Maureen Maguire April 1 2009

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Maureen Maguire April 1 2009

  1. 1. The Lucentis-Avastin Trial for Age-related Macular Degeneration –  A Non-Inferiority Trial for which the Company Refuses to Pay for the New Drug Center for Clinical Trials Seminar Series Johns Hopkins University Maureen G. Maguire, PhD Department of Ophthalmology University of Pennsylvania
  2. 2. Disclosures I have no relevant commercial entity relationships or financial interests to disclose . I will discuss off-label use of Avastin  
  3. 3. Overview <ul><li>Comparative effectiveness </li></ul><ul><ul><li>Health Care and the American Recovery and Reinvestment Act </li></ul></ul><ul><ul><li>Robert Steinbrook, MD – NEJM, March 12, 2009 </li></ul></ul><ul><ul><li>“ studies that directly compare the risks and benefits of different treatments for a particular condition are essential for improving practice and slowing cost escalation.” </li></ul></ul><ul><li>Case study on how one CE trial fared </li></ul><ul><ul><li>Comparison of AMD Treatment Trials (CATT): Lucentis-Avastin Trial </li></ul></ul>
  4. 4. Public Health Significance of Age-Related Macular Degeneration (AMD) <ul><li>Leading cause of blindness among adults in US and most western countries </li></ul><ul><li>8.5 million affected in US – 2000 </li></ul><ul><ul><li>>6.6 million early AMD </li></ul></ul><ul><ul><li>>1.8 million late AMD </li></ul></ul><ul><li>By 2020, these numbers will DOUBLE due to the aging US population </li></ul>
  5. 5. Early AMD <ul><li>Early AMD or age-related maculopathy (ARM) </li></ul><ul><li>Drusen - yellowish deposits </li></ul><ul><li>Pigmentary change </li></ul><ul><li>Both eyes affected often </li></ul>Normal Early AMD
  6. 6. Impact of Early AMD on Vision <ul><li>Visual acuity usually good - often 20/20 rarely worse than 20/40 </li></ul><ul><li>Some problems with </li></ul><ul><ul><li>Night vision </li></ul></ul><ul><ul><li>Color vision </li></ul></ul><ul><ul><li>Contrast sensitivity </li></ul></ul>
  7. 7. Late AMD <ul><li>Choroidal neovascularization </li></ul><ul><ul><li>~2/3 of late AMD is CNV </li></ul></ul><ul><ul><li>~90% of legal blindness due to CNV </li></ul></ul><ul><li>Geographic atrophy </li></ul><ul><ul><li>~ 1/3 of late AMD is GA </li></ul></ul><ul><ul><li>~ 10% of legal blindness due to GA </li></ul></ul>Fluorescein Angiogram
  8. 8. Impact of Late AMD on Vision http://www.nei.nih.gov/photo/sims/index.asp
  9. 9. Age-Specific Prevalence of Late AMD in Whites Eye Diseases Prevalence Research Group. Arch Ophthalmol 2004; 122:564-572
  10. 10. Proportion of Adult Blindness by Race Eye Diseases Prevalence Research Group. Arch Ophthalmol 2004;122:477-485
  11. 11. Established Risk Factors for AMD <ul><li>Age and race </li></ul><ul><li>Genes </li></ul><ul><ul><li>Complement Factor H </li></ul></ul><ul><ul><li>HTRA1 </li></ul></ul><ul><ul><li>Others </li></ul></ul><ul><li>Cigarette smoking </li></ul><ul><li>Diets low in specific nutrients </li></ul><ul><ul><li>Beta-carotene, vitamins C & E, zinc </li></ul></ul><ul><ul><li>Lutein/zeaxanthin </li></ul></ul><ul><ul><li>Omega-3 Fatty Acids </li></ul></ul>
  12. 12. Prevention <ul><li>Age-Related Eye Disease Study (AREDS) – NEI </li></ul><ul><ul><li>Daily, high dose anti-oxidant vitamins and zinc </li></ul></ul><ul><ul><li>Reduction of risk of progression to Late AMD and vision loss by 25% over 5 years for patients with large drusen </li></ul></ul><ul><li>AREDS 2 </li></ul><ul><ul><li>Supplementation with lutein and/or omega-3 fatty acids </li></ul></ul><ul><ul><li>Ongoing </li></ul></ul>
