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Perspectives on Non-Inferiority Clinical Trials – based on draft FDA guidance doc DSBS 20 May 2010

Perspectives on Non-Inferiority Clinical Trials – based on draft FDA guidance doc DSBS 20 May 2010. Key contents in FDA draft guidance. Margins M1 = effect of active control M2 = ”clinical” margin (fraction of M1) Analysis methods Fixed Margin method Synthesis method. Notation.

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Perspectives on Non-Inferiority Clinical Trials – based on draft FDA guidance doc DSBS 20 May 2010

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  1. Perspectives on Non-Inferiority Clinical Trials– based on draft FDA guidance docDSBS 20 May 2010 H. Lundbeck A/S24-May-141

  2. Key contents in FDA draft guidance • Margins • M1 = effect of active control • M2 = ”clinical” margin (fraction of M1) • Analysis methods • Fixed Margin method • Synthesis method H. Lundbeck A/S24-May-142

  3. Notation • δCP = effect of active control vs placebo • δTC = effect of test drug vs active control • δTP = effect of test drug vs placebo = δTC + δCP NB: A positive figure indicates ”better” H. Lundbeck A/S24-May-143

  4. Base logic of NI test • If δCP = M1, then showing that δTC > -M1 amounts to showing that δTP > 0, since δTP = δTC + δCP • Showing that δTC is greater than some fraction f of M1, δTC > -fM1 (=M2), amounts to showing that δTC + fδCP > 0 or δTC + δCP = δTP > (1-f)δCP , i.e. that a fraction (1-f) of the effect of C has been preserved H. Lundbeck A/S24-May-144

  5. Inferences based on 95% CI for δTC T superior to C demonstrated Preservation of p % benefit demonstrated T superior to P demonstrated δTC=0 M1(δTP=0) M2 Preserved: p=0% 0%<p<100% p=100% H. Lundbeck A/S24-May-145

  6. Analysis methods • Fixed Margin • Use historical estimate of δCP and its SE to derive a fixed margin for the test (typically lower limit of 2-sided 95% CI) • Synthesis • Treat historical estimate of δCP as a random variable • Assume independence between historical data and NI trial and use as analysis basis • δTP = δTC + δCP • V(δTP) = V(δTC)+ V(δCP) H. Lundbeck A/S24-May-146

  7. Fixed Margin versus Synthesis criteria H. Lundbeck A/S24-May-147

  8. Fixed Margin versus Synthesis criteria • Fixed margin method inefficient and overly conservative (Rothmann et al., Stats in Med 22: 239-264, 2003) • Synthesis method more efficient and takes the variability of both historical data and NI trial data into account in a natural way H. Lundbeck A/S24-May-148

  9. Fixed Margin M1 Fixed Margin M2 Synthesis M1 Synthesis M2 FDA position on margins and methods More conservative method Preferred option More conservative margin H. Lundbeck A/S24-May-149

  10. The case for ”One Standard of Evidence”(PhRMA PISC Expert Team White Paper, BASS XV, 2008) • The traditional standard of evidence for efficacy of a new treatment T is statistically significant evidence that δTP > 0 • Why should an arbitrarily higher standard of evidence (δTP > δ > 0) be used when an active-controlled (AC) trial has been used? • Preservation margin is arbitrary • Preserving less than p% does not imply ineffectiveness of T • In contrast, δTP = 0 has a definite objective clinical meaning • Requiring a higher standard of evidence for AC trials institutes a regulatory bias in favor of the first drug to be approved (requiring preservation of p% may lead to rejection of T even thought T is better than C) H. Lundbeck A/S24-May-1410

  11. Hypothetical example: 95% CIs relative to P T and C are both superior to P and data suggests that T might be better than C but because C was approved first and T does not meet the p% margin T can’t be approved C vs P T vs P p % margin δTP=0 H. Lundbeck A/S24-May-1411

  12. Example: Metastatic Bladder Cancer • Randomized trial* of Gemzar + cisplatin compared to MVA + cisplatin • An earlier randomized trial** showed superioty of MVA + cisplatin to cisplatin • In our notation T=Gemzar