12 not clear really what's being scored. If you are told that 13 a subject scored a slight improvement or a moderate 14 improvement, that doesn't bring any particular clinical 15 picture to mind. 16 A variation on the dynamic scale would be where 17 the improvement is reported by percent change, and the same 18 argument could be made that if you say a subject is 25 percent 19 improved or 50 percent improved, that doesn't bring a 20 particular clinical picture to mind. 21 Now, this is an example of a scale that begins 22 to meet the criteria presented so far. It has a limited number 23 of levels, namely five. But when we look at the definitions, 24 we see that grade 0 which is said to be none is not none because 25 it's defined as having occasional comedones. And then if we

53 1 examined a definition for minimal acne, the question is, is 2 this definition really minimal acne or might it be too severe 3 to be considered minimal? 4 This scale, similar to the one before, has a 5 limited number of levels, again five. It does have a level 6 which identifies the clear state. However, if we look at 7 almost clear, the same question could be raised. Is this 8 definition really one that would be considered almost clear 9 or is this too severe to represent the almost clear state? 10 And the last example is a scale that's considered 11 to meet the proposed criteria. It has six levels, so the number 12 of levels is limited. It does have a level which defines the 13 clear state. The almost clear state is defined by rare 14 inflammatory lesions and papules are permitted, but if present, 15 they can't show any signs of active inflammation. I'm not 16 going to go through all the levels, but they are considered 17 to be sufficiently defined so as to minimize observer 18 variability. The scale is of a static design, and it does 19 have a correlation with lesion counts. 20 So with that, I'll close my scaly presentation, 21 and we look forward to the comments from the committee. 22 DR. STERN: Thank you very much. 23 I guess I'd like to take the chair's prerogative 24 and ask one question of any of the three presenters who would 25 like to answer. We've been hearing about

54 1 comedonal/noncomedonal, about various scales in terms of what 2 are usually descriptors of number of lesions and type of 3 lesions. What I haven't heard about in terms of approvability 4 of products is -- and we've been seeing only faces. The 5 question gets to be, is the criteria for approving a product 6 that is only assessed on the face necessarily applicable for 7 other anatomic areas? At least in my clinical experience, 8 what works on the face may not necessarily either be tolerated 9 or acceptable for use or effective on the trunk, another site 10 of mild to moderate acne. 11 So none of these scales have broken it down 12 into -- or do we want to break down products into those that, 13 yes, they work on the face but we don't know whether they work 14 on the trunk or other acne-prone areas, or yes, they work on 15 both? Or if they work on one, we'll assume they're safe and 16 effective on another. That's one other dimension of the scale 17 business, be it counts, but particularly for the kind of scales 18 Dr. Carr just alluded to. 19 So I'd be interested in knowing both the agency's 20 position on that and Wilma's feeling about it as well. 21 DR. WILKIN: Well, we haven't required that, for 22 example, a topical product be active on acne lesions of the 23 back and chest in order to get approval. All a sponsor really 24 needs to do is demonstrate success on those criteria on the 25 face alone. However, we do encourage in the trials that the

55 1 medication, which may be the active or the vehicle, be applied 2 to lesions elsewhere on the body so that especially if we can 3 find that it's clearly not working in some other area, we could 4 put that advice into labeling. But we've pretty much limited 5 it to the face. That's what the sponsors are requesting when 6 they come in. Their labeling is directed in that way, and 7 we've only asked for the face. 8 DR. STERN: So the labeling actually says approved 9 for facial acne mild to moderate, or does it just say -- 10 DR. WILKIN: It wouldn't say that necessarily in 11 the indications section, but that may be a suggestion of the 12 committee that we want to craft that into the indications 13 section of labeling. I think the place where one would find 14 it would be in the clinical studies section. 15 DR. STERN: Questions. 16 DR. BERGFELD: I'm not sure I have too much to 17 add to you, Rob, but I will agree with you that the truncal 18 lesions, the extremity lesions sometimes are a little bit 19 resistant, and they do require oral medications, rather than 20 topical even though topicals are used. 21 I would also mention that to use topicals on the 22 trunk and the extremities for broad generalization of acne 23 is a very expensive deal. These are very costly products and 24 to spread them over the body in that nature is hard to do 25 cost-wise.

56 1 DR. ABEL: I would also like to bring up the issue 2 of resolving acne lesions. There is an element of they may 3 not be completely clear, but they may be significantly 4 improved. The lesions may be smaller. They may be resolving 5 toward a post-inflammatory, hyperpigmented state and still 6 might be counted as lesions, but yet they are almost clear. 7 How does one take that into account? 8 DR. STERN: Dr. Wilkin, Dr. Carr? 9 DR. CARR: That is one of the factors that is 10 raised as a question as to what should be counted on the global 11 severity scale. Some people have raised the question to what 12 extent should resolving lesions be counted in the scale. 13 DR. BERGFELD: I'm sorry. I'd like, Elizabeth, 14 to have you define resolving. Hyperpigmentation for me is 15 a resolved lesion with residual hyperpigmentation which I would 16 not count as an active lesion. 17 DR. ABEL: Well, I see varying degrees of 18 inflammation. In new severely inflamed papules, 19 papulopustules, as they resolve, they may still be elevated. 20 It's not just the hyperpigmentation, but they may be less 21 inflammatory, be significantly less inflamed, but they are 22 still papular. I have patients who come to me and say, well, 23 their acne is not that much better, but yet when you look at 24 it, there are many lesions in the resolving stage, maybe not 25 completely resolved. They'll have some mild erythema, and

57 1 yet they won't be inflammatory papular. They are resolving 2 but are not completely clear, but yet they're definitely, to 3 my assessment, improved. 4 DR. STERN: Along that line, we're going to be 5 hearing after the break from a number of true acneologists, 6 if there are such things. 7 I think one question that speaks to that is, do 8 we believe that acne therapy in fact treats prevalent lesions 9 when you start the therapy or does it reduce the incidence 10 of new acne lesions. I think, at least in my probably, as 11 usual, wrong concept, when we treat acne, with the exception 12 of using things like oral steroids or anti-inflammatories, 13 for the kind of agents we're largely talking about, we're trying 14 to reduce the incidence so that in time, as prevalent lesions 15 resolve, eventually the prevalence will go down as the new 16 incidence is lower than the old. 17 I'd really like to hear from perhaps Dr. Pochi 18 and Dr. Kligman and Dr. Leyden and Dr. Shalita, any of you 19 or all of you, about is that your concept for most of the 20 products, that we're treating incidence and not prevalence. 21 The ideal thing would be to measure incidence. 22 DR. LEYDEN: I could answer it now if you like. 23 DR. STERN: Could you, Jim? Jim, would you 24 introduce yourself? 25 DR. LEYDEN: Yes. My name is Jim Leyden. I'm

58 1 Albert Kligman's personal valet. 2 (Laughter.) 3 DR. LEYDEN: I think all of us would agree the 4 answer is both. The primary mechanism of action is working 5 on one of the multiple areas of pathophysiology for most drugs. 6 Most drugs only work on one area. There's one drug that works 7 on all of them. We call it Accutane. Most drugs only work 8 on one area and slightly on another and basically help to 9 prevent the formation of new lesions and also to a certain 10 degree -- and the vehicle also to a certain degree has effects 11 on speeding the resolution of more superficial, less inflamed 12 lesions. So it's primarily the prevention of new lesions. 13 DR. STERN: Well, I'm glad I got that one right 14 for once. 15 Dr. King. 16 DR. KING: Under the concept of beauty is in the 17 eyes of the beholder, is the FDA going to look at the global 18 assessment by the patient? We're talking about the operation 19 was a success and the patient died. You can reduce comedones 20 by a lot sometimes and we all have experience of the patient 21 not necessarily thinking it was a great therapy. So is that 22 somehow going to be in this discussion or not? 23 DR. CARR: At present the subjective evaluation 24 is not part of what we're considering. Part of the problem 25 with quality of life or patient perception of improvement is

59 1 two subjects can have the same extent of clinical improvement, 2 but there can be other factors that might make for different 3 conclusions. And their assessment to treatment response such 4 as an adverse event that one subject might rate in one way 5 and another subject might rate in a different way so that you 6 can have the same clinical outcome, but because of other events 7 might have two totally different assessments as to their 8 overall impression of treatment. So right now we're just 9 looking at the objective assessment. 10 DR. STERN: Dr. Plott. 11 DR. PLOTT: I have two questions. First for Dr. 12 Bergfeld. I'd like to ask when you see a mild to moderate 13 acne patient in your clinic, what is your expectation for 14 treatment over the first 12 weeks of your therapy with the 15 whole armamentarium that you have to throw at them? 16 DR. BERGFELD: My expectation for the therapeutic 17 response in the 6- to 8-week period would be a moderate 18 improvement. Over a 3-month period, though, I would expect 19 to be at 60 to 80 percent improvement. So moderate might be 20 defined as 30 to 50 percent with a mixture of combined 21 therapies. It might be combined topicals as well as combined 22 orals. 23 DR. PLOTT: How many patients would you expect 24 to get clear or almost clear in 12 weeks? 25 DR. BERGFELD: Clear or almost clear in 12 weeks?

60 1 70 percent maybe of the mild to moderates. 2 DR. PLOTT: And my next question to Dr. Carr. 3 In your example number 6, the score number 3 and number 4 -- it 4 appears that they really differ by the type of lesion that 5 predominates, the inflammatory in number 3 and inflammatory. 6 It suggests that inflammatory lesions are a more severe type 7 of lesion. I wonder if you would comment on if you believe 8 that inflammatory lesions are more severe. 9 DR. CARR: Well, the inflammatory lesion does seem 10 to drive the global evaluation. They do seem to predominate 11 in the global picture. So I don't know if it would be termed 12 a more severe lesion necessarily, but in terms of the global 13 evaluation, they do have more impact. 14 DR. STERN: Dr. Kilpatrick. 15 DR. KILPATRICK: Thank you, sir. I have a number 16 of questions coming after Dr. Plott. 17 Wilma, what I heard you describing was an ideal 18 treatment of a patient. That may not be what actually happens 19 with non-dermatologists. But what I was hearing seemed to 20 imply that there were limitations on actually trying evaluating 21 in clinical trials because how can you treat the patient at 22 the same time if you're going to be in a double-blind clinical 23 trial? Basically perhaps I'm indicating my ignorance of the 24 natural history of the disease. Does it allow for the 25 intercession of a clinical trial to answer these questions

61 1 while preserving the rights of the patient? 2 DR. BERGFELD: I think that most dermatologists 3 would agree that with combined therapies, the responses are 4 quicker and more long-lasting. In a clinical trial, it's a 5 solo monotherapy. So those patients who were picked for that 6 would have some limitations on their full responses. But 7 perhaps Alan Shalita and Jim, Peter, you might want to respond. 8 Al? 9 DR. SHALITA: I think a very important question 10 has just been brought up and I was actually going to bring 11 it up later in my talk. We do have an IRB member on your 12 advisory panel. 13 But increasingly we are seeing IRBs, particularly 14 community representatives, who are opposed to the concept of 15 vehicle control or non-treatment control, et cetera. I know 16 that this creates enormous problems for those that rely on 17 evidence-based medicine and the concept of using a vehicle 18 or placebo, but it is contrary to the best interest of the 19 patient to be treating them with something other than an active, 20 even the concept of treating them with monotherapy when you 21 have strong inclinations that more than one therapy would be 22 best. 23 And then finally, Todd just brought up a concept. 24 We don't use monotherapy generally to achieve a clear or almost 25 clear status, and to use that then as a criteria becomes

62 1 self-defeating if you're talking about monotherapy. 2 DR. KILPATRICK: Dr. Wilkin wants to get in. 3 DR. WILKIN: If I could speak to the issue of 4 vehicle control. I think in virtually every study that we've 5 gone back and looked at the data, people who were assigned 6 vehicle or an oral placebo get better in acne trials. 7 I would say that the second piece is we're talking 8 about mild to moderate. We're not talking about something 9 that is going to damage someone for years if it turns out they're 10 assigned to one of these so-called inactives. 11 And the third thing is you'll have to look at some 12 of the data and see what the actual differences are between 13 the contribution of the active over the vehicle. I think you 14 may from that decide that it really is informative to have 15 a vehicle control. 16 And then if I could come back to an earlier 17 question, and that is do we ask for the patient's perception 18 of how well things happened during the acne trial. And I think 19 Dr. Carr answered that we don't request that information. 20 Often we get it as a secondary kind of an endpoint, and we'll 21 look it over. 22 But for the exact reasons that she mentioned, I 23 would like to lift up for the committee's consideration a very 24 thoughtful editorial that appeared in Lancet by Mark Lebwohl. 25 It's not on acne. It's actually on psoriasis. He was

63 1 referring to a paper in the British Journal of Dermatology 2 by Fountain on psoriasis. What they found out was that looking 3 at objective measures of the severity of the psoriasis didn't 4 really correlate very well with the patient's perception of 5 quality of life change during therapy. In Dr. Lebwohl's 6 thoughtful account, he indicates what Dr. Carr was saying and 7 that is that patients bring an awful lot to that equation, 8 what they want out of something, what their expectations are, 9 what others' expectations are, around them. 10 Our thought is that that is important to that 11 person in that trial. I don't want FDA to ever sound like 12 we're not interested in quality of life. We're enormously 13 interested in quality of life. But our thought is if we can 14 somehow craft into the package insert some fairly objective 15 measures of outcome, then we actually convert the quality of 16 life discussion to the clinician's office where he or she is 17 sitting with the patient and can say, well, you could expect 18 this sort of thing, and then it's that patient in real time 19 that can come up with the quality of life assessment. But 20 clearly, we're all interested in quality of life. That's 21 actually a big part of the mild to moderate acne indication. 22 DR. KILPATRICK: Sir, may I continue because my 23 light is on? 24 (Laughter.) 25 DR. KILPATRICK: I find myself in the position

64 1 of disagreeing with my friend and colleague, Dr. Wilkin. As 2 a non-M.D. but as a statistician, I'm interested in the 3 accession of information, and the subjects I think can bring 4 information to a clinical trial in terms of their subjective, 5 albeit it subjective, evaluation of their improvement or lack 6 of improvement over time. 7 The fact that this may not be highly correlated 8 with scores leads me to a second question directed at Dr. Carr. 9 I'm not surprised that in the global evaluation one of the 10 conditions for a scale is that it is highly correlated with 11 the score. I would have thought that they would want it not 12 correlated with the score in order to get some different 13 perspective. If it's highly correlated, if you go to the 14 extreme, if it's a correlation of one, then the two are 15 redundant. So I'm looking to broaden the evaluation of acne 16 therapy not limit it. If we have two things that are measuring 17 the same thing, let's take the simpler one. 18 Finally, since I'm on the microphone, let me ask 19 again a simplistic question to Dr. Wilkin. This must be done. 20 Why cannot we take photographs and literally count the number 21 of comedones rather than evaluate them in a patient-doctor 22 contact? Jon? 23 DR. WILKIN: I would actually like to defer the 24 photography question to the acne numerology experts who do 25 the counting. There is a published system of getting really

65 1 very well-controlled photographs and then doing counts. 2 DR. STERN: Would you introduce yourself first, 3 Dr. Kligman, just for the record? 4 DR. KLIGMAN: Al Kligman from Philadelphia. 5 Jonathan, in the first group when we met to lay 6 out rules for assessing the efficacy, at that time we denounced 7 and made light of photography. It wasn't meticulous enough. 8 It missed little lesions, especially comedones and closed 9 comedones. 10 All that has changed. The improvement in 11 photographic procedures now is unbelievable with digital 12 photography, with video microscopy, with the ability to look 13 at UVA photography, fluorescent photography, PRIMOS imaging. 14 An enormous amount of bioengineering skill and resources are 15 now available. 16 Of course, they're expensive and the lighting has 17 to be defined. The film has to be defined. It's a very 18 rigorous procedure, but in my opinion it's going to offer much 19 more believable, credible, and objective results of what we 20 are actually seeing considering the fact that we have a mixture 21 of lesions and they all have their own history and their own 22 outcome. 23 So I think that's a very good idea. Those 24 resources are now available and they could be put into place 25 by anyone with money.

66 1 (Laughter.) 2 DR. STERN: Ms. Knudson. 3 MS. KNUDSON: It's Paula Knudson. 4 I would like to speak to the IRB issue. I do know 5 that over the years placebo-controlled trials have become an 6 anathema to many IRBs. 7 However, I would say that one of the things that 8 we would be asking is for mild acne would the acne resolve 9 by itself most usually, in which case I think a trial with 10 placebo would certainly be countenanced. For moderate acne, 11 we would ask what is the likelihood of scarring, and the other 12 thing that we would ask would be what's the length of time 13 for it to resolve. So those would go into the makeup as to 14 whether a vehicle-controlled trial would be approvable or not 15 for mild to moderate acne. 16 But I wanted to ask a different question of Brenda 17 Carr and that is, is it anticipated that at every visit that 18 a patient comes to the dermatologist, the scale would be used? 19 DR. CARR: You're speaking of in the clinical 20 trial? 21 MS. KNUDSON: Yes. 22 DR. CARR: Yes. 23 DR. STERN: Are there other questions? Yes. 24 DR. TEN HAVE: I'd just like to make one comment 25 about the monotherapy versus combined therapy issue. In other

67 1 areas such as psychiatry where therapy is usually done in a 2 sequential, complicated way, people are thinking about 3 enhancements to the simple clinical trials design in terms 4 of using adaptive randomization as opposed to a single baseline 5 randomization to possibly attempt to make a more realistic 6 comparison and evaluation. 7 DR. STERN: I'd like to make a statement and ask 8 a couple of questions, one at least of Jonathan. In the issue 9 of combination therapy, one of the things that to my knowledge 10 has not been looked at is by combination therapy I think we 11 all agree that using multiple agents seems to be more effective 12 than using one agent alone for mild to moderate acne, whether 13 it be a combination of a topical and an oral agent or 14 combinations of appropriately used topical agents. 15 Sometimes when people think about combination 16 therapy -- and if you look at a number of the recent approvals, 17 they are in fact taking two agents that are available 18 individually, putting them together and marketing them and 19 approving them as being better than the individual agents. 20 The question gets to be then one of frequency. We learned 21 from topical steroids and from topical antifungals where the 22 paradigm was you always had to do everything at least twice 23 a day, and in fact for many agents once a day is sufficient. 24 So some of the question gets to be can you just use the 25 individual agents as well or better in terms of tolerance than

68 1 the combined agent as opposed to combination therapy. 2 So I think there are some added complexities of 3 combined agents, that is, an agent that take two active agents 4 known to be independently therapeutically active and puts them 5 together in terms of what should be the criteria of approving 6 a combined agent as opposed to having those two individual 7 agents available separately. What are the real advantages 8 of that agent? Do they really work better than the individual 9 application? Is there anything that makes them better? 10 And then for Jonathan I wanted to ask just a 11 question. One of the interesting things to me about your 12 results were that the anchor point was 101 lesions for the 13 worst ever or 200 lesions. If you looked at the two curves 14 that essentially said once we overestimate the number of 15 lesions through most of the interval, they were almost 16 superimposed on each other. That to me, being the victim of 17 one of those curves in terms of overestimating the number of 18 lesions, was interesting. You're saying at least within this 19 spectrum, a lot is a lot and how we view that a lot in terms 20 of estimating, once we're given the anchors, is subject to 21 the same kind of biases. 22 Now, if you're looking at lesion reduction, the 23 worse the patients you have, it may impact on how many lesions 24 you have to reduce when on your last curve, I believe it was, 25 you showed how much down the scale you have to go to get one

69 1 level of improvement by your non-quantitative scale. 2 So could you talk a little bit more about that? 3 Because I found that interesting in terms of what it might 4 mean for evaluating agents with these non-quantitative scales. 5 DR. WILKIN: Yes. I think maybe what you're 6 leaning towards is what actually happens in an acne trial. 7 You can imagine that those who come into the trial -- there 8 will be inclusion criteria and there will be a range of the 9 non-inflammatory lesion numbers that one can have to be in 10 the trial and also the inflammatory lesion numbers. People 11 who are at the upper end often are the folks that drive success 12 on the lesion count analysis. Those who come in, they just 13 barely had enough acne to get into the trial, they are the 14 folks that drive the global. Is that the point you were -- 15 DR. STERN: That's the data I took away from it, 16 and it seemed to me that a system like that was less than 17 desirable on the one hand. To Dr. Kilpatrick's point, it did 18 allow two independent measures, one of which was in a sense 19 active and robust at the low end of severity and the other 20 perhaps more active and robust at the higher ends of severity 21 within the spectrum. But somehow that lack of correlation 22 in what sort of we think should be correlated across the 23 spectrum of people coming in the study is a bit bothersome. 24 Dr. Kilpatrick? 25 DR. KILPATRICK: Well, yes, again I heard earlier

70 1 from was it Dr. Fraser who talked about specificity of objective 2 in going into a trial, and I'm all for that. What I'm hearing 3 now is stratification. But that has to be very carefully 4 crafted between the FDA and the sponsor beforehand. 5 DR. STERN: I'm sorry. Dr. Tan. 6 DR. TAN: Yes. I'm still trying to get to what 7 is the real problem here. Can Dr. Wilkin and Dr. Carr clarify 8 for me how exactly you define the percent of reduction? Dr. 9 Fraser presented that the percent of reduction is patients 10 from the baseline to 12 weeks, for example. 11 I think one of the problems is the number of lesions 12 because all the lesions are different. And when you just lump 13 them together that causes all this problem. I think you have 14 these stratifications, non-inflammatory, inflammatory. In 15 molecular biology these days they're counting different cells, 16 but this is all related. There are different clusters that 17 are related. They should be weighted a little bit differently 18 when you consider them together to derive a global scale. 19 So there should be a weighted type of scale that you should 20 use for the final endpoint. 21 And another problem I have is -- that's why I asked 22 the percent of reduction. 23 The last thing is percents, that is between 0 and 24 1. Right? So when you analyze this kind of data, I was 25 remembering in the past several Derm meetings, from what I

71 1 remember, it's just a comparison, ANOVA type of comparison 2 using normal distribution comparing the percent of reduction 3 for the control versus the active treatment. 4 And there is a profound problem if it's a percent, 5 as we say, it's a ratio, and that percent, if it is a ratio -- if 6 the numerator and denominator are normally distributed, 7 mathematically you can prove that the ratio is not normally 8 distributed. So actually a lot of these things are -- you're 9 assuming it's normally distributed and there is a problem with 10 that. So I don't know how that ratio is really analyzed. 11 Probably we'll hear more in a later presentation. 12 DR. STERN: Dr. Wilkin. 13 DR. WILKIN: I think those are important 14 questions. Actually Dr. Alosh this afternoon has some 15 material that he can present some numerical analyses that I 16 think will help. They'll be very responsive to that. We were 17 thinking that the first part would be sort of to go over 18 clinically what the different lesions look like and whether 19 or not we want different lesions, and then the analytical part 20 and whether there's normal distribution -- you'll get to see 21 data from NDAs that have been suitably anonymized this 22 afternoon. 23 And I would like to just add a third disclaimer. 24 Once again, I gave a disclaimer at the beginning and at the 25 end of mine. I want to emphasize again that was a model.

72 1 That was not real acne. It was intentionally simplified. 2 The curvilinear relationship, while it looks kind of neat when 3 you're looking at little dots painted on a face in kodachromes, 4 real acne is not that simple. I think the acne experts will 5 indicate that you really can't predict where someone is going 6 to fall out in the global scale based on the lesion counts. 7 DR. STERN: I think with that last comment, 8 perhaps we'll end questions here since we'll be going on to 9 this in greater detail as the day goes on. Thank you very 10 much. We'll resume at 10:45. 11 (Recess.) 12 DR. STERN: I think we're particularly fortunate 13 this morning to have our four next speakers with us. In my 14 mind they represent certainly the majority of individuals who 15 have made a substantial contribution. Notice, Dr. Kilpatrick, 16 I did not say significant contribution. 17 (Laughter.) 18 DR. STERN: A substantial contribution to our 19 understanding of acne, and in fact, I know significant is okay 20 in that non-statistical usage as well. 21 DR. KILPATRICK: I'd like to make a comment about 22 the difference between clinical significance and statistical 23 significance. 24 (Laughter.) 25 DR. STERN: But they're all clear thinkers and

73 1 inspiring teachers, and I'm very much looking forward to 2 hearing from them. Our first speaker will be Peter Pochi who 3 knows not only how to do the research, how to teach, how to 4 practice, but also where to live, and Peter will be talking 5 to us about the American Academy of Dermatology. He is 6 Professor Emeritus at the Boston University School of Medicine 7 and lives in Boston, the right place to live. 8 DR. POCHI: Thank you, Dr. Stern. When Dr. Wilkin 9 invited me to speak today, I accepted with some trepidation 10 since I hadn't given a lecture in 11 years, and I hope I have 11 not forgotten how to talk. 12 In 1990 the American Academy of Dermatology 13 sponsored the convening of a consensus conference to look at 14 the problem of the classification of acne. I'll just read 15 for you, for those who don't have the article before you, the 16 first sentence or so. "A number of systems have been described 17 for the classification of acne vulgaris, but there's no 18 universally accepted method for assessing gradations of acne 19 severity. This lack of uniformity from one classification 20 system to another has made it difficult to compare therapeutic 21 efficacy among different studies." 22 It's 12 years later and the issue is still being 23 addressed. 24 The academy prefaced the report. The proceedings 25 of the conference were published subsequently in 1991 in the

74 1 Journal of the American Academy of Dermatology, and the report 2 was prefaced by the academy saying that the results of future 3 studies may require alteration of the recommendations as set 4 forth in this report. 5 The proceedings that were reported were not really 6 proceedings. They did not go into any detail of the various 7 presentations that were made on the first day of that 8 day-and-a-half conference. A number of speakers, including 9 Professor Cunliffe and Professor Plewig from abroad talked 10 about their classification systems, and as the day droned on, 11 it became evident to most of us at least who were interested 12 in the subject -- and among the participants were, beside 13 myself, Dr. Kligman, Dr. Shalita, and Dr. Leyden who are here 14 today -- that trying to define acne is not a walk in the park 15 and that it might be better to present it in almost a global 16 sense, which I'll come to ultimately. But first I want to 17 go over what the conference intended to provide. 18 The purpose of the conference was twofold. The 19 first was, as I've already indicated, to review and to assess 20 the suitability of the grading systems that were in place at 21 that time, and there were a number of them. I'm not going 22 to go into detail at all, not discuss them at all really except 23 to allude to one or two as I go along. It became evident, 24 as I've already said, that it was very difficult to arrive 25 at sort of a universality of a type of system that could be

75 1 used in all situations. 2 The second purpose of the conference, which was 3 really an outgrowth of the first, was to categorize what is 4 meant by severe acne. It's very difficult to know when a 5 moderate case of acne ends and a severe case of acne begins. 6 Patients are treated with oral medications such as the oral 7 tetracyclines, which are FDA approved as adjunctive therapy 8 in individuals with severe acne, and oral isotretinoin, or 9 Accutane, for not adjunctive therapy but prime therapy. It 10 was hard to know just exactly what constitutes a patient with 11 severe disease. So these were the two goals of the conference. 12 Now, in assessing acne activity I think there are 13 two aspects to consider. One is the practitioner's assessment 14 and the other, which you are more concerned with today, the 15 investigative therapeutic trials. These are really two quite 16 different areas of consideration. The practitioner 17 assessment I think gets divided into two types of assessment. 18 One is the individual physician, dermatologist, 19 pediatrician, or family practitioner, who sees the patient 20 on every visit from the beginning of treatment until the 21 treatment is concluded. Here the examiner has latitude in 22 assessing what the activity of the patient's acne is, creates 23 his own grading system, as I did in my own patients -- I would 24 grade the patients as mild, moderate, and severe, for 25 example -- and then would have clinical descriptors for each

76 1 of them, inflammatory predominates, non-inflammatory 2 predominates, they're both present, is there scarring, et 3 cetera. And when the patient is seen again by the same 4 examiner, it is really easy to do an assessment in my experience 5 and the experience of those to whom I have spoken to get a 6 reasonable evidence-based, if you will, outcome of the disease 7 of that particular patient. 8 The problem is that different examiners may see 9 the same patient. This is particularly true in clinics and 10 especially true in university clinics where there are resident 11 physicians who rotate around, say, every month, and it's almost 12 uncommon for a patient to be seen by the same physician on 13 subsequent visits. And this really would relate to the problem 14 that we have in investigative therapeutic trials wherein a 15 system has to be established that's fairly objective with 16 subjectivity intercalated among the objective observations. 17 Now, the oldest system I could found was this 18 neolithic textbook of dermatology published in 1956. I'm 19 being actually unkind. It was really the breakthrough 20 textbook of dermatology in this field by Pillsbury, Shelley, 21 and Kligman, and they were the first to really attempt to give 22 some sort of a subjective/objective, if you will, evaluation 23 of acne. And they graded acne into four grades, and they gave 24 descriptors: simple, banal; no significant inflammation. 25 That really is simple. And then grade II, moderate severity,

77 1 occasional inflammatory lesions. These are not my words. 2 I've taken these directly from the text of that book. And 3 grade III, more severe; grade IV, most severe. 4 Well, really this is okay, but really inadequate. 5 One really has to fit in more describing attributes to the 6 patient's acne. Nonetheless, this is what really is done in 7 a global assessment of acne, is to try to divide the disease 8 into several grades and then to give little descriptors of 9 what one sees, and that should be adequate but is it? 10 Now, it's already been mentioned that acne is 11 difficult to classify because it is pleomorphic. It's highly 12 pleomorphic. Let me just go through each of these steps one 13 by one. 14 First of all, as you'll recognize, there may be 15 both inflammatory and non-inflammatory lesions. In a global 16 or even in a counting technique, trying to integrate these 17 together I think leads to specious information. And I agree 18 with Dr. Kligman. Perhaps he doesn't agree with himself any 19 longer, but I agree what he has written that the inflammatory 20 lesions and the non-inflammatory lesions really have to be 21 considered separately and they need separate grading because 22 you can have situations where the non-inflammatory lesions 23 so predominate and yet the patient doesn't really look that 24 bad with only mild inflammatory disease. 25 I noticed, if I recall, in one of the grading

78 1 systems that Dr. Carr spoke about, she showed with increasing 2 severity of the disease, an increasing number of comedonal 3 lesions. In my experience usually the opposite occurs, that 4 as the disease becomes aggressive, there are fewer 5 non-inflammatory lesions. But, of course, there are many, 6 many exceptions to that. 7 Secondly -- and this is the most important, the 8 second point -- the inflammatory lesion which is really the 9 hallmark of the disease, what brings 90 percent of the patients 10 to doctors for their disease -- is variation in size, density, 11 and severity. 12 Acne lesions vary greatly in size not just from 13 patient to patient but within a given patient, and I'll show 14 you some clinical photographs in a moment. If you look at 15 patient, no one lesion looks -- well, they do look alike but 16 they're quite different in their size. They can be large, 17 they can be small. And where to draw a line as to what is 18 small and what is large is arbitrary but is subject to, I 19 wouldn't say, misinterpretation but difficulty in classifying. 20 And they vary in density. There are two meanings 21 of density. One is the number of the inflammatory lesions 22 that are seen in a square area of involvement, and the other 23 is the distribution, clustering versus a more even 24 distribution. This latter aspect has never, to my knowledge, 25 been considered in any classification of acne. Does an