  13. 13. Treatment Efficacy for CNV at 1 Year- 2005 <ul><li>≤ 15 Letter ≥ 15 Letter Mean Change </li></ul><ul><li> Loss Gain ≥ 20/40 VA (letters) </li></ul><ul><li>No Rx 39% 2% 1% -- </li></ul><ul><li>Laser 50% 1% --- -- </li></ul><ul><li>PDT 67% 6% 5% - 10 </li></ul><ul><li>Macugen 70% 6% --- - 7 </li></ul>
  14. 14. Next Clinical Trial for CNV <ul><li>Macugen – intravitreal injection every 6 wks, $1000 per injection </li></ul><ul><li>PDT ~ 3 treatments per year, $5000-$7500 </li></ul><ul><li>Can treatment frequency be reduced with combination therapy? </li></ul><ul><li>May 2005 – submit grant June 1 for trial of : </li></ul><ul><ul><li>Macugen </li></ul></ul><ul><ul><li>PDT + Macugen </li></ul></ul><ul><ul><li>PDT + triamcinolone </li></ul></ul>
  15. 15. History - Lucentis Arrives <ul><li>May 23, 2005 – News release </li></ul><ul><li>Phase III trial MARINA by Genentech </li></ul><ul><ul><li>Intravitreal Lucentis 0.3mg every 28 days </li></ul></ul><ul><ul><li>Intravitreal Lucentis 0.5 mg every 28 days </li></ul></ul><ul><ul><li>Sham injection every 28 days </li></ul></ul>
  16. 16. MARINA: 2 Doses of Lucentis vs Sham Rx Mean Change in Visual Acuity Over Time 21.4 letter difference* 20.3 letter difference* +7.2 +6.5 -10.4 2 4 6 8 10 12 14 16 18 20 22 24 Month -15 -10 -5 0 5 10 ETDRS letters -14.9 +5.4 +6.6 Note: Vertical bars are ± one standard error of the mean. * P <0.0001 (Rounded values) Sham (n=238) Ranibizumab 0.5 mg (n=240) Ranibizumab 0.3 mg (n=238)
  17. 17. Treatment Efficacy at One Year <ul><li>≤ 3 Line ≥ 3 lines Mean Change </li></ul><ul><li> Loss Gain ≥ 20/40 VA (letters) </li></ul><ul><li>No Rx 39% 2% 1% -- </li></ul><ul><li>Laser 50% 1% --- -- </li></ul><ul><li>PDT 67% 6% 5% - 10 </li></ul><ul><li>Macugen 70% 6% --- - 7 </li></ul><ul><li>Lucentis </li></ul><ul><li>MARINA 95% 34% 40% + 7 </li></ul><ul><li>ANCHOR 95% 40% 39% + 11 </li></ul>
  18. 18. Planned Trial <ul><li>May 2005 – grant to be submitted for trial of : </li></ul><ul><ul><li>Macugen </li></ul></ul><ul><ul><li>PDT + Macugen </li></ul></ul><ul><ul><li>PDT + triamcinolone </li></ul></ul>
  19. 19. History – Avastin Arrives <ul><li>July 18 2005 – ASRS meeting </li></ul><ul><ul><li>MARINA results presented </li></ul></ul><ul><ul><li>Report of a 1 pt treated with intravitreal Avastin </li></ul></ul><ul><li>Avastin – anti-VEGF agent, FDA approved for colon CA, intravenous administration </li></ul><ul><li>Derived from the same molecule as Lucentis, but larger </li></ul><ul><li>Believed not to penetrate the retina from the vitreous </li></ul><ul><li>Previous case series with intravenous Avastin – showed promise but concern over systemic side effects </li></ul>
  20. 20. Avastin Quickly Adopted by Many <ul><li>August – December 2005 </li></ul><ul><ul><li>Lucentis not generally available </li></ul></ul><ul><ul><li>Salvage cases only  first line therapy </li></ul></ul><ul><ul><ul><li>Chemically similar to Lucentis </li></ul></ul></ul><ul><ul><ul><li>Dramatic results in the short term </li></ul></ul></ul><ul><ul><ul><li>Inexpensive (~$50 per injection) if 4 ml vial divided </li></ul></ul></ul><ul><ul><ul><li>Medicare and insurance carriers started covering Avastin and the injection procedure (no National Coverage Decision) </li></ul></ul></ul><ul><ul><ul><li>Off-label use </li></ul></ul></ul><ul><ul><ul><li>Unknown safety </li></ul></ul></ul><ul><ul><ul><li>No controlled trials of short- or long-term efficacy </li></ul></ul></ul><ul><ul><li>Widespread debate on ethics of off-label use </li></ul></ul>
