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Superiority Trials Versus Non-Inferiority Trials to Demonstrate Effectiveness (3rd Anti-Infectives Summit)

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Superiority Trials Versus Non-Inferiority Trials to Demonstrate Effectiveness (3rd Anti-Infectives Summit)

  1. 1. Superiority Trials Versus Non-Inferiority Trials to Demonstrate Effectiveness Kevin A. Clauson, PharmD 3rd Anti-Infectives Summit
  2. 2. Why I Should Not Be Allowed to Fly http://xkcd.com/651/
  3. 3. Objectives • Explore superiority, equivalence, and non-inferiority (NI) trial designs • Compare critical differences between superiority and NI trials and stumbling blocks involving issues such as the non-inferiority margin • Examine potential issues with non-inferiority studies: study design, scientific, statistical, and regulatory
  4. 4. If I asked you to stand up and define randomization, assay sensitivity, and null hypothesis, are you confident you could do so? 1. Yes 2. No
  5. 5. Randomization Allocation method where all subjects have equal chance of study group assignment
  6. 6. Controls Active Placebo
  7. 7. Blinding Reduce risk of observation bias
  8. 8. Null versus Alternative Hypotheses • H0 – no difference in treatments • H1 – there is a difference in treatments Errors • Type I error (false ) • Type II error (false )
  9. 9. FDA. E 10 Choice of Control Group and Related Issues in Clinical Trials, 2001. Assay Sensitivity Property of a clinical trial that can distinguish an effective treatment from a less effective or ineffective treatment
  10. 10. Superiority Trials Purpose  To detect a difference between two drugs Goals  Establish new drug is statistically superior to active control (and/or placebo) [Easier]  Establish new drug is clinically superior to active control (and/or placebo) [Harder]
  11. 11. Equivalence Trials Purpose: To confirm the absence of a meaningful difference between treatments
  12. 12. Equivalence Trials Equivalence is inferred when ENTIRE confidence interval falls exclusively within equivalence margins (between –Δ and Δ)
  13. 13. What is the PURPOSE of a non-inferiority trial? 20% 1. To show the new drug is as good as comparator 20% 2. To show the new drug can be better than comparator 20% 3. To show the new drug is not unacceptably worse than comparator 20% 4. To show the new drug is clinically equivalent to comparator 20% 5. To show the new drug performs no better or no worse than comparator
  14. 14. Non-inferiority (NI) Trials Purpose: To demonstrate that a new drug is not worse than an active comparator by more than a pre-specified amount* NOT: That the two drugs are equivalent NOT: That the new drug isn’t inferior to the active comparator *non-inferiority margin, delta (Δ), 
  15. 15. from Certain Clinical Trials, July 2010. GAO. FDAs Consideration of Evidence What Factors Are Prompting Increased Scrutiny of NI Trials? 1. Regulatory (volume) 2. Scientific 3. Political
  16. 16. Regulatory Factors (Volume) Source: GAO. FDAs Consideration of Evidence from Certain Clinical Trials, July 2010.
  17. 17. Scientific Factors Two most common reasons FDA failed to approve sponsors NDAs with NI evidence: 1. Poor selection of active control 2. Unclear determination of non-inferiority margin
  18. 18. Political Factors
  19. 19. Clinician understanding of non-inferiority purpose, margin, and issues
  20. 20. What is the biggest factor in navigating NI research? 1. Regulatory 2. Scientific 3. Political 4. They are tied too closely together to separate
  21. 21. Balance Needs in NI Study 1. Determine historical evidence of sensitivity to drug effects exists (constancy assumption) 2. Design a trial 3. Set a non-inferiority margin FDA. E 10 Choice of Control Group and Related Issues in Clinical Trials, 2001.
  22. 22. Historical Evidence of Sensitivity Similarly designed trials in the past regularly distinguished effective treatments from less effective or ineffective treatments Barring this, demonstration of efficacy from a showing of non-inferiority is not possible FDA. E 10 Choice of Control Group and Related Issues in Clinical Trials, 2001.
  23. 23. Designing an NI Trial Non-inferiority trial should mimic design of superiority trial Primary variables, severity of condition, concomitant illnesses, method of diagnosis, etc. MJA 2009;190(6):326-330.
  24. 24. Active comparator (drug) should ideally be widely used with established efficacy via superiority trial and identical indication & conditions Biometric Journal 2009;51(1):185-92.
  25. 25. Structure of NI Trial Design Ideally incorporates a placebo AND active comparator Validate/establish internal validity
  26. 26. Data Analysis Use of BOTH intent-to-treat (ITT) and per protocol (PP) methods of data analysis should be employed Guidance used to suggest PP analysis for NI due to dilution of effect by ITT Assumptions since proven faulty Stat Med 2005;24(1):1-10.