79 1 individual who has a lot of their acne concentrated in given 2 areas in the face versus the patient with the same number of 3 lesions but more evenly distributed look better or look worse? 4 And this is another aspect that I think should be looked into. 5 And then the severity, the severity of the 6 inflammation, not the severity of the disease. Some lesions 7 are quite red. Some lesions are not as red. Some are only 8 pink, and this is roughly the same for a given individual but 9 can vary so much in the same region of the face. You have 10 a variation of erythema even if the lesions are roughly of 11 the same size. Of course, they're not. So the degree of 12 inflammation is important, particularly in doing a global 13 evaluation. 14 The patient's background pigmentation is often 15 not considered in global assessments. If an individual has 16 light skin and has inflamed lesions, red on white looks much 17 worse than red on dark. If a person is sunburned, the 18 inflammatory lesions will look so much less intense, and this 19 is why individuals probably improve when they go out in the 20 sun. It's not that the acne improves from the sun, but it's 21 globally they look better because it's red on red instead of 22 red on white. 23 In some individuals who are darkly pigmented, the 24 inflammatory aspect is quite difficult to see. In fact, people 25 who are not familiar with seeing black patients at first they

80 1 say it's very hard for them to perceive that a lesion is even 2 inflammatory. So this is an important aspect again that I 3 think has been largely neglected. 4 Individuals with black skin also, on the other 5 hand, as Dr. Abel has pointed out, have the problem of 6 pigmentation and this becomes a clinical problem. Does one 7 assess persistent pigmentation as part of the global 8 assessment? 9 Then there's finally the variability in the 10 evolution and healing of lesions with or without treatment. 11 Some patients heal quickly even without treatment. Their 12 lesions just subside more quickly than others do. In some 13 it is much more persistent, probably having to do with P. acnes. 14 Dr. Leyden I'm sure can address this far better than I can. 15 And under treatment some patients just simply get better, 16 and lesions can evolve more slowly. Unless you have 17 significant numbers of patients who are being treated, this 18 variability would be an important aspect. 19 Now, let's look at some acne. I don't know if 20 you can see this in the not totally darkened room. This is 21 a patient with mild disease, not maybe to the patient's eye, 22 but to the physician's eye, just a few scattered erythematous 23 papules. 24 This is a patient with terrible disease, large 25 numbers of inflammatory lesions, pustules, nodules, sometimes

81 1 referred to as cysts over the course of the face. These 2 patients present no problem in global evaluation and certainly 3 at baseline. The problem that comes up is the patients who 4 are in between. If you call this grade V and you call the 5 slide before grade I, how many grades in between are necessary 6 to get an "accurate" assessment and what should be included 7 in them? Well, this is what this conference is about, and 8 I would hope that something will come of it in this regard. 9 Now, going back to the milder side, this is a 10 patient, a little more severe than the one I first showed you, 11 but still no scarring, and the lesions are all small. This 12 would probably be called moderate. Some may call it mild, 13 but certainly not minimal and certainly not severe. 14 This is a patient with somewhat more severe 15 disease. A few more lesions, but some of them are larger, 16 not terrifically large, but they're certainly approaching 17 nodular size which by definition arbitrarily is a lesion that 18 is 5 millimeters or larger. These lesions may be 4, they may 19 be 5. There are other lesions that are much smaller. There 20 are a few areas which may show this post-lesional inflammation 21 that Dr. Abel referred to as these flat, macular erythematous 22 areas. When an acne lesion heals, it sometimes leaves no 23 erythema; it sometimes leaves erythema that can persist for 24 many weeks and months. Do we count these? Do we not? Would 25 high resolution photography that Dr. Kligman suggested earlier

82 1 today be able to discriminate papular lesions from these healed 2 inflammatory lesions? Should they be counted? They're 3 difficult to see by photography but perhaps with virtual 4 reality photography they will be able to be seen. 5 This individual actually has more severe acne, 6 and if you count the number of lesions that this patient had 7 with the number of lesions the patient on the previous slide 8 had, they're about the same. But this patient is worse. Why? 9 Because several of the lesions are quite large. They're 10 nodular, and so this patient has a more intense appearance. 11 So counting lesions by themselves I shouldn't say is 12 hazardous, but it has to be taken with not a grain of salt 13 but has to be appreciated. 14 This individual has obviously bad acne, not the 15 type of patient that would be considered in topical therapeutic 16 trials. I want to point out something and that is her lesions 17 are quite clustered. She doesn't have any nodular lesions. 18 She has a large number of small papular and pustular lesions. 19 She also has scarring. A word about that in a moment. But 20 one of the things that one sees in acne -- not commonly but 21 it does occur -- is perilesional erythema, erythema surrounding 22 the lesion and this can make a patient look much worse. If 23 you have a patient that has, say, 10 inflammatory papules and 24 another patient has 10 inflammatory papules but with 25 surrounding erythema, then that patient looks worse. And here

83 1 this patient has a lot of this and happens to have lesions 2 concentrated in an area, so this looks like almost something 3 other than acne. It's very highly inflammatory, but yet does 4 not have a large number of lesions. 5 I mentioned scarring in a moment. This person 6 has had disease for a long time. This should never happen 7 to a patient nowadays. But in scarring, in global evaluation 8 of a patient and when you're considering the type of therapy 9 in a private setting or in a clinic setting, the presence or 10 absence of scarring is very important. While most scarring 11 of this type that you see here will occur in individuals with 12 severe acne, you can occasionally get scarring in patients 13 with mild acne. In fact, the reverse of the case, you can 14 get no scarring in patients with severe disease. So there's 15 not a one-to-one correlation in individuals with mild disease 16 and the prospective scarring. 17 I only mention this because if an individual is 18 being considered for a study who has very minimal scarring, 19 such scarring should be a contraindication. The individual 20 should not have any scarring. It's not going to affect the 21 outcome of the inflammatory component of the disease. 22 Therefore, it should be excluded. 23 I'm afraid this doesn't show up too well, but it 24 illustrates a problem. We have here the forehead of a young 25 man with highly inflammatory lesions. They're actually not

84 1 quite nodular in size. They're about 4 millimeters with 2 pustular centers. So this would be a pustular lesion with 3 surrounding erythema. And then there are some smaller 4 lesions, and then there are some of these seemingly flat, 5 erythematous lesions. If you were to count these lesions, 6 you would have to count smaller lesions in the same count as 7 lesions that are much more intense looking, and yet they would 8 be classified as a papule or a pustule less than 5 millimeters. 9 This is very difficult. This narrow area of papular and 10 pustular lesions. Should attempts be made to grade those? 11 I'm getting into lesion counts, which I don't want 12 to get into, but Burke and Cunliffe back in the original report 13 divided papules and pustules that were smaller than 5 14 millimeters, which is the definition of a papule and pustule, 15 into two categories: active, larger, more inflammatory; less 16 active, smaller, less inflammatory. Highly descriptive. And 17 they mention that "some 40 percent of the lesions fell between 18 these two types but in practice we assigned the lesion according 19 to its major component." This statement is a direct quote. 20 It's inscrutable to me, and I don't understand how they could 21 arrive at this attempt at least to classify lesions smaller 22 than 5 millimeters by more active, less active. I would have 23 great difficulty doing this. It shows the problems and the 24 tenacity with which this issue is approached. 25 Now, the last slide, which is literally the bottom

85 1 line. From the result of the conference that I was supposed 2 to discuss and have been, it was concluded by the members that 3 it was very difficult to approve, if you will, or to recommend 4 a grading system for acne dependent upon lesion counting and 5 other aspects, and it was better felt that a grading system, 6 at least on baseline in patients with acne, would be best 7 achieved by what was called pattern diagnosis. I think this 8 term was suggested at the time of the meeting by Dr. Kligman. 9 Patients with acne would have either mild, 10 moderate, or severe disease -- they were talking only about 11 inflammatory acne, leaving non-inflammatory acne aside -- and 12 describing the degree of papules and pustules and nodules. 13 A patient with mild acne would have few to several papules 14 and pustules, again no numerical definition, descriptive 15 definition, and no inflammatory nodules, no cysts or nodules. 16 Patients with moderate acne would have several to many papules 17 and pustules, again no numbers, and few to several nodules. 18 And patients with severe disease would have numerous and/or 19 extensive papules and pustules and many nodules. 20 Let me preface my dubious comment about this slide 21 and the conclusion of the conference. This is not applicable 22 for treating mild to moderate acne in terms of successive 23 assessments of patients because you would have to go from here 24 to here or here to 0, which is not part of the grading. So 25 this is not what is germane to the discussions at hand.

86 1 However, I think that this is wrong. I think that there was 2 a mistake in calling moderate acne as having few to several. 3 This should have been only few, and several to many should 4 be under the category of nodules. 5 So the conclusion of the consensus conference in 6 1990 was that one could not clearly identify a single 7 classification system for grading acne or even for the global 8 assessment of acne on a longitudinal basis, but this at least 9 provides some guideline for the use of therapies in acne in 10 patients seen in the office and in the clinics. 11 Thank you. 12 DR. STERN: Thank you very much, Peter. 13 Our next speaker is Jim Leyden who is a professor 14 of dermatology at the University of Pennsylvania and another 15 person with a long and illustrious track record in the 16 evaluation and treatment of acne. 17 DR. LEYDEN: It's great to be here just to hear 18 Peter come out of hibernation and give one of his usual very 19 thoughtful presentations. 20 While we're doing that, I'll tell you a story about 21 my oldest grandson who is just 5. About a couple of months 22 ago he said, Pop-Pop, could you get me some cream? And I said, 23 yes, sure, what for? He said, I got a couple of little red 24 dots here that won't go away. They were two little inflamed 25 milia. And I said, I'll get you some cream, but let me tell

87 1 you why you get them. He likes to play chess with the computer 2 a lot. I said, when you're playing chess and you're thinking, 3 you're doing this all the time. If you stop doing that, you 4 won't get them and you won't need the cream. He said, okay. 5 And a couple of hours later, his mother called 6 me and said, Jamie just came to me and said, I don't think 7 Pop-Pop is a very good skin doctor. 8 (Laughter.) 9 DR. LEYDEN: Well, he told the story and he said, 10 I'm not doing that. Why would he say that? 11 And then the dagger in the heart. He said to his 12 mother, I want to talk to another doctor. 13 (Laughter.) 14 DR. LEYDEN: So I hope you won't feel that way 15 when I'm finished. 16 (Laughter.) 17 DR. LEYDEN: I'm going to talk about global 18 assessment primarily. I thought I'd begin by just reviewing 19 what you've already heard, that currently the approval process 20 involves what I like to refer to as the meatloaf approach, 21 you know, two out of three ain't bad. You have to have 22 reduction in non-inflammatory lesions, inflammatory, and total 23 lesions, two out of three, plus some kind of evaluation, overall 24 global assessment. 25 And this is where all the problems are as all of

88 1 you are getting the sense. This has worked more or less 2 reasonably well probably because the majority of drugs that 3 we've had have been either topical antibiotics or topical 4 combination antimicrobial/antibiotics and topical retinoids, 5 and then more recently oral contraceptives. 6 Oral contraceptives have enough effect on sebum 7 that the overall severity of the disease, both inflammatory 8 and non-inflammatory, goes down enough that this kind of system 9 works. 10 Antibiotics work mainly by suppressing the 11 organism that creates the inflammation, but we have also known 12 for a long time that there is a modest but consistent effect 13 on non-inflammatory lesions. We now understand the mechanism 14 by which that occurs. 15 Topical retinoids work mainly on the abnormal 16 desquamation and have the most obvious clinical effect on 17 non-inflammatory lesions although they all have been shown 18 to have effect on the inflammatory phase. And now we have 19 some understanding, at least of some of the molecular 20 mechanisms in terms of their effect on total receptor 21 expression. 22 So the drugs we've had have worked well enough 23 with this kind of system even though we have all kinds of issues 24 dealing with the global assessment. 25 However, I think in your considerations, the drugs

89 1 of the future may well work only on one area of acne 2 pathophysiology to the exclusion of others. And I think to 3 some degree that day is already here. We have very low dose 4 doxycycline. While an initial study showed some effect on 5 non-inflammatory lesions, whether that effect will be great 6 enough to make sure that two out of three is reached and whether 7 that's reproducible needs to be seen. There are 8 non-antimicrobial antibiotics that have anti-inflammatory 9 effect. We're all familiar as dermatologists with the 10 macrolide derivatives that have anti-inflammatory activity. 11 In a series of regional derm meetings that I've 12 been involved in over the last three or four months, it's quite 13 clear that many dermatologists have decided that Eladil, for 14 example, and also to a certain degree, Protopic have effect 15 in the inflammatory phase of acne. Whether or not that can 16 be substantiated enough or whether or not the manufacturers 17 will choose to try to substantiate that in terms of an approved 18 FDA claim remains to be seen. But I would suggest to you that 19 if and when that's the case, it's very unlikely that a pure 20 anti-inflammatory drug will have any effect on the 21 non-inflammatory phase. So the day of thinking about approval 22 of drugs for aspects of acne I think is here and should be 23 part of your overall considerations. 24 A couple of general issues before we get into the 25 global assessment I'd like to bring up -- and you heard a little

90 1 bit of it already. It's very clear from investigator meetings 2 that -- I try not to attend them. I try to send my nurse 3 coordinator. It's very clear that recruitment of patients 4 has become a big deal. It used to be relatively easy when 5 there was not the kind of access that the population in general 6 now has to recruit patients by telling them you're going to 7 be in a study for 3 months or 6 months, if it's an oral 8 contraceptive, or whatever, and you have a 50/50 chance of 9 getting something that's not likely to be very useful, and 10 at the end of that, you're going to get paid for your time 11 and we're going to treat you free. 12 Now people say, well, I don't think I want to wait 13 for that, particularly as we'll get into when you discuss about 14 where the line is for mild and moderate. Right now the current 15 guidelines suggest that you must have at least 20 inflammatory 16 lesions, which means most of the patients have more than 20 17 and lots of them are at a point where you would have to say 18 would you want your child in that study if that meant 3 months 19 of no treatment. Leaving aside that their life is not going 20 to be ruined, it's a difficult discussion particularly when 21 people now have access. 22 So I think the time may well come -- and it has 23 come -- with the recent study a year or two ago with the new 24 formulation of systemic isotretinoin. That was a positive 25 controlled study because I think there it was easier to say,

91 1 well, this is very, very bad acne that isn't likely to get 2 better spontaneously, or if it does, we'll call the cardinal 3 and tell him a miracle has taken place. So that study was 4 a comparative between a new formula and an old formula. And 5 I think you really have to consider that because I think the 6 time is coming when our IRBs will be more and more like Europe 7 and just not permit it unless it's very mild disease. 8 And vehicle for topical and placebo systemic 9 controls are less and less acceptable to potential patients. 10 This is something I would hope you would at least consider 11 and that's a placebo or vehicle run-in. If you look at every 12 study that's ever been done, as Dr. Wilkin said, the vehicle 13 patients always got better, or at least as a group they got 14 better. The mean goes down. Most of that is in the first 15 visit after starting the trial. You can particularly see that 16 most clearly in those where there's a relatively early first 17 visit at week 2 or week 3 after stopping. So consider a placebo 18 or vehicle run-in where everybody gets in and they're in. 19 Then at a certain point no matter what they have, they're still 20 in even if they're below the initial minimal inclusion 21 criterion. 22 Let's get to the global assessment, and I was asked 23 by Jonathan to stress the inflammatory aspect in terms of global 24 assessment. 25 One question you can ask is, is it needed?

92 1 Actually as it stands now, a group of 9 or 10 of us was brought 2 together at the academy meeting last year by a company new 3 to dermatology who was somewhat perplexed by the requirements. 4 And the group of us decided, as it stands, it probably should 5 be removed. Should not lesion counting be sufficient? You'll 6 hear from Dr. Kligman later how difficult lesion counting can 7 be. With the imaging techniques that we have now, I think 8 all of us agree that that can be greatly improved. 9 I'll also tell you a secret if you promise not 10 to tell him that I said it. He's never counted pimples ever 11 in the 35 years that I've worked with him. But as is often 12 the case, he knows things without having to go through the 13 work that the rest of us have to. 14 (Laughter.) 15 DR. LEYDEN: And he's rarely been wrong. So one 16 has to just remember that. 17 In the past the global assessment was a so-called 18 dynamic, a pre-post therapy, and the question of, well, how 19 can you remember? Well, obviously you can't remember, but 20 you can have images, large transparencies. Some companies 21 now have very sophisticated ways you can just type in a number 22 and up comes a large, life-size image of the person, right 23 side and left side, from the initial visit. That kind of 24 analysis was done with the photo damage for the tazarotene 25 clinical trial, for example. So you don't have to remember.

93 1 You can have an image to compare with. 2 I would agree that in the past without an image, 3 the global assessment was probably done mostly by "how are 4 you doing" and seeing what the lesion counts were and then 5 making some assessment, various so-called static global 6 assessments with varying scales, and you heard of the 7 difficulties with some of those scales. 8 But I just want to make sure you all know that 9 success means 100 percent clear or near clear with no further 10 treatment required as being part of the near clear. We'll 11 get into that. Is that a reasonable, clinically relevant 12 endpoint? It's a crisp endpoint. Nobody would argue that 13 someone that's totally cleared up has gotten better unless 14 they had practically nothing to begin with, but if they have 15 at least 20 inflammatory lesions and they have none at the 16 end, and they had, say, no comedones and they have none at 17 the end, I don't think anybody would argue. They're better. 18 The question is where should you draw the line in the sand 19 to constitute a degree of improvement that's meaningful and 20 should be part, therefore, of the overall analysis. And one 21 of the questions in your book is how to best present in the 22 package insert information. 23 And I'll show you people who would qualify as not 24 successful, failures. Not to include the fact that they 25 achieved that kind of improvement with monotherapy I think

94 1 is not fair and does not accurately present the benefit that 2 a given monotherapy in this disease with multiple areas of 3 pathophysiology. As I think all of us would agree, it's an 4 uncommon patient that gets one drug for acne, and that reflects 5 the fact that it's multiple areas of pathophysiology and you 6 can counteract multiple ones. 7 Using this kind of facial diagram that Anne Lucky 8 first came up with in making sure that you go into each quadrant 9 means that if you take your time and are careful, you can count 10 these individual non-inflammatory lesions and even count the 11 most difficult ones, the ones that are best seen by stretching 12 the skin, the so-called closed comedones. They can be counted 13 on the hoof, so to speak, with the patient there. They can 14 also now be visualized and counted without the patient sitting 15 there and hoping you'll get finished quickly so they can get 16 out of the room. 17 I'd just like to emphasize a couple of things that 18 Dr. Pochi said and others during the discussion. This is a 19 patient who would qualify by today's -- this patient actually 20 has 37 inflammatory lesions, but the quality of the 21 inflammation is very, very different than this patient who 22 actually has almost 100 inflammatory lesions because just about 23 every individual follicle is involved, although the quality 24 of the inflammation is quite different. I think by trying 25 to put words to a description of how bad a patient is is part

95 1 of the problem, which I'll say a little bit more about in a 2 few minutes. 3 So, as I see it anyway, some of the problems with 4 current success, meaning 100 percent clear or practically 5 nothing such that a patient wouldn't need any kind of treatment, 6 assuming they stayed at that point -- is very uncommon with 7 a single mode of action treatment. Acne, as we all know, is 8 a chronic, relapsing condition. Three months of therapy is 9 almost -- that's it. You can go home now. Your acne is gone 10 is just something I'm not personally familiar with. And to 11 think that at the end of three months it's over -- or at least 12 that's implied in the fact that you've gotten to a point where 13 you're clear or near clear, not requiring further therapy. 14 The more inflammatory lesions you have, the less 15 likely -- and I think you've heard from Jonathan's presentation 16 that that makes sense from his point of view. 17 Again, certain drugs have more effect in one area, 18 and drugs that have primarily effect in the non-inflammatory 19 phase of the disease without influencing the precursor of 20 inflammatory lesions, if such drugs are in development -- I 21 would suggest they will be developed because we now understand 22 some of the molecular aspects of comedogenesis -- could fail 23 by today's standards. 24 I'll just show you one example of combination drugs 25 that work on multiple areas of pathophysiology and seem to

96 1 be susceptible to some statistical quirks that don't make sense 2 to me when you have a low responder rate. When you take the 3 endpoint of 100 percent clear, you end up with very low, but 4 highly statistically different. You know, 6 percent versus 5 0. Even I can do the statistics. But when you have multiple 6 cells, then there is the potential for very good drugs not 7 showing a statistically significant difference while the 8 clinical effects may be obvious. 9 So, these are not as good as they would be if the 10 lights were completely out, but this is a patient who's got 11 mild disease, and you could say, well, he's almost clear if 12 the other side were the same. 13 But here's a patient with much more severity. 14 Those up front can see the non-inflammatory lesions, a lot 15 of inflammation. He's clearly, definitely better. But by 16 today's standards, he has failed. 17 And this patient who is not clear but really better 18 has failed, as has this patient. This is a failure because 19 it's not 100 percent clear nor almost 100 percent clear. 20 So it just seems to me that doesn't make good sense 21 clinically. One could envision a drug that did this in 75 22 percent of patients failing because not enough patients reached 23 total clearing or almost total clearing. 24 Now, for the statistical quirk. If one knows from 25 some preliminary work that a global assessment was 18 percent

97 1 clearing versus 11 percent in the vehicle, if you wanted to 2 have an 80 percent power, you'd need somewhere in this 3 neighborhood of patients, and then to allow for dropouts, 4 something like 2,000 patients for a four-arm trial. What 5 happens if the response rate was 18 percent versus 12 percent 6 instead of 18 versus 11? You're down to 65 percent power 7 apparently. That I think reflects this low responder rate 8 can have influence on studies with multiple cells. 9 I personally like a scale called the Allen and 10 Smith, which was not mentioned this morning. It's a validated 11 scale that was published in the Archives in '82 or '83. It 12 involves evaluating both the non-inflammatory and the 13 inflammatory aspect of the disease separately instead of trying 14 to jumble them together with words, as you saw on some of those. 15 That Cook scale. I always loved that one where one of them 16 begins with loaded with comedones, whatever that means. That 17 was the first line in the grade. So this has been shown that 18 investigators can reproducibly give the same kind of grade 19 for both phases of the disease. 20 I personally think that the pre and post use, the 21 so-called dynamic evaluation by investigators, with either 22 transparencies or digital images or, as I'll go into in a 23 second, using the same kind of images for an external panel 24 of judges makes it a lot easier than trying to come up with 25 words that describe what we're trying to integrate.

98 1 This is practically no acne. You can see a pimple 2 or two. As you start to get a little more pimples, if you 3 want, you can put words. It's getting a little more. This 4 is just looking at the inflammatory phase. Getting more 5 intense inflammation, more, and then more severe. 6 Now, I did this with a company who eventually 7 decided they weren't going to do it, but it was an oral 8 contraceptive. And they had a group of potential 9 investigators, gynecologists and their nurse coordinators. 10 And I went through a series of pictures with grades for 11 inflammation, and they had a little booklet with those pictures 12 in it. And then I showed maybe 30-35 patients and asked them 13 all to grade it. Having never done it before, it was amazing 14 how easy it was for them to look through and match up, with 15 very little discordance, on their first attempt. 16 So I think you can use this kind of system if you 17 have standardized photography. All of us who do studies know 18 of the Canfield systems. And you can have these kind of images 19 which, when you see them, the way they do it, they're much, 20 much larger, and you can count individual lesions or you can 21 look at whether they got worse a little, a lot. They got 22 definite improvement, marked improvement, or they completely 23 cleared up. 24 And you can begin to get a sense of it with these 25 photographs which again are not as good as what you can actually

99 1 achieve. But you can begin to, I think, say, well, that patient 2 is a whole lot better, and maybe you would put them in the 3 almost clear and maybe somebody wouldn't. This patient is 4 clearly better but is not anywhere near totally clear. 5 So you can use this kind of system, and we have 6 used it in the past. A group of us, Alan Shalita, myself, 7 Diane Thibitot, Guy Webster, and Ken Washinik looked at over 8 600 individuals with inflammatory acne. We looked at a 9 subgroup over three days, a subgroup every day to see how 10 reproducible we were and what our intergrading variability 11 was. Fortunately, our concordance was very, very high, and 12 we were able to clearly delineate drugs from vehicles, as well 13 as to see some differences between various drugs within a 14 category. 15 So I think those kinds of things which many people 16 are aware of and have been using for their own purposes but 17 have not really used them in clinical trials yet because they 18 kind of get the feeling that, well, this is what you got to 19 do to get your drug approved, and once you start talking about 20 modifications of the way it's been done, then all kinds of 21 legitimate questions. Well, how do we know that that method 22 is better than what we're doing? And so people have not really 23 pursued them. 24 So my final slide here. I would say the time has 25 come or soon will be here even for moderate acne where you'll

100 1 have to consider positive control studies and/or at least 2 significantly unbalanced trials in order to get by IRBs. I 3 think the real question is, would you want your daughter in 4 this study if they're going to have 12 weeks of no treatment? 5 I think we have to consider possibly setting not only lower 6 but upper limits for mild to moderate if we're going to have 7 vehicle controlled studies persist, and only in the most severe 8 forms are positive controls going to be used. 9 Either we eliminate this global assessment we have 10 now which picks out only that small handful of people with 11 monotherapy who reach total clearing or we bring back a 12 comparative or dynamic kind of assessment using some of the 13 advances in terms of imaging that all of us have become aware 14 of that add to the ability to do this in a way that's meaningful 15 and also consider a vehicle or placebo run-in. 16 I believe that's my last slide, Rob. 17 DR. STERN: Thank you very much, Jim. 18 The panel will have an opportunity to ask questions 19 of our experts at the end of the four talks. 20 Our next speaker is Dr. Alan Shalita who is the 21 Chairman of the State University of New York in Brooklyn Medical 22 School, and he will talk about considerations on success 23 criteria in acne trials. Thank you, Alan. 24 DR. SHALITA: Thank you, Rob, Dr. Wilkin, 25 colleagues.

101 1 First I would like to tell a couple of stories 2 so that one does not think that I'm being facetious in some 3 of my remarks. 4 I had the great privilege, when I was a resident 5 at New York University, to be allowed to go periodically down 6 to the University of Pennsylvania and sit at the feet of 7 Professor Kligman. And I remember grand rounds where one of 8 the residents gave an elaborate description of laboratory 9 values on a patient trying to make the point that the patient 10 had lupus erythematosus, and Dr. Kligman said, is she sick? 11 And the resident couldn't figure out what he wanted, and 12 finally he got the point across that lupus did have some 13 implications other than laboratory values. 14 Well, I think the same thing applies to our 15 judgment of acne. The bottom line is are these patients 16 getting better or aren't they. And we can go through all the 17 statistical manipulations and evaluations of lesion counts. 18 I think that Jim Leyden's grandson and mine are a month apart, 19 and I think that if you show them the pictures that Jim just 20 showed you, that they could both tell you whether those patients 21 got better or not. 22 I know that we need numbers and we need objective 23 criteria to be able to evaluate something to get formal 24 approval, but I also think we make it a hell of a lot more 25 complicated than we need to.

102 1 Now, because Dr. Wilkin mentioned this earlier, 2 I hadn't intended to show this slide, but I wanted to show 3 you what the background noise is in acne because you alluded 4 to it. This was a group of student nurses that we looked at 5 about 30 years ago without any treatment. They all had acne. 6 And you can see that they were getting a little bit better 7 and a little bit worse at roughly 2-week intervals, and it 8 absolutely had nothing to do with the menstrual cycle in spite 9 of a paper that I co-authored a couple of months ago. So that's 10 background noise in acne, and there is a high degree of 11 variability. 12 The other thing, shortly after Dr. Kligman and 13 his colleagues at the University of Pennsylvania described 14 the effect of tretinoin in acne, there were a series of clinical 15 trials initiated. To the best of my knowledge -- and please 16 correct me if I'm wrong -- this is the first drug that was 17 officially approved as a formal NDA for acne. Everything else 18 had either been grandfathered or was being used without 19 approval. For example, I think the tetracyclines are still 20 adjunctive use for acne. 21 But at any rate, so we enrolled patients in 22 clinical trials and we did this at the New York University 23 skin and cancer unit. I'm sorry. I want to come back to this. 24 I apologize. 25 This was, I said, the original formulation. You

103 1 can see that there was significant improvement in lesion 2 counts. We didn't know any better and that was the methodology 3 that they used at Penn. The company that put the NDA together 4 used that methodology. But notice that there's a very, very 5 poor vehicle response in spite of the fact that this is a fairly 6 sophisticated and irritating vehicle. The obvious question 7 is why. 8 My hypothesis is that these were all patients that 9 were coming to what in New York was considered the mecca, the 10 skin and cancer unit at New York University, and they had all 11 been to three or four dermatologists. Their philosophy was 12 prove to me that you can get me better. They also put up with 13 irritation that the average patient in a dermatologist's office 14 would not put up with. That's a side issue. It shows the 15 motivation that they had to find a new drug to treat their 16 acne. 17 On the other hand, this was a study done many years 18 later in which I understand -- and this is strictly 19 hearsay -- one of the reviewers from the agency told the 20 company, why don't you market the vehicle? This happened to 21 be 2 percent erythromycin in one of the original vehicles, 22 which actually happens to be probably mildly effective in acne 23 because had polyoxyl lauryl ether is in it which is a fairly 24 potent substance. In point of fact, they were violating 25 somebody else's patent and never could market this drug.