  21. 21. CATT History <ul><li>January 2006 – grant submitted to NEI for Lucentis-Avastin trial; expedited review </li></ul><ul><li>June 2006 – NEI will fund clinical and resource centers - $16 million over 4 years </li></ul><ul><li>June 2006 – Lucentis receives FDA approval for treatment of CNV – price ~ $2000 per dose </li></ul><ul><li>February 2008 – First patient enrolled </li></ul><ul><li>What took so long??? </li></ul>
  22. 22. Centers for Medicare and Medicaid Services (CMS) <ul><li>2006 - Not positioned to support comparative effectiveness studies </li></ul><ul><li>95% of AMD CNV patients covered by Medicare/Medicaid </li></ul><ul><li>Drug cost to CMS (80% of total) if 1200 patients receive: </li></ul><ul><li> Lucentis similar to Genentech trials $50 Million </li></ul><ul><li> Treatments as in CATT $25 Million </li></ul><ul><li>Savings to CMS during study $25 Million </li></ul><ul><li>CMS estimates total cost reduction (AMD claims data) is $1 to $3 Billion dollars each year </li></ul><ul><li>Talks between CATT and CMS began Nov 2005 – involvement contingent on NIH approval of design </li></ul>
  23. 23. Centers for Medicare and Medicaid Services (CMS) <ul><li>July 13, 2006 Meeting at CMS Headquarters with CMS (OCSQ) and NEI leaders </li></ul><ul><li>Funding </li></ul><ul><ul><li>100% payment for Lucentis? </li></ul></ul><ul><ul><li>Avastin? </li></ul></ul><ul><ul><li>Drug distribution costs? </li></ul></ul><ul><li>Response </li></ul><ul><ul><li>CMS is enthusiastic about the trial </li></ul></ul><ul><ul><li>CMS pays bills conduct </li></ul></ul><ul><ul><li>CMS does not conduct research </li></ul></ul>
  24. 24. Centers for Medicare and Medicaid Services (CMS) <ul><li>July 13, 2006 Meeting at CMS Headquarters with CMS (OCSQ) and NEI leaders </li></ul><ul><li>Funding </li></ul><ul><ul><li>100% payment for Lucentis? </li></ul></ul><ul><ul><li>Avastin? </li></ul></ul><ul><ul><li>Drug distribution costs? </li></ul></ul><ul><li>Response </li></ul><ul><ul><li>CMS is enthusiastic about the trial </li></ul></ul><ul><ul><li>CMS pays bills conduct </li></ul></ul><ul><ul><li>CMS does not conduct research </li></ul></ul><ul><ul><li>Current CMS policy appears to prohibit payment of Lucentis in CATT </li></ul></ul>
  25. 25. 2000 Clinton Clinical Trial Policy <ul><li>Intent: to open participation in clinical trials to Medicare beneficiaries </li></ul><ul><li>Language focused on by CMS lawyers </li></ul><ul><ul><li>“ Medicare covers the routine costs of qualifying clinical trials …except: the investigational item or service, itself” </li></ul></ul><ul><li>Other language not cited </li></ul><ul><ul><li>“ Routine costs in clinical trials include: Items or services that are typically provided absent a clinical trial (e.g., conventional care);” </li></ul></ul><ul><li>Scheduled for revision in Summer 2007 to explicitly allow coverage of treatments otherwise covered by Medicare </li></ul>
  26. 26. CMS Options for CATT <ul><li>Wait a year to allow Lucentis to be covered (80%) </li></ul><ul><li>CMS Payment Demonstration Project </li></ul><ul><ul><li>Intended for exploring alternative payment mechanisms </li></ul></ul><ul><ul><li>Very few had ever been approved by CMS/DHHS lawyers </li></ul></ul><ul><li>An Act of Congress </li></ul>
