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Multi-dose Analgesic Development for Acute Pain.
- 1. Multi-dose Analgesic Development for Acute Pain A Brief to the FDA Arthritis Committee July 30, 2002 Najib Babul, PharmD
- 2. Najib Babul, PharmD Conflict of Interest Statement • Pharmaceutical sponsors with submissions or pending submissions before Divisions 550 and 170 • Funding: No external funding • Views expressed are solely those of TheraQuest Biosciences
- 3. Najib Babul, PharmD Single-Dose Evaluation in Acute Pain • Screen patient • Initiate acute insult • Recovery • Pain stimulus threshold • Dose patient • Evaluate response over one dose • Terminate assessments after dosing interval or first rescue
- 4. Najib Babul, PharmD What about multidose evaluation in acute pain?
- 5. Najib Babul, PharmD Multidose Analgesic Evaluation • Growing request for data • “Rhetoric” far outpaces the “science” • Objectives: Establish efficacy? Demonstrate effectiveness? Establish dosing frequency? Test draft Package Insert? Evaluate safety?
- 6. Najib Babul, PharmD Challenges to Multidose Evaluation in Acute Pain • Natural trajectory • Assay sensitivity • Reduced hospitalization • Reduced postsurgical pain • Consent to multidose placebo control • “Data contamination” with rescue use • Shortage of trained analgesic observers/raters • Approaches to data analysis
- 7. Najib Babul, PharmD Proposed Solutions • Use only active controls • Use pseudo-placebos • Rescue analgesic consumption as an endpoint • Integrate rescue and pain assessment data • Substitute serial assessments with pain recall • Use take-home diaries
- 8. Najib Babul, PharmD Integration of Pain and Rescue: Rationale • Traditional studies discard data after first rescue • Rescue confounds analgesic response evaluation • Rescue differentially confounds data within and between treatment groups (single and multiple dose phases) • How to evaluate analgesic response in the face of rescue? • Integrate pain and rescue scores
- 9. Najib Babul, PharmD Use of Pain Recall Instruments • Pain recall is prominent in diagnosis and Rx • Validity of pain recall viewed as “suspect” • Recall frequently used in chronic pain RCT’s • Frequent serial pain assessments the norm in acute pain RCT’s • Hourly assessments a challenge in multidose studies • Are less frequent assessments a substitute?
- 10. Najib Babul, PharmD Study Design • 88 patients - 77 evaluable • Orthopedic surgery • Hourly pain intensity VAS assessments (pain now) for 48 hours • 24 and 48 hour assessments of “Worst” (maximum), “Least” (minimum) and “Usual” (average) pain Babul et al. Annals of Pharmacotherapy 1993;27:9-12 & Pain 1994;57:131-32
- 11. Najib Babul, PharmD Experienced vs Recalled Pain Intensity Actual and Recalled Pain Intensity 0-24h 0-48h Pain Intensity on VAS (mean+ SE) (mean+SE) Worst (recall) 65.4+SE) 60.2+3.4 Maximum (hourly VAS) 66.2+2.8 66.7+2.8 Differenceb -0.8+1.7 -6.4+1.9c Least (recall) 9.7+1.2 5.0+0.9 Minimum (hourly VAS) 9.4+1.2 4.3+0.8 Differenceb 0.3+0.7 0.6+0.5 Usual (recall) 31.4+2.1 25.2+2.1 Mean (hourly VAS) 32.1+1.9 25.8+1.8 Differenceb -0.6+0.9 0.6+1.0 a n=77. b Mean recall variable minus corresponding mean hourly VAS variable. c p=0.001 Babul et al. Annals of Pharmacotherapy 1993;27:9-12 & Pain 1994;57:131-32Babul et al. Annals of Pharmacotherapy 1993;27:9-12 & Pain 1994;57:131-32
- 12. Rescue Analgesic Consumption: Is it a Suitable Endpoint?