104 1 But I think one of the reasons one sees this kind 2 of so-called placebo or vehicle response, the exigencies of 3 doing clinical trials today basically because of the short 4 patent life, by the time preclinical trials are done and a 5 drug gets to phase III clinical trials, when a company decides 6 to do a clinical trial, they want the data yesterday because 7 then they have to submit it to the agency. There's time to 8 review it till the drug gets to market to recruit what has 9 been estimated as a $500 million minimal investment. 10 So what happens around the country, you'll see 11 people advertising in local newspapers, college dormitories, 12 student unions, looking for volunteers for acne. For many 13 cases, these are not volunteers that are actually coming to 14 the doctor seeking treatment for their acne. It's what I call 15 drugstore acne. And I think that the proportion of vehicle 16 response increases almost geometrically in relation to the 17 motivation. If the motivation is strictly that they're going 18 to get reimbursed for participating in a clinical trial, then 19 you have created a real problem in terms of vehicle response 20 and that's where the placebo run-in can come in. 21 On the other hand, with the so-called placebo 22 run-in or placebo washout, we once conducted a clinical trial 23 in a reform school in Hartford, Connecticut looking at zinc. 24 And this was published in the Archives where we said that 25 zinc was ineffective in acne, and it probably is not

105 1 ineffective. But the reason for that was these were kids that 2 were all incarcerated for crimes related to narcotics or drug 3 addiction and therefore probably very susceptible to the 4 effects of drug. Well, after lactose capsules for a month, 5 they had 50 percent improvement. And it was pretty hard to 6 prove that zinc was going to do any more than 50 percent because 7 that's the average of what you get with most acne drugs. So 8 that can be, depending on the population, a very dangerous 9 route to take using the so-called placebo washout. 10 These are all confounding factors. I don't have 11 a simple answer for you because if you're going to use real 12 patients that are coming to a dermatologist for treatment, 13 you're pretty hard pressed to use a vehicle control. Now, 14 if you're using a drug such as oral isotretinoin for very severe 15 acne, it's obvious that you're not going to use a vehicle and 16 you can use a positive control. But that gets much grayer, 17 as we discussed before, when you're talking about drugs for 18 moderate acne. 19 I don't know why we're discussing mild acne. I 20 didn't know that the agency actually regulates the OTC drugs, 21 or at least not this division. It seems to me that most of 22 the approvals that are being sought are for a little bit more 23 severe than mild disease, but maybe that's semantic. 24 Then the other point I wanted to bring up -- and 25 this has, I think, been emphasized a few times -- in the concept

106 1 of clear/almost clear, which I think Dr. Leyden has spoken 2 very eloquently about, we tend to use polychemotherapy in 3 treating acne, particularly moderate to moderately severe 4 acne. But the submissions are going to be for monotherapy 5 drugs for the most part, although you have some combinations. 6 Here was a classic study by the late Dr. Sidney 7 Hurwitz, which had been published in 1976, showing that using 8 vitamin A acid, or tretinoin, and benzoyl peroxide at separate 9 times a day produced exceptional results, actually better than 10 I get, but he was treating more of a pediatric population. 11 And in other parts of the study, he showed that it was better 12 than you could get with either drug used alone. So you don't 13 get to the clear or almost clear till you use a combination 14 of drugs in the most part, not always. 15 Then finally, in terms of where we're at -- and 16 I think Dr. Leyden has demonstrated this very clearly, so I'm 17 not going to belabor the point, just to show you a couple of 18 different formulas. This was that series of photographs that 19 he talked about where we looked at over 600 patients. I think 20 it's pretty clear that this patient has improved, although 21 it's not clear/almost clear, but there is significant 22 improvement. 23 Again, I don't think you need a rocket scientist 24 to evaluate these. We've had medical students look at these 25 photographs. We've had nurses look at them and non-medical

107 1 personnel, and they've all come to the same conclusion. 2 Dr. Kligman I think is going to refer to it and 3 did earlier, about some of the specialized techniques. This 4 is just one. I think this happened to be one particular 5 retinoid, but that's not what's important. I think the 6 progression of improvement over the treatment period is very 7 obvious. Again, one could try to quantify this, but you don't 8 need anything else. 9 Finally, there are several other advantages I 10 believe in using the photographs as a method for evaluation. 11 Number one, it gives you a record that is permanent and not 12 fudge-able. I'm not talking about digital photography which 13 can be altered. But it gives you a permanent record of what 14 actually happened. It gives you a confirmation of the 15 investigator's evaluation, and it also allows for an 16 independent third party, including the agency, if you so 17 desired, to examine the results and say, this is a drug that 18 works, this is a drug that should be on the market. 19 Thank you for your attention. 20 DR. STERN: Our next speaker has already been 21 introduced at least five times this morning because of his 22 eminence in the field, and it's Dr. Albert Kligman, one of 23 the true luminaries in dermatology. Among his contributions 24 are those in the field of acne. And he's also from the 25 University of Pennsylvania.

108 1 DR. KLIGMAN: Well, Dr. Stern's remarks validate 2 what I have learned. If you live long enough, people will 3 start to say good things about you. It's just a matter of 4 age. 5 (Laughter.) 6 DR. KLIGMAN: I am 86 years old, by the way, and 7 it demonstrates that the practice of dermatology is 8 life-giving. 9 (Laughter.) 10 DR. KLIGMAN: My talk is about counts and counts 11 are the popular, traditional, so-called objective way of 12 demonstrating and measuring efficacy. The popularity of 13 counts, of course, are obvious. You get numbers. Numbers 14 bring joy to the heart of statisticians. You can make 15 statistical analyses which gives confidence to regulatory 16 agencies. We approved this drug because there was a 17 statistical difference in the comparative assessments. So 18 this is regarded as the gold standard, one of the objective, 19 unbiased ways of assessing efficacy. 20 And I will tell you forthrightly that the most 21 that could be assigned in terms of standards is bronze, after 22 silver perhaps, but not much better than that. And the 23 limitations are enormous. The accuracy and precision has 24 never been looked at. Worse than that are the reproducibility 25 and repeatability of lesion counts. I know of no instance

109 1 in which five different observers were looking at the same 2 group of patients and their estimates correlated. There is 3 no such objective evidence. Even within observers, the 4 variance may be extraordinary. 5 We did a test years ago which I undertook in kind 6 of a mirthful, mischievous way. We had Otto Mills who spent 7 most of his days counting lesions and considered himself an 8 expert. We had 10 patients with a mixture of lesions, and 9 all he could see of the patient was a hole in a sheet. He 10 could not see the patient and only this template. And he made 11 counts, and then we scrambled all the patients and he made 12 the counts over again. I am ashamed to tell you what the 13 results were. The variance was enormous. He did very well 14 on open comedones, big black lesions. They were easy, but 15 for inflammatory lesions he did really very badly. So this 16 method, as it now exists, is certainly full of difficulties. 17 Well, another way of knowing that the counting 18 is an imperfect and difficult method and very unreliable is 19 to see what the literature says. When you read the literature 20 on acne comparative trials, if you are young and sensitive, 21 you could get nauseated. If you're old like me, you just get 22 cynical. It's just unbelievable. 23 May I remind you? And maybe you know, Dr. Stern. 24 I don't think there's ever been an NIH-supported acne 25 protocol. It's all industry supported. I'm not here to bash

110 1 industry, but we all know that the capitalistic system often 2 does not produce honorable people or results which are 3 meritorious depending on how the study is set up. And that 4 makes a very big difference in what you might see. 5 A recent review of all the papers that have been 6 published in the last 50 years, based on evidence medicine, 7 double-blind, placebo-controlled, randomized studies, about 8 10 percent of the studies that were reviewed fulfilled even 9 minimal requirements for assessing efficacy. There will be 10 improvements and the endpoints all mixed up. So it's kind 11 of a mess. Let me give an example of how bad it is. 12 Azelaic acid in several studies was shown to be 13 as effective as benzoyl peroxide in suppressing P. acnes and 14 in clinical improvement. Anybody with experience knows that's 15 nonsense. Benzoyl peroxide is a powerful antibacterial agent. 16 In 10 days you get a tremendous decrease in the P. acnes count, 17 and Jim Leyden has certainly showed that. And there's no 18 comparison. And yet these studies were apparently conducted 19 by responsible physicians under reasonably good conditions. 20 That's just not acceptable. I could give you innumerable 21 examples in which equivalence is achieved for drugs which are 22 completely different. 23 Another example, for example, would be 2 percent 24 erythromycin against 1,000 milligrams of tetracycline orally. 25 Three studies show equivalence. That's nonsense. Oral

111 1 tetracycline beats the hell out of 2 percent topical 2 erythromycin certainly in inflammatory acne. So that's kind 3 of silly stuff. 4 And then another issue here is what do you count. 5 Do you count microcomedones which you can hardly see? Closed 6 comedones, open comedones, nodules, papules? Which kind of 7 papules? Little ones, big ones? Dr. Pochi has already gone 8 into that. 9 And in fact you have to decide many other troubles. 10 Do you count the whole face or do you do it regionally? You 11 have counts based upon the forehead, cheek, chin, and nose 12 as Anne Lucky has sometimes indicated. You get very different 13 results. 14 You also get very different results when you divide 15 acne into categories, and there are many categories. We have 16 all heard about the pleomorphism and the multiplicity of 17 expressions, the phases of acne are so variable. If you start 18 with early acne in prepubertal girls, they just have a few 19 comedones. Boy, they do swell with comedolytic agents. Then 20 you get into adolescent acne. That's a little more difficult, 21 and you get variable mixtures. And then you get into 22 post-adolescent acne in females, and they tend to get lesions 23 on the lower part of the face, and those are deep, ferocious 24 papules and they're damned difficult to treat. So the outcome 25 of much of this is depending on what you start with.

112 1 We have also heard about the placebo effect. Let 2 me emphasize what Alan has said. You can't imagine a more 3 labile disease which involves psychosomatic aspects. The 4 psychological factors are profound, and the placebo effects 5 are profound. 6 Alan, nobody showed you this, and both of us like 7 to say in some of the drug studies where you look, you use 8 the eyeball test. I'm a great believer in the eyeball test. 9 When I see two curves and they're pretty comparable -- you 10 know, there's only a little bit of difference between them -- I 11 don't give a damn what the statisticians say. They may have 12 all the power in the world. The confidence limits are 13 wonderful. But the fact is clinically and biologically 14 there's no difference when the curves are almost superimposed 15 upon each other. In fact it would be possible to sell the 16 vehicle with a perfectly good outcome. 17 I can tell you for sure that using exactly the 18 same procedure, double-blind, randomized, the whole religious 19 stuff on how to do a study, that Jim Leyden is always going 20 to get better results than most practitioners all over the 21 world. And the reason is he's Irish, he's romantic, he's 22 optimistic, we know how to treat acne. I've seen 1,000 23 patients. You just do what I tell you to do. He gets more 24 compliance and he gets much better results. These are all 25 part of the emotional difficulty, in fact, impossible problems

113 1 to measure, and yet, they come into our concerns all the time. 2 Well, another thing that I want to talk about is 3 what's already been mentioned. Acne is an astonishingly 4 mischievous disease. It's very labile. Lesions come and go 5 very rapidly. The life cycle of individual lesions is 6 remarkably unpredictable. We have done a study using target 7 areas taking digital photographs every 3 days. And this is 8 something that's really difficult to understand, why it's so 9 fluctuating, why it's so episodic. Those of us that have 10 experience know this to be true. Sometimes you see a pustule 11 come up in 1 day and 2 days later, it's gone. I'm talking 12 about one area which is a target and we're measuring what's 13 happening to each lesion. Other times you see a papule come 14 up and it stays there for 2 weeks. Comedones will suddenly 15 disappear. I have no idea what controls this kind of uncertain 16 behavior, but it is certainly something that we have to take 17 into account. Not only do we made a global estimate, a severity 18 estimate, but we should be able to follow individual lesions. 19 There are many biological problems that remain. 20 I don't know why two pustules or papules that look exactly 21 the same, one leaves a scar and the other does not scar. What 22 the hell determines that? There must be some way for us to 23 qualitatively assess lesions and predict what would happen. 24 All of this lability leads to what most of us have 25 been saying. Use modern, highly precise imaging devices and

114 1 a lot of this difficulty of classifying lesions, about their 2 size, their shape, their color will all disappear. 3 Duration of the study is also extremely important 4 business. If you're going to do a 3-month study and that's 5 the end of it, as Jim has pointed out, it's not the end of 6 it. But as a result of the fluctuating course of lesions, 7 if 3 months is acceptable because that's all the companies 8 can pay for and you at least get to some kind of a 9 result -- they're moderately improved, greatly improved, or 10 cleared -- you have to take multiple assessments. I can tell 11 you it's damned near worthless to do a pre-assessment and then 12 for the next 3 months, you just wait till the end, and you 13 take your photographs, so you do your counts. That's almost 14 worthless unless you have a fantastic drug which clears 75 15 percent of patients which would be a very nice endpoint. 16 What's happening in between is absolutely 17 important in view of the fact that most of what we do -- as 18 Jim pointed out, it's not what happens to existing lesions. 19 Let me emphasize what Jim told you again. Most lesions, if 20 you don't do anything, comedones and papules, you don't do 21 a damned thing but watch them, they spontaneously regress. 22 So in therapy what we are really doing is measuring the 23 inhibition of the evolution of new lesions. The existing 24 lesions are going to get better anyway over a period of time. 25 It's the prevention of new comedones, the prevention of new

115 1 papular pustules that is really extremely important. All of 2 these, of course, become issues. 3 Now, let me tell you what the most important thing 4 is in counting lesions and why it's so variable. It's a 5 tedious, onerous, bitchy business. It takes time, and if you 6 see a study being carried out in a clinic situation, an office 7 with patients waiting, and you have a technician, let's say, 8 who's counting the lesions, I can assure you it will take at 9 least a half an hour per subject to do the cheeks, do the 10 forehead, do the chin and get accurate lesions. What mostly 11 happens is that people are not experts, they're not seasoned, 12 they're not well trained, and it's easy enough when the doctor 13 is saying, you know, you can't take a half an hour for a patient. 14 I can't make a living unless you cut it down to 5 minutes 15 or 10 minutes. And that's a reasonable assumption. 16 So what very often happens -- I've watched 17 this -- unless you're in the domain of Anne Lucky -- when Anne 18 Lucky makes lesion counts, you can damned well believe them. 19 When most other people make lesion counts, they're up for 20 grabs. You start looking at them and then the technician says, 21 my God, well, it looks like 15 comedones and 20 papules look 22 like a good idea. 23 What Jim has said is absolutely right. I have 24 never counted papules in my life. I've always depended upon 25 other people who have better vision and more patience. It's

116 1 an extremely difficult thing. 2 I just want to show you a couple of slides to 3 highlight some of the things that I've told you. Well, this 4 is to tell you that the so-called placebo 5 effect -- incidentally, there are no placebos in dermatology. 6 That's another story I'd like to tell you about some day in 7 bar-like situation. 8 (Laughter.) 9 DR. KLIGMAN: There are no placebos. Everything 10 you do to skin, Nivea cream, any lotion, goose grease has a 11 beneficial effect because it improves the stratum corneum. 12 It prevents injury. They even have some anti-inflammatory 13 effects in their own right. You have a lousy stratum corneum 14 in acne. It's punctured and you've got inflammatory lesions. 15 Just putting the Nivea cream down long enough, in 50 percent 16 of the cases in 3 to 4 months, a pretty damned good result, 17 no activity whatever. 18 Here's a study that was done for 4 months using 19 Cetaphil lotion. It's a non-medicated lotion. And just 20 looking at the general assessment, well, 10 percent got 21 excellent. Look at the good results. And you see that's a 22 pretty good number in terms of percentages. We've got 40 or 23 45 percent of people achieving a pretty good result with what 24 amounts to a vehicle. 25 The spontaneous events, the placebo effect here

117 1 again is very important. Here's a study done by Lucky, who 2 I think is an extremely rational and meticulous and vigorous 3 minded clinician. This is a study on ethinyl estradiol. You 4 heard from Dr. Bergfeld about the estrogens. Well, these are 5 cycles. The difference between the hormone and the 6 non-hormone, the placebo pill, notice that they're getting 7 steadily better as you get up to five cycles. This is part 8 of the placebo effect. The minute that patients are put into 9 a study, when they're recruited, their compliance becomes 10 better. If the doctor is a very supportive, cheerful doctor, 11 then the results get even better so that the temporal effects 12 always have to be considered. 13 Well, Jim mentioned this and I certainly second 14 it. A run-in effect is a very, very good idea, and I think 15 it should be incorporated in the published outcome of this 16 meeting. Recruiting people, putting them in a study and just 17 using either nothing or a vehicle, you see what happens here 18 with comedones and papulopustules. Before the study starts, 19 minus 4, minus 2. There already is a significant reduction. 20 You need to know what the slope of that curve is, what you're 21 starting with. So I think it's a very, very good practical 22 strategy for doing controlled, comparative studies, a run-in 23 period in which you do nothing or you use a non-medicated 24 medication. 25 I just want to show you a couple of little tricks

118 1 that add to the fun of being an acneologist, if there is such 2 a category. This is crazy glue, and what you do is you simply 3 put some glue down on the skin and you cover it with a slide 4 and then you let it polymerize. It's a cyanoacrylate, and 5 you lift it off, and you see all that stuff, all follicular 6 contents, hairs and sebum and horn, and any debris in the 7 follicle comes out. And you can look at the slide and make 8 some judgments. 9 I want to show you this because it shows what a 10 smart lady Anne Lucky is. It was Anne Lucky who made us really 11 aware of adrenarche, the time when prepubertal acne is a real 12 phenomenon and important to make the diagnosis because if you 13 can identify high-risk patients who are in an early stage of 14 acne, which happens to be comedonal acne, in girls as young 15 as 8 and 9 years of age, one way to recognize such people in 16 the prepubertal acne due to the secretion of adrenal androgens 17 which promote growth of the sebaceous gland -- here is an 18 11-year-old girl who is not at high risk. Neither parent has 19 acne. Neither parent has scars. So she's normal. And this 20 is what the cyanoacrylate looks like. 21 I'm hot on this subject of pre-acne and pre-rosacea 22 and identifying diseases years before they become clinically 23 apparent. It's a favorite thesis of mine called invisible 24 dermatology. As far as I know, I'm the sole practitioner of 25 invisible dermatology.

119 1 Here's a normal person. Here is an 11-year-old 2 girl without visible acne, a few little comedones in the nose 3 and the forehead. 4 And incidentally, the pattern of acne is another 5 thing, which is troublesome. This damned disease behaves in 6 pesky ways. When it starts, it tends to start up here, and 7 then the older you get, it sinks down. You get down to the 8 point in post-adolescent acne which is in the lower part of 9 the face and it's a lot more difficult, for reasons unknown 10 to me, why the lesions on the lower part of the face are much 11 more refractory to treatment than the upper part of the face. 12 Well, you can see in a moment this kid is in 13 trouble. The time to treat her is right then and there with 14 a comedolytic agent, and our preliminary study shows that that 15 works very well. 16 Another way of doing that is to look at sebutape 17 and just look at the number of dots. We can image analyze 18 this, determine the density of sebaceous follicles, how much 19 they're making, the size distribution and do all the 20 statistics. This is the same girl I showed you who is 21 cyanoacrylate positive. She's making sebum. If I showed you 22 a 1-hour sebum excretion rate on sebutapes of the control 23 person, you will see little or no droplets. 24 And here is looking at the sebutapes with a 25 fluorescent light for porphyrins and you look at it with

120 1 porphyrins. And that's another way, incidentally. Another 2 possibility of looking at acne is to just turn out the lights. 3 Let your eyes get accommodated and look at it with a Wood's 4 light and see how many follicles are fluorescing. It's another 5 attribute which is really quite useful. It's a nice little 6 trick. 7 Here is post-adolescent acne, and I think now that 8 there are more women with acne, troublesome, deep papules, 9 than all other forms of acne. Post-adolescent acne in females 10 is increasing in prevalence and is a very important thing. 11 Notice that she's got some lesions up here, but many of the 12 ones are down below and they're tough to treat. And the reason 13 that they're tough to treat is when you do a biopsy -- and 14 we would like to avoid doing this. We now have, believe it 15 or not, things that you have never heard about, optothermal 16 coherent tomography. We can outline without touching the skin 17 just what this lesion looks like from the surface down. 18 Confocal microscopy does the same thing, and we can make cuts 19 without touching the skin, all optically done, which is going 20 to increasingly give us the kind of resources that will enable 21 us to make the comparisons that we're interested in. 22 Finally, this was brought up. When you talk about 23 acne, you have to define blacks, orientals. It's a common 24 belief among dermatologists -- and because they are 25 dermatologists, they have many, many myths that they have to

121 1 deal with -- that acne in blacks is less aggressive, less 2 important, less scarring. That's absolutely wrong. Halder 3 and myself at Howard have shown that that's not the case. 4 And here's a good example in the case of a black 5 person. If you take a regular photograph like that, well, 6 you can count those papules and pustules. That's pretty good. 7 But the fact is if you look at digital photography, which 8 faces all surface contours -- you don't see any 9 micro-topography. All the surface texture is obliterated. 10 So now you're looking beneath the surface. Then you can see 11 that there are many more lesions than you saw before and that 12 each of these lesions are a great deal more disseminant. They 13 have spread well beyond what you see on the surface. This 14 is just an example of what you can do with digital photography. 15 So my message is this. We really have a repertoire 16 of drugs for the treatment of acne which is really superb. 17 You know what you're doing. You have a tremendous choice of 18 oral drugs and topical drugs. And we now have within our hands, 19 if we just bring about the necessary resources, to take this 20 pleomorphic disease, this disease with so many different 21 expressions, and really establish criteria rigorously defined, 22 all the things that we have been talking about, and to make 23 assessments which are reliable and believable and which will 24 allow regulatory agencies to make their approvals based on 25 objective science.

122 1 Thank you. 2 (Applause.) 3 DR. STERN: I'd like to thank all four of the 4 speakers for giving what I at least thought were extremely 5 lucid, informative, and fun to listen to presentations. 6 We're now open for -- yes, I'm sorry. Could I 7 ask the four speakers to come over to the side so it will be 8 easier for us to ask them questions and for them to respond? 9 Dr. Kilpatrick. 10 DR. KILPATRICK: I don't really have a question 11 as yet. I may come up with one as I think. But I wanted to 12 inform you, sir, that statisticians have gone beyond the level 13 of development in our subject that we can deal with categories, 14 ordinal or otherwise, as well as counts or measures. So there 15 are techniques and perhaps Dr. Tan and other statisticians 16 here will come to this as we come to the quantitative aspects. 17 Thank you. 18 DR. STERN: I want to address a question to Jim. 19 My own biases are very much along yours in terms of the need 20 for objective photographic assessment. In fact, that's done 21 by people who weren't involved in the investigation who are 22 blinded to both the temporal order of when the photographs 23 were taken and also obviously what treatment group they were 24 in. 25 One question I had, though, is you mentioned the

123 1 use of photographic or digital images for doing dynamic 2 assessment by investigators at the time. One of my 3 observations has been that when I look at a photograph of an 4 individual taken very recently where there couldn't have been 5 much change in their clinical status, they often look worse 6 in the photograph. There's something more impressive about 7 many clinical conditions on a photograph than if two days later 8 you look at that person in vivo. And I was wondering if you 9 could comment. Is that just my own bias or have you tried 10 to look at it? 11 DR. LEYDEN: Well, I haven't looked that soon. 12 The soonest I've looked at is a month. I mean, I think the 13 criticism that was covered this morning about the former ways 14 where people were judging how much better they got based on 15 memory -- you know, you can't remember. You had to have some 16 kind of interaction with the patient and kind of look at the 17 case report form and see whether they got better or not. So 18 it wasn't very distinct from what was already done. But I 19 think now, as Alan pointed out, if your grandson can tell you 20 that they're better, they're probably better. 21 I would just stress again I think clear or almost 22 clear doesn't tell the whole story and greatly understates 23 the value of drugs. It seems to me that what should be done 24 is something should be done to see whether or not drugs are 25 safe, number one and two. Are they safe? Are they safe? And

124 1 number three is do they work. Not how much do they work. 2 Are they better than what we already have or a big step forward 3 or a little step forward? Those are things to be decided by 4 us in the clinic in combination with other drugs when you have 5 a multi-factor disease, not as monotherapy. Monotherapy just 6 establishes it has activity, and then we decide whether it's 7 good enough for us to use sometimes, all the time, or never. 8 DR. STERN: Other questions? 9 DR. KATZ: Jim, I have a question. I wasn't aware 10 of studies -- you probably know of some -- where the drug is 11 evaluated as whether it works or is clear or almost clear. 12 DR. LEYDEN: They're not presented to us by the 13 pharmaceutical companies in that way, but the approval process 14 for the last whatever number of years -- you know, eight or 15 so -- has been the global assessment. Whether there was 16 statistical difference between the vehicle and the active was 17 based on complete clearing or almost complete clearing. 18 That's the way it's done, but that's not the way it's presented 19 to you. 20 DR. KATZ: Most of the studies or all the studies 21 that I see in the literature are 50 percent better or they're -- 22 DR. LEYDEN: Yes. The last century. 23 DR. KATZ: Those studies that I remember that are 24 presented in the literature that are only almost clear or clear 25 or 0, there's a certain amount of improvement, how many people

125 1 get clear and how many people get 50 percent better. 2 DR. LEYDEN: Well, Jonathan can tell you that 3 right now, as of so many years, the criterion for clinical 4 success has been complete clearing, absence of disease, or 5 almost complete clearing. And the qualifier to that would 6 be such that further treatment would not be indicated. That 7 is the current standard. 8 DR. STERN: Is that in fact the case, Dr. Wilkin? 9 DR. WILKIN: That's essentially correct, and as 10 it turns out, in the acne studies often there aren't many 11 subjects who fall into the win category, if you will, on global 12 in either the active group or the inactive, the vehicle, group. 13 What we ask for is it doesn't have to be a majority. It just 14 simply has to be a statistically significant proportion of 15 those who are in the active got better compared to the 16 proportion of those who were in the vehicle who got better 17 in terms of that dichotomous cutoff. 18 Now, I think actually it was Dr. Leyden that 19 earlier made the point that that is an easy cutoff where one 20 can look and see the difference between whether it's a 1 plus, 21 2 plus, or exactly what. It's a little bit more, if you will, 22 objective than perhaps some of the other changes in grades 23 through that kind of scale. I think that that's basically 24 part of why the agency began using that way of looking at it. 25 That's not to say that someone who doesn't make

126 1 it all the way down to the almost clear or completely clear 2 category isn't a success. I mean, someone may get something 3 less than that and they may feel happy with it and they might 4 need some other form of therapy. 5 But sponsors come in -- again, I can never remember 6 a sponsor coming in and saying I want my product only for this 7 one lesion type so that dermatologists can use it in sort of 8 their polytherapy. 9 Having been in practice in Houston and Richmond 10 and Columbus, Ohio, I can say I got an awful lot of patients 11 who came after being seen by general practitioners, and I don't 12 think in general they practice the way Dr. Bergfeld described 13 at the beginning. I mean, I just have not seen general 14 practitioners picking out lesion types and targeting that. 15 I think we have the best experts in acne in the world here 16 today, and they're describing to you not a bronze standard, 17 not a silver standard, but -- and it's probably not even gold. 18 It's probably the osmium. I think that's the most expensive 19 element. It's probably the osmium standard for treating acne. 20 And ultimately one of the questions that the 21 committee will need to think about tomorrow morning is what 22 kind of indication really fits for these kinds of products. 23 Are we sending products out for this small subset of 24 osmium-standard practice, or is it for really the bulk of the 25 practitioners who are using these products out there who are

127 1 not dermatologists? I think that's pretty clear. 2 DR. LEYDEN: Could I just comment on that? The 3 other thing is that dermatologists figure how good drugs are 4 or aren't. Those of us who have been around long enough know 5 of several drugs that were out and are no longer on the market. 6 They got approved, but they didn't make it. There are drugs 7 that get out there that have a very small market and they never 8 increase, they have a tiny use, and then there are other drugs 9 that are used very commonly. 10 So I would just say again I think the aim should 11 be to establish the safety and whether or not there is efficacy, 12 not how much efficacy or how good it is. That's up to us to 13 decide. 14 MS. KNUDSON: I'd just like to ask about inclusion 15 criteria. We mentioned several times the population of 16 patients that are included in trials. Do you make a 17 distinction between naive patients, patients who've never been 18 on any therapy, and patients who might have failed other 19 therapies? 20 And then my second question is, how do you control 21 for all of the over-the-counter medications that are available 22 for people to take? And certainly if someone is in a trial 23 for a long time and they're not immediately getting better, 24 I suspect they're also using over-the-counter remedies. So 25 how do you control for those things in your outcome assessments?