  27. 27. Comparative Effectiveness <ul><li>Major needs for CATT </li></ul><ul><ul><li>Supply of drugs </li></ul></ul><ul><ul><li>Payment for Lucentis and Avastin </li></ul></ul><ul><ul><li>Masking </li></ul></ul><ul><li>Needs pertain to most comparative effectiveness trials </li></ul><ul><li>Comparative effectiveness is not embraced by industry </li></ul><ul><li>“… some are concerned that the government or insurers may use the results to mandate specific approaches to treatment or to deny coverage. “ </li></ul><ul><li>NEJM, Steinbrook, March 12, 2009 </li></ul>
  28. 28. Demonstration Projects <ul><li>Major needs (even with coverage of Lucentis) </li></ul><ul><ul><li>Central supply of both drugs for clinical centers </li></ul></ul><ul><ul><li>Payment for Lucentis co-pay </li></ul></ul><ul><ul><li>Masking (Medicare EOB names drug) </li></ul></ul><ul><li>Many plans, ultimately not feasible or deemed illegal </li></ul><ul><ul><li>CMS Acting Director Leslie Norwalk </li></ul></ul><ul><ul><li>NIH Director Zerhouni </li></ul></ul><ul><ul><li>Ophthalmology professional organizations </li></ul></ul><ul><ul><li>Congressmen and senators </li></ul></ul><ul><ul><li>High level contacts in White House </li></ul></ul>
  29. 29. Plan Proposed by CATT Group <ul><li>CMS provides funds to purchase drug supply (both, 100% of cost) - $24 million </li></ul><ul><li>Avastin repackaged into vials identical to Lucentis </li></ul><ul><li>CATT accounts for all drug used (Medicare beneficiaries only) </li></ul><ul><li>Pay back any unused funds to CMS at end of trial </li></ul><ul><li>Favorable features </li></ul><ul><ul><li>Drug cost (no cost) identical to patients in all groups </li></ul></ul><ul><ul><li>No billing expenses for Penn, clinical centers </li></ul></ul><ul><ul><li>No EOB with drug name </li></ul></ul><ul><ul><li>Allows complete masking </li></ul></ul>
  30. 30. CMS “G” Code Plan <ul><li>Penn/NEI buys supplies of both drugs </li></ul><ul><li>Avastin repackaged into vials identical to Lucentis </li></ul><ul><li>CATT supplies and bills clinical centers </li></ul><ul><li>Centers treat pts, bill “CATT Drug” using a “G” code, receive Medicare payments, and pay back CATT </li></ul><ul><ul><li>Amount equal to 80%/ 100% of the average cost </li></ul></ul><ul><ul><li>Use weighted average based on predicting ratio of Lucentis:Avastin injections </li></ul></ul><ul><ul><li>Use weighted average with allowance for breakage </li></ul></ul>
  31. 31. CMS “G” Code Plan <ul><li>Disadvantages </li></ul><ul><ul><li>$ Millions in “up front” costs </li></ul></ul><ul><ul><li>Dependent on efficient billing from clinical center and payment to Penn </li></ul></ul><ul><ul><li>Huge loss if weighting ratio incorrect </li></ul></ul>
  32. 32. CMS Capitated Plan <ul><li>Penn/NEI buys supplies of both drugs </li></ul><ul><li>Avastin repackaged into vials identical to Lucentis </li></ul><ul><li>CATT supplies clinical centers </li></ul><ul><li>Clinical centers enroll patients in CATT and receive capitated payments for all CATT care, regardless of actual treatments, pay CATT a portion to cover drugs </li></ul><ul><ul><li>Payment 100% anticipated costs </li></ul></ul><ul><ul><li>Only need 1 request to start the flow of payments </li></ul></ul><ul><li>Disadvantages </li></ul><ul><ul><li>$ Millions in “up front” costs </li></ul></ul><ul><ul><li>Dependent on clinical center paying Penn </li></ul></ul>
