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Superiority, Equivalence, and Non-Inferiority Trial Designs

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Superiority, Equivalence, and Non-Inferiority Trial Designs This lecture was presented as part of the Drug Literature Evaluation course at Nova Southeastern University. Guided notes and an audience response system were used to augment to lecture. Context for my decision to share these slides can be found at the provided link. This lecture was presented as part of the Drug Literature Evaluation course at Nova Southeastern University. Guided notes and an audience response system were used to augment to lecture. Context for my decision to share these slides can be found at the provided link.


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Superiority, Equivalence, and Non-Inferiority Trial Designs

  1. 1. Superiority, Equivalence, and Non-inferiority Trials: A Gold Standard? Kevin A. Clauson, Pharm.D. Associate Professor February 15, 2010
  2. 2. Objectives • Review randomized controlled trial design • Preview elements of a journal club • Examine purpose(s) of superiority, non-inferiority and equivalence trials • Assess non-inferiority trial design
  3. 3. Tr ue 0% Fa l se 0%
  4. 4. How is data from a Likert Scale classified? 1. Nominal 2. Ordinal 3. Interval 4. Ratio 0% 0% 0% 0% tio al al al rv in in Ra m te d Or No In
  5. 5. Randomized Controlled Trials (Review) • Randomization = allocation method where all subjects have equal chance of study group assignment • Controls = placebo, active (comparator), historical • Blinding = reduce risk of observation bias (single, double, triple) AJR 2004;183(6):1539-44.
  6. 6. Randomized Controlled Trials (Review) • Method to determine if a cause-effect (causal) relationship exists between treatment and outcome • Other designs can detect an association, but can‟t rule out that an association was caused by third factor BMJ 1998;316:201.
  7. 7. What is the BEST design to answer a clinical question? 1. Cross-sectional study 2. Meta-analysis 3. Epidemiological analysis 4. Randomized 0% 0% 0% 0% 0% controlled trial is ds dy is . ys ys t.. en tu 5. It depends al al d ep ls an an lle na d a- ro al It t io et nt c gi M c co se lo io s- ed m os iz de Cr om i Ep nd Ra
  8. 8. While randomized, controlled trials are capable of providing the most robust evidence, they are not always appropriate or indicated - Jacqueline Limpens Paraphrased from
  9. 9. When would a RCT not be the best choice? 1. The condition or outcome is rare 2. The unit of randomization is too large 3. Ethical issues such 0% 0% 0% 0% 0% as pain management 2 3 .. ... 4. Answers 1 and 2 ... d d pa an an m tio co as iza s1 s2 ut h m er er uc o do sw sw or ss 5. Answers 2 and 3 an An An ue on fr ss it i to li nd ica i un co h e e Et Th Th
  10. 10. K-Type Questions and the NAPLEX I. Answer II. Answer III. Answer A. I only B. II only C. I and II D. II and III E. I, II, and III
  11. 11. Effects of Coke on Sperm Motility 45 40 35 30 25 Old Coke 20 New Coke 15 Diet Coke 10 5 0 Motility @ 1 min pH of Coke N Engl J Med 1985;313(21):1351.
  12. 12. A Few Words About…
  13. 13. What has your experience been with journal clubs so far? 1. I have presented a journal club 2. I have only observed a journal club 0% 0% 0% 3. What is a journal club? b? . n. .. c lu a. ur jo d al ve a n ur r d se te jo ob n sa se y ti re nl ha ep eo W av av Ih Ih
  14. 14. Don’t be this guy
  15. 15. This is the really important bit
  16. 16. Which of your course articles is NOT a RCT? 1. Discontinuation of Drug Therapy in Patients with Atrial Fibrillation 2. Ginkgo biloba for Preventing Cognitive Decline in Older Adults 0% 0% 0% 3. Rituximab, B- Lymphocyte Depletion, ... ... ... ve ug yt oc and Preservation of e Dr Pr ph of r ym fo n t io ba -L Beta-Cell Function ,B ua lo bi ab tin o xim on g nk sc tu Gi Di Ri
  17. 17. 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]
  18. 18. The consequence when a Type I error occurs is that you mistakenly assume: 1. both treatments work. 2. neither treatment works. 3. there is a difference between treatments. 4. there is no difference 0% 0% 0% 0% between treatments. . k. ks ... or ... or be e sw tw c en ce t en en er en m ff tm r di ffe at ea e no di tr tr a is er th is e ith bo er re ne th e th
  19. 19. 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 )
  20. 20. Superiority Trials • If the active control is very effective – it is difficult to demonstrate that a new drug is more effective • If active control is not very effective AND the new drug is slightly better – superiority can be established with a large sample size
  21. 21. Superiority Trials • New drug can only be superior to active control if active control is also effective in current trial
  22. 22. What can be concluded about the efficacy of SJW in major depression from those results? 1. SJW doesn‟t work 2. SJW doesn‟t work as well as sertraline 3. 1/3 of antidepressant trials find an FDA- approved comparator doesn‟t work 0% 0% 0% 0% 4. You can only conclude k that you can‟t conclude .. l .. or .. ria th el w tt w de ’t an sn as clu ss anything e k do re on or ep yc w W t id ’t SJ l on sn an e n do of ca 3 u W 1/ Yo SJ
  23. 23. What did the mainstream press conclude about this study based on their „evaluation‟?
  24. 24. Is JAMA a reputable journal? 1. Yes 2. No 0% 0% s No Ye