128 1 DR. SHALITA: If I may respond at least to start. 2 You're absolutely right. Compliance is an extraordinarily 3 important issue and unfortunately we don't have a good way 4 to measure compliance. The most popular measure is to have 5 the volunteers bring back the empty tubes to see how much 6 they've used. Well, they're not stupid and they know they're 7 not going to get paid if they bring back a full tube. And 8 they do what I refer to as the sink test. 9 Dr. Bergfeld showed a paper of actually mine or 10 I was a co-author on it where two drugs were compared. One 11 was shown to be more effective than another, which is not 12 terribly important. And they were shown to be roughly equal 13 in side effects in spite of the fact that one of those two 14 drugs was promoted as much, much less irritating than the other. 15 Well, the answer is they didn't use the irritating drug, but 16 you couldn't tell that by measuring the empty tubes because 17 they're not going to let you know. 18 In terms of what else they use over the counter, 19 they sign a consent that they're not going to use anything 20 else, and you tell them. But there's no way to control that 21 unless you have a captive population like we did with that 22 zinc study in reform school. We actually put the medicine 23 on. They have no access. And that's very difficult to do. 24 The final part of your question. We'd love to 25 be able to use people who have not responded to prior therapy,

129 1 but in real life it's very difficult to do that. 2 DR. KLIGMAN: Can I add something? There's ample 3 evidence that dermatologists are much more effective in 4 diagnosis and treatment than general practitioners. And I 5 think, Jonathan, in the regulatory requirements, these kinds 6 of studies should not be monitored by general practitioners. 7 They just simply don't know enough, and they're very often 8 affected by other things. 9 For example, they like drugs that are 10 non-irritating. Most non-irritating drugs are less 11 effective. In fact, there is some relationship between the 12 amount of inflammation induced in the case of retinoids and 13 of efficacy. If they are influenced by the notion this is 14 a nice drug because they're not complaining of stinging and 15 burning and redness and all those adverse effects, that shifts 16 their bias toward drugs that really don't work. So I hope 17 that having an M.D. doesn't qualify you to become an 18 acneologist. 19 DR. LEYDEN: There's one point I think that might 20 be worth mentioning to the panel, and that is that I can tell 21 you that at least in the last maybe 8 or 10 years, every company 22 that I know of who has been involved in a clinical trial, when 23 they've had investigator meetings, they have conducted 24 sessions where they establish the reproducibility of counting 25 lesions, both non-inflammatory and inflammatory. It's a big

130 1 part of what they do. And the reason that they've had to do 2 that is that in order to get enough patients into a study, 3 they've had to expand the number of investigators and sites 4 because all of us are having trouble getting patients. So 5 if you're going to expand the number of sites and you can't 6 have three or four or five centers doing all the studies, you 7 have to make sure that people know how to count, and they are 8 doing that. 9 DR. BERGFELD: I'd like to go back to a little 10 bit about the FDA standards and these tests first. What I 11 heard was that one of the endpoints was a 3-month treatment 12 and no need for further treatment as being one of the targeted 13 endpoints. Is that correct? 14 DR. WILKIN: Well, if you're talking about the 15 global, the global has come in different ways. I would say 16 some of the globals that have been used, the success criteria 17 included patients that probably still wanted more treatment. 18 So, no. 19 One of our difficulties is we don't have one global 20 that we recommend industry use. We are really coming to the 21 committee to find out if there is a global that the committee 22 that would recommend that we recommend to industry. 23 DR. BERGFELD: Well, I would like to, as a 24 consultant, recommend that that not be used because if we truly 25 believe that acne is basically familial and it's driven by

131 1 androgens, which are high in the adolescent and in some of 2 the women are high in their older years, that we have a continued 3 hormone stimulation for this and that does not go away in 3 4 months. 5 DR. WILKIN: Let me be more responsive to your 6 question then. I took it to mean would someone need any 7 additional treatment, meaning in addition to what is being 8 tested. I realize if someone discontinues a product that has 9 got them under control, they're likely to have a flare. No, 10 that's not what we're asking. 11 DR. BERGFELD: Well, the second part of that in 12 your statement is you heard today from everyone who's a 13 dermatologist that it's polypharmacy that we use that is most 14 effective, and obviously after a study those patients will 15 then resume the polypharmacy which includes the topical agents 16 and some systemic depending on the degree of acne. That's 17 one thing. 18 The second question and sort of statement I'd like 19 to direct to the experts. If you were to design an ideal study, 20 it seems to me that what you've all said is that it should 21 be simple. The second part is that there would be some lesion 22 counting in some way and they would be differentiated between 23 non-inflammatory and inflammatory. And, Dr. Leyden, you 24 suggested there be two different judgments made, not that they 25 be combined statistically, and that we use current technology

132 1 that has been mentioned by all of you and that includes some 2 of the new photography methods, digital photography. 3 DR. LEYDEN: And that you draw a more clinically 4 relevant line in the sand of what constitutes success because 5 I think you can have great success without being anywhere near 6 almost clear, especially when you have monotherapy. 7 DR. BERGFELD: Would there be any additions to 8 what I've outlined, other than Jim's? 9 DR. ABEL: I'm asking the members of the panel 10 if they feel the sponsors might seek approval for different 11 lesional types, comedonal versus noncomedonal, 12 inflammatory -- 13 DR. LEYDEN: I think that's likely to evolve 14 because we are now in the age of the development of 15 non-corticosteroid anti-inflammatory agents, but until 16 somebody discovers that some of these things can't or shouldn't 17 or whatever be used on the face, so far that's one of the reasons 18 why we use them is that they don't have the problems that 19 steroids have. I'm hearing every place I've been how 20 dermatologists are. As soon as there's a new drug, they try 21 it on everything. Dermatologists have already decided those 22 drugs work. Now, the manufacturers may just say the hell with 23 it, why bother with all this stuff, let them do it. 24 But if they decide or if some of these other 25 molecules that are not yet approved for any indication were

133 1 to be used -- and I know one company who has several molecules 2 that make a lot of sense to me. I can't imagine them having 3 an effect on the non-inflammatory part of acne. If it happens, 4 great. It will give us something to think about. But right 5 now I can't just imagine that. So to say that they're going 6 to have to do a study that shows effect on non-inflammatory 7 lesions to me is ludicrous. 8 DR. KING: I guess when I thought about this 9 conference, I came up with the thought, that if you're going 10 to generate a new system or a consensus, then you're going 11 to come up with the issue of innovator versus generic products. 12 What kind of approach would you take or give guidance to the 13 FDA about if you're going to implement a new system, what 14 standard would you hold for the innovator versus generic 15 products to give guidance? 16 DR. LEYDEN: I have an easy answer which I know 17 is not popular with the dermatology division. I have a great 18 deal of difficulty thinking how a product that is absolutely 19 identical is different clinically. I mean, it just doesn't 20 make any sense. 21 So if I were doing it, which I'm not, what I would 22 do is just show that this formulation has the same release 23 characteristics, penetrates in skin, Franz chamber or some 24 modification of that, to say that it's not fundamentally 25 different because of some quirk in the manufacturing process,

134 1 et cetera. That is the way it's done for solutions. As soon 2 as minoxidil went off patent, there were generic formulations 3 within a week because they didn't have to do anything. 4 Nobody can agree upon a surrogate method so far 5 other than doing clinical studies which are laborious and 6 difficult and expensive. How the same formula can be different 7 I think just brings up all the issues of clinical trials, and 8 whether it's tinea pedis or eczema or acne or whatever it is, 9 it's just not easy to clinical trials. 10 DR. KING: A related question, but to follow up, 11 then how do you decide when you're doing dose response? We 12 know about how enzymes respond and they have parallel curves. 13 So I disagree with the concept of parallel curves don't mean 14 statistics, but they do. But how do you deal with the dose 15 response in even the same drug? 16 DR. LEYDEN: I think there you have to look for 17 a non-effect or a low effect and a dose above which there's 18 no increase. 19 DR. PLOTT: I have a question for Dr. Leyden. 20 You suggested eliminating global assessment. 21 DR. LEYDEN: As it currently stands at least. 22 DR. PLOTT: As it stands. And replacing that with 23 kind of a comparative pre-post -- 24 DR. LEYDEN: Dynamic. 25 DR. PLOTT: Dynamic --

135 1 DR. LEYDEN: Or leave it out. One or the other. 2 DR. PLOTT: Well, assuming that you have it in 3 there, is this scale of better or no change simply a different 4 dichotomization to say -- 5 DR. LEYDEN: Well, I'll tell you what we did in 6 a study that Alan and I were involved in. We decided that 7 a two-grade change was clearly something that -- I'll say it 8 negatively -- nobody would disagree was not meaningful. And 9 they all constituted people who had at least a definite or 10 marked improvement. So you can do it a couple of ways. 11 DR. PLOTT: So you agreed upon a clinically 12 meaningful change -- 13 DR. LEYDEN: Yes. It was easy for us to do. I 14 guess it's more difficult when you're in a regulatory position. 15 You have to be careful because when you deny somebody approval, 16 you have to be prepared to defend it. So it was easier for 17 us to make that decision, I recognize, but that's what we did. 18 DR. STERN: Just a quick clarification. This is 19 two grades out of your six grades? 20 DR. LEYDEN: Yes. 21 DR. STERN: Just because there have been so many 22 scales -- 23 DR. LEYDEN: Yes, of that. Yes, right, exactly. 24 And looking at the photographs, we all said, yes, that person 25 is better. We didn't have, well, maybe they're a little

136 1 better. That person is better. 2 DR. STERN: I understood that part. 3 DR. LEYDEN: Yes, two grades. 4 DR. STERN: There have been ones from anywhere 5 from 4 to 10 grades within the scale. 6 DR. KLIGMAN: Dr. Stern, another source of 7 mischief -- and Dr. Kilpatrick can respond to this -- is to 8 put the data not in absolute numbers but in percentage 9 differences. I think that's really unacceptable. And that's 10 done very often because it's easier to make the drug look better 11 than it is. 12 If you go from 4 pimples to 2 pimples, that's a 13 50 percent reduction. That's great. If you don't know what 14 the actual starting condition was, the number of lesions, and 15 the actual number of lesions at the end, you can end up 16 recommending drugs which are damned near ineffective, and it's 17 very often done. Instead of giving real numbers, you get 18 percentage differences from the baseline. 19 DR. KILPATRICK: Dr. Kligman, may I answer that 20 at length this afternoon? 21 DR. KLIGMAN: Yes. 22 DR. KILPATRICK: Because there's a lot going on 23 here and I think some of the rest of us may want to get in 24 on this. But repeatedly -- I'll just say this and then stop 25 talking -- the thing that I keep hearing is the difference

137 1 between clinical significance and statistical significance. 2 I think that will affect what we come up with in terms of 3 our recommendation. 4 DR. KLIGMAN: That's true. 5 DR. ABEL: Getting back to monotherapy versus 6 combination therapy, most commonly dermatologists use 7 combination therapy from the beginning and different types 8 of therapy for the inflammatory component and different types 9 for the comedonal component. So I guess this is more of a 10 question for the FDA. Would they consider using different 11 standards for drugs which are not usually given as monotherapy? 12 DR. LEYDEN: It's a tough thing to do. 13 DR. WILKIN: Different standards? Well, in other 14 words, you're saying if a sponsor comes in and says we would 15 like monotherapy because we know a lot of docs are going to 16 use only this product, would that have different standards 17 than, say, another product might get if that sponsor comes 18 in and says, well, we'd like this to be only for inflammatory 19 lesions. Is that the -- 20 DR. ABEL: No. I think it's more the disorder, 21 the acne being the type of disorder it is, that most agents 22 are used in combination with other agents. So would this 23 affect your bottom line response criteria necessary for this 24 drug to be approved? Could it be lower than, say, completely 25 clear knowing that it is going to be used in combination therapy

138 1 because there are different elements to acne? 2 DR. WILKIN: There is a word for that. I mean, 3 the word is adjunct or adjunctive. In other words, if a patient 4 is already on a particular product and then you look and see 5 what adding a second product can do in addition, yes, I could 6 see that as having some different ways of looking at it. But 7 it would be in the indications section of the labeling. It 8 wouldn't be that nice, clear-cut, marketing-friendly, you 9 know, treats all of acne kind of indication that sponsors are 10 now seeking. It would be more limited. It would say 11 adjunctive. The benefit is documented while using -- and then 12 another product or class of products. 13 DR. ABEL: That might be more realistic. 14 DR. STERN: Dr. Raimer. 15 DR. RAIMER: I just wanted to ask our panel of 16 experts, who have done a lot of studies, do you think it would 17 be at all practical to count inflammatory lesions by size, 18 like count the number up to, say, 3 millimeters and the number 19 that were 3 to 6 millimeters or above? So if you started out 20 with a patient that had 50 5 millimeter lesions and they went 21 down to 50 1 millimeter lesions, that's definite improvement. 22 Do you think that would be at all practical to do? 23 DR. LEYDEN: No. 24 (Laughter.) 25 DR. RAIMER: And why not?

139 1 DR. STERN: How about with digital photography, 2 though? 3 DR. LEYDEN: You might be able to do it better 4 with image analysis, yes. The volume of the lesion could be 5 determined. But it's hard enough to count them accurately 6 on the hoof. The patient wants to get out of the room. They're 7 embarrassed. They start looking down. They want to leave. 8 They just want to get out. So if you're going to have to 9 start sizing them, it will never happen other than on 10 photographs or -- 11 DR. KLIGMAN: And dermatologists have to make a 12 living, you know. There's a matter of time. 13 (Laughter.) 14 DR. TAN: Yes. I just want to ask the panel. 15 Dr. Kligman mentioned the inhibition of new lesions, emerging 16 lesions is important. I just wonder how this is incorporated 17 in current lesion counts. 18 DR. LEYDEN: It's done over time. You do it over 19 typically a 3-month period except for oral contraceptives. 20 So anything that comes in month 3 is new or month 2 is new. 21 What he was saying is that you don't want to just do a count 22 at the beginning and the end. You get a better overall view 23 of the change by counting at multiple time points. 24 DR. TAN: But it will be hard to track individual 25 lesions because some of those are hidden.

140 1 DR. LEYDEN: Some of them what? 2 DR. TAN: Are hidden. A few months ago you 3 wouldn't see it. Right? It would be hard to track how the 4 individual lesions change. 5 DR. LEYDEN: When they're gone, they're gone. 6 There may be a residual pigment or residual redness that 7 gradually fades, but we don't count them, as was mentioned 8 a couple of hours ago. Somebody brought it up. 9 DR. STERN: Dr. Katz. 10 DR. KATZ: Jonathan, a question. I just want to 11 get something clear because it's not logical to me. You mean 12 products are approved only if they get people clear or almost 13 clear? There are so many things on the market that have been 14 approved, except for Accutane, that don't make people clear 15 up. I don't understand that. 16 DR. WILKIN: Yes. I was hoping to clarify that 17 in response to Dr. Bergfeld's question. We have what are 18 called end of phase II meetings with industry and different 19 things get proposed to FDA, and ultimately what we convey back 20 to industry is we agree with this. If you do these sorts of 21 things, we will find efficacy in that. On the other hand, 22 if they sometimes can fall a little bit short of that, they 23 may still get approved. We can be really definitive on things 24 that for sure are strong enough that we know that they're going 25 to cross home plate right at waist level and right down the

141 1 middle, and that's what we describe. But there are some things 2 then that sometimes go to the edge of that. So there may be 3 a product that doesn't often lead to almost clear, but 4 nonetheless when you compare that product with its vehicle 5 or with its placebo, if it's an oral, it may have a statistically 6 significantly greater proportion who fell into that success 7 criterion than the inactive. 8 So I think it's just as Dr. Leyden has pointed 9 out and as you've mentioned, that these are not like another 10 therapy that you mentioned that can completely clear and 11 perhaps keep things completely clear. Dr. Leyden mentioned 12 that the marketplace is actually more Darwinian in what happens 13 to the eventual success of these products than coming through 14 FDA. 15 I think one of the things that we really want to 16 hear from the committee is where are we with what we've been 17 doing. That ought to affect where you think the compass ought 18 to be set or the goal posts, how wide they ought to be tomorrow 19 morning when you consider this. Do we have the goal posts 20 too narrow? Or do you want some products that might even be 21 somewhat less effective than what we currently have going 22 through? Or do you want it tightened up a little bit? 23 I think the other part that especially the invited 24 experts have articulated today is what if we could have 25 monotherapy really sort of being moved into a polytherapy which

142 1 fits with the practice of many dermatologists. I think it 2 would necessitate a different kind of labeling structure, you 3 know, products that are for specific acne lesion types. I 4 think that would be fine if the committee believes that that's 5 the way American physicians in general, not just the osmium 6 standard dermatologists who are here, but in general that's 7 how it's going to be, or if you think there's something we 8 can do in labeling that will help maybe bring 9 non-dermatologists up to that standard of therapy. 10 DR. STERN: I'd like to give Jim a chance to make 11 a closing comment, but I think we should close this part of 12 the program. Preceding even his comment, I'd just like to 13 thank the expert panel who took their time to come and educate 14 us and were so helpful and clear and straightforward about 15 their opinions and have been, at least to me, extremely helpful. 16 It's also nice to get to see all of them. 17 DR. LEYDEN: You don't really think we're 18 opinionated, do you? 19 (Laughter.) 20 DR. STERN: I don't think. I know. 21 (Laughter.) 22 DR. LEYDEN: I was just going to say I think trying 23 to do studies where you take multiple classes of drugs for 24 a new drug will be kind of a nightmare situation. I think from 25 my viewpoint anyway, it's more realistic to try to modify what's

143 1 been going on to a more clinically relevant endpoint, perhaps 2 using some of these newer ways of evaluating efficacy, rather 3 than trying to design studies where you're going to have this 4 new drug added to a certain other -- I mean, don't do that. 5 DR. STERN: Again, thank you all very much. We'll 6 come back at 35 past the hour, 45 minutes from now, and resume 7 after lunch. Thank you. 8 (Whereupon, at 12:52 p.m., the committee was 9 recessed, to reconvene at 1:35 p.m., this same day.) 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 AFTERNOON SESSION 25 (1:44 p.m.)

144 1 DR. STERN: The first presentation of the 2 afternoon will be by Dr. Alosh of the Food and Drug 3 Administration, and he's going to speak in two parts. So we'll 4 have his first presentation on statistical analyses of acne 5 clinical trial data, questions about that. Then he'll give 6 a second part presentation and questions about that to follow. 7 DR. ALOSH: Thank you. Good afternoon. 8 The stat presentation, as Dr. Stern pointed out, 9 will be two parts. The first part, I'll be speaking about 10 efficacy assessment, evaluation in acne clinical trials, where 11 I'll be touching on some of the issues which were raised this 12 morning concerning counts, change in lesion counts or percent 13 change. I'll be touching also on the efficacy assessment by 14 baseline category. I'll stop, take some questions. Then in 15 the second part I'll be speaking about global evaluation and 16 how it's related to lesion counts. 17 The first presentation is joint with my 18 colleagues, Kathy Fritsch and Shiowjen Lee, from the team. 19 The outline of my presentation is as follows. 20 I will revisit choice of the primary endpoints from a 21 statistical point of view. I'll be discussing the statistical 22 analysis methods and data transformations, and I think this 23 is very relevant because we had a lot of questions this morning 24 about the appropriateness of using percent change. It was 25 raised twice.

145 1 Then the other point, which Dr. Wilkin pointed 2 out, whether we should take multiple assessments instead of 3 just taking the final assessment. With that approach one could 4 increase the power of the study. But there are issues which 5 we need to address. 6 I'll be, as I said, talking about the effect of 7 baseline severity, and this really came from questions raised 8 by industry, and Dr. Leyden in particular, whether we should 9 have people with a smaller number of lesion counts for 10 enrollment in the study. So I'll be examining the efficacy 11 results across categories by breaking people according to the 12 baseline severity. 13 Then I will conclude with final comments about 14 the statistical analysis. 15 The primary endpoints, as the discussion came this 16 morning, we talked in terms of lesion counts in general or 17 in terms of the investigator global assessment. When someone 18 speaks in terms of lesion counts for the statistical analysis, 19 we look for inflammatory, non-inflammatory, and total lesion 20 counts. And the discussion came this morning whether one 21 should analyze only inflammatory or non-inflammatory without 22 the need for total lesion counts. 23 I think Dr. Ten Have also questioned the rule to 24 win in two out of three, whether there is a need for a 25 multiplicity adjustment. I'd like to point out really the

146 1 interpretation for two out of three is a nested hypothesis 2 approach. So first you need to win on the total lesion counts. 3 And now if you win on the total, you go to the subhypothesis 4 to test whether you have a result for inflammatory or 5 non-inflammatory. So with that nested approach, we don't need 6 a multiplicity adjustment. 7 I think concerning the discussion this morning 8 here, if someone wins on inflammatory and has a trend in 9 non-inflammatory, you will be winning in the total lesion 10 counts. So consequently, the drug will get the acne indication 11 in general. Similarly, if you win on non-inflammatory and 12 you have only a trend in inflammatory, you will be getting 13 the general indication. 14 One of the issues, which I think the committee 15 needs to think about, is whether in the study at the design 16 stage you need to claim for the two types of lesions, for 17 inflammatory or non-inflammatory, and if you don't win in one 18 of them, how would you adjust for that. So those issues 19 probably need to be discussed later. 20 So now once we have each type of lesion count, 21 whether inflammatory or non-inflammatory or total, you could 22 analyze the final lesion counts by comparing the active versus 23 the vehicle and look for a statistical difference. 24 I would like also to touch on the point of the 25 discussion this morning that we should look for safety and

147 1 if there is efficacy. If the vehicle itself has efficacy, 2 then one needs to judge the magnitude of the difference between 3 the active versus the vehicle. So the point I would like to 4 bring here is that the vehicle itself will show efficacy. 5 Then the second one will be analyzing change from 6 baseline and we could analyze percent change. There was a 7 lot of discussion whether percent change is appropriate or 8 not. I agree with Dr. Tan. A statistician would not prefer 9 such a measure. I would agree that it does not have normal 10 distribution which is what we look for in terms of statistical 11 hypothesis testing, and I'll be touching on that. But really 12 we were driven by the clinical request in a way. This is the 13 preferable measure, but for a statistician I would agree that 14 percent change is not the ideal measure to look at and I'll 15 examine the data in a short while. 16 Then the other endpoint is the investigator global 17 evaluation. In the first part of the presentation, I'm not 18 going to discuss the investigator global evaluation, but the 19 second part will deal with that. 20 When you analyze percentage of change, there are 21 pros and cons. Definitely change is easy to interpret and 22 analyze, and the goal here is to attempt to remove the influence 23 of baseline counts, how it will affect the final assessment. 24 The cons of that, baseline may still have influence since 25 change is negatively correlated with the final counts. The

148 1 point which was made this morning, when you look for change 2 or percent change scores, it may have highly skewed 3 distribution. There will be a heavy tail distribution. With 4 that, probably you don't need the .05. It might be not precise 5 which we use for symmetric distribution for normal data. 6 Coming to present to you some data from acne 7 clinical trials, as we have discussed this morning, there is 8 a large variability in acne data. So it's difficult to choose 9 one drug or one data set which will be representative for the 10 acne data which we see in practice. 11 With that in mind, I tried to present here data 12 sets from two drugs and will show you the range of what's the 13 delta, the magnitude of the delta you need to reach statistical 14 significance. Also, one of them has led to a very small p 15 value, highly significant, but the other one is not. We'll 16 see one of them at work on inflammatory lesions, but the other 17 one at work on non-inflammatory lesions. One of them, the 18 study was for 12 weeks; the other one was a contraceptive drug 19 for six cycles. So with that representation for the data from 20 the two drugs, I think you should get some good idea about 21 the range of variability in the data which we observe in real 22 life. 23 Here the first drug we'll call drug X. We have 24 a plot here. The study was for 12 weeks with about 400 subjects 25 enrolled in the trials. There is an evaluation done at weeks

149 1 4, 8, and 12. So what I have here on the x axis is the week, 2 and I have on the y axis the mean lesion counts. This is broken 3 by inflammatory, which is the red line. The solid line is 4 for the active, and the dotted line for the vehicle. So we 5 have lesion counts over time for inflammatory for the active 6 arm as well as for the vehicle. 7 If you could compare the lesion counts, you see 8 a very small difference here. It's, I'd say, roughly about 9 2 lesion counts between the active and the vehicle. We'll 10 see the impact of this in the p value. 11 The blue line represents the non-inflammatory 12 lesions, and you start to see here separation. This is the 13 magnitude of the difference. We are looking between the active 14 and the vehicle, which we'll see about probably 6, 7 lesions. 15 The total, which is the black line, which is the magnitude 16 of the difference, about 11 lesions. With that magnitude of 17 difference, we see drug X resulted in a highly significant 18 p value. 19 The point I want to make here is you could see 20 subjects who are on the vehicle, as was indicated this morning, 21 will achieve some kind of efficacy. So the point that we should 22 look for efficacy, disregarding the magnitude, one needs to 23 tell how much difference between the active and the vehicle 24 because the vehicle itself, as you could see, has an effect 25 there, as indicated in the morning.

150 1 So this is for drug X. I'll move next to drug 2 Y. 3 As I have indicated, this was done in 400 subjects. 4 It's for six cycles. It was a contraceptive drug. Again 5 you have the red line for inflammatory, blue line for 6 non-inflammatory, and total. And you can see the difference 7 between the active and the vehicle here a little bit bigger, 8 and you see this drug will make it even with about a 3 lesion 9 count difference in inflammatory lesions. This is about 5 10 lesions. Here we have non-inflammatory, and the total about 11 8-9. 12 So if we're analyzing final lesion count, we'll 13 be comparing, as I said, the active versus the vehicle at the 14 final study endpoint. If we are analyzing the change, we might 15 take the baseline measurement minus the final assessment, which 16 will give you the magnitude of change. And if you are analyzing 17 the percent change, you'll take the change divided by the 18 baseline. 19 Here we have plot for inflammatory counts by 20 baseline which is on the x axis, and what we have on the y 21 axis is the inflammatory lesion counts at week 12. This is 22 here for the vehicle arm. I will have a similar plot for the 23 active. What we have here, the 45 degree line. People below 24 this line achieve reduction in terms of inflammatory lesion 25 counts. People between the 45 degree line and the other line

151 1 experience an increase in their lesion counts between 0 to 2 100 percent. Of course, the closer you are to the 45 degree 3 line, there is no improvement. Here you could see people with 4 an increase over 100 percent. 5 Just to make the point about percent change, let 6 us take this dot here which represents a subject. You can 7 see the subject at the baseline. They have about a 10 lesion 8 count, but at the final assessment at week 12, they have roughly 9 a 60 lesion count. So if you calculate the change, it would 10 be about a 50 lesion count, and the percent change will be 11 about 500 percent. 12 Now, we had the discussion you could have one 13 subject like this subject to account for so many patients 14 here in this group because the percent change here is very 15 small numbers, compared to one subject that would have 500 16 percent. And you might end up having a few patients driving 17 the results. The impact of this -- you can see here a lot 18 of scattered points in that plot. You would be increasing 19 the standard deviation for your percent change, and we need 20 that to calculate the statistical test for efficacy assessment. 21 So in addition to the magnitude of change, we would like to 22 look also to the scatter or the dispersion of those data, i.e., 23 the standard deviation. So keep in mind how much variability 24 scattered points here for the vehicle. 25 And the next plot, we'll see the same plot but

152 1 for the active arm. You can see here for the active arm, again 2 it's for inflammatory lesions, and you can see we don't have 3 much variability for those lesion counts compared to the 4 vehicle, and you can see much more improvement here in this 5 section. We don't see people here with increasing their lesion 6 counts over 100 percent. You see the scatter is less, so you 7 expect the standard deviation to be less here. 8 Those will bring the point with those outlier 9 observations whether one should analyze original data or some 10 type of transformation of the data. And dealing with the 11 transformation, we got a lot of ways from sponsors for what 12 kind of transformation to be done. Sometimes we get people 13 have proposed to use log transformation or add constant to 14 the log transformation. Sometimes we have ranks. 15 And I want to make the comment about using log 16 transformation or adding constant to that log transformation. 17 It's difficult to interpret when you have log transformation. 18 I mean, there is no interpretation which I see reasonable 19 to convey it to a non-statistician. I don't see its appeal. 20 Also adding a constant is subjective. Someone 21 could add 10. Another one could add 20, and you would lose 22 a lot if there is any constant which you could add. 23 The third point I want to make, this type of 24 transformation can data dredging. In a way you have to wait 25 until the study is completed, and now you'll go and see what

153 1 transformation will bring this. 2 So the point, percent change needs to be used and 3 if it does not meet the normality assumption, normally what 4 we'll take, the rank transformation, and the way you order 5 the data and by working with the ranks, you get rid of the 6 magnitude of those outliers. 7 Here the point we are making, if you analyze 8 percent change, you can see the trend over time from week 4 9 to week 12. And those quantities here represent the standard 10 deviation, and you can see the magnitude of the standard 11 deviation is very large compared to that. 12 So to summarize, because of those outliers and 13 percent change, we tend to analyze, in addition to the original 14 data, transformation and, in particular, the ranks. 15 What I have here, people in acne trials, as has 16 been discussed in the morning, experience a flare. In a way 17 you could come at one time point and the subject have many 18 lesion counts, and you could examine at another time point. 19 Those lesion counts disappear. This again raises an issue 20 in terms of how you analyze those data. 21 To make the point here, I'm taking data from study 22 X for one investigator, and they have here about 8 subjects. 23 Every line of those represents the time trajectory for a 24 patient, total lesion count. So you can see here the blue 25 line. You have the subject experienced a high lesion count

154 1 at week 8. Then it dropped. Similarly the red line here, 2 this subject at week 12 started to show a high increase in 3 total lesion counts. 4 This brings the point whether we should take some 5 kind of average repeated measurement toward the end of the 6 study once the drug reaches its plateau, instead of dealing 7 with the final assessment. The point here which needs to be 8 discussed, once you decide on using a repeated measurement, 9 you need to consider how many time points you are going to 10 take into account in the repeated measurement. Definitely 11 you could increase the power by having several repeated 12 measurements just because you reduce the standard deviation, 13 but also I think a clinician would like to see clinical benefit 14 not only reaching statistical significance by having so many 15 repeated measurements. 16 So in terms of the statistical analysis, the 17 analysis unit could be the original data. You examine the 18 original data. You could analyze the transformed data, and 19 we discussed you could use the ranks. We don't prefer to use 20 the log or adding a constant to the log because of 21 interpretation. And we talked about the pros and cons in terms 22 of interpretation findings. 23 Now, in terms of the analysis method, if we are 24 looking at the final assessment, i.e., week 12 or cycle 6, 25 you could do a simple comparison between the active and the

155 1 vehicle. You could do what the statisticians call an analysis 2 of variance in which you could fit a model with the treatment 3 centers and their interaction and look for the treatment 4 effect. And you could do an analysis of covariance to include 5 baseline as a covariate in the model. Remember change and 6 percent change, we try to account for baseline severity in 7 the model. What we are doing here in analysis of covariance, 8 we are putting the baseline as a covariate in the model to 9 account for that. 10 So we'll be comparing the efficacy results later 11 for the two drugs which we have seen their plots. 12 The next bullet is about repeated measurement 13 versus final assessment. When you talk about repeated 14 measurement, as I have indicated, you might increase power 15 for detecting a treatment effect. But the question was the 16 number of time points to be included in the repeated measurement 17 model. In terms of the statistical model or technique, we 18 have multivariate analysis of variance. We have the 19 generalized linear model or a mixed model. There is a battery 20 of stat methodology which someone could use for the repeated 21 measurement approach. 22 I'll be coming now to compare the efficacy results 23 for the original data versus rank data for change, percent 24 change, and I'll be taking a comparison also for the final 25 assessment versus the repeated measurement.

156 1 Here this is for drug X which I want to remind 2 you we did not see much activity going on for the inflammatory 3 lesions, but we have seen something for non-inflammatory and 4 total lesions. This table is for the counts and the way you 5 analyze the final assessment. We'll be coming to analyze 6 change and percent change. 7 I want to point out normally we don't compare this. 8 We look for change and percent change, but I thought in terms 9 of logical sequence, I'll present this quickly and I'll move 10 to the next one. 11 So this is week 12, which is the final assessment. 12 Those two columns for inflammatory lesions, this column for 13 the original data, and this is for the rank data. The next 14 two columns for analysis of non-inflammatory lesions, which 15 is again data and ranks. Here you have the total for the 16 original data and ranks. We have the week 12 assessment here. 17 You could see highly significant p values for total lesion 18 count in the non-inflammatory. 19 I want to point out the delta which we are getting 20 the highly significant p values. We are speaking about a delta 21 of about 9 points roughly in non-inflammatory lesions, and 22 about 12 lesions in terms of the total. 23 Now, that drug, we did not see separation in terms 24 of inflammatory lesions, and you can see the difference is 25 about 2 units. So it did not make it.

157 1 As you can see here, I have results for week 8 2 and week 4. They are not intended really to examine efficacy, 3 but to make the point how do previous weeks, week 4 and week 4 8, impact the efficacy result of the repeated measurement. 5 Again, you look here to the analysis of covariance. You have 6 an almost significant p value here for inflammatory lesions 7 because you are adjusting for the baseline covariate. And 8 this is the multivariate analysis of variance where we take 9 repeated measurements, the last three values, generalized 10 linear model, repeated measurement, and analysis of 11 covariance. But you are diluting the treatment effect here 12 because the previous measurements were not significant. 13 The reason I included them, if you analyze change 14 or percent change, you start to see effect for the drug. So 15 in that repeated measurement approach, I took week 4, week 16 8, and week 12. 17 I'll move to the next slide where we'll talk about 18 analysis of change which normally we consider it secondary 19 in addition to the percent change. So we'll be looking usually 20 for percent change as well as change. 21 Again, you see here the result for change. Week 22 12, now inflammatory lesions make it when you analyze percent 23 change. And you look here how much difference. We are talking 24 about a 2.8 difference in terms of mean change, inflammatory 25 lesions. Highly significant p values for non-inflammatory

158 1 and total. I'd like to point out the non-inflammatory p value 2 is close to those of the total, and the reason most of the 3 total inflammatory lesion counts, they are coming from 4 non-inflammatory. There is high correlation between them. 5 So if you win on non-inflammatory, almost with certain 6 probability you'll be winning in the total. 7 Again here we have the discussion. The analysis 8 of covariance. The p value .03 which for a statistician is 9 expected because week 12 -- when you analyze change, it's 10 already you are accounting for baseline which is the same like 11 analysis of covariance in which you take into account the 12 baseline as a measure. 13 The multivariate analysis of variance which takes 14 the repeated measurements has a bigger p value because you 15 have the previous week, they are not significant. 16 So to summarize, highly significant p values for 17 non-inflammatory and total lesions. And you can see really 18 all what you need, as you indicated, is a small number of lesions 19 between the active and the vehicle. 20 In this slide, we'll be looking at analysis of 21 percent change, and this is the result for week 12. Again, 22 it's highly significant, however you look at it, for 23 inflammatory lesions, even though we have seen 2 lesions 24 originally the difference. For non-inflammatory lesions, 25 almost you make it however you look at it. You have a

159 1 significant p value for analysis of covariance, multivariate 2 analysis of variance. There's the repeated measurement. It 3 starts to show close to the significant level here. 4 Now I'll move to drug Y. Before I go to drug Y, 5 let me just summarize the comments, which probably I listed 6 most of them. The results for total lesion count are similar 7 to those of non-inflammatory because of the strong correlation 8 between non-inflammatory and total, most of the total coming 9 from non-inflammatory lesions. 10 There is no general pattern for the p value for 11 ranks versus the original data. I generally found the rank 12 has a smaller but really there is no rule practically. It 13 switched. 14 For inflammatory lesions percent change has a 15 smaller p value than counts or their change. 16 For change and percent change, the analysis of 17 covariance has similar results to week 12 analysis because 18 in the two ways we are accounting for change from baseline. 19 The p values for repeated measurement in general 20 are larger than those at the final study endpoint, and the 21 reason for that, the results at the previous week, they were 22 not significant. 23 Now here I'll be presenting the results for drug 24 Y, and I want to remind you for this drug we have seen a small 25 activity for inflammatory lesions. It's about less than 3

160 1 lesions roughly. And the drug shows separation early. So 2 you expect the repeated measurement to result in a smaller 3 p value compared to drug X where we did not see that separation 4 early. 5 Now you can see here we analyze the count, which 6 is the final assessment at cycle 6. The drug makes it for 7 inflammatory lesions, even though the difference is like 2.8 8 lesions. But it does not make it for the non-inflammatory 9 or the total lesions, which was opposite the drug X where we 10 have seen the results coming from the total and 11 non-inflammatory and we did not see much activity for 12 inflammatory lesions. This is the intention to see drugs 13 working differently by presenting two data sets. 14 In this study we looked at the results. We started 15 to see some significant p values for change or percent change 16 at cycle 4. So in the repeated measurement approach, we 17 considered cycles 4, 5, and 6 to be included in the repeated 18 measurement. Again, here you can see the analysis of 19 covariance which takes into account the baseline. You have 20 a significant p value. Once you take the baseline into 21 account, you make the result also for non-inflammatory as well 22 as for total lesion counts by just taking into account the 23 baseline in the model. 24 For the multivariate analysis of variance, you 25 see a .06 p value which is close to the significant level.