  33. 33. CMS “Dr Fine Treats All” Plan <ul><li>Penn/NEI buys supplies of both drugs </li></ul><ul><li>Avastin repackaged into vials identical to Lucentis </li></ul><ul><li>CATT supplies clinical centers </li></ul><ul><li>Clinical centers enroll patients in CATT and send billing information to CATT Coordinating Center </li></ul><ul><li>Coordinating Center generates bills based on data collected on treatments </li></ul><ul><li>UPHS bills their Medicare carrier with “Stuart Fine, MD” as the treating physician </li></ul><ul><li>UPHS Medicare carrier reprograms computers so that EOB does not list drug name </li></ul>
  34. 34. Genentech Offers Drug <ul><li>May 2007 ARVO meeting </li></ul><ul><ul><li>Genentech leaders contact CATT leaders </li></ul></ul><ul><ul><li>Some believe helping CATT is best </li></ul></ul><ul><ul><li>Will supply both drugs, masked vials </li></ul></ul><ul><ul><li>Planning date of drug fill, distribution of supplies </li></ul></ul><ul><li>June 2007 – DSMC approves trial plans </li></ul><ul><li>Training meeting set for end of September </li></ul><ul><li>July 2007 – Genentech board decides to not supply drug </li></ul>
  35. 35. Moving Forward <ul><li>July 2007 – Revised Medicare Clinical Trials Policy explicitly allows payment for drugs under study if otherwise available </li></ul><ul><li>CMS/NIH leaders re-interpret Medicare laws to allow another government entity to pay the co-pay </li></ul><ul><li>NEI agrees to pay the Lucentis co-pay (15% of patients without supplemental insurance) </li></ul><ul><li>NEI says do the best you can, start trial </li></ul><ul><li>Early September, DSMC approves revised plan </li></ul><ul><li>Late September – Investigator’s Meeting </li></ul>
  36. 36. CATT Resource Centers <ul><li>Daniel F. Martin MD Study Chair (Emory) </li></ul><ul><li>Stuart L. Fine MD Study Vice-Chair (Penn) </li></ul><ul><li>Maureen Maguire PhD Coordinating Center (Penn) </li></ul><ul><li>Glenn J. Jaffe MD OCT Reading Center (Duke) </li></ul><ul><li>Juan Grunwald MD Fundus Photograph Reading Center (Penn) </li></ul><ul><li>Supported by Grants from the National Eye Institute </li></ul>
  37. 37. Primary Study Questions <ul><li>Is Avastin as safe and effective as Lucentis? </li></ul><ul><li>Does “as needed” dosing of either drug compromise long term visual outcome relative to fixed dosing? </li></ul>
  38. 38. Objective <ul><li>To evaluate the relative efficacy and safety of treatment of subfoveal, neovascular AMD with </li></ul><ul><li>1) Lucentis ® on a fixed schedule (every 4 weeks) </li></ul><ul><li>2) Avastin ® on a fixed schedule (every 4 weeks) </li></ul><ul><li>3) Lucentis ® on a variable* dosing schedule </li></ul><ul><li>4) Avastin ® on a variable* dosing schedule </li></ul><ul><li>* Depending on lesion activity </li></ul>
  39. 39. Major Eligibility Criteria <ul><li>Choroidal neovascularization (CNV) or sequelae subfoveal </li></ul><ul><li>Fibrosis < 50% of lesion </li></ul><ul><li>Visual acuity (VA) 20/25-20/320 </li></ul><ul><li>Age > 50 yrs </li></ul><ul><li>>1 drusen (>63μ) in either eye or late AMD in fellow eye </li></ul><ul><li>No previous treatment for CNV in study eye </li></ul><ul><li>No other progressive retinal disease likely to affect VA </li></ul><ul><li>No contraindications to injections with Lucentis ® or Avastin ® </li></ul>Goal: Be as inclusive and simple as possible
  40. 40. Randomization Informed Consent Variable Avastin ® Variable Lucentis ® Fixed Avastin ® Fixed Lucentis ® Randomization
  41. 41. Randomized Treatment Assignment 0 Time 1 yr Lucentis Fixed Avastin Fixed Lucentis Variable Avastin Variable Fixed Vari-able Fixed Vari-able Lucentis Variable Avastin Variable Eligible Patients