- 13. Rofecoxib Postorthopedic Surgical Pain (Days 2-5) ** PP=0.005 rofecoxib 50 mg compared with placebo.=0.005 rofecoxib 50 mg compared with placebo. Data on file.Data on file. Lortab 7.5 mg Use PostsurgeryLortab 7.5 mg Use Postsurgery Mean%Mean% 2020 4040 6060 8080 PlaceboPlacebo (n=53)(n=53) RofecoxibRofecoxib 50 mg50 mg (n=54)(n=54) Patients With Good to ExcellentPatients With Good to Excellent ResponseResponse 00 11 22 33 44 PlaceboPlacebo (n=53)(n=53) RofecoxibRofecoxib 50 mg50 mg (n=54)(n=54) MeanTablets/Day±SEMeanTablets/Day±SE ** 00 ** PP=0.005 rofecoxib 50 mg compared with placebo.=0.005 rofecoxib 50 mg compared with placebo. Data on file.Data on file. Lortab 7.5 mg Use PostsurgeryLortab 7.5 mg Use Postsurgery Mean%Mean% 2020 4040 6060 8080 PlaceboPlacebo (n=53)(n=53) RofecoxibRofecoxib 50 mg50 mg (n=54)(n=54) Patients With Good to ExcellentPatients With Good to Excellent ResponseResponse 00 11 22 33 44 PlaceboPlacebo (n=53)(n=53) RofecoxibRofecoxib 50 mg50 mg (n=54)(n=54) MeanTablets/Day±SEMeanTablets/Day±SE ** 00 Najib Babul, PharmD
- 14. Najib Babul, PharmD 6 8 10 12 14 16 18 20 22 24 26 28 Placebo Celecoxib Rofecoxib Placebo 22 19 20 19 18 18 Celecoxib 14 16 21 19 19 18 Rofecoxib 14 13 11 11 11 11 4 hr 8 hr 12 hr 16 hr 20 hr 24 hr MeanMorphineUse perTimeInterval(mg) * * ** † Postoperative Time Interval Anesth Analg. 2000;91: 1221-1225. * Significantly less morphine used in the rofecoxib group vs. the placebo group (p<.0001) ** Significantly less morphine used in the celecoxib group vs. the placebo group (p<.03) † Significantly less morphine used in the rofecoxib group vs. the celecoxib group (p<.01) * **** † * † * † * † MORPHINE CONSUMPTION Pre-operative Analgesia with Rofecoxib and Celecoxib
- 15. Najib Babul, PharmD 71 mg ± 7Rofecoxib 107 mg ± 17Celecoxib 117 mg ± 13Placebo Morphine UsedGroup Total Morphine Used for 24 Hours Anesth Analg. 2000;91: 1221-1225. MORPHINE CONSUMPTION Pre-operative Analgesia with Rofecoxib and Celecoxib
Editor's Notes
- Good Morning. My name is Najib Babul. I would like to address the FDA Arthritis Advisory Committee and the Division on the issue of multi-dose analgesic development. This is one of the questions that the Division has asked the committee to consider in terms of evaluating analgesics in acute pain. Najib Babul. Transcript of the FDA Arthritis Advisory Committee, Tuesday, July 30, 2002, Bethesda, MD.
- I have previously provided a conflict of interest statement and that stays on record so I won&apos;t repeat it here. Najib Babul. Transcript of the FDA Arthritis Advisory Committee, Tuesday, July 30, 2002, Bethesda, MD.
- This slide shows the essential approach that we have been taking for the last two decades to evaluation and approval of analgesics in acute pain. Certainly, from an efficacy perspective, we do some of those studies by screening a patient, initiating some sort of an acute insult, having some sort of a period of recovery when the pain stimulus reaches a particular intensity, moderate or severe usually. We will then dose the patient. We evaluate the response over a single dose and then we terminate assessments either after the dosing interval is over, which is generally 8, 12 or 24 hours, or at the time that the patient requests their first rescue analgesic. Najib Babul. Transcript of the FDA Arthritis Advisory Committee, Tuesday, July 30, 2002, Bethesda, MD.
- There are compelling reasons why pharmaceutical sponsors have not gone down the path of efficacy evaluations in the multi-dose arena, and I would like to address these and propose some potential solutions. Najib Babul. Transcript of the FDA Arthritis Advisory Committee, Tuesday, July 30, 2002, Bethesda, MD.
- There is no doubt that there is no growing request for data. I recall that even at the Vioxx FDA advisory committee meeting there was discussion of the availability or relative lack of multi-dose data in the dossier. There have been increasing requests from both FDA Division 550 and 170 for such data. I think the challenge here is, if I can just be frank and I guess this is for the record, that our collective rhetoric perhaps outpaces the actual science of drug development. In other words, our methodologic ability, to echo what Dr. Laska was saying, to actually tease out some of those differences is not always there. In order to address this issue of multi-dose analgesic evaluation from an efficacy perspective, we need to ask ourselves precisely what our objectives are. Are they to establish efficacy? Are they to demonstrate effectiveness? Are we trying to establish dosing frequency? Are we trying to prospectively test a draft package insert? Or, are we merely trying to provide some sort of supportive safety data in a perioperative setting where perhaps patients might be critically ill and otherwise compromised? Najib Babul. Transcript of the FDA Arthritis Advisory Committee, Tuesday, July 30, 2002, Bethesda, MD.