  25. 25. What if I told you that I could cite a study in JAMA which found that 2400 mg of ibuprofen/day was used in a patient population and ZERO adverse reactions were reported (not even GI)?
  26. 26. What JAMA; 239 (1): 34-5 year? • Ibuprofen in the treatment of acute gouty arthritis [Abstract] How many patients? ___ patients with acute gouty arthritis were treated with daily doses of 2,400 mg of ibuprofen. All patients had rapid improvement and complete resolution with 72 hours; no adverse reactions were reported. Ibuprofen may be an effective alternative in the treatment of this disorder.
  27. 27. Equivalence Trials • Purpose: To confirm the absence of a meaningful difference between treatments • Equivalence is inferred when ENTIRE confidence interval falls exclusively within equivalence margins (between –Δ and Δ)
  28. 28. Non-inferiority 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 is not inferior to the active comparator *non-inferiority margin, delta (Δ), 
  29. 29. Who is This? 1. Bizarro 2. Deadpool 3. DeadMan 4. Spiderman 5. Superman 0% 0% 0% 0% 0% an l rro an an oo dM rm m za dp r Bi pe de a a De De i Su Sp
  30. 30. Non-inferiority Trials – Null vs Alternative/Research • Type I error – “erroneous acceptance of an inferior new treatment” Note the S is reversed • Type II error – “erroneous rejection of a truly non-inferior treatment” JAMA 2006;295:1152-1160.
  31. 31. Non-inferiority Null & Alternative Hypotheses • Null – no difference in treatments [Desirable in non-inferiority] • Alternative/Research – there is a difference in treatments [Undesirable in non-inferiority]
  32. 32. Erroneous acceptance of an inferior new treatment in non-inferiority trial is: 1. Type I error. 50% 50% 2. Type II error. . r. or ro rr er Ie II pe pe Ty Ty
  33. 33. Non-inferiority Margin* • Non-inferiority margin was traditionally chosen as: – The difference between the active comparator and placebo in a previous trial • Arbitrary choice and may NOT even assure superiority over placebo *delta (Δ), 
  34. 34. Non-inferiority Margin • There is no single way to assess if non- inferiority margin (Δ) is appropriate • Margin (Δ) must be determined by COMBINATION of statistical means and clinical considerations ˆ ˆ ~ ~ PrH 0 {ln(T / C )  1.96 tc  0.5[ln( P0 / C0 )  z(1 x ) / 2 cp 0 ]} 1.96 tc  0.5 z(1 x ) / 2 cp 0  ( )  tc  (0.5) 2  cp 0 2 2 DO NOT MEMORIZE 1.96  0.5 z(1 x ) / 2 f  ( ), 1  (0.5) f 2 where  cp 0 2 # of events in NI trial f  2   tc # of events in historical trials
  35. 35. Non-inferiority – Design • Trial design ideally incorporates a placebo AND active comparator • Presence of placebo allows to establish superiority to placebo and thus validate/establish internal validity (along with non-inferiority to active drug) European Medicines Agency 2005
  36. 36. Non-inferiority – Design • Failure to include placebo can lead to lack of internal validity in non-inferiority trials, but is common • Design flaws TEND TO BIAS RESULTS towards a finding of equivalence • Ethical issues MJA 2009;190(6):326-330.
  37. 37. Non-inferiority – Design • Compliance/adherence • Losses to follow-up • Withdrawals • Missing data • Inclusion/exclusion • Any deviation from criteria protocol Study must be even more closely examined if assessments of any of the above reveal inconsistencies
  38. 38. Non-inferiority trials established which drug as 1st line treatment for Dysphoric Social Attention Consumption Deficit Anxiety Disorder? 1. Alprazolam 2. Avafynetyme 3. Eszopiclone 4. Zaleplon 5. Zolpidem 0% 0% 0% 0% 0% m n em e e lo on m la ep ty d zo cl pi ne pi l ra Za l Zo zo fy p Al a Es Av
  39. 39. Non-inferiority – Comparator • Active comparator (drug) should ideally be widely used with established efficacy via superiority trial and identical indication • Non-inferiority trial should mimic design of superiority trial – Primary variables, doses of comparator, inclusion/exclusion criteria, etc. Biometric Journal 2009;51(1):185-92.
  40. 40. Non-inferiority – Design • Design should be implicitly stated in protocol/methodology • Lower bound of equivalence margin should be clearly stated • Margin determination should be detailed and justified
  41. 41. Non-inferiority – Method of data analysis • Use of intent-to-treat (ITT) is generally misunderstood and its role should be examined carefully – Does not confer same conservative estimates in non-inferiority Curr Control Trials Cardiovasc Med 2000;1(1):19–21.
  42. 42. Inference for Non-Inferiority Delta Limits (95%) and Confidence Intervals Non-inferiority shown Non-inferiority shown Non-inferiority not shown Non-inferiority shown/ superiority issue* - 0 Control Better Test Agent Better Treatment Difference
  43. 43. T has a <10% increase in risk “NI” C inferior by at least 10% T superior increase in risk T/C T = Test Drug 1.0 =1.10 (NI margin) C = Active Control NI = non-inferiority Hung/Wang 2006
  44. 44. Non-inferiority – Conclusion • Determination can be made from observing a non-significant test result of the null hypothesis REMEMBER
  45. 45. Which design tries to prove a drug is no worse than the comparator drug? 1. Superiority 2. Non-inferiority 3. Both 4. Neither 0% 0% 0% 0% th er y y rit r it ith Bo io r io Ne r pe fe in Su n- No
  46. 46. Summary • Superiority: detect a difference between two drugs • Equivalence: confirm absence of significant difference between two drugs • Non-inferiority: show new drug is not worse than active by more than pre-specified amount
  47. 47. Images • • • • • • • • • • •
  48. 48. Images • • • • • • •