  42. 42. CATT Study Drugs <ul><li>Ranibizumab (Lucentis ® ) </li></ul><ul><ul><li>0.5 mg (0.05 mL) </li></ul></ul><ul><ul><li>Supplied same as outside the study </li></ul></ul><ul><ul><li>Billed to primary and supplemental insurance, residual paid by study (NEI) </li></ul></ul><ul><li>Bevacizumab (Avastin ®) </li></ul><ul><ul><li>1.25 mg (0.05 mL) </li></ul></ul><ul><ul><li>Supplied by the study </li></ul></ul><ul><ul><li>No charge </li></ul></ul>
  43. 43. Treatment Guidelines <ul><li>ALL patients treated immediately after randomization </li></ul><ul><li>Patients assigned to FIXED schedule treated at each visit </li></ul><ul><li>Patients assigned to VARIABLE schedule treated if </li></ul><ul><ul><li>Fluid on OCT </li></ul></ul><ul><ul><li>OR </li></ul></ul><ul><ul><li>One or more of the following </li></ul></ul><ul><ul><ul><li>New subretinal or intraretinal hemorrhage </li></ul></ul></ul><ul><ul><ul><li>Decreased VA (relative to last visit) w/o explanation </li></ul></ul></ul><ul><ul><ul><li>Lesion growth on FA </li></ul></ul></ul><ul><ul><ul><li>Leakage on FA </li></ul></ul></ul>
  44. 44. Masking <ul><li>Masked to drug and schedule </li></ul><ul><ul><li>Visual acuity examiner </li></ul></ul><ul><ul><li>OCT and photograph graders </li></ul></ul><ul><li>Masked to drug </li></ul><ul><ul><li>Ophthalmologist </li></ul></ul><ul><ul><li>Patient initially, billing statements may unmask </li></ul></ul>
  45. 45. CATT Treatment Masking Procedure Decides to treat Obtains drug Syringe filled and labeled Prepares the eye Injects Ophthalmologist Observes Clinic Coordinator
  46. 46. Maintaining Masking (CATT Training Mtg) <ul><li>Patients will not be told the identity of the drug by clinical center staff. </li></ul><ul><li>Patients will be told that they may learn the identity of their drug from billing and insurance statements. They will not be told that patients receiving Avastin® will not be billed. </li></ul><ul><li>Patients will be asked not to discuss the name of their anti-VEGF drug with anyone but the clinic coordinator if they learn which drug they are on. </li></ul><ul><li>Clinic Coordinators and ophthalmologists should use terminology such as “study drug” or “anti-VEGF drug” or “VEGF drug” when they talk to patients rather than the names of the two drugs. </li></ul><ul><li>For many conversations about side effects, mode of action, time course for visual improvement, etc, the same explanations apply to both drugs. </li></ul><ul><li>The goal is to minimize opportunities for the patient to volunteer which drug they are taking, if they become aware of it. </li></ul>
  47. 47. Maintaining Masking (CATT Training Mtg) <ul><li>Patients </li></ul><ul><ul><li>Not told the identity of the drug </li></ul></ul><ul><ul><li>Told that they may learn the identity of their drug from billing and insurance statements </li></ul></ul><ul><ul><li>Not told that Avastin® will not be billed </li></ul></ul><ul><ul><li>Told not to discuss the name of their anti-VEGF drug </li></ul></ul><ul><li>CATT Clinic staff - use “study drug” or “anti-VEGF drug” or “VEGF drug” when talking to patients </li></ul><ul><li>Most side effects, time course for visual improvement, etc, the same </li></ul><ul><li>The goal is to minimize opportunities for the patient to volunteer which drug they are taking, if they become aware of it. </li></ul>
  48. 48. Would Our Central Masking Have Worked? <ul><li>Over-labeling </li></ul><ul><li>Change to double vented stopper </li></ul>
  49. 49. Remove Plastic Caps
  50. 50. Foil Wrap to Cover the Tattoo
  51. 51. Vial Shape Different!