- Here are some of the challenges to evaluating these drugs in acute pain. The first issue, and this has been alluded to earlier, is that the natural trajectory of acute pain is such that, whether treated or untreated, for the most part it diminishes. To be sure, and Dr. Katz referred earlier to thoracotomy patients or lumbar laminectomy patients who may have somewhat long-term pain. To be sure, some patients may have a longer trajectory, but a majority of these patients have a relatively short trajectory. So, this introduces an issue that most analgesiologists have called assay sensitivity. We are also faced with a reduced duration of hospitalization. A significant number of patients after major surgery are home within four days to a week&apos;s time. There is also a growing trend towards surgical techniques that reduce surgical pain. For instance, hip arthroplasty, as is currently being conducted, requires substantially less postoperative opioids than perhaps 10 or 15 years ago and this presents a bit of a challenge. Furthermore, patients will sometimes refuse to consent to multi-dose placebo controlled studies. It is one thing to convince patients to do a single-dose placebo controlled study, but to tell them you are going to repeatedly be give placebo over the next five or seven days presents a bit of a challenge. We also have this issue of data contamination when you give rescue analgesia, and we have a problem in terms of availability of trained analgesic observers or nurse raters. This is a very specific discipline requiring an exceptionally well-trained individual who truly understands analgesic methodology, and there is a real shortage of such folks. Your most senior study coordinator usually wants to work the day shift so you have 72 hours more to go beyond that to evaluate the patient. Najib Babul. Transcript of the FDA Arthritis Advisory Committee, Tuesday, July 30, 2002, Bethesda, MD.
- I would like to suggest some proposed approaches without getting too prescriptive. Some of these have really been spurred through discussions with Division 550 with Dr. Witter and Dr. Simon and others. One option clearly is to use active controls, with the Division&apos;s prior consent. That is certainly one possibility to consider. The other option is to use what I call pseudo placebos. So, these would not be placebos but would be perhaps ultra low dose of an approved agent, to allow us to get some assay sensitivity. Yet another option, and this was discussed previously by Dr. Laska, is to use rescue analgesia as an endpoint. This has been used successfully but only with a modest degree of success in the past. We can also integrate rescue and pain assessment data, and there are some techniques available for that. Of course, because of the shortage of trained study coordinators, we can perhaps consider doing serial assessments long term. We can use recall instruments to assess pain. Najib Babul. Transcript of the FDA Arthritis Advisory Committee, Tuesday, July 30, 2002, Bethesda, MD.
- The rationale for integrating rescue and pain scores to come up with some composite scores is given on this slide, and I am going to be brief here. Traditional studies have tended to discard rescue after the first dose. The issue is that rescue tends to confound our analgesic evaluation. Furthermore, rescue differentially confounds the analgesic response. Dr. David Silverman in the Department of Anesthesiology at Yale, for instance, has suggested a rather elegant but simple approach to integrating rescue and analgesia scores. Najib Babul. Transcript of the FDA Arthritis Advisory Committee, Tuesday, July 30, 2002, Bethesda, MD.
- Alternative approaches that are available involve the use of recall instruments. We know that recall, at least among analgesiologists, is viewed as somewhat suspect but we, and others, have shown and have published data demonstrating that recall is actually quite sensitive. We have done studies where we have looked at recall in orthopedic pain and other models, and we think that this allows you perhaps to conserve on the resources that are a problem in multi-dose studies. Najib Babul. Transcript of the FDA Arthritis Advisory Committee, Tuesday, July 30, 2002, Bethesda, MD.
- Alternative approaches that are available involve the use of recall instruments. We know that recall, at least among analgesiologists, is viewed as somewhat suspect but we, and others, have shown and have published data demonstrating that recall is actually quite sensitive. We have done studies where we have looked at recall in orthopedic pain and other models, and we think that this allows you perhaps to conserve on the resources that are a problem in multi-dose studies. Najib Babul. Transcript of the FDA Arthritis Advisory Committee, Tuesday, July 30, 2002, Bethesda, MD.
- Najib Babul. Transcript of the FDA Arthritis Advisory Committee, Tuesday, July 30, 2002, Bethesda, MD.
- The last potential option that one ought to consider is rescue analgesia as an endpoint. I believe it is a potential endpoint. It does have some risks because the variability is not insignificant. Najib Babul. Transcript of the FDA Arthritis Advisory Committee, Tuesday, July 30, 2002, Bethesda, MD.
- These are data that were presented in 1998 at the Arthritis Advisory Committee in the review of the Rofecoxib submission. As you can see in this particular study, over day two to five there was a difference between placebo and rofecoxib in terms or rescue consumption. It was a one tablet per day difference. Now, whether this is clinically meaningful is a separate issue but it certainly provided some assay sensitivity in an attempt to look for differences. In summary, the methodology for multi-dose efficacy evaluation is not quite cooked; it is not established. I think there are some possible options that are available, but we need to understand that there are some compelling reasons why evidence from single-dose studies have formed the primary basis for efficacy evaluation. None of these techniques can meaningfully, in my opinion, answer questions related to the time course of effect and dose response. Those questions, and they are critical questions, need to be addressed in single-dose efficacy evaluations. Thank you Najib Babul. Transcript of the FDA Arthritis Advisory Committee, Tuesday, July 30, 2002, Bethesda, MD.