161 1 The generalized linear model with repeated measurement, you 2 have significant p values because you have observed a trend 3 in non-inflammatory lesions, some separation early. 4 Again, as I indicated, this is the delta, which 5 generated those p values here at the bottom. You can see it. 6 We are talking about 2.8, roughly about 6 non-inflammatory 7 lesions, and about 8 to 9 total lesions. So this is the 8 magnitude of the difference. The delta between the active 9 would generate, as you will see, significant findings when 10 you analyze change or percent change. 11 In this table, we analyze the change from baseline. 12 And you can see now you have non-inflammatory lesions. They 13 start to show significant results, as well as the total. And 14 remember the delta was very small. 15 You analyze cycle 6. You have analysis of 16 covariance. You make it and there an issue here. We have 17 interaction, center-by-treatment interaction. So you have 18 the analysis of covariance, significant p values, and the 19 repeated measurement. You make it in the generalized linear 20 model in which you have a treatment effect. The MANOVA will 21 take into account other factors which could be 22 time-by-treatment interaction. 23 On the next slide, I'll be talking about analysis 24 of percent change from the baseline. Again, you can see the 25 drug makes it for non-inflammatory and total lesions.

162 1 However, things shifted for inflammatory lesions because of 2 that high variability would generate larger standard 3 deviation. At the bottom here, what I have is the mean percent 4 change for those. 5 So, the results for the total and non-inflammatory 6 lesions are, as in drug X, similar. But when you analyze the 7 count, they are less significant because you have a small delta 8 between the active and the vehicle. 9 Again, there is no general pattern for the p value 10 when you analyze ranks versus the original data. 11 For inflammatory lesions, percent change has 12 larger p values than the count or the change. 13 And for change and percent change the analysis 14 of covariance gives similar results to cycle 6. 15 The p value for repeated measurement in general 16 are smaller than the final assessment, and the reason for that, 17 we have seen separation in the drug at an early period compared 18 to drug X, between the vehicle, I mean, and the active. 19 Here we are looking at the efficacy results by 20 baseline category. As I indicated, when discussing a phase 21 III protocol with the sponsor, frequently a sponsor would like 22 to enroll subjects with a smaller number of lesion counts to 23 start with. So we tried to see if you include subjects with 24 a smaller number of lesion counts, what impact does it have, 25 if any, and the efficacy results.

163 1 So to address this issue, we divide the subjects 2 according to their baseline category. We put them into groups. 3 You could do any number of groups. Here I'm going to consider 4 four groups, i.e., quartiles. So I divide the subjects by 5 the baseline category with almost an equal number of subjects 6 in every group. I'll be comparing the efficacy results across 7 baseline category. Of course, I'm not going to do formally 8 statistical testing because you are reducing the sample size. 9 The study is not done. 10 All that I'm going to do is look for the delta 11 between the active and the vehicle in every group and see if 12 there is some kind of a trend or pattern with the baseline 13 category. I'll be doing this for inflammatory lesions, 14 non-inflammatory lesions, total lesions, and I'll be looking 15 also at investigator global assessment. This morning it came 16 for people with a smaller number of lesions it might be easier 17 to achieve success according to the investigator global 18 evaluation. So we'll be addressing that. 19 Here I have a plot. This is week 12 lesion counts 20 for drug X, which we discussed. We have seen this drug has 21 very small p values, highly significant p values. What we 22 see here at the bottom, this is people in category 1. We divide 23 them inflammatory active, which is the dark one, and the 24 inflammatory vehicle. Then we have the green one which is 25 non-inflammatory for the active arm and the other one

164 1 non-inflammatory for the vehicle. Then we have category 2 2 is the same thing. Category 3. So we break down those people 3 by the type of lesions they have. And this is the mean lesions 4 again. 5 I'd like to bring the point here. You can see 6 most of the difference among those categories coming from 7 non-inflammatory lesions. You can see a number of 8 inflammatory lesions across the four categories. There is 9 an increase, but you can see there is much more difference 10 in non-inflammatory lesions for category 4 versus category 11 1. So it sounds like most people who come with a high number 12 of lesions at the baseline, mainly they are coming from 13 non-inflammatory lesions. So this is for drug X. 14 I think we have another plot for drug Y, which 15 is this efficacious. Again, you can see it here, the same 16 phenomenon. You have people in group 1 which we have the 17 smallest number of baseline lesion counts. Then people in 18 the second category, they are classified. Again, you can see 19 it's more pronounced here that the difference at baseline 20 lesion count is coming mainly from non-inflammatory lesions. 21 In this table, we are comparing for drug X the 22 delta, which is the difference between the vehicle and the 23 active in each category to see if there is a trend across 24 categories. In a way if it's easier to win if you have a smaller 25 number of lesions at baseline, this will be reflected in the

165 1 delta. 2 So first I'm taking the count. Those are the 3 people in category 1. The first column is the active. The 4 second column is the vehicle, and the third column is the 5 difference. So people in the first category for inflammatory 6 lesions have 13.3 at the final assessment for the active versus 7 13.2 for the vehicle, which gives you a delta of .1 if you 8 are in category 1. 9 If you go to category 2, in the active you have 10 17 versus 20 in the vehicle. So there is a difference of minus 11 3 negative. 12 If you go to the active category 3, the difference 13 is minus 3.5; the last one, minus 3.6. 14 So this is the magnitude of the delta. As you 15 can see, we do not see a trend. You have in category 1 really 16 .1, the other one minus. It's not much of a trend to speak 17 about. 18 If you look to non-inflammatory lesions, again 19 the same comparison. In category 1, you have a difference 20 of minus 5.4; for category 2, minus 11. Then it goes back 21 to minus 5.7, minus 25. So there is no pattern if you are 22 looking to lesion counts. 23 If you look to the total, the same phenomenon. 24 The difference, minus 5.3, minus 13.9, minus 9. So there is 25 no clear pattern. Anyway the delta will increase as the

166 1 baseline increases. 2 If you examine the change, again for the 3 inflammatory in category 1, you have 1.9 versus 1.6 in the 4 second category. So there is no linear trend or any type of 5 trend in which you could examine -- you could see people with 6 a small number of lesion counts at the baseline. They'll have 7 a better chance of winning in terms of lesion counts. 8 If you analyze percent change, again you have for 9 inflammatory the same phenomenon. So this is for drug X. 10 Let's see for drug Y. I'm sorry. What I'm doing 11 here before I go to drug Y, I'm still examining the investigator 12 global assessment to see the delta in terms of success across 13 categories. 14 So for category 1, you have 35 percent of the 15 subjects achieve success. I think the question in the morning 16 was whether the drug achieved a clearance. We don't expect 17 everyone in the active to achieve a clearance for the drug 18 to win. All that you need to achieve is a significant 19 difference. We see here the total overall for the active. 20 For example, you have 18 percent versus 11 percent for the 21 vehicle. So all that we are looking for, 7 percent, the delta. 22 This is for the study overall to win in the investigator 23 global. So we don't expect everyone in the active to achieve 24 a clearance or almost a clearance. 25 So let me go back. So people in category 1 have

167 1 the chance of achieving a clearance or almost a clearance. 2 You have 35 percent which is higher than those in category 3 2, 21 percent, or category 3, 9 percent, or the other one. 4 But look what would happen. If you look to the 5 vehicle and you are in the low category, you have also a higher 6 success probability. You have 27 percent compared to people 7 in the other arm. 8 So the point I want to make here is you would not 9 look to the absolute number when talking about efficacy. We'll 10 be looking at the delta, which is the difference between the 11 active and the vehicle. This is really what's important. 12 This is what drives the p values. So just to say that we'll 13 achieve efficacy, we need to compare it to the vehicle. 14 So you take a higher chance of winning if you are 15 in category 1, but this is again the same. So you end up with 16 delta 8 percent if you are in category 1, 10 percent if you 17 are in category 2. You have it reversed, minus 1 percent, 18 3 and 10 percent. And the overall difference is 7 percent. 19 So again you don't see some kind of a trend in that probability 20 to achieve success. 21 Next I'll go to drug Y which we have seen has lower 22 efficacy than drug X. Again, we look at the results by baseline 23 category. We divided again into four groups, and the first 24 part of table 1 for the count change and the last part for 25 percent change. And I'll go quickly through it since it's

168 1 the same discussion. 2 So you have the active, 9.6 versus 10. The 3 difference, minus .6. In the second group, you have 2.3, minus 4 2.9. So really there is no general trend for inflammatory 5 lesions. 6 If you take non-inflammatory lesions, it's the 7 same phenomenon. The total is the same. There is no general 8 trend there. 9 You look for change. You have .4, .4, 3.2, 5.8. 10 Again, there is no clear pattern, if you are having a smaller 11 number of lesions at baseline, that implies you'll have a better 12 chance of winning in terms of lesion counts. 13 In the next one, I'm looking here to the 14 investigator global evaluation and the success rate across 15 the categories. You look for people in category 1. If you 16 are in the active, you have a 65 percent chance to be in the 17 win category compared to 49, 46 if you are in category 2 or 18 3. So here really the smaller the number of lesion counts 19 at baseline, you have a higher chance of winning. 20 But again, it's the same phenomenon if you look 21 to the vehicle. People who are not taking the active, if they 22 are in category 1, they have a chance, 57 percent of them, 23 they end up in the win category. So you take the delta. You 24 end up with 8 percent if you are in category 1. This is the 25 delta between the active and the vehicle, and this is what

169 1 we look for statistical testing. 2 You come to category 2, the delta, 9 percent, 20 3 percent, 8 percent, with an overall delta 10 percent. 4 I'd like to remind you for this drug, we have seen 5 a small difference between the active and the vehicle. In 6 particular, it was about less than 3 lesion counts for the 7 inflammatory lesions, about 5 lesion counts for 8 non-inflammatory, which translates to 8 or 9 lesions total. 9 And we have a delta here of 10 percent for the investigator 10 global, and the drug makes it in terms of statistical testing. 11 So a comment about the efficacy results by baseline 12 category for the two drugs we considered, there is no general 13 pattern for the results for lesion counts by type, their change, 14 or percent change. 15 Similarly, for the two drugs, there is no general 16 pattern for the investigator global evaluation. 17 For the range of lesion counts in these studies, 18 efficacy results do not appear to vary by baseline severity. 19 And the following, I give general comments about 20 the stat analysis overall. 21 Analysis of change from baseline or percent change 22 and final counts with baseline as a covariate, all those 23 approaches are an attempt to address or to take into account 24 the baseline severity in the model. 25 Percent change data could have extreme outliers

170 1 and could have heavy tail distribution when the baseline count 2 is relatively small. We have see that by taking a plot for 3 inflammatory lesions because I tried to make the point 4 inflammatory lesions are the smallest of the three groups and 5 we plot the data. So you end up with extreme outliers which 6 have impact on the efficacy assessment. 7 A repeated measurements approach attempts to 8 reduce the influence of outliers, the flares, by averaging 9 over time, but the impact of repeated measurements on the p 10 value depends on whether efficacy reached a plateau at the 11 previous time points or not. 12 For the data sets we considered, treatment 13 efficacy did not vary by baseline severity whether one 14 considered analysis of lesion counts or the investigator global 15 assessment. 16 I think this will end the first part of the stat 17 presentation. I will stop here to take questions about this 18 part. Then, as I said, the second part I think is exciting 19 probably for statisticians, as well as clinicians. We'll 20 investigate the relationship between a global assessment and 21 lesion count. 22 DR. STERN: I'll take the chair's prerogative and 23 make a comment, which is really not very much statistical. 24 From a clinical perspective, one reason that looking at 25 multiple points is perhaps a pro and a con and could be counted

171 1 in many ways is when I look at an agent for acne, what do patients 2 want, they want consistency of effect and persistence of 3 effect. So an agent that persistently removes 50 percent of 4 lesions and keeps it that way may in some ways be more desirable 5 than an agent that on two occasions reduces the lesion count 6 by 80 percent but on another occasion, unpredictable, had no 7 effect on the disease. I think you have to consider the 8 clinical aspects of repeated measures and if in fact, in 9 addition to reducing variance because of measurement error, 10 something has to be put into our equation that from my clinical 11 perspective that agents that are less persistent and consistent 12 in their effect are, in fact, less clinically desirable than 13 agents you know what they do and they keep on doing it. 14 Would you like to comment on that? 15 DR. ALOSH: Yes. I'm in complete agreement. I 16 think the point which needs to be made, you could achieve 17 statistical significance, as you pointed out correctly, by 18 taking repeated measurements and averaging them and reducing 19 the standard deviation. But a clinical judgment needs to be 20 made whether that significant p value is clinically meaningful 21 or not. 22 So this will bring the design issue -- I mean, 23 like in this trial we have assessment at weeks 4, 8, and 12. 24 If we are going with the repeated measurements approach, how 25 many repeated measurements are you going to take. We don't

172 1 want to go too far by taking several repeated measurements, 2 reduce the standard deviation, and get significant p values. 3 We need to maintain, I think as Dr. Stern pointed out, whether 4 the results are clinically meaningful or not. 5 DR. BERGFELD: I'm going to speak as a 6 non-statistician, but when you displayed all this information 7 regarding the activity of the vehicle, it brought to mind that 8 perhaps there needed to be a third arm here of petrolatum 9 because the vehicles are chosen not only to suspend the active, 10 but because they offer some efficacy in themselves and patient 11 acceptance. So we expect the vehicle to be active in some 12 way. But you would have a greater delta if you use it against 13 petrolatum. 14 DR. ALOSH: Well, I think it was proposed in the 15 morning whether it's ethical to have people on the vehicle 16 or not I thought. From the data set which we have, I think 17 it showed efficacy. The vehicle itself, as you pointed out 18 correctly, has a large impact on the efficacy and the delta. 19 DR. KATZ: I'd hate for the positive effect of 20 vehicle to enter the vernacular as being vehicle efficacy. 21 That's an assumption. Vehicle positive effect could be 22 investigator bias. In fact, the original reason for 23 controlled studies was not because we had such a fantastic 24 number of efficacious vehicles but the reason is to help us 25 measure investigator bias which is -- I don't mean any

173 1 pejorative sense, but it's something that exists. So just 2 because there's a positive effect of vehicle, we shouldn't 3 use that as vehicle efficacy. 4 DR. TAN: Yes. Dr. Alosh, you presented a lot 5 of information here. I'm trying to digest it. 6 I think the percent change under the changing total 7 lesions, they reflect two different aspects of the measurement 8 of the clinical efficacy. 9 What does percent change mean? The patient's 10 condition improved over the pretreatment condition. Right? 11 So that could be anything. What you're talking about, those 12 abnormalities you observed is natural by the definition of 13 percent change. This is just relative to the patient's 14 previous condition. So, therefore, you do need to the absolute 15 change. That's the original data. So you need both aspects. 16 I think the statistical significance here is 17 not -- I mean, this is not relevant because you have a designed 18 study and in the protocol you should specify specifically what 19 kind of change you're looking for. This would have to come 20 to agreement from the clinical point of view, what kind of 21 change, 10 percent change, is relevant or not. So this will 22 be determined before you even start the trial. 23 DR. ALOSH: Well, a couple of points. As a 24 statistician, I would not prefer percent change personally. 25 And for the same reason which you have seen, you have extreme

174 1 outliers, et cetera. I would agree with you in terms of 2 interpretation. If you have someone who started with 10 3 lesions, a reduction of 5 lesions would be translated to 50 4 percent compared with another one who started with 200 lesions. 5 I think it's a measure which to me a clinician prefers. 6 We do look for percent change as well as change, 7 by the way. So we analyze both of them jointly, having said 8 that. 9 In terms of the magnitude of the difference, I 10 think in terms of a clinical trial, we came across several 11 trials. I gave two examples of what is the range to achieve 12 statistical significance. I think Dr. Wilkin could speak to 13 that. With that range, it seems clinically it's acceptable. 14 Now, concerning the point of it needs to be 15 prespecified or not, definitely we have communication with 16 the sponsor at phase II and phase III trials, and we agree 17 on what endpoint needs to be analyzed, in particular percent 18 change, and we'll be looking for change in addition to the 19 investigator global assessment. 20 So I share the concern you have about analysis 21 of percent change, but really, we look at it with other factors. 22 Percent change would reflect what happened to the patient 23 over time, whereas investigator global -- this is the 24 co-primary endpoint. You are looking at the final assessment, 25 the assessment at final study endpoint. So it's a co-primary.

175 1 It's not the whole story behind winning because you still 2 need to win to achieve clearance or almost clearance. 3 DR. STERN: But if you come to those two charts 4 you showed of drug and placebo, the scatter diagrams, my 5 interpretation of those results -- one interpretation would 6 be we have an active agent that prevents people with a little 7 bit of acne from flaring substantially, and otherwise the 8 effects seem about the same. And the question gets to be, 9 if all of the essentially significance comes from a difference 10 in a few people on vehicle who started out with not much disease 11 flaring, is that really an effective agent for acne? 12 DR. ALOSH: Yes, I think this is a good point. 13 As a matter of fact, the plot which I presented was for 14 inflammatory lesions only. And that drug in particular what 15 we have seen at week 12, there is a difference only of about 16 2.8, if I remember the number of lesions. So the drug with 17 that scatter, in a way it showed you the drug controlled the 18 flare because you have more scatter data in the vehicle arm 19 compared to those on the active arm. So the drug has activity 20 in reducing that variation. But when you come to analyze final 21 lesion count, it did not make it. 22 But I think the point here, we have the baseline 23 as the other measure. We need to take into account the baseline 24 score. In the plot we tried to show the baseline by week 12 25 assessment. When we took the baseline as a covariate in the

176 1 model, you make it whether you analyze the change or you analyze 2 the final count and you take the baseline into account, which 3 is what we call the analysis of covariance. 4 DR. STERN: Dr. Kilpatrick. 5 DR. TAN: Just one. 6 DR. STERN: Sorry. Dr. Tan. 7 DR. TAN: Does that mean your baseline 8 analysis -- you have several slides showing that. Does that 9 just confirm that you do need a randomized study because there 10 is no pattern in terms of the response? You have four 11 categories there. Right? 12 DR. ALOSH: Right. 13 DR. TAN: But if you do randomization, you have 14 a sufficient number of patients in the two groups. That should 15 not make any difference. 16 DR. ALOSH: Well, let me clarify in case it wasn't 17 clear. You have a randomized trial at the baseline. So, of 18 course, people at the baseline you expect to be distributed 19 randomly in every category. We are looking to the efficacy 20 result at week 12 by baseline category. So anyway, if I divide 21 the people according to the baseline severity, do people who 22 have a lower number of lesion counts at the baseline achieve 23 higher probability of success if you look to lesion count or 24 the investigator global compared if they have -- let's take 25 an example.

177 1 If I started with a subject with a 50 lesion count, 2 what's the efficacy result for that subject compared to someone 3 at enrollment that has a 200 lesion count? So you need to 4 compare what's the delta for those people in the lower category 5 of the baseline compared to the delta -- what I mean by delta 6 is the active minus the vehicle -- at the high category. 7 The point here is if you have high efficacy results 8 for people with a smaller number of lesion counts at baseline, 9 you might be better off to win if you enroll subjects with 10 a smaller number of lesions. We are looking at here is most 11 of the difference coming from non-inflammatory lesions, from 12 those plots which we have seen, and the delta is similar. 13 If you look to lesion counts, change, or percent change, we 14 looked again to the investigator global, what we have seen 15 in the investigator global, the people in the lower category 16 have a higher probability of success, but the same thing holds 17 for the vehicle. So you end up with a delta roughly the same. 18 Does that answer the question? 19 DR. TAN: Yes. 20 DR. KILPATRICK: Thank you. 21 I can get into this in a roundabout way or follow 22 my own personality and be more direct. I've looked ahead, 23 Dr. Alosh, into your next section in which I notice -- and 24 again, I presume in this one, when you talked about IGE, the 25 percent of success, you used a logistic regression, logistic

178 1 regression I presume because the proportions are not normally 2 distributed. Counts are not normally distributed. So my 3 question is, are some of these phenomena that you're talking 4 about explicable by the fact that you use a normal distribution 5 in your analyses rather than the Poisson distribution? 6 DR. ALOSH: Dr. Kilpatrick, I think going to the 7 second presentation, which I'll come through it in some detail, 8 what I'm modeling in the second part of the presentation -- 9 DR. KILPATRICK: No, sir. I'm really asking 10 about the modeling of counts when you say you're going to be 11 use an ANOVA, a MANOVA, et cetera. Why not use log linear 12 regression? 13 DR. ALOSH: Okay. This is another point. I 14 think when you talk about logistic regression, logistic 15 regression came in the second part. But I agree with you. 16 If you are going to analyze counts which has a Poisson 17 distribution, the number is small. 18 Yes, indeed, I use the normal approximation. We 19 are talking about a trial with about 400 subjects. So if you 20 take 400 subjects with number of lesions not small, we have 21 seen the normal approximation for the data works. 22 But I agree fully with you. If I have a small 23 number of lesions with a small number of patients, as you 24 pointed out correctly, I'll use the Poisson regulation. But 25 that type of lesion, as you know, the normal theory would work

179 1 for that. 2 DR. KILPATRICK: This may be my only opportunity 3 to say this in front of other statisticians from FDA. I don't 4 see why we should continue to use the normal distribution when 5 it is not appropriate, when there are other models that we 6 can use. I have really little feel for how much of what we've 7 seen today is due to the non-normal distribution or how much 8 of it is due to the true differences between small and large. 9 As regards the baseline, I agree with Ming that 10 if it's randomized, you shouldn't have to use it, but then 11 if you do use it, I agree with you that you should put it in 12 the right-hand side as a covariate rather than dividing which 13 assumes linearity, et cetera. 14 DR. ALOSH: Well, definitely it's a good comment. 15 Personally I think I'll go back -- the normal approximation. 16 I'll not say really the analysis here is not appropriate 17 because you could take -- I mean, it's a technical point. 18 I'll be happy to discuss it with you. As you know, n times 19 lambda where lambda is the mean of the Poisson distribution, 20 10 to something, it will go to the normal. 21 It's a technical point. I don't expect personally 22 the p value which I'll get from fitting a log linear model 23 to be different than that. But definitely I could investigate 24 it. We could discuss it. It's a technical point. There are 25 other statisticians who might give their opinion as well.

180 1 DR. STERN: I actually think, though, it's more 2 than a technical point. It's a bit of a conceptual point going 3 to this whole issue of how much does baseline status affect 4 what happens with the data subsequently, if I understood you 5 correctly, and your feeling about what is, in fact -- is this 6 distribution of changes a normal one or not and how it's 7 related. 8 DR. KILPATRICK: Well, I reiterate. I think both 9 my feeling -- I'm perhaps more of an idealist than members 10 of the FDA. Since I've taught these methods to my students, 11 some of whom are now employed by CDER, I know they have the 12 techniques. Why don't they use them? But I agree with Dr. 13 Alosh that it may be unconventional, but it's certainly modern 14 statistics. 15 The logistic model is much easier to explain than 16 the log linear model, but I'm concerned not so much with p 17 values as with error distributions and predicted values. 18 Predicted values may be quite different under the normal 19 assumption and the log linear. 20 Thank you. 21 DR. TEN HAVE: Yes. I'm the third statistician 22 here. I guess I should probably make a comment. 23 But getting back to this issue of the normal 24 distribution, there's another related issue and that's this 25 variability issue which has come up a number of times in today's

181 1 conversation, in addition to your consistency comment. And 2 I have a couple of questions. 3 One is, you mentioned the difference in 4 variability between the active arm and the vehicle arm, and 5 that also has consequences obviously for your test statistics. 6 And that's related to whether they're normally distributed 7 or Poisson distributed or whatever. 8 But there's a second issue which is probably more 9 difficult to consider and that's should variability itself 10 be a measure of efficacy. You're looking at differences in 11 mean scores or mean counts. Should you be considering 12 differences in variability whether one is more consistently 13 better than the other across patients but also across time 14 within patients? 15 DR. ALOSH: That's definitely a good argument. 16 I think in the morning we had an example in which a drug was 17 approved for the indication and the other drug not approved. 18 What we look for is collective evidence. We look for 19 consistency of finding across centers. So, for example, one 20 might get an application which barely makes it. We could go 21 back. We don't take just this p value. We look for 22 consistency across centers what you see. Definitely at one 23 point in time, we were looking at the final assessment. We 24 are going back here to look at the repeated measurement approach 25 whether we see some kind of a plateau reached, whether there's

182 1 a consistent finding or not. 2 I would agree both with you and Dr. Kilpatrick. 3 There are many assumptions underlying the statistical test 4 which I presented here about the generalized linear model or 5 repeated measurement. What's the type of the H matrix you 6 need, et cetera. So there is a lot behind those p values which 7 are reported here. 8 But I want to make the point, definitely we look 9 for consistency across centers. If there are outliers, we'll 10 go and investigate back. 11 In the second presentation, I'll be fitting a model 12 and I'll discuss exactly how far we go to see if there is an 13 outlier and how we dealt with that. 14 DR. TAN: Yes. I just want to add just one point 15 to the log linear model here. I noticed on your slides, you 16 already mentioned the generalized linear model. I think 17 nowadays all those models are falling into this generalized 18 linear model. That includes the log linear model. And it's 19 readily available. I agree with -- 20 DR. KILPATRICK: I think the term "general linear 21 model" -- 22 DR. TAN: Generalized linear model. 23 DR. KILPATRICK: But to me generalized linear 24 model involves the Nelder -- I call it Nelder generalization 25 of the general linear model. Dr. Kligman, are you with us,

183 1 sir? Okay. 2 DR. TAN: Yes. That would include what is called 3 a log linear model into that. 4 But actually I have another question. You said 5 for the repeated measures analysis -- I actually have a 6 different view from what we talked about this morning. You 7 talked about the inhibition of the new, emerging lesions. 8 We all agreed in the morning that it is important to see the 9 consistent improvement throughout the course of this 10 treatment. There are certain defined periods. So, 11 therefore, the success really should be defined as not just 12 at one shot. It should be at maybe 8 weeks and 12 weeks. 13 So instead of you increase your power, you actually have less 14 power. You need to have more patients in this way. You should 15 have the improvement both at 8 weeks -- maybe not 8 16 weeks -- maybe 6 weeks. At two points maybe. 17 Actually in the cancer research area, people have 18 been using this because patients who have cancer respond to 19 a new therapy and then come back again. So people now redefine 20 responses. The tumor has to be shrunk by 50 percent at two 21 time points. And this would capture that emerging new lesions. 22 DR. STERN: That was exactly the point I was trying 23 to make, that rather than combine, it's probably more 24 appropriate to do multiple, independent testing, and you've 25 got to pass both tests as opposed to combining the data to

184 1 reduce variance across them so you can pass one test more 2 easily. 3 DR. TAN: Yes. 4 DR. STERN: Dr. King. 5 DR. KING: Actually I have a lot of trouble with 6 this, the concept of the washout and the whole area. I think 7 clinically they say, quick use the drug because it quits working 8 soon enough. So if you're going to start off with the baseline, 9 should not all the patients start with a washout period that 10 would stabilize it and then you actually measure the 11 consistency or persistency of effect? Because the fact that 12 you may be better at one time point that's being stressed here 13 is, like cancer, you may have a recurrence. It seems to me 14 that you not only have to start with everybody having a washout 15 period, but you need multiple measurements at the end. Where 16 like two points make a line or three points make an even better 17 line, it seems to me that just having one point is going to 18 lead to an erroneous result. 19 So would you comment on the washout period and 20 then the multiple points showing a persistent effect? Because 21 that's really what patients are after, persistent effect. 22 DR. ALOSH: Yes. Thank you for the question. 23 I don't think really I'm in the position to comment 24 on the washout. I think it's clinical. But I think the point 25 here, if we are seeing people could experience a flare during

185 1 the course of the trial, whether they take the active or not, 2 we expect even if we observe people before enrollment in the 3 trial, they could experience this flare as well due to some 4 factors. As a clinician, probably you know it more. 5 So, consequently as a washout period -- do we put 6 people on a certain drug and we are looking for improvement 7 or just examine them? I don't understand much about the nature 8 of the disease, whether we could control things here in terms 9 of washout. 10 I think in terms of the repeated measurements, 11 indeed it's a good point, because that flare, that high 12 variability should come having outliers. We'd like to get 13 rid of them, reach to a more reliable measure by taking probably 14 two or three repeated measurements instead of one. 15 Now, the question we are addressing here, how many 16 measurements you are going to take and we need to maintain 17 a clinical relevance not only to reach a statistical 18 significance. 19 DR. KING: My point is quite simple. With the 20 washout period, it's been my experience and probably others' 21 that once people start getting bad, it doesn't matter which 22 therapy you give them. They just keep on getting worse. You 23 start off with a small bump and it just keeps going. The 24 purpose of the washout period is to try to pick up those who 25 are going to become outliers. As you showed, the outliers

186 1 can really affect the outcome, and so you'd like to have a 2 period where they end up truly being stable because when you 3 start off with saying you can't have medicine or any other 4 therapy for about 4 weeks, some of the delayed effects are 5 such that once you stop their polypharmacy or the multiple 6 drugs, somewhere around week 6 after stopping that, they start 7 off getting a lot worse. So it seems to me you have to control 8 for the outliers, and then you average the last three or four 9 visits. 10 DR. ALOSH: Thank you. 11 DR. STERN: Thank you. This will be the final 12 comment in this section. 13 DR. PLOTT: I have a question regarding the 14 analysis of covariance. Are you in this analysis taking into 15 account the different numbers, inflammatory and 16 non-inflammatory lesions, and how that impacts the total lesion 17 count? Because consistently in clinical trials, we've found 18 about a quarter of the total lesions are inflammatory, maybe 19 two-thirds or something like that, three-quarters are the 20 non-inflammatory lesions, and in the analysis of covariance, 21 how is that taken into account? 22 DR. ALOSH: This is a good point. In terms of 23 the analysis of covariance, if we're analyzing the total lesion 24 count, what I'm taking into account in the model would be total 25 lesion count at the baseline. And if I am putting a model

187 1 for inflammatory lesions, I'll be putting in the analysis of 2 covariance inflammatory lesions at baseline. So whatever the 3 model I'm using there, whatever the final assessment I'm 4 modeling, I'll put the corresponding value at the baseline. 5 I think you could ask the question, when I did 6 the efficacy assessment by baseline category, there you could 7 break it by number of inflammatory lesions at baseline or 8 non-inflammatory lesions or total lesions. For the data I 9 presented here, I break it down by total lesions. I felt this 10 is more representative. 11 You could do the analysis for any one of them, 12 but when we presented the data, most of the difference is really 13 coming from non-inflammatory. There is a little bit of change 14 in inflammatory lesions from one category to the next, but 15 most of the difference between the different categories is 16 in terms of non-inflammatory lesions. 17 DR. STERN: Thank you. I think we need to move 18 on to the remainder of Dr. Alosh's presentation, and there 19 will be questions after that as well. 20 DR. ALOSH: The second part of presentation -- I 21 think we heard this morning a lot of discussion whether 22 investigator global evaluation is more rigorous, whether it's 23 needed in addition to lesion count. And we have seen also 24 a discussion on the other side that probably we should do only 25 with lesion count without the investigator global assessment.