  52. 52. Outcome Measures <ul><li>Primary </li></ul><ul><ul><li>Mean change in VA at 1 year </li></ul></ul><ul><li>Secondary </li></ul><ul><ul><li>Number of treatments </li></ul></ul><ul><ul><li>3-line change in VA (15 letters on ETDRS chart) </li></ul></ul><ul><ul><li>Change in fluid on optical coherence tomography </li></ul></ul><ul><ul><li>Change in lesion size on fluorescein angiography </li></ul></ul><ul><ul><li>Incidence of endophthalmitis, retinal detachment, cataract, uveitis </li></ul></ul><ul><ul><li>Incidence of other adverse events </li></ul></ul><ul><ul><li>Cost </li></ul></ul>
  53. 53. Follow-up <ul><li>Every 4 weeks for 2 years </li></ul><ul><li>Data collection </li></ul><ul><ul><li>History Each visit </li></ul></ul><ul><ul><li>Refraction Every 3 months </li></ul></ul><ul><ul><li>Visual Acuity Each visit </li></ul></ul><ul><ul><li>Eye examination Each visit </li></ul></ul><ul><ul><li>OCT Fixed: Months 1,2,3,6,12,18,24 </li></ul></ul><ul><ul><li>Variable: Each visit </li></ul></ul><ul><ul><li>Photography Months 12 and 24 </li></ul></ul>
  54. 54. Sample Size <ul><li>Non-inferiority limit = 5 letters (>5 is inferior) </li></ul><ul><li>Confidence limits will be used </li></ul><ul><li>All pairwise comparisons accommodated </li></ul><ul><li>Loss to follow-up (death, missed visits) = 8% </li></ul><ul><li>300 (292) patients per treatment group </li></ul><ul><li>1200 (1168) patients total study </li></ul>
  55. 55. Is 5 Letters Close Enough? <ul><li>CATT Non-inferiority limit is 1.0 line (5 letters) </li></ul><ul><li> % </li></ul><ul><li> Time Mean (VA Letters) 15-letter Loss </li></ul><ul><li>Trial/Treatment (Yrs) Rx Control Difference Difference </li></ul><ul><li>MPS / Laser 2 -15 -22 7 20% </li></ul><ul><li>TAP/PDT 1 -11 -17.5 6.5 15% </li></ul><ul><li>TAP/PDT 2 -13.5 -19.5 6 15% </li></ul><ul><li>VIP/PDT 2 -19 -25.5 6.5 12% </li></ul><ul><li>Eye001/Macugen 1 - 8 - 15 7 15% </li></ul>
  56. 56. Interpretation of CATT Not A Strict Non-Inferiority Trial http://bmc.ub.uni-potsdam.de/1468-6708-5-8/1468-6708-5-8-1.jpg Avastin - Lucentis Avastin Fixed Lucentis Fixed 5 5 Difference
  57. 57. Status April 2009 <ul><li>43 Clinical centers, 50+ sites </li></ul><ul><li>200 ophthalmologists certified </li></ul><ul><li>700 patients enrolled </li></ul><ul><li>Recruitment targeted for completion Nov 2009 </li></ul><ul><li>1-year results due early 2011 </li></ul>
  58. 58. Medicare Act of 2008 <ul><li>SEC. 184. COST-SHARING FOR CLINICAL TRIALS. </li></ul><ul><li>“ The Secretary may develop alternative methods of payment for items and services provided under clinical trials and comparative effectiveness studies sponsored or supported by an agency of DHHS … to the extent such alternative methods are necessary to preserve the scientific validity of such trials or studies, such as in the case where masking the identity of interventions from patients and investigators is necessary to comply with the particular trial or study design. ” </li></ul><ul><li>Due in large part to the work of Sen. Herb Kohl (D-Wisc) </li></ul>
  59. 59. Medicare and Clinical Trials 2009 <ul><li>Could 100% of Lucentis be paid for? </li></ul><ul><li>Could the Avastin be paid for? </li></ul><ul><li>Could CATT be paid “up front” to allow central distribution? </li></ul><ul><li>No response from CMS </li></ul>
  60. 60. Summary <ul><li>CATT – before revised Clinical Trial Policy and Kohl amendment </li></ul><ul><li>Comparative effectiveness trials still face challenges in implementation </li></ul><ul><li>Financing and study design are intertwined </li></ul><ul><li>Methods for communicating between CMS and researchers need to be developed </li></ul>

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