  27. 27. Remember for NI Margin… Defined effect size for (active) control from previous trials ―Comprehensive synthesis‖ of evidence justifying effect size of active control (and thus the proposed NI margin) necessary during protocol development and submission to FDA PLoS ONE 2010;5(10):e13550.
  28. 28. Remember for NI Margin… Adequate support must be provided to FDA (21 CFR 314.126) FDA strongly prefers clinical endpoint over surrogate endpoint when possible PLoS ONE 2010;5(10):e13550.
  29. 29. MJA 2009;190(6):326-330. NI Margin must be determined by combination of clinical considerations and statistical methods
  30. 30. Inference for Non-Inferiority Delta Limits and Confidence Intervals (95%) Non-inferiority shown Non-inferiority shown Non-inferiority not shown Non-inferiority shown - 0 NI Margin Treatment Difference
  31. 31. H0=null hypothesis. Ha = alternative hypothesis; Δ =difference in event rates between new and standard treatments; S=Δ in superiority trials. E=Δ in equivalence trials; NI =Δ in non-inferiority trials *Testing for non-inferiority is in one direction only — even if superiority exists (dashed arrow), it is not the hypothesis being tested. MJA 2009;190(6):326-330.
  32. 32. What is the most commonly used NI margin in anti-infective studies? 1. 0.5% 2. 1% 3. 5% 4. 10% 5. 20% 6. 25%
  33. 33. How did published non-inferiority trials do at exam time?
  34. 34. Good Enough?  Review of 8 NI trials from JAMA & NEJM  6 of 8 trials gave detail on justifications of NI margin  6 of 8 concluded NI  However, analysis by Kaul & Diamond only concluded NI in 4 of 8 trials Ann Intern Med 2006;145(1):62-69.
  35. 35. Wangge et al. review showed less than half (45.7%) of 232 NI trials reported method used to generate NI margin Less than 5.0% reported on similarity of current trial with comparator trials No overall difference pre & post release of CONSORT (2006); method of NI margin actually reported less frequently PLoS ONE 2010;5(10):e13550.
  36. 36. There were 53 trials (22.9% of total N) of anti-infective drugs Most (77.8%) anti-infective trials used an NI margin of percentage difference between 10 to 20%. PLoS ONE 2010;5(10):e13550.
  37. 37. Blinding Superiority vs Non-inferiority PLoS ONE 2010;5(10):e13550.
  38. 38. Superiority Investigator with bias of new drug’s superiority cannot directly manipulate results to support belief Non-inferiority Investigator in NI trial can bias results by assigning similar ratings regardless of patient response/arm PLoS ONE 2010;5(10):e13550.
  39. 39. What is Biocreep?
  40. 40. What is Biocreep? 20% 1. Inability to demonstrate bioequivalence 20% 2. Slow crawl towards finding of non- inferiority with ITT analysis 20% 3. Temporal reduction of efficacy of drugs using NI trials as evidence 20% 4. Process of insertion of biologics into drug pipeline 20% 5. The name of the villain from the Hellraiser movies
  41. 41. FDA Guidance on Clinical Drug Trials
  42. 42. Food and Drug Administration Guidance Origin (FDA), Center for Drug Evaluation and Research (CDER), Division of Anti- Infective and Ophthalmology Products and the Division of Special Pathogen and Transplant Products, Office of Antimicrobial Products Anti-Infective Drugs Advisory Committee (sponsored by FDA)
  43. 43. However, there is not a FDA consensus for all infectious disease indications
  44. 44. Non-inferiority, Bugs, and Drugs  Acute bacterial sinusitis (ABS)  Acute bacterial exacerbation of chronic bronchitis (ABECB)  Acute bacterial otitis media (ABOM) CDER. Antibacterial Drug Products: Use of Noninferiority Trials to Support Approval , November 2010.
  45. 45. FDA Guidance on Anti-infectives
  46. 46. Predicated upon reviews of data for ABS, ABECB, and ABOM along with Anti-Infective Drugs Advisory Committee findings FDA unable to determine recommended NI margin for those three areas Issue clearer for nosocomial/more serious infectious disease indications FDA Guidance on Anti-infectives
  47. 47. ICH9 ICH10 CHMP/EMEA CONSORT FDA GAO
  48. 48. If this had been an elevator prep (not pitch) • Assay sensitivity and historical evidence is crucial for determination of NI feasibility • Sponsor NI margin selection is contingent upon multiple factors in eyes of FDA • Let guidance by FDA, other bodies, and CONSORT help inform protocol development on front end
  49. 49. Research Is Like Eating Marshmallows
  50. 50. Images • http://xkcd.com/651/ • http://www.null-hypothesis.co.uk • • http://www.gao.gov/new.items/d10798.pdf • http://www.nature.com/nrd/journal/v5/n10/pdf/nrd2170.pdf • http://images.wellcome.ac.uk/indexplus/obf_images/7c/e7/dcef0f0fef89d4824b39357b57b5.jpg • http://upload.wikimedia.org/wikipedia/commons/b/b0/CDC-10046-MRSA.jpg Unreferenced pictures are licensed images
  51. 51. Burning Questions clauson@nova.edu www.unhub.com/kevinclauson

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