188 1 Most of the work come here really -- we don't do 2 it in analyzing clinical trial data, but we get questions from 3 the sponsor in many cases that they would like to power the 4 study for change or percent change, but they found it more 5 demanding to power the study for the success criteria according 6 to the investigator global evaluation. 7 So in this presentation, I'm going to talk about 8 assessing the relationship between the success on the 9 investigator global evaluation and the acne lesion count. 10 In the morning, Dr. Wilkin presented data in which you have 11 some artist draw lesions. Here I'm going to take actual data 12 distinguished between inflammatory and non-inflammatory 13 lesions, fit the model, and see whether the investigator global 14 evaluation expressed as a success is more rigorous for efficacy 15 evaluation than analysis of change or percent change. 16 The outline of this part of the presentation. 17 I'll be giving some background, why is this needed. I'll be 18 modeling the investigator global evaluation, the success 19 criteria. We are reducing this to success/failure, even 20 though we start with a 6-point scale or a 5-scale. I'll give 21 an interpretation and assessment of the fit, and I'll conclude 22 with some final comments. 23 Just to go back a little bit, we talked about the 24 measure for efficacy evaluation in acne trials consists of 25 two parts. In the first part, we are talking about a lesion

189 1 count based measure. What I mean by that, change or percent 2 change. And the other co-primary endpoint is the investigator 3 global evaluation which is ordinal data on a 5- or 6-point 4 scale. 5 Now, lesion counts is based on counting the data. 6 It's more rigorous probably. The second one is based on 7 visual evaluation or visual assessment. But we need to keep 8 in mind we have the same subject. We are doing the efficacy 9 on the same subject whether we are counting lesions or we are 10 giving a score to the subject. 11 Then also the same investigator doing the 12 assessment, one time counting the lesion count and then the 13 second time giving a score. 14 For those two reasons, we expect the two measures, 15 whether lesion count and investigator global assessment, to 16 be related to each other. 17 The goal here is to investigate the relationship 18 between the dichotomized investigator global evaluation and 19 the lesion count. 20 Specifically I'll be using empirical modeling to 21 address the following issues. Was the impact of lesion count 22 or their change on success according to the investigator global 23 evaluation? 24 The second question I'm going to consider, whether 25 a certain type of lesion has more impact on the investigator

190 1 global evaluation success. We talked about inflammatory as 2 well as non-inflammatory lesions, and I'd like to see whether 3 one type of lesion has more impact than the other. 4 And then I'll be talking whether there is utility 5 of adding the baseline count to the model. 6 What we have here, I'm going to use logistic 7 regression model to model that relationship. The reason we 8 use that, what we term it as a binary data which we express 9 it as a success or failure. The p here represents the 10 probability of success. So I'll be modeling the odds of 11 success or failure. I'll be taking the log of that which is 12 what's known as logistic regression. This is what we call 13 a dependent variable. And I'm taking this as a function of 14 the covariate here. The beta is what we call a set of 15 parameters of the model. And the X's could be lesion counts 16 by type, inflammatory, non-inflammatory, or whatever, but also 17 to call it independent variables. 18 Now, the interpretation of the parameters of the 19 model. For example, if you take what's the meaning of beta 20 1, if you increase X1 by one unit, beta 1 will give you the 21 magnitude of change and the log odds of success on the 22 investigator global assessment as a result of increasing X1 23 by 1 unit. 24 Now, as I said, X1 could be number of inflammatory 25 lesions or non-inflammatory lesions or baseline. So this is

191 1 just the generic form of the model, and when I'm going to the 2 actual modeling, I will replace X1 by a certain type of lesion. 3 The data set I'm considering for this analysis 4 is what I presented in the previous presentation, which is 5 drug X. I have 400 subjects. The study was, as you have seen, 6 for a 12-week duration with assessment done at weeks 4, 8, 7 12. We have the investigator global evaluation done on a 8 6-point scale from 0 to 6 where 0 means clear or no lesions 9 to 5 which is very severe. 10 Now, success here is defined as to be in category 11 0 or 1. And 1 says "minimal," but there's a definition of 12 what's meant by minimal. A certain number of inflammatory 13 lesions and non-inflammatory. A clinician will judge that. 14 Now, in the investigator global assessment, the success 15 criteria is defined, as I said, as 0 or 1. 16 In this model, I'm taking the final lesion count. 17 I'm modeling this. This is X1 and X2 which are the 18 inflammatory lesions and non-inflammatory lesions at week 12. 19 What we have here, as I said, is the probability of success 20 according to the investigator global evaluation. 21 I would like to point out in this study I excluded 22 one outlier from the model. And the reason for that, I fit 23 the model in the beginning and I got barely the model make 24 it in terms of interpreting the data. Going back, I found 25 an extreme outlier. I looked to that outlier. One subject

192 1 that was assessed as a success was given a score of 1, and 2 this subject had 17 inflammatory lesions and 41 3 non-inflammatory lesions. This does not fit with the criteria 4 of 1. I mean, that subject would not be defined as a success. 5 So I ended up taking that subject from the study and refit 6 the model because that subject definitely should not be 7 classified a success. 8 Now, in terms of interpreting the parameters of 9 the model here, what I want to point out, this is the beta 10 and what we call the intercept. This is the coefficient for 11 inflammatory lesions and this is non-inflammatory lesions. 12 I would like to point out the coefficient for inflammatory 13 lesions is about four times in terms of magnitude as 14 non-inflammatory lesions. So inflammatory lesions have much 15 more impact on the success criteria compared to that of 16 non-inflammatory lesions. 17 The second point I want to make is those 18 coefficients are negative. So as the number of inflammatory 19 lesions increases, your chance of winning decreases. And you 20 could say it differently. As the number of lesions decreases, 21 you have a higher chance or higher probability to achieve 22 success. 23 The interpretation of the parameters. We could 24 say a 1 unit increase in inflammatory lesions at week 12 would 25 imply a decrease of e to the power minus 41 or .662 in the

193 1 odds for success according to the investigator global 2 evaluation. 3 The same thing for non-inflammatory lesions. A 4 1 unit increase in non-inflammatory lesions at week 12 implies 5 a decrease in the odds for success. As I said, you could put 6 it differently. You could say what's the impact of a 1 unit 7 reduction in inflammatory lesions at week 12, how much it has 8 an impact to increase your chance of winning. 9 I want to go back to this slide. What we see here 10 is only the final lesion count, inflammatory and 11 non-inflammatory, in the model. We don't have the baseline 12 lesion count in the model. I think this is very logical. 13 If you have the final assessment, you could judge whether the 14 patient is clear or almost clear. You don't need to know the 15 baseline because you have the final count. 16 The coefficient of inflammatory lesions, as you 17 have seen, is about four times that of non-inflammatory 18 lesions. This might be due to appearance, color, size, or 19 the surrounding halo of erythema of inflammatory lesions. 20 When the final lesion counts are given, as we said, baseline 21 values provide no additional information for explaining the 22 investigator global success. 23 Here we fit the model, but we'd like to see how 24 good the model fit the data. For a good model, we could predict 25 the probability of success according to the investigator global

194 1 evaluation from the number of lesions at week 12. A good model 2 will give you the predicted value from the model similar to 3 the observed successes in real life. 4 Now, this statistical test here, which is the 5 Hosmer-Lemeshow test, breaks down the number of subjects in 6 the trial presumably into 10 categories, but we have 8 here 7 because you don't need to have a smaller number of categories. 8 If there is a smaller number of categories, you need to lump 9 them with the other categories. But here we have only 8 10 categories. 11 In every category, as you said, you calculate the 12 probability of success and you could calculate the number of 13 successes and compare it with the actual number of successes 14 in that category. Now, those categories are based on the 15 predicted probability of success. 16 Of course, you could make the correct 17 classification in every category. You might have in one 18 category 20 people a success and 10 failures. You could 19 classify 21 a success and 9 failures. The total will be the 20 same, but once you make an error in one of them, it will be 21 reflected to the next category. 22 So, for example, if we go to group 1 here, we have 23 a total of 135 subjects. The observed number of successes 24 in this group is 0. From the predicted model we got .01. 25 Of course, we don't expect to get an integer value from the

195 1 model, but the observed are going to be integers. 2 Now, if you take this, it means if we have observed 3 success as 0, the observed number of failures is going to be 4 135, and you could see the expected from the model is 134.99. 5 And the sum of those two should give you the total 135. The 6 same here. 7 You go through this. You come to the second 8 category. You compare it. You could see the observed 9 successes is very close to the expected. And we come in terms 10 of goodness of fit statistic. We give the chi-squared test 11 .95 with 6 degrees of freedom, which gives us a p value of 12 .98, indicating a very good fit for the data. 13 On the previous slide, we modeled the final lesion 14 count. What I'm going to consider here is a model for change 15 from baseline, because this is what we analyze in an actual 16 clinical trial. 17 The same model we have here. On the left-hand 18 side, we have the probability of success according to the 19 investigator global evaluation divided by the failure, and 20 we take the log. On the right-hand side, this is the intercept. 21 X1 is change in inflammatory lesions; X2, the change in 22 non-inflammatory lesions. Now we have two terms added in the 23 model which are X3 and X4, and those are the baseline 24 covariates. So X3 is the baseline for inflammatory lesions 25 and X4 is the baseline for non-inflammatory lesions.

196 1 I want to point out in fitting the model, I used 2 what's called the step-wise approach. You fit the simple model 3 in the beginning and you include covariates in the model if 4 they could explain some additional variation from the model. 5 So the addition of those covariates to the model in the 6 beginning, the intercept would find X1 which is change in 7 inflammatory lesions more important. So we'll enter this one. 8 Then non-inflammatory change will explain additional 9 variation. So the model will take that. But still the 10 baseline could explain the variation in the model. 11 Again, the point I want to make here is you could 12 see the coefficient for inflammatory lesions, .412. It's 13 still about four times of that of the change in non-inflammatory 14 lesions. The same holds if you are looking at the baseline 15 lesion count. You could see the coefficient for inflammatory 16 lesion count at baseline, .43 compared to .089 for 17 non-inflammatory. So again we could see the inflammatory 18 lesion coefficient is about four times. It's a more important 19 covariate than non-inflammatory lesions, probably for the same 20 reason we discussed. It could be the color of inflammatory 21 lesions, more red. It could be the halo of erythema, just 22 different factors. 23 Again in this analysis, I'm excluding the one 24 subject which showed success even though this subject has 17 25 inflammatory lesions and 41 non-inflammatory lesions. I'm

197 1 excluding that subject from the analysis. 2 On the next slide I show the comment. Change in 3 inflammatory lesions do not fully explain the investigator 4 global evaluation. This is in contrast to the previous model. 5 When I modeled final lesion count, I did not need the baseline 6 lesion count. All you need is the final assessment. But here 7 when you are talking about change, it's not sufficient to tell 8 me that I have a reduction of 50 lesions. I would not know 9 from where you started. So baseline is still an important 10 covariate in the model to explain that variability. 11 So we have seen larger reductions in inflammatory 12 and non-inflammatory lesions increase the odds of investigator 13 global success. So the more reduction you have in inflammatory 14 or non-inflammatory, you have a higher probability of winning. 15 On the other hand, increases in baseline 16 inflammatory or non-inflammatory lesions reduce the odds of 17 investigator global assessment. So if you start with a higher 18 baseline, you have a lower chance. 19 Inflammatory lesion again has about four times 20 the impact as non-inflammatory lesion on the investigator 21 global success. 22 Here again the same discussion about assessing 23 the goodness of fit or using the Hosmer-Lemeshow test statistic 24 in which by calculating the predicted probability of success 25 for every subject we divide the subjects in the trial into

198 1 groups, and here it's 8. In every category or in every group, 2 you could see the number of successes observed and those 3 expected from the model. Definitely the closer the two to 4 each other, the better the fit is. 5 In terms of calculating the chi-squared goodness 6 of fit, we have chi-squared of .83 with 6 degrees of freedom, 7 giving again a very good fit for the data. 8 So to summarize, if you have final lesion count, 9 you don't need baseline assessment to tell success in the 10 investigator global, but if you have the change, you need the 11 baseline. So the success according to the investigator global 12 assessment is more rigorous criteria for success than analyzing 13 change in lesion count. I think this will bring the question 14 now we understand why industry would like to power for change 15 but not require more patients for the trial to power it for 16 success according to the investigator global assessment. 17 I think the discussion came also this morning 18 whether one should do an analysis of count without the 19 investigator global or vice versa. The discussion came on 20 two sides. We see really here is they're in a way complementary 21 to each other. I see change in lesion count. You are looking 22 to the time trajectory what happened over the course of the 23 trial, whereas the investigator global assessment will give 24 you the shot at one time point, what happened to that patient, 25 whether he's clear or almost clear.

199 1 The final comments. Inflammatory lesions have 2 more impact on the investigator global evaluation success than 3 non-inflammatory lesions. Absolute change in lesion counts 4 alone do not fully explain variability in the investigator 5 global success because baseline is still an important covariate 6 in the model. The fitted model is useful for checking 7 consistency of a study finding based on the investigator 8 global. 9 And I'd like just to remind you about that outlier. 10 Without fitting the model, we wouldn't be in a position to 11 see that there's some observation. The data is not consistent 12 in that observation. 13 I'll stop here. If there are further questions, 14 I'll be happy to answer them. 15 DR. STERN: Dr. Kilpatrick. 16 DR. KILPATRICK: Thank you, Dr. Alosh. I want 17 to congratulate you on introducing goodness of fit. That's 18 the first time I've heard that in an FDA presentation. That 19 is not a joke, sir. 20 I wanted to ask at what level would you consider 21 the goodness of fit test failed. What p value would you use? 22 This is something that really has to be discussed I think 23 and put up because would you use the 5 percent? Are you going 24 to be as stringent? And then again, the ramifications, as 25 you well know, of how much leeway will you or the sponsor have

200 1 in bringing in subjects or throwing out subjects, et cetera. 2 There's a whole feeling there. 3 DR. ALOSH: Well, thank you first about the 4 comment of goodness of fit. I'd like to point out indeed we 5 do a lot of statistical methodology. We read papers. We do 6 extensive work in the background. Although I think for the 7 purpose of a presentation such as this, we tend not to 8 bring -- because, as you know, the background. So we'd like 9 to communicate just the main findings. 10 The second point is addressing how good is good, 11 the way I see it. It's a matter of judgment. You could see 12 data. You get a p value, for example, for goodness of fit, 13 20 percent. At .2 we could say it's acceptable. 14 In this case, when I found I'm getting a small 15 p value, I ran SAS, examine influence, and I find just extreme 16 in terms of the percent chi-squared. One observation has 17 16.something. So with that, I said it cannot be. There's 18 something wrong here. So I go back, examine the data, and 19 just one subject has 17 inflammatory lesions and 41 20 non-inflammatory lesions, and this subject was classified a 21 success. So I think both you and me and probably most of the 22 audience here will agree that this subject should not be 23 classified as a success in the first place. Now, you take 24 that subject out, and practically we do a sensitivity analysis 25 to see how much improvement in the fit. And by taking that

201 1 subject, my p value went from .05 to .98. 2 I think this will give you an indication that 3 really you are looking for consistency in findings. I think 4 the model itself has a good check on the data. If we go analyze 5 the number of successes without looking deep, as I pointed 6 out, and consistency across centers, looking for 7 outliers -- and this I think brings why we do rank analysis 8 because the point we made about outliers, we look to the data 9 in different ways to reach to collective evidence about 10 approval. So really there is a lot of work done behind the 11 scene before we arrive at the final comments in our report. 12 DR. STERN: I may be completely off base here, 13 but I've never seen a model fit so well, and I wonder whether 14 it's appropriate to do it this way or one should have randomized 15 half the data set and bootstrapped it and see how well it fitted 16 on the other set. Maybe it's just me, but this is an 17 extraordinary fit for a model of this kind in my very limited 18 experience. And I'd ask the experts about that. I've never 19 had any data I've worked with produce a model with this kind 20 of fit. 21 DR. TAN: I just want to mention here that the 22 purpose of doing this analysis was to see the probability of 23 success based on the global assessment, how that success is 24 related to other factors. I think that's legitimate just to 25 use the whole data.

202 1 If you want to do a prediction, now in the future 2 I'm just going to use this total lesion to predict the global 3 success score. Then you may need to validate the model and 4 use the bootstrapping. 5 DR. STERN: Is this an unusually good predictive 6 model? 7 DR. TAN: Not entirely. I have seen data fitted 8 this well, yes. 9 DR. ALOSH: Well, let me give you my reply since 10 I fitted the model, at least. 11 How good the model, I think it depends on how close 12 the two variables are to each other. Now if you take into 13 account -- as I said in the beginning, you have the same subject, 14 the same investigator, one time doing the counting, counting 15 lesion counts, and then the second time seeing if we have either 16 success or failure. So if you are doing it, I would not expect 17 you to give a patient a 50 lesion count and to classify him 18 as a success. 19 On the other hand, if I'm doing, let us say, getting 20 data on different phenomena in real life, especially 21 epidemiological data or social science data, we reached a p 22 value of .4. So I'm in full agreement, but I think we need 23 to keep in mind here the theory behind it, the same investigator 24 doing the two evaluations. And unless there's some error, 25 I don't think you will be -- and you are dealing with intelligent

203 1 people, I mean, with dermatologists. So it's not like someone 2 who might do something on the side or someone not educated. 3 So for that type of data, I think it's reasonable. 4 I'm going to take your point and fit it to another 5 data set because this is for drug X which we have seen a high 6 efficacy result. This also will play a role in that data. 7 DR. KILPATRICK: May I ask a follow-up question? 8 May I take it then that you did do -- did you do goodness 9 of fit in the count data also? Were you looking at how well 10 this model fitted in the earlier presentation? 11 DR. ALOSH: The earlier presentation, yes. We 12 fit analysis of variance, generalized linear model, and the 13 p value was very small -- I'm sorry. 14 DR. KILPATRICK: I'm asking about the goodness 15 of fit. Did you test the model in the analysis of variance, 16 MANOVA, et cetera? 17 DR. ALOSH: You look to that, what's the 18 proportion of variance explained by the model. And that 19 proportion is small compared to what we have here. You might 20 end up to have a significant treatment effect, but how much 21 variability in the model is explained. 22 DR. TEN HAVE: You mentioned that the companies 23 are saying that they have a hard time powering their studies 24 for the IGE as opposed to the lesion count outcomes. 25 DR. ALOSH: That's right.

204 1 DR. TEN HAVE: I was just wondering in your 2 experience has it usually been that the lesion counts are where 3 the statistically significant differences occur between the 4 active treatments and the vehicles and it's not such the case 5 in the IGE outcome based analysis? 6 DR. ALOSH: That's right. As a matter of fact, 7 since we analyze the change, if you look to the second model 8 in which you have the investigator global assessment as a 9 dependent variable and we have change in inflammatory lesions 10 and non-inflammatory as the independent variable, they did 11 not explain the variability in the model. So you still need 12 the baseline to interpret -- 13 DR. TEN HAVE: Right, but I'm just thinking in 14 general terms across studies. When the pharmaceutical 15 companies submit their analyses and you look at the results 16 based on the lesion counts using, say, analysis of covariance 17 where you do adjust for baseline versus whatever analysis they 18 use, logistic regression or Fisher's exact test, or a 19 chi-squared test for the investigator evaluation, where do 20 you usually see the treatment differences occurring? In both? 21 Is there consistency usually or is there usually 22 significance for lesion counts but not the IGE outcome? Just 23 in general terms. Is it harder to get significance with the 24 IGE than it is with the lesion counts? 25 DR. ALOSH: We see a result -- consistency in

205 1 general. You will observe results, for example, in total 2 lesions probably in one type of lesion, and you'll see it in 3 the investigator global. But it's harder in the investigator 4 global compared to the analysis of change or percent change 5 from baseline. So analysis of success according to the 6 investigator is more rigorous. I mean, you need really more 7 number of patients to achieve it compared to analysis of change 8 or percent change. 9 DR. STERN: I think we'll have to stop now, and 10 for the remainder of the afternoon, I'm going to become much 11 more stern with presenters and keep them to their time. I 12 think if everyone would like to take literally a 5-minute break 13 for those who need to, and then we're going to start in 5 minutes 14 with the first presentation and go on through in a sterner 15 manner. 16 (Recess.) 17 DR. STERN: For the next 15 minutes, Dr. Markham 18 Luke is going to talk to us about combination topical products 19 for the treatment of acne vulgaris. 20 DR. LUKE: Thank you, Chairman Stern, members of 21 the committee, Dr. Wilkin, Dr. Bull. I'm going to address 22 the combination topical products for the treatment of acne 23 vulgaris. I am not going to be speaking about adjunctive 24 therapy or about co-packaging issues that you had raised. 25 Those are issues for a different time.

206 1 The Code of Federal Regulations has in it a passage 2 by which the agency addresses fixed combination drugs. Notice 3 the term "fixed" combination. So there's a set ratio. These 4 are drugs that have two actives mixed together. "Two or more 5 drugs may be combined in a single dosage form when each 6 component makes a contribution to the claimed effects and the 7 dosage of each component (amount, frequency, and duration) 8 is such that the combination is safe and effective for a 9 significant patient population requiring such concurrent 10 therapy as defined in the labeling for the drug." And I cite 11 21 C.F.R. 300.50(a). 12 For the situation of acne combination drugs, the 13 combination topical products for the treatment of acne vulgaris 14 require evidence for the contribution of each active component 15 or components that are purported to provide for added efficacy. 16 To clarify a little bit more, in applying the 17 combination drug policy for two drugs, component substances 18 A and B having the same endpoint, in a three- or four-arm 19 clinical trial, success is demonstrated by A plus B, the 20 combination drug product, being better than either of the 21 monads, A or B, and both of these monads being better than 22 the placebo. 23 For the acne combination drugs, we have currently 24 marketed combination topical drug products that have the 25 combined topical antibiotic either erythromycin or

207 1 clindamycin -- and for our purposes they can equal A -- with 2 benzoyl peroxide, which I have put on the slide as equaling 3 B. The safety and efficacy of other combinations for the 4 treatment of acne are also currently being investigated. 5 Studies to address the combination policy for acne 6 drugs have shown that the most difficult superiority to 7 demonstrate is the contribution of the antibiotic, or A, to 8 the efficacy already achievable with benzoyl peroxide alone, 9 or B. And so demonstrating A plus B better than B is something 10 that needs to be strived for. 11 In conclusion, each component of a fixed 12 combination drug for the treatment of acne must demonstrate 13 a contribution to the claimed effects of the drug product. 14 This may be difficult if the contribution of one of the actives, 15 for example, the topical antibiotic, is minimal and hard to 16 discern when combined with another active, for example, benzoyl 17 peroxide. 18 DR. STERN: Thank you. 19 We'll now have our next talk by Dr. Porres who 20 will talk labeling for efficacy, and then there will be 21 questions for both at the same time. So Dr. Luke can come 22 back up. 23 DR. PORRES: Hi. I'm Joseph Porres, medical 24 officer, Division of Dermatologic and Dental Drug Products. 25 This will be a very brief presentation on what

208 1 is usually included in the clinical studies section of the 2 labeling for products approved for the indication acne. 3 As has been touched upon before, efficacy is 4 measured by looking at endpoints such as acne lesion counts 5 and the investigator global evaluation. So I won't delve into 6 this in any greater detail. 7 In this section of labeling, the clinical studies 8 section, we include a description of the types of studies that 9 led to approval, the phase III pivotal studies, describing 10 what kind of studies they were, how long they lasted, the number 11 of patients who received the drug treatment or who received 12 the placebo, if it was an oral medication, or the vehicle, 13 if it was a topical medication, the mean age at enrollment 14 for each one of the two arms, and whether a statistically 15 significant difference was observed and for which endpoints. 16 Also, we include information about the types of patients which 17 were included or excluded in the studies. It may be important 18 for the clinician to know whether maybe patients who had severe 19 acne were not included or whether pregnant women were excluded 20 or perhaps whether certain age groups were not included in 21 the studies. 22 In this slide I'm going to show an example of the 23 kind of text that we include in labeling to denote the 24 information that I just referred to. Here we have a paragraph 25 describing that product P was evaluated for acne vulgaris in

209 1 two randomized, double-blind, placebo-controlled, multicenter 2 phase III studies which lasted for six cycles of 28 days each. 3 Here we have another sentence indicating that 4 there were 295 patients who received the active while there 5 were 296 who received placebo, and the mean age at enrollment 6 in both arms was about the same, 24 years old. The study lasted 7 six cycles, and at the end of the studies, in both of them 8 a statistically significant difference was observed between 9 the drug product and the placebo both for mean change from 10 baseline in lesion counts, which we will show later in a table 11 and a figure, and also for the investigator global evaluation. 12 We also noticed that in this particular set of 13 studies, patients who were deemed to have severe androgen 14 excess were excluded from the design. 15 Now, we also used, besides text, tables and 16 figures. That way we convey different types of information, 17 trying to facilitate to the clinician to have a bird's eye 18 view or a glimpse of what the data from the pivotal studies 19 showed. 20 Here we have an example of a table and there are 21 several pieces of information. First of all, we tell that 22 this is a study done for acne. Normally we evaluate each study 23 separately and there must be a win on both to win approval, 24 but here for the sake of simplicity, I'm presenting to you 25 the pooled data.

210 1 So there were two studies, P1 and P2, and both 2 of them lasted six cycles. We showed the types of lesions 3 that were studied, inflammatory, non-inflammatory, and total, 4 and for each one of them we showed what the baseline mean count 5 was and the count at the end of the six months or cycles. 6 We also show in these columns the actual counts 7 for both the active and the placebo. For instance, for 8 inflammatory lesions, we started with 29 lesions for the active 9 arm, and we ended up with 14, which translates in a 52 percent 10 reduction in lesions. However, for the placebo, we started 11 with 29 and ended up with 17, so that means a 41 percent 12 reduction in the counts. Here we have similar numbers for 13 non-inflammatory and for the total. 14 On the last column we show the treatment effect 15 which is the difference between what was observed with the 16 drug product and the placebo. And as you can see, in this 17 case for inflammatory lesions a difference of barely 3 18 plus/minus 2 lesions was enough to reach approval. I'd like 19 to stress this because sometimes I hear that people have the 20 impression that it's very hard to approve things at FDA, and 21 as you can see, a difference of just 3 lesions can sometimes 22 make it statistically. 23 Again, for non-inflammatory, the difference was 24 a little larger, 5 plus/minus 3.5, and for total lesions, 7 25 plus/minus 5.

211 1 Now, sometimes there are differences in between 2 the two arms, the active and the placebo arm in which case 3 we may want to add a sentence or a paragraph denoting the 4 differences. For instance, in this particular case, drug 5 product users who started with about 74 acne lesions had about 6 42 after 6 months of treatment. The placebo users started 7 with about 72 and ended up with 49 lesions after the same 8 duration of treatment. 9 Now figures can also help to provide important 10 information at a glance especially because you can get a time 11 relationship of the effect. Now, again, in this case we're 12 just showing a graph for the mean total lesion count where 13 we use against cycles what happened to the mean percent 14 reduction. And this slide is the one for placebo, and this 15 one is for the active. 16 Although we apply statistics only to the 17 prespecified evaluation time, in this case 6 months, I'd like 18 to show you that in this case some differences were noticeable 19 even at the second cycle. However, they don't reach 20 statistical significance until cycle 6. 21 In summary, presenting information as text, 22 tables, and figures offers prescribers a comprehensive summary 23 of the efficacy data observed in phase III trials. The three 24 formats complement each other since each one is helpful in 25 conveying a particular aspect of the data.

212 1 Thank you. 2 DR. STERN: Thank you very much. This section 3 is now open for questions. Dr. Katz. 4 DR. KATZ: Dr. Porres, I assume that was two 5 topical trials. Is that correct? 6 DR. PORRES: No. The information that was 7 conveyed here was for an oral medication. 8 DR. KATZ: Did you list the difference in side 9 effects between the placebo and the oral medication? Was there 10 a significant difference there? You didn't show it. 11 DR. PORRES: Yes. We didn't show that here 12 because we wanted to concentrate on the efficacy aspect, but 13 of course that information is reflected and it's in the package 14 insert and it's in the labeling of the drug product. It is 15 there. So it's not like we didn't look at it. 16 DR. KATZ: My point is that 17 many -- many -- double-blind studies -- that's used as some 18 godlike quality, double-blind studies, and it gets repeated 19 in the literature that they were double-blind studies -- start 20 as a double-blind study, but they don't end up as a double-blind 21 study, and nobody ever mentions that, not in the first study 22 and then not in any literature that follows, especially with 23 topical medications. So a double-blind study that shows 24 perhaps an 11 percent advantage to the drug, but if you look 25 at the side effects, 70 percent of the patients in the drug -- I

213 1 won't mention drugs, recent topical drugs for acne -- 70 percent 2 have irritation versus 10 percent with the vehicle. 3 Well, somebody should mention that those did not 4 end up being double-blind. They were controlled, but the blind 5 was broken and nobody mentions that. That's why even with 6 an oral medication it's important to know is there a significant 7 difference in the side effects because that breaks the blind. 8 I think that's very important. And that's not mentioned in 9 any studies in any of these borderline effective drugs that 10 come out. 11 DR. PORRES: The point is well taken. In fact, 12 that information is collected at the time of approval, and 13 it may even have a bearing as to whether or not the drug is 14 approved if the side effect profile turns out to be horrendous. 15 But that information is collected and it goes into labeling, 16 and most of it is probably reflected in the PDR. 17 DR. KATZ: No. But my point is that it's not that 18 the side effects might be horrendous. The side effects might 19 be very minimal. After all, when we treat patients in the 20 office, a very high percentage have some dryness with, let's 21 say, topical retinoids. That's an acceptable side effect. 22 But it does bias the investigator. It breaks the blind in 23 the study. 24 DR. PORRES: Well, oftentimes in these studies, 25 the blind is actually not broken until the end if the side

214 1 effect is not severe enough to break the study or to interrupt 2 the continuation of such patients within the study. You may 3 not actually find out whether the adverse effect was related 4 to drug or to the vehicle until the study is completed. 5 DR. KATZ: But the investigator would be biased. 6 DR. STERN: Right. I think Dr. Katz is bringing 7 up a point that's always a problem with products that have 8 irritancy, which is unblinding of the investigator. In fact, 9 there was a huge discussion about this with retinoids and the 10 treatment of photo-aging where the effects were perhaps even 11 more subtle than they are in the treatment of acne. That's 12 always a methodologic problem. Are you really unbiased and 13 blinded as you go on? And how does the agency deal with that, 14 Dr. Wilkin? 15 DR. WILKIN: Well, after Dr. Katz' comment, we'll 16 be thinking about it just a little bit differently in the future 17 because I think the question that he's asking is should we 18 not craft into the clinical studies section of labeling, where 19 we're talking about outcomes, whether there actually was such 20 a difference in local adverse events as to disclose which was 21 the active and the inactive arm. Dr. Porres is correct. One 22 can move further into the package insert and find that 23 information in the adverse reaction section of labeling, but 24 I think the point that Dr. Katz is making is should we not 25 also put that contextual piece in right there where we're

215 1 talking about the efficacy. 2 DR. STERN: It's not either a formal inclusion 3 or exclusion criteria, but it's some other parameter that lets 4 you look at these data and say what are possible things that 5 make them either more or less believable given the limitations. 6 Is that the point you were trying to make? 7 DR. KATZ: That's correct. 8 DR. STERN: Let me ask a question. You've shown 9 here an oral agent versus placebo, and Dr. Luke talked about 10 combination agents. When you present data for a newly approved 11 combination agent, do you then present A plus B versus A versus 12 B versus placebo to show the differences in efficacy versus 13 all of your choices so in one summary you can say this is how 14 much I gain or this is how they played out within this trial? 15 DR. LUKE: In general, combination studies have 16 multiple arms, and you would have an arm with A plus B in new 17 vehicle and A and B arms in the same vehicle, and then the 18 vehicle arm. 19 DR. STERN: I understood that in terms of the 20 trial, but I didn't know whether you would report that in the 21 manner that Dr. Porres had where you'd give the results of 22 all four arms. 23 DR. LUKE: Not all the arms are reported in 24 labeling in the past. 25 DR. STERN: And which ones are generally reported?

216 1 DR. LUKE: Actually I'd like to ask the committee 2 here. Do you think it would be helpful for us to put all of 3 the arms in labeling? 4 DR. STERN: I certainly think it's extremely 5 useful, if it's a combination agent, to compare it against 6 the single agent, as well placebo, that came closest because 7 really what you're asking is if I give this combination agent, 8 how much better am I doing than either of the alternatives. 9 Now, the reason not to give all four is it's kind of confusing, 10 but I'd want to know that what you implied, that if BP has 11 results almost comparable, how much did the combination beat 12 BP by? 13 DR. LUKE: I can see your point and I also see 14 your point regarding the labeling can be very cumbersome if 15 you were to put a lot of data in there and it would confuse 16 the issue. I think we've addressed that in some labeling by 17 indicating in writing, rather than in the table itself, that 18 one of the arms may be less efficacious or they haven't proven 19 efficacy for that arm. 20 DR. STERN: And I guess if it was a combination 21 against an established therapy, as a clinical decision maker, 22 although I want a placebo arm in the trial, the four arms you 23 described, I guess my own opinion would be what would be most 24 useful for me as a clinical decision maker is how much better 25 is it than either agent alone and having BP were the stronger

217 1 agent with the single agent that did better comparing the 2 combination versus BP would be the most meaningful in terms 3 of clinical decision making, not either placebo or not versus -- 4 DR. LUKE: That may be difficult to discern from 5 the data from a given study because keep in mind that the monads 6 are in the same vehicle as the combination A plus B. And 7 therefore, with the new vehicle, you throw in a different twist 8 to the product. They're not the approved benzoyl peroxide 9 alone product that's on the market. This would be a monad 10 with the new vehicle that is being studied that has been 11 developed for the combination, and that vehicle often, one 12 would think, would help enhance the stability or do something 13 to improve the efficacy of the combination. 14 DR. PLOTT: I'd like to ask from your presentation 15 are you suggesting that combination drugs could be studied 16 with one of the ingredients that is thought to be the most 17 difficult to show superiority? And jumping off the last 18 question, maybe that most difficult product would be an 19 approved product versus the product in its vehicle. 20 DR. LUKE: I'm not suggesting that. I think we 21 are governed to some extent by the rules. The Code of Federal 22 Regulations does state that we have to demonstrate a 23 contribution of each of the actives in the combined product. 24 So comparing it to an active in another vehicle probably would 25 not provide any regulatory utility for a 505(b)(1) application.

218 1 DR. KING: I guess I have a conceptual problem. 2 I thought the purpose of having combination drugs was to make 3 it for convenience. That is, it seems to me the appropriate 4 trial would have been if you're taking drug A in the morning 5 and drug B in the night, which is how most dermatologist 6 prescribe things, the purpose of having combination drugs is 7 assuming that the nighttime and the morning are efficacious 8 in synergy, that the combination drug would provide just 9 convenience. So I guess I'm lost here. 10 DR. LUKE: Dr. King, that's a very good issue. 11 I think the concept that you're visualizing is a combined 12 product or a co-packaged product perhaps where you have -- 13 DR. KING: I'm just saying what the standard 14 practice is now. You give one in the morning and one at night. 15 And why you put them together is you noticed there's a 16 synergism between A plus B in the morning and night, and giving 17 the combination one time a day, in this fast-paced world, is 18 likely to get done by the kids as they run to the school or 19 classes. 20 DR. LUKE: Right. I think the regulation 21 addresses the fixed combination drug. You are combining two 22 actives in one product. What you're saying is when you take 23 one product in the morning and one product in the evening and 24 the two products are given together, you're either 25 co-prescribing, which is the practice of medicine, or if a

219 1 drug company wants to market the two together, that's 2 co-packaging. And that's a different issue. 3 DR. WILKIN: Coming back to the point of which 4 arm is the most rigorous, there's nothing in the CFR or any 5 of the stat guidance documents that says that all of the arms 6 have to be equal-sized in the studies. So I would say that's 7 one of the take-home messages. If you know one particular 8 comparison that is the most difficult, you may want to increase 9 those arms to get more information. 10 The second part, which is Dr. King's comment on 11 let's say you have product A that you take in the morning, 12 product B that you take in the evening. One is an antibiotic. 13 One is benzoyl peroxide because that's the sort of standard 14 sort of thing. If those are products that are already on the 15 market, even if they have the active in the same concentration, 16 they're going to have different vehicles than the vehicle in 17 the combination product to be marketed. One of the things 18 that we've found over the years is there is an enormous 19 difference in performances of products when you change the 20 vehicle, even if you keep the active constant. It becomes 21 one of the hurdles to getting generics approved if they're 22 topical semi-solids because it's not the same thing as the -- I 23 think Dr. Leyden is gone, but he talked about how simple it 24 is for the solutions and wished it might be that for the 25 semi-solids. But there are multiple phasic structures. They

220 1 can affect the stratum corneum, some of the inactive 2 ingredients. So to interpret 300.50 in the CFR in the 3 combination products, it really needs to be in the same vehicle. 4 So that's what makes it different from just comparing two 5 products that are already on the market. 6 DR. STERN: Thank you. Our next speaker will be 7 Dr. Lehmann from Johns Hopkins and he will be speaking on his 8 methodologic review of acne therapy. 9 DR. LEHMANN: Good afternoon. Thank you very 10 much for this opportunity. I'm very honored to be speaking 11 here. I'll be speaking about the work that we did over a couple 12 of years for the Agency for Health Care Research and Quality. 13 The full report is two volumes, and I brought a number of 14 spare copies in a box near the slide projector if anybody would 15 like a free copy. My mother has enough copies. She'd be happy 16 to share them with you. 17 That was the joke. 18 (Laughter.) 19 DR. LEHMANN: So the Agency for Health Care 20 Research and Quality has kind of a mission to document evidence 21 for controversial or concerning clinical issues. They get 22 nominations for different topics every year, and one year both 23 the Academy of Pediatrics and the American Academy of 24 Dermatology nominated acne therapy as a question that needed 25 a synthesis of evidence. So we put that together.

221 1 So the process of the Education Policy Committee 2 is to recruit technical experts. In fact, a number of 3 dermatologists, including Dr. Shalita, were involved in 4 reviewing what we did, although we take all the blame for any 5 of our results. 6 We identify the patient population, formulate, 7 refine specific questions, perform a comprehensive literature 8 search. 9 Also, before this point, besides recruiting 10 technical experts, we also recruited a kind of committee of 11 people who would be interested. We went to the pharmaceutical 12 industry, to a number of the lobbying organizations and 13 research organizations who declined involvement, but we did 14 get involvement by a number of professional societies, such 15 as ACOG and others. 16 So perform a comprehensive literature search, 17 summarize the state of the literature, construct evidence 18 tables, and submit a report for peer review. 19 So the objective was to evaluate types and quality 20 of evidence available to support decision making, clinical 21 decision making, after what Dr. Stern was just talking about, 22 in the treatment of acne vulgaris. So we're taking a little 23 bit of a step back from the approval process and saying now 24 the medication is approved, what should or what do clinicians 25 do with them.

222 1 So our perspective was that of the practicing 2 generalist. I'm sorry that the dermatologists aren't here 3 to argue, but I think it's clear that generalists have to take 4 care of acne at some level. We were hoping to find out what 5 the evidence basis was for the phase at which you refer for 6 a dermatologist to take care of acne. So these are the type 7 of generalists we had in mind. 8 Now let me go through this diagram a little bit. 9 This is a causal diagram. The idea is what is the nature 10 of clinical decision making. What should the nature of 11 clinical decision making be, and then can you define the type 12 of evidence that you would need to support that model, that 13 decision making. 14 So for instance, all -- I'll say kids, but all 15 patients are assumed to have some level of self-care. And 16 so one immediate question is what do we know about the patient's 17 care of their own acne. They may come into the physician, 18 and at that point the physician makes an assignment, knows 19 what the baseline characteristics of the patient are, not so 20 much for determining the efficacy of the treatment, but in 21 terms of actually making a decision of what needs to be done. 22 So at the point of making the decision, which is in the box, 23 they've made an assessment of the baseline characteristics. 24 They've made an assessment of what the acne is like, and 25 they've made some assessment about how likely this patient

223 1 is to comply with therapy. And then they prescribe therapy, 2 and then the patient comes back. And then if the patient 3 "fails" therapy, then something else is done. 4 We were hoping that at some point we could see, 5 again, as I say, that one of the things to do is to refer to 6 dermatologists. 7 At each point along the way, in talking to 8 clinicians and thinking about this, we figured there were at 9 least four major axes or major dimensions that weigh on a 10 clinician's mind. What will be the result of the acne long 11 term? What will be the patient's current quality of life? 12 What is the cost, and what are other morbidities, depression 13 and so forth? 14 So ideally we would like to see data that says 15 given certain baseline characteristics, what do patients do? 16 Given baseline characteristics, what should be prescribed? 17 Given certain prescriptions, what are the long-term results? 18 What's the quality or life? What's the cost and what's the 19 morbidity? So that would be the ideal literature on acne. 20 We searched through the Cochrane Collaboration, 21 their hand-assembled database of randomized clinical trials, 22 the Medline, OldMedline, PsycInfo, the nursing literature, 23 and reference lists from key articles. 24 By the way, we did not include the European 25 literature and this became important, for instance, in

224 1 isotretinoin where some of the best work was done in Germany, 2 but we didn't have enough money basically to pay for 3 translations. 4 In the review process, all abstracts were screened 5 by two independent reviewers. All the articles were read. 6 They were read serially by two or more abstracters and then 7 me and one other senior methodologist. And then, as I said, 8 we tried to include dermatologists on the reading staff and 9 other reviewers. 10 Articles that were excluded were those that did 11 not address the management of acne, so articles talking about 12 resistance to medication were not included, evidence that was 13 not directly on humans, articles that addressed non-acne 14 vulgaris, review articles or letters to the editor, and again 15 as I said not in English. 16 We started out with about 4,800 citations. We 17 ended up with 237 controlled trials. I should say we ended 18 up with 275 studies which were 298 trials because some articles 19 contained more than one study within the article, and then 20 we had to exclude some. So we ended up with 237 controlled 21 trials. 22 Just to give you a sense of over time, going back 23 to 1951 -- I think those were Dr. Kligman's articles -- and 24 a lot of the people you saw here today and then a lot of the 25 work done in the '80s and the '90s.

225 1 So just in terms of the results of our review, 2 if you had the ideal literature, you'd be able to know how 3 generalizable the results were. The studies should have been 4 performed well. The treatments should be well defined. A 5 small set of comparisons so you know what to say, a consistent 6 set of outcomes, stratified outcomes, and free of commercial 7 influence. I don't think I have to tell you what the punch 8 line is, but we're going to go piece by piece. 9 So in terms of geography, it is worldwide, 10 continental, United Kingdom, USA, Asia, Middle East, Oceania, 11 and Africa. Obviously, most of it is in the Anglo-Saxon world. 12 Enrollment. There were only 42 studies that 13 actually used word "recruited," otherwise it really was unclear 14 how patients got into the study. Now, recall clinicians want 15 to say given certain baseline characteristics, given a certain 16 history of therapy, what's the next best thing to do. If the 17 literature doesn't record these data, then the working 18 clinician has no idea really when to use a certain therapy 19 at what point in time. 20 In terms of comparability of the arms, most of 21 the arms were comparable. Only four studies had arms that 22 were clearly not comparable. 23 Study quality. Dr. Kligman I think referred to 24 this study before in his talk. It's a little bit hard to see 25 in this graph. There was no clear-cut assessment tool for

226 1 saying whether you have a bad study or a good study. We used 2 a very qualitative judgment. If the paper said it was 3 double-blinded and it said how it was randomized, we said that 4 that was a good thing. If they told you nothing about who 5 the patients were in the study, we said that was a bad thing. 6 We simply said a study could be good, good and nothing, good 7 and bad, or nothing/nothing. So just looking at studies that 8 had only high quality elements or only had low quality elements, 9 you can see that they're mixed throughout time. 10 Unfortunately, quality does not go up in time. 11 In terms of treatment administration, 90 were 12 systemic. The rest were topical. Just in reference to the 13 question that came up several hours ago about whether 14 treatments that are effective in other parts of the body, this 15 represents the total amount of controlled trial data that we 16 have in the published literature to answer that question. 17 These are the therapies. I think these are all 18 without repeats. Vitamin A and vitamin A palmitate. So in 19 terms of a small set of therapies, we were kind of in the hole 20 here, and these are about 150 different treatments, including 21 tea tree oil and some other therapies, as well as FDA approvable 22 medications. 23 In terms of characteristics, these are the number 24 of trials simply providing data. Tanner stage is referred 25 to as pubertal stage. It was mentioned before as being a very

227 1 key element. No studies referred to pubertal stage. Age, 2 74 percent of the studies reported on the age of the patients; 3 73 on the sex of the patients; 8 percent on race; 2 percent 4 on the skin type, and decreasing there. 5 In terms of where the patients were being cared 6 for, about 80 percent -- you could tell whether this was a 7 generalist study or a dermatologist study. 8 Again, in terms of the clinician or people trying 9 to figure out whether or not the study applies to their 10 patients, this is an unfortunate state of affairs. 11 Let me go through what this graph is showing, which 12 is a little complicated. We divided the therapies in terms 13 of classes of therapy, which is not radical, anti-androgens, 14 antibacterial, combinations, antibacterial and other 15 keratolytics and retinoids. So this is the comparator arm 16 and this is the target arm. So this study represents an 17 antibacterial versus an anti-androgen study. It's a little 18 bit hard to see on this because it's cut off. 19 So this gives you a map of what the comparisons 20 are that have been done. 21 The size of the box gives you a sense of the sample 22 size. So you can see, for instance, the whole keratolytic 23 and others are relatively small sample size studies, whereas 24 the antibacterials have a fair number of large. And the 25 anti-keratolytics should include -- the retinoids are up here,

228 1 if I'm not mistaken. And then the little star indicates high 2 quality. So you can see these tend to be high quality. These 3 tend to not too have much high quality. Irritation is mild, 4 moderate, severe. We'll say a little bit more about that in 5 a minute. But this gives you a quick map of the entire world 6 of acne therapy. 7 This recaps what we've been talking about 8 basically all day. These are some of the scales that were 9 used in the studies, and we basically said, okay, we're going 10 to call all these mild in our synthesis. These are all 11 moderates and these are all severes. This is the 6-plus stage 12 that Dr. Leyden was talking about. 13 This simply points out how many studies used 14 different types of outcomes. Most of the measures are in terms 15 of either overall change, physician change, either in terms 16 of the patient or the physician, the integrated global 17 assessment that we've been talking about, or then counts, 18 percent change, delta percent, and delta counts and so forth. 19 If we are concerned about outcomes other than just 20 counts, we would imagine that there should be a study or two 21 that actually assesses quality of life. This is not in your 22 handout. A couple of slides I put together sitting in the 23 back during the session to show you the power of PowerPoint. 24 There was one study I think that had a quality of life scale 25 separate from the overall assessment. This is in distinction

229 1 to a number of clinical trials in other areas where either 2 SF-36's or other quality of life scales are used. 3 In terms of stratified outcomes, when we started 4 the review, a lot of the dermatologists said it's really 5 important to stratify patients. You can't say anything 6 helpful unless you know whether a patient is mild, moderate, 7 or severe or categorized by age and sex. Only eight studies 8 stratified their results sections by these factors that were 9 deemed to be really crucial in terms of evaluating efficacy 10 of treatment. 11 In terms of funding, Dr. Kligman mentioned this 12 before. There were seven NIH-funded studies. Eight were 13 miscellaneous and 100 were drug sponsored. Of those, 12 were 14 first author, 38 with a co-author. 13 provided the funding 15 to the authors, and 35 simply provided medication or analytic 16 support. And then the rest were basically, I suppose, 17 hobbyists. 18 So that says something about the state of the 19 literature and the problems, and it's easy to say that there 20 were a lot of problems with the literature. 21 One analysis that I did after we published the 22 report was to say if in fact the literature is a mess, then 23 in fact there should be inconsistencies in the literature. 24 We just heard that if you're going to look at combination 25 therapies, if the combination is better than A or B and better

230 1 than nothing, that's a good thing. If you have treatment A 2 is better than B, and treatment B is better than C, and then 3 treatment C is better than A, you have an inconsistency in 4 the literature. So there was a question. Can we find an 5 inconsistency? 6 To do that, we said let's divide our studies up 7 by the studies that seem to be mostly mild patients, mild, 8 moderate, and severe. So let's see what the results were. 9 So the iconography here is that an open arrow or 10 an open bar means level B evidence, that is, only one clinical 11 trial that had good data. A dark bar or arrow meant two or 12 more clinical trials that gave pretty good evidence. So, for 13 instance, we can be pretty certain here that doxycycline is 14 better than placebo. Thank goodness. 15 So here's a little island that salicylate and 16 vitamin A are better than placebo. Doxycycline is better than 17 placebo, but doxycycline seems to be as good as fusidic acid 18 from the literature. Here tetracycline topical seems to be 19 as good as tetracycline oral from the literature. I understand 20 that dermatologists could say that this is not true, but I 21 just want to say this is just straight from the literature. 22 So here we have a nice little island, another island here, 23 and here a little island compared with benzoyl peroxide. 24 Mild and moderate. Now we have two smaller 25 islands, a little bit more certain data. This is weird that

231 1 tetracycline was as good as placebo in the moderates, but that's 2 what the data seem to say. These are separate studies. We 3 have clindamycin, erythromycin, isotretinoin, and tretinoin. 4 This is the combination. 5 Moderate. Basically no solid evidence but we have 6 this notion that these guys are above these guys. 7 And moderate to severe, again a bit more 8 complicated. 9 And in severe, not much that we have to say. These 10 were two different doses of isotretinoin. 11 The only thing I can say is although people might 12 argue about the specifics of the comparisons, I was surprised 13 to see that there were no inconsistencies in the literature, 14 which suggests that way we divided mild, moderate, and severe 15 made sense and may have some clinical import. 16 Then this is where we couldn't assign a severity 17 from this paper and this is just a mess. 18 Now, one point I did want to make is that while 19 we were doing this review, we were thinking does it make sense 20 to use something other than placebo as the control, and this 21 little analysis that shows that these islands are not 22 inconsistent suggest that maybe placebo could be used as an 23 anchor point in the treatment of most of these different 24 severities of acne without biasing the results. In other 25 words, I think there's some evidence from this review that

232 1 benzoyl peroxide could be at least that active arm if you're 2 not going to use a placebo. 3 Since we were talking about placebos, I drew this 4 out of the database while we were sitting. These are studies 5 divided by mild, moderate, severe, just the placebo arms of 6 the studies, just looking at their percent change. And I 7 apologize for percent change. This is 0 percent. A minus 8 is good; positive is bad. So here you see in the mild it's 9 kind of mixed. Mild/moderate, it's still mixed in terms of 10 placebo response. The studies that reported placebo, they 11 were almost evenly divided, and as you get towards surprisingly 12 even some of the severes, the placebo still did pretty well. 13 This is just at 12 weeks. We did record 4 weeks, 14 6 weeks, and 12 weeks or whatever data we could get our hands 15 on. 16 So in summary, it's difficult to generalize from 17 the studies because the studies don't say who is in them. 18 The studies were mixed, performed well. In terms of a 19 well-defined set of treatments, it's difficult to say, and 20 the bottom line is that clinicians are not left with a clear 21 road map on how to treat acne even given approval. So too 22 many comparisons, an inconsistent set of outcomes. The 23 outcomes are not stratified, and it's not clear how much the 24 commercial influence is. 25 So there's a limited basis for comparison of acne

233 1 treatment from the controlled trials, even though we have to 2 do it. Using available comparisons does not lead to internal 3 contradiction. So that's a good thing. 4 On the other hand, only industry-sponsored 5 research is available to help clinicians make clinical 6 decisions, which means as a clinician, my thinking is as you 7 ponder what outcome measures to use in sponsor studies -- I 8 don't know how much you're allowed to say, but since no other 9 studies are going to be done because, as we heard, there's 10 no research in this outside of getting these drugs 11 approved -- clinicians desperately need usable outcomes to 12 help them make clinical decisions. 13 I'll stop with that. 14 DR. STERN: Thank you. May I start with a 15 question? 16 It seems to me you are in part implying -- if you 17 look at publication, there's both publication bias in all the 18 ways we know, and in fact what is going to be published is 19 written by people who are either employed by or under the 20 sponsorship of industry trying to put forward their argument 21 in a way to advance a product. It seems to me that some of 22 what we're hearing today is we may have an opportunity to have 23 data presented in a way that is neutral or judged by the same 24 third party, that is, the FDA, across all products. 25 We know that some authors are much more successful

234 1 at getting data -- the inference is presented in one way than 2 others are, even with the same data set, or at least that's 3 my experience. 4 So perhaps one of the lessons here is one can't 5 rely on the current kind of data that is published in the 6 somewhat variable peer-reviewed literature and that what we 7 need is some objective uniform set of referees. I guess that 8 goes to one specific question. 9 Did you look at the quality of papers -- and I 10 recall that you did according to where they were 11 published -- and what the impact factor was? 12 DR. LEHMANN: We did not do it in terms of impact 13 factor. At the time we discussed this, we thought we would 14 have to subjectively rate the journals, and we were not ready 15 to subject ourselves to that level of abuse. 16 (Laughter.) 17 DR. LEHMANN: But impact factor is an excellent 18 thought. Thank you. 19 DR. STERN: Other questions. 20 DR. WILKIN: There's another source also. I 21 don't know if you explored FOIA, the Freedom of Information 22 Office. You can obtain the reviews on products that have been 23 approved, and then you can go on and compare those reviews 24 with how it's portrayed in the literature. It's not that the 25 data are changed, but often the emphasis is somewhat different.

235 1 DR. LEHMANN: That's an excellent suggestion. 2 I don't know if the HRQ talks about that tactic with their 3 EPCs. That should be a tool that we use in our systematic 4 reviews and we just don't. I suspect one reason is that we 5 have a narrow time frame, and that's a lot of effort. But 6 it's an excellent suggestion. 7 DR. KILPATRICK: Thank you. 8 I think Dr. Lehmann's presentation has brought 9 us firmly back to Dr. Katz' point. I mean, that may be obvious, 10 but maybe we should come back to that tomorrow and see how 11 we can try to eliminate that type of bias that he was describing. 12 DR. PLOTT: Just a comment. I think many 13 investigators take a lot of pride in the work that they do 14 in the unbiased evaluations. It may be unfair to suggest that 15 an industry-sponsored trial has that bias. While I admit that 16 there are many that undergo a lot of data dredging, probably 17 the substantial trials that you see published in the literature 18 have gone through the FDA reviews, not just by the Dermatology 19 Division, but also by the advertising group, and are quite 20 thoroughly scrutinized. So while I acknowledge that there 21 is bias, there's probably an equal number of substantial 22 articles that have been reviewed. 23 DR. STERN: Having at times been industry 24 sponsored, I would certainly hope that some of the published 25 research was good. But in fact in my local medical journal

236 1 in the last week or so was a series of a sounding board, an 2 editorial, and a paper that looked at the difficulties in 3 maintaining objectivity and in fact putting out results in 4 academia when you're under the sponsorship of industry. As 5 I say, that's in the last two or three weeks in the New England 6 Journal. So I think there are issues and it doesn't mean that 7 everyone is good or everyone is bad, but there are certainly 8 issues that seem to be out there in this area. 9 DR. TAN: Yes. I just wanted to ask Dr. Lehmann, 10 for the industry-sponsored trials, how many of them are 11 investigator initiated? How many are, do you know, just for 12 NDA purposes? 13 DR. LEHMANN: All the information we had was in 14 the article, and it said at the bottom "sponsored by" or 15 whatever. 16 DR. TAN: Yes, I would actually differentiate that 17 if the investigator initiated this trial and then find a sponsor 18 versus the trials that the industry want to do an NDA for. 19 There is a crucial difference I think. 20 DR. LEHMANN: And that distinction is not made 21 in the literature. 22 I do want to stress that my stress about industry 23 versus non-industry is not so much bias as much as once the 24 drug is approved, there's no energy, funding or otherwise, 25 to evaluate the effectiveness in practice of these medications.

237 1 So the approval process is the only shot the clinicians get 2 to see what works, and that's a different perspective than 3 FDA has, I understand. 4 DR. KING: I guess in terms of what the committee 5 is deliberating, what suggestion are you making to this group 6 or to the FDA that would have the highest impact on providing 7 the information and high quality studies? It's your forum. 8 DR. LEHMANN: Thank you. So, first of all, the 9 work that you're doing here is terrific, and just saying maybe 10 we need to have one outcome measure, that would be terrific 11 because then you can start measuring across studies. 12 Number two is it sounds like from both the 13 dermatologists and Dr. Alosh's presentations to have at least 14 two measures, one the global and -- let me backtrack. 15 An acne outcome is a multi-axial, a 16 multi-dimensional outcome. There's what the skin looks like. 17 There's the lesions. There's how the person feels. It's 18 multi-dimensional. 19 The drug companies and the FDA are kind of being 20 forced into a situation where they have to take a 21 multi-dimensional problem and squash it down to one dimension. 22 That's always a problem. 23 Now, there are a number of ways of doing that. 24 Most of them are subjective, utility measures and stuff like 25 that. At the minimum, you can have a measure that is two or

238 1 more dimensions, the global assessment, some sort of lesion 2 counting. I don't know if you want to throw in a quality of 3 life measure to give some sense of what's going on. On the 4 outcome measure side, those would seem to be the 5 recommendations. 6 On the incoming side, more explicit mention of 7 who is in the studies, who the patients are in the studies 8 in terms of where they've been before they got into the trial, 9 what their age, sex, and race breakdown is. Pubertal status 10 I'm not ready to say at this point. But some notions that 11 when I see the study, I have a lot more to say. As a clinician, 12 I have more to make my decisions on. 13 Now, it's interesting that there's a project 14 called Trial Bank going on from UCSF where details of trials 15 that are really specific can be stored separately from what 16 the output of what the article is, which means that a reader 17 can actually see more details of the trial, not necessarily 18 the raw data but more details than the space of an article 19 allows for. So a project like that that uses these new 20 informatics tools, in addition to new statistical tools, might 21 be a way to go. 22 DR. PORRES: Sometimes we see drugs that come for 23 approval and don't make it and yet we see publications coming 24 from academia or some groups where the drug appears to be 25 wonderful. I'm wondering if you have a suggestion as to how

239 1 to obtain this kind of data so that you could analyze it. 2 DR. LEHMANN: You mean the data on the stuff that's 3 not submitted to you. 4 DR. PORRES: Well, we cannot divulge information 5 about the drugs that don't make it, unfortunately. That 6 wouldn't go into the Freedom of Information aspect of it. 7 But you would need the kind of information or you would need 8 to be able to assess whether the results that are being 9 published by a certain group match the results, say, for the 10 drug that we approved that in our hands seemed to be barely 11 making it, and yet when you look at group X, they claim the 12 drug is super wonderful. 13 DR. LEHMANN: I can only report on what I see to 14 one degree, number one. Number two, that's one of the reasons 15 why we made that map of the islands of care. I don't know 16 if it really will work. 17 DR. STERN: Other questions. 18 (No response.) 19 DR. STERN: Thank you very much, Dr. Lehmann. 20 We have about 50 minutes for committee discussion 21 in general, and I think what might be useful is to use the 22 questions we've been presented with and rather than trying 23 to answer any of them now, since we have at least some of the 24 resources, in terms of guests -- I hope Dr. Lehmann doesn't 25 leave -- try to think about any other points that we may have

240 1 heard some information or want clarification to answer these 2 questions so we can think where we are going forward. Does 3 that seem like a reasonable way to proceed for the remaining 4 time? 5 So the first question is -- again, this is not 6 to answer the question but further information. Should the 7 current success criteria using the co-primary endpoints be 8 retained? I guess I would say the idea of co-primary endpoints 9 as opposed to necessarily the current two that we have or the 10 current multiple ones that we have. 11 DR. KILPATRICK: Since there may be some experts 12 here, I'd like to hear more about incidence. This came newly 13 to me. The concept of identifying new comedones and pustules, 14 et cetera and following them is rather different from this 15 counting facility that I've heard and even the IGE. But how 16 would you effect that is the problem. Is it feasible is what 17 I'm asking. 18 DR. STERN: Well, I think that's probably not 19 feasible short of frequent visits and computer mapping. I 20 think what you're doing is you know that certainly in an 8-week 21 time frame that with the exception of large nodular lesions, 22 a single comedonal or inflammatory lesions, most will have 23 resolved spontaneously, certainly inflammatory lesions. So 24 what you're doing is comparing prevalence to time points and 25 you're assuming that if there are fewer prevalent lesions at

241 1 the latter time point that the incidence in those 8 weeks was 2 lower or particularly the incidence in the couple, 3 weeks 3 before that was lower than it was in the 2 or 3 weeks before 4 your entry to the study. I think those are the assumptions. 5 But when I brought up the concept of incidence, 6 I wanted to make it clear that -- which is a common misconception 7 among patients. A lot of patients think that when you put 8 them on a drug, you're clearing the pimples that are on their 9 face on the day they start the drug. Rather, what you're hoping 10 to do is reduce the incidence over time so that the prevalence, 11 because of self-healing, will be lower sometime in the future. 12 DR. PLOTT: Dr. Stern, if I may, just to address 13 this question. The difficulties I think were echoed in some 14 of the presentations today, some of the clinical and 15 statistical presentations, and maybe more clearly by the 16 statistical presentation, that doing lesion counts where 17 inflammatory lesions are at a minority in the total number 18 of lesions that are being considered, a product that is acting 19 solely on inflammatory lesions is biased against in that 20 situation where they're only able to affect a small number, 21 a minority of the total lesion count. And a win in that count 22 requires winning both in inflammatory lesions and totals. 23 So a product that just purely affects inflammatory lesions 24 is biased against. 25 On the other hand, with a global evaluation, we've

242 1 heard that a change in inflammatory lesions has four times 2 the impact in global than a non-inflammatory lesion. Here 3 the inflammatory lesion has the advantage. A drug that's 4 hitting just inflammatory lesions is at great advantage. 5 So you could see the difficulties in putting these 6 two together being as co-primaries and why there is some 7 frustration in requiring that we win in all of these. 8 Now, the resolution for that may be to allow a 9 product that is only effective at inflammatory lesions to have 10 simply an inflammatory lesion claim and handle that problem 11 in labeling as opposed to a product that's not able to hit 12 this great goal of having an indication for acne vulgaris as 13 a whole. 14 DR. STERN: Since you speak for industry, I guess 15 my question would be does a company, on the basis of phase 16 II studies -- if we're going to have such a thing, would you 17 be willing to say, and we will tell you in advance whether 18 this product is for inflammatory acne and judge it according 19 to the inflammatory lesion count and the global count? We 20 won't use the comedones unless they're worse and they count 21 against efficacy. We won't use the comedones or the total 22 count before you do the phase III study. Because again, it's 23 the whole problem of anytime you go back and you dredge through 24 the data, you can figure out a way of cutting it and make small 25 differences significant and sometimes even chance significant

243 1 if you're a very good statistician or a poor one as the case 2 may be. 3 (Laughter.) 4 DR. PLOTT: Of course, every firm must make a 5 decision for themselves, but I could imagine a product that 6 was purely effective at an inflammatory mechanism and how you 7 would not expect to have effect in a comedone. And doing drug 8 development in the proper way, you might find in a phase II 9 trial where there was really no efficacy against comedones 10 and that you had a dose response and you picked the appropriate 11 dose. And moving into phase III trials, I think that there 12 could be a situation where a product had just anti-inflammatory 13 activity. You've heard of possibly some of them here today. 14 DR. STERN: Why don't we go on to clarifications 15 for the second question, which is really the point that Dr. 16 Plott brought up. How should lesion counts be analyzed? 17 I guess here I would like to put forward one 18 question for the agency. Some of what we've heard from the 19 experts is one way to reduce variance is to, in fact, use modern 20 measurement techniques that rely on types of photography that 21 are more standardized that also allow you to look at people 22 truly side by side over the course of their treatment rather 23 than trying to remember how they were, use observers who were 24 not involved in the care who were perhaps less likely to bias. 25 And in fact, with digital imagery, one can even take out the

244 1 background irritation and just concentrate on the lesions. 2 When you see a patient, you know whether they're kind of rough 3 and pink. With digitalization, there are probably ways of 4 taking out the roughness and pinkness and just leaving the 5 blackheads, whiteheads, and inflammatory lesions. 6 Is part of this that we can recommend not only 7 what you should count but how you should count it in order 8 to make these studies more scientifically valid? 9 DR. WILKIN: I'd like to speak to sort of the 10 technological imperative aspect of this. It's possible to 11 have sort of NASA-level technology that would detect lesions 12 that could be adequately treated that the patient didn't even 13 know they had. So I would hope that there would be some 14 correlation of what was found with these high tech apparatus, 15 how it related to actual clinically apparent lesions. 16 But having said that, that's sort of a validation 17 stage. Assuming that validation stage can be made, then it 18 seems like it's very objective. Once you buy the machinery, 19 then it probably is cost effective to do lots of studies. 20 It seems like it's a rational approach, yes. 21 DR. STERN: I guess what I was trying to imply 22 was for once I saw the cup half full rather than half empty. 23 In fact, some of these methods would allow you to look at 24 not only lesion counts but lesion volumes, for example. One 25 of our guests talked about a real success is taking 50 large

245 1 inflammatory lesions on day 1 and 8 weeks later turning it 2 into 50 much smaller inflammatory lesions. That was the kind 3 of thing I was talking about, not using ways of elevating what's 4 not important, but rather in fact measuring the things that 5 we all agreed and the experts agreed are very difficult to 6 measure over time as an individual investigator because we're 7 all human. 8 DR. WILKIN: I think certainly a sophisticated 9 equation that would take those sorts of things into it -- but 10 I did hear from the experts and from members of DODAC and Dr. 11 Bergfeld, before she left. Her first word was "simplicity." 12 There's this great appreciation for elegance of simplicity 13 when one is looking at something that's supposed to be 14 clinically meaningful. So I would come back to that. 15 DR. KILPATRICK: I'm very much attracted to the 16 concept of using modern technological screening and measuring 17 techniques and picked up on the suggestions that perhaps it 18 even may be feasible now or nearly in the near future to do 19 what you're saying, Jon, but not only number but size, density, 20 color. And we have all of those things. 21 My problem then is, given these three, four, five 22 different parameters, how do you combine them. My feeling 23 is that the physician, the dermatologist, is the best person 24 to do that, and in fact that's what he's doing in the IGE. 25 He or she.

246 1 DR. STERN: Other comments on question 2? 2 (No response.) 3 DR. STERN: Question 3 then, which is, what 4 investigators' global scale should be used? At what level 5 should it be dichotomized into success and non-success? 6 DR. KING: I've always had trouble with the 7 concept that it's totally clear. I don't think I've ever seen 8 any acne therapy except perhaps acne treated with Accutane 9 where you get totally clear. So I guess a study set up so 10 that your only measure of success is that a topical therapy 11 is going to get totally rid of everything seems to me to be 12 unrealistic. So I always wanted that scale in there 0 and 13 1 where, I think as Leyden said, should the Pope declare this 14 sainthood, I'd like to see some weight given to nearly clear 15 or cosmetically acceptable because it is true that we recognize 16 our mother in a crowd because she looks like that, but we all 17 have different mothers and we all have different variations 18 of success in a simple kind of thing. 19 So I would like for the agency to take something 20 to the effect that success, as far as the physician and the 21 patient, is different, and it's unrealistic I think to demand 22 total clearance. Perhaps you can totally clear inflammatory 23 but not comedones. 24 DR. STERN: I guess along that line, to me success 25 depends on where you start. If you start with a larger problem

247 1 in terms of the disease and make it into a smaller problem, 2 that's successful. If you start with not much of a problem 3 and only make it somewhat better, was it worth the trouble? 4 So I think that's an issue in how we guide that. 5 DR. WILKIN: I'd like to say that I believe the 6 FDA dermatology group is very much on the same page as Dr. 7 King on his comment of having a good grade that is not completely 8 clear but something that is close to that well defined. I 9 think that would be incredibly helpful for us to hear from 10 the committee what that mild category might be that would be 11 regarded as appropriate for a win. 12 DR. STERN: Another sort of procedural question. 13 In our business, especially in things like acne, things are 14 often visual. So one set of criteria often used for many kinds 15 of things is a set of standard photographs, that when a person 16 looks like -- and you obviously have to have some differences 17 because there will be two inflammatory papules and very few 18 comedones or a small number of comedones, no inflammatory -- if 19 you make it to A, B, C, or D, if your patient looks like this, 20 this we regard as good as you have to get to consider it a 21 success. And is there a possibility of developing, in fact, 22 standardized photographs for this or photographic standards? 23 DR. WILKIN: Well, yes is the answer. But along 24 with that, it might be nice to have something in writing which 25 would say this photograph allows post-inflammatory

248 1 hyperpigmentation, allows X number of comedones, and sort of 2 gives a description and has a photograph so you've got two 3 ways of thinking about it. 4 DR. STERN: In fact, they may be, for example, 5 gender because people look at -- at least I look at men's and 6 women's faces differently. They may be gender- specific and 7 they may be skin type-specific for some of the reasons that 8 you spoke about as well. 9 DR. KING: Just as a commentary, having been in 10 on the Accutane brouhaha, it seems to me that this may be 11 something that the American Academy of Dermatology in some 12 subcommittee should help generate this so that it would not 13 be viewed as coming from the FDA down, but it would be an 14 evolutionary process. And you've got to get a community to 15 buy into change if you're going to effect change. So I'd rather 16 see the FDA charge the academy and other interested folks to 17 develop that and then go for agreement. 18 DR. STERN: Dr. Ten Have. 19 DR. TEN HAVE: I may have missed this, but didn't 20 Dr. Leyden earlier today talk about standardized pictures? 21 Is that what you're referring to? 22 DR. STERN: That's exactly what I -- he was talking 23 about standardized pictures within individuals under 24 investigation. Extending that concept, if that's not going 25 to be required, one question gets to be, for judging success,

249 1 can you give investigators a set of photographs that say this 2 is what people who are successful by our criteria look like 3 at the end of therapy which is a less technological way. You 4 can just give people a bunch of 5 by 8's. 5 DR. PLOTT: I would second the motion for 6 photographs. I think that we use that in alopecia. That's 7 been a helpful measure. That might be useful. 8 Also that the global evaluation that may have been 9 proposed -- I have some concerns about the biases toward certain 10 types of lesions, whether inflammatory or non-inflammatory, 11 and difficulty with inflammatory lesions moving from one 12 category into another. 13 DR. STERN: Yes, Dr. Katz. 14 DR. KATZ: A question for information. Now, is 15 question 3 for final approval? Or why can't success be 16 evaluated comparing lesion counts? 17 DR. STERN: I think that goes back to question 18 1, and I guess question 3 presupposes that we're going to say 19 that you need to make it by criteria in addition to lesion 20 counts. However, we recommend whether that's total, separate 21 for inflammatory and non-inflammatory. So that question 22 presupposes that we come down that in addition to making it 23 in terms of some way of someone quantifying disease, that there 24 be some measure of success that is a qualitative one. And 25 I think the question is, well, what are good qualitative

250 1 measures of when you're successful, and there are all sorts 2 of combinations there. 3 DR. TAN: My question is very appropriate, 3.5, 4 in between 3 and 4. I think when I've seen an analysis, I 5 think presented this afternoon, the problem is really with 6 the quantification of non-inflammatory lesions. I think the 7 immediate improvement for all of this is probably a refined 8 measurement of this non-inflammatory lesion, either using the 9 digital photo technology or some more refined procedure by 10 comparing the pictures, even by physicians, investigators. 11 Of course, it will have some subjectivity, but it still would 12 be more refined and would immediately improve the process. 13 DR. STERN: This is strictly a clinical bias 14 statement, and I'd be interested in the other dermatologists' 15 on the panel feeling about this. When I see people with mild 16 to moderate acne, including my two teenage daughters, it's 17 the inflammatory lesions that prompt them to have care and 18 how much they care about the comedones, unless they're on their 19 nose and want to use Biore strips on them, is decidedly less 20 of a problem. That's my experience with only two children 21 plus a few thousand patients who are other people's children. 22 I'd be interested to know if I have a deviant experience. 23 DR. RAIMER: I was just agreeing, shaking my head. 24 DR. KATZ: Being a practitioner and doing this 25 every day, I take care of both. And there are people, as Dr.

251 1 Pochi pointed out, who have a massive amount of comedones and 2 no inflammatory lesions. It also points to what you're saying. 3 And there are people with horrendous cystic acne needing 4 Accutane who have very few comedones. So I think it's very 5 important to separate these as far as the appropriate proposed 6 medications being indicated for one or the other. 7 I don't think that it's much different for the 8 FDA to have criteria on whether a drug works relative to what 9 we do in the office really every day, which is trying to evaluate 10 people from month to month or 6 weeks and to decide whether 11 that patient has improved on that therapy because there's all 12 these very effective therapies that don't work for everybody. 13 We all know that. Tetracycline might work in 80-90 percent 14 of patients. Well, we try to discriminate those where it 15 doesn't work, and we don't remember. I can't remember 6 weeks 16 later what that patient looked like. So I count lesions and 17 the comedones. I don't count every comedone obviously, but 18 are they numerous, are they a few, are they massive? And we 19 can judge, and I don't see why the FDA can't use the same 20 criteria. 21 DR. WILKIN: Actually I think it's almost like 22 Dr. Katz has been in some of our internal meetings at FDA. 23 (Laughter.) 24 DR. WILKIN: It's just eery. 25 I think what you described is to get this dynamic

252 1 sense, what is happening over time. You're actually doing 2 quantification. Is that what I'm hearing? 3 DR. KATZ: In a loose way. 4 DR. WILKIN: In a loose way, but you're doing that 5 sort of thing. 6 I think if you come back to question 1 and our 7 earlier discussion of how we have framed these points, the 8 co-primaries in the past is we see lesion counts as sort of 9 a baseline and then what folks look like at the end, often 10 12 weeks. So we have sort of a dynamic piece to that. 11 The global we've sort of thought of as an 12 incredibly imprecise tool, but it comes closest perhaps to 13 the clinical answer of what people may actually look like in 14 terms of do they need more treatment or not. It's kind of 15 a one-time snapshot because, as Dr. Leyden said, it's hard 16 to go back and remember what folks actually looked like at 17 baseline. 18 So I think that's the history of how we got there. 19 I should say that the folks -- and they're all 20 over here. No one at FDA is wedded to a particular way of 21 doing this. We really want to do exactly what Dr. Katz said. 22 We would like somehow, if we can, to make it simple and to 23 have the efficacy determination for approval based on a similar 24 kind of measuring stick that clinicians use when they make 25 their decisions with the patient. That really is why we're

253 1 bringing the whole thing to the committee. 2 Having said that, Dr. Plott I think gave an 3 articulate summary of some of the advantages that we may not 4 be tapping into just yet by thinking about indications for 5 other than acne vulgaris, the indication of perhaps 6 inflammatory lesion. You never know, when you write up the 7 questions a month-and-a-half in advance, how the discussion 8 is going to evolve. But of course, if I could go back and 9 redo this, I would make question number 4 number 1 because 10 I think question number 4 is really -- if you think that 11 inflammatory lesions and non-inflammatory lesions by 12 themselves would stand as indications and then also acne 13 vulgaris would be an indication that would be separate, you 14 may want to go down and suggest different efficacy endpoints 15 for the different indications. 16 DR. STERN: It seems to me it may not be 17 unreasonable to change the order of the questions tomorrow 18 because, as you've pointed out, that kind of decision making 19 about should there be separate approvability for an agent only 20 for inflammatory acne and what would be the criteria for doing 21 that could in some ways drive a lot of the rest of the 22 conversation in terms of all these other things. So I think 23 that's a very reasonable thing to do and perhaps we'll change 24 the order tomorrow. 25 Shall we go on to question 4 which we've been really

254 1 talking about? I'm sorry. 2 DR. SAWADA: Before you go on, I just wanted to 3 address Dr. King's comment about bringing the American Academy 4 involved in this so it didn't seem like the Accutane debacle. 5 I wasn't present for that. And I knew that Jonathan had kind 6 of a feeling for that, and I was wondering what his thoughts 7 were with regard to this with the American Academy so it didn't 8 seem like it was a one-way street. 9 DR. WILKIN: Well, I mentally jotted down Dr. 10 King's excellent suggestion. Actually I like having the 11 clinical group think about what the clinical endpoint ought 12 to be. That makes a lot of sense to me. 13 DR. STERN: On to question 5. Should lesion 14 counts be assessed at multiple time points late in the study 15 and averaged to increase power? 16 I think the discussion perhaps should be two 17 separate questions. One is how important it is to assess the 18 outcomes at multiple time points when you expect the therapy 19 to work, and then the second is how does one handle those in 20 terms of what's the appropriate analysis. 21 Dr. Kilpatrick. 22 DR. KILPATRICK: On the matter of order, can we 23 also bring in the IGE in terms of evaluating at different time 24 points? That may not be feasible but maybe given photographs. 25 Does this presuppose we're going counts rather than IGE?

255 1 That's your decision, sir. 2 DR. STERN: I think it's our decision. 3 DR. KING: Actually it approaches an interesting 4 to me which is that oftentimes we talk about giving therapy 5 and it's evolutionary and we have history and all those things 6 going on, but it seems to me that when the patient comes back 7 at visit 2, 3, or 4, you're actually already doing that 8 globally. When you're not doing a study, you're trying to 9 decide, well, is this patient going to go on toward Accutane. 10 So oftentimes you tell them the bumps and lumps you've got 11 for the next 6 weeks are yours. After that time, they're mine 12 and then the drug's. So you do these kind of outcomes saying, 13 okay, this looks like it's an explosive episode. It's just 14 going to get worse and worse and worse and go toward scarring. 15 And I'm willing to put up with all the hassle of Accutane 16 and prequalification. 17 So in these kind of multiple time points, we're 18 doing that already. We may not be doing it in a study, but 19 you're actually seeing them at visit 3, 4, 5, and you're 20 averaging and saying, well, I think the response is working 21 pretty well. Hang in there. Keep taking the medicine. Check 22 on diets and so forth. So I think we're actually doing that 23 in real practice. 24 I don't know statistically about the power. That's 25 why I was interested in this conversation because I think

256 1 dermatologists do it routinely. We are measuring whether or 2 not you're on the slope going up or down or you're plateaued, 3 and if you don't get better in a certain time frame, you're 4 already looking for other therapies for two reasons: one, 5 you want altruistically to get them better; and two, you don't 6 want to lose them as a patient. 7 DR. STERN: Dr. Tan, you had talked about this. 8 DR. TAN: I have a lot of related questions for 9 the FDA and Dr. Wilkin here. Has the agency ever considered 10 an endpoint using time to dramatic or satisfactory improvement 11 as an endpoint? Maybe for Dr. Alosh as well. Using the time 12 to great improvement, satisfactory improvement. 13 DR. ALOSH: I'm sorry. Could you repeat the 14 question again? 15 DR. TAN: It's a time to event analysis instead 16 of repeated measure. 17 DR. ALOSH: Time to event until you achieve 18 success? 19 DR. TAN: Yes. How long does it take for the 20 patients to reach a certain good clinical endpoint? 21 DR. ALOSH: Well, I think we need to agree what's 22 a good clinical because, I mean, if you have well-defined 23 evidence such as death or some well-known defined evidence, 24 then we could talk about time to achieve that evidence. 25 Now, in terms of the investigator global

257 1 assessment, we could have someone clear or almost clear. So 2 now this is a clinically acceptable endpoint, and then I think 3 we need to see what's the purpose of that. Are we looking 4 in terms of a duration? What's the duration of the study to 5 achieve that clinical endpoint? So this is one point of two 6 endpoints, count versus investigator global. 7 DR. TAN: Yes. Something like from the time you 8 give the therapy to maybe 25 percent of the inflammatory lesions 9 were resolved or gone. 10 DR. ALOSH: Yes, we could have this. In some 11 application it could be a secondary endpoint, not necessarily 12 for acne. But some sponsor might claim their product could 13 achieve faster success in terms of time than other products, 14 and this could be a secondary endpoint. We have not seen it 15 in terms of acne yet. 16 DR. STERN: My question was a little bit 17 different. When you look at acne and you have two products, 18 one of which at 8 -- and I understand there will be variance 19 around each observation, but one of which just in the ideal 20 was a 50 percent reduction at 8, 12, and 16 weeks, or 8, 10, 21 and 12 weeks, and you have another product that was 75 percent 22 reduction at 8 and 12, but at week 10, that intermediate point, 23 it was 10 percent worse, which is the better product? 24 If you average them, those products will be, if 25 I did the math right in my head, identical in terms of the

258 1 average percent reduction. It would be 75/75 and 10 to the 2 worse. It would give you the same percent reduction as the 3 50 long. But yet, in fact, as a clinical experience, they 4 would be very different products from a patient's point of 5 view. I don't know which would be better or worse, but they'd 6 certainly be different in terms of persistence of effect or 7 consistency of effect. And I think that's one of the things 8 you have to talk about once you do multiple times. 9 I think the problem here, although I can see a 10 sponsor doing that if they have something that acts more quickly 11 than the usual 6 to 8 weeks minimum, you got to remember things 12 can act too quickly because unless they have something that 13 also is anti-inflammatory and reduces prevalent lesions at 14 entry to the study, what we're really depending on for healing 15 and improvement in acne is a natural course of healing. So 16 they'd have to have more than an anti-acne effect. They'd 17 actually have to be working on existing lesions, and then they'd 18 have a big advantage. 19 The other thing is, of course, with these studies, 20 they're not under daily or weekly observation. That would 21 add a huge burden to the investigator, and you get to the problem 22 of timing. The curves were very nice in that you saw the degree 23 of separation just increased a little bit as time went out 24 and probably the statistical testing, I would guess, for a 25 life table analysis and for these differences in counts would

259 1 not be that different. If anything, it would be my guess that 2 meeting that criteria in a life table might be a little bit 3 more stringent. 4 DR. TAN: Yes, that could be. 5 But I think here the question is we do want to 6 see how the lesion counts compare between the two groups during 7 a defined period of time. We don't want to average them. 8 DR. PLOTT: One of the concerns with repeated 9 measures is possibly an interaction between the treatment and 10 time. As we've seen, acne may wax and wane, but during a 11 clinical trial invariably, because it seems to work that way, 12 the patients on placebo tend to get better. If we were to 13 extrapolate that, eventually they may even clear if we waited 14 long enough. What type of consideration is given to this 15 interaction between the treatment and time? 16 DR. ALOSH: Yes, I agree. I think if you are 17 dealing with repeated measurements, the issue of time by 18 treatment interaction will arise, and you need to test for 19 it. Those analyses which I put, one of them multivariate 20 analysis of variance and the other one generalized linear 21 model, the distinction really, one of them would take the 22 treatment effect for that repeated measurement. The other 23 one you could measure treatment by time interaction. 24 Now, all of this, I want to reemphasize what Dr. 25 Tan and the discussion here going toward the repeated

260 1 measurement approach, really we haven't done it in the past. 2 It was mainly the final assessment which could be week 11 3 or week 12 or cycle 6 in those contraceptives. 4 But there is a host of issues when considering 5 repeated measurements. Among them how many time points you 6 are going to consider, and I think this would be related to 7 your question for treatment by time interaction and how close 8 those measurements will be to each other. And if you are 9 reaching week 12 and taking measurements at week 11 and week 10 12, it would have a different impact than if you analyze at 11 week 8, 9, 10, 11. So there is an issue in terms of design 12 I think, how many time points you want to assess, how close 13 to each other. 14 Again, I think it's a clin stat issue. So there 15 is more to be done, I agree with you, in that area. 16 DR. TEN HAVE: A follow-up to your question, Dr. 17 Platt. I thought most of the narrowing occurred early on 18 actually during the washout period and less narrowing occurred 19 later on in the follow-up periods, that most of the placebo 20 effect was that first couple of weeks. 21 DR. PLOTT: I think what we've seen in most of 22 the graphs, there is a dramatic effect initially. Usually 23 that next visit is at week 2 or 4, and there is quite a 24 dramatic -- but still there's some improvement, maybe even 25 a flattening, but just in the course of the disease, you might

261 1 expect that acne gets better or worse or, as individuals grow 2 older, if you stretch that line out to some number in the 20's, 3 much of it will improve dramatically. 4 DR. KATZ: I don't think that's a big problem. 5 DR. PLOTT: No, not for clinical trials. 6 DR. KATZ: No, because in 3 months, the natural 7 history of acne doesn't get better. Now obviously a certain 8 percentage, a small percentage would get better by itself. 9 But in 3 months it's not rapidly, spontaneously clearing the 10 problem like you would say over 3 years perhaps. 11 The other thing is that that's taken care of by 12 placebo control. The fact is when you have a 60 percent placebo 13 response, like Wilma pointed out in one of her studies with 14 the Ortho Tri-Cyclen, 60 percent of those people -- I mean, 15 talking about that saying, oh, 60 percent of the placebo 16 patients get better. They're not getting better. They're 17 getting recorded as getting better. But we know that 60 18 percent of people don't get better with nothing over a period 19 of 4, 8, 12 weeks. So they're getting recorded. It's 20 investigator bias which I don't use as a pejorative term for 21 investigators. It's a natural bias. That's the original 22 reason why controlled studies were done way back decades and 23 decades ago. 24 DR. TEN HAVE: Could they be using something else 25 on the side?

262 1 DR. KATZ: Well, the something else is that there 2 are 200 things in the drugstore that don't help very much anyway 3 unless it's a little benzoyl peroxide and that's borderline 4 effectiveness. 5 DR. STERN: Question 6, how should the efficacy 6 outcomes of clinical trials be portrayed in labeling to be 7 maximally useful to clinicians and patients? What graphics 8 and tables should be provided? 9 I think we had a rather nice presentation of at 10 least one way that it's being done currently. I guess one 11 question I have, for this very consumer oriented product, since 12 we are certainly unlikely to be increasing life span in our 13 society by treating mild to moderate acne, should there be 14 different information or a different portrayal of information 15 in fact for the learned intermediaries, the prescribing 16 doctors, and for patients? Is this the perfect time to have 17 patient inserts that are, if you'll pardon my use of the words, 18 generic for acne? 19 MS. KNUDSON: Dr. Stern, I'd like to say as a 20 consumer representative, if you will, unless I misunderstood 21 earlier the discussion about patient satisfaction surveys, 22 they were discounted in the consideration of a drug. I would 23 like to suggest that perhaps a decent patient satisfaction 24 survey or quality of life survey should be demanded for every 25 study and that part of the patient insert material should be

263 1 what the reaction of patients has been to the various drugs. 2 DR. STERN: I think there is at least a group of 3 us in dermatology who would love to see that happen, but so 4 far, if you asked me for a validated acne instrument, I'd have 5 a hard time coming up with one that I would believe gave one 6 robust and interpretable results. 7 MS. KNUDSON: Does that mean it's just not 8 possible to ever have one? 9 DR. STERN: Absolutely not. We've heard about 10 where all the funding -- I assume all those NIH-funded trials 11 were all the ones that were for isotretinoin and that was by 12 happenstance because the drug was being investigated for 13 keratinization at the NIH and Gary Peck made the observation 14 that this stuff was dynamite for people who had a disorder 15 of keratinization as well as acne. But to my knowledge, the 16 NIH and government agencies, with the exception of the funding 17 you have, have been particularly silent on this disease, and 18 I don't think industry has seen it as being an avenue likely 19 to be in their benefit. 20 MS. KNUDSON: Are other kinds of investigators? 21 Psychologists might be willing to do this. There are people 22 who construct surveys for a living who could, with some input 23 from the appropriate persons, develop a scale. 24 DR. STERN: I think we have the talent within 25 dermatology. It's the important thing you said, who do it

264 1 "for a living." And the question is where will the funding 2 come from. That was my point. 3 DR. LEHMANN: I want to add one thing. We haven't 4 been talking about side effects. As you start talking about 5 how to balance efficacy and what to tell patients, you want 6 to start saying, okay, is the side effect and the degree of 7 side effects worth even the efficacy that has actually been 8 demonstrated. 9 DR. STERN: I think that's clearly the key point 10 in any clinical decision making, and I think we've been asked 11 to focus particularly on the efficacy side. But I always 12 assume that the agency will pay good attention to side effects 13 and think about ways to portray them. I think as has been 14 said over here, the best way of balancing it is if you had 15 a good measure for patients to express their opinions about 16 how much better on balance did this therapeutic experience 17 make them feel. 18 DR. WILKIN: That was the clarification that I 19 was seeking. I wanted to know that this wasn't just quality 20 of life based solely on efficacy but based on everything related 21 to using the product. It's helpful to have that clarified 22 in the transcripts because we'll be pouring over these 23 transcripts for months. 24 DR. STERN: Any other comments? 25 DR. SAWADA: Well, in terms of all the modern

265 1 technology and all, as a practicing dermatologist who looks 2 at the package inserts and tries to glean pertinent information 3 in between patients, if they get too complicated, it's way 4 beyond me. The fine print is getting harder and harder every 5 year to see. 6 I do not know, but does the FDA have a web site, 7 since so many more of us are becoming computer savvy, where 8 these studies can be consolidated for individual interest for 9 docs who want to do some more exploration in the subject or 10 have some sort of clinical research interest rather than trying 11 to fit it all on the piece of paper? 12 DR. WILKIN: Well, we do have a web site, and 13 certain drug products get labeling, and special warning 14 discussions and public health advisories and these sorts of 15 things show up on the web site. Independent of that, we're 16 looking to a future some day of electronic labeling where you 17 may still have your PDR and it will be a paper version and 18 if that's what you like, you can -- what I always did, a new 19 product came out and I would actually walk around and in my 20 white coat, I'd have a couple of the new labels so that whenever 21 I wanted to prescribe, I could go over things and sort of learn 22 about them in the clinic. 23 But in the future, you'll be able to -- it will 24 be updated in real time, and it will be a lot easier system. 25 So if you're computer literate -- but that's in the future.

266 1 We don't have that just today. 2 DR. KING: I guess to come back to one of my issues, 3 which is "yes but" in terms of labeling, it seems to me that 4 once a product, regardless of its original indication, is 5 labeled as effective for inflammatory acne or non-inflammatory 6 acne, most people are just going to prescribe it. And if I 7 were cynical and in industry, I would just try for one 8 indication of inflammatory acne realizing that once it's out 9 there, people are going to use it anyway. 10 So sometimes I worry about the labeling because 11 when I saw the data that said the difference between placebo 12 was only 7 lesions, if I were a computer game, jean jock kid, 13 I'd say you mean I'm going to go through all this hassle for 14 7 bumps that are better? I don't think so. So I think we 15 have to be careful with this. I think that sometimes it's 16 better just to talk about efficacy and especially side effects. 17 DR. WILKIN: Yes, these products are approved with 18 that level, but you have to remember there's a certain 19 artificiality in a phase III study. In your office, you never 20 ever give someone a prescription and say, this may work for 21 you, or half of the people that get this prescription, they're 22 not going to get anything active and the other half are. 23 There was an abstract that was presented at the 24 ASCPT meeting. It must have been about 5, 6, 7 years ago now. 25 They looked at the efficacy for a product when it was compared

267 1 against an active control and showed that it was a much higher 2 impression of efficacy than when that same product would be 3 compared with its vehicle or placebo. So I think there are 4 enormous differences between what happens in phase III and 5 what happens in the clinical setting. So you might actually 6 get more. You do more for your patients than just give them 7 a prescription. You give them all sorts of other things to 8 do. 9 So I feel that our approval of products that may 10 only change a couple of lesions at the end of the day is 11 consistent with what we've heard from clinicians in the past 12 in terms of something that they find useful and meaningful. 13 And as Dr. Leyden said, not all those products make it on 14 the market. The market can be more Darwinian than the FDA. 15 Nonetheless, I think it's a level of efficacy that we should 16 feel comfortable with. That's my impression. 17 DR. STERN: It's now 5:30 and I'd like to hear 18 a motion to adjourn the meeting, and we'll begin again at 8:00 19 tomorrow morning. 20 DR. KING: So moved. 21 DR. RAIMER: Second. 22 DR. STERN: Thank you. 23 (Whereupon, at 5:30 p.m., the committee was 24 recessed, to reconvene at 8:00 a.m., Tuesday, November 11, 25 2002.)

268 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

3904T1.doc

by Prezi22 on Nov 11, 2010

Accessibility

Categories

Upload Details

Usage Rights

Statistics

3904T1.doc Document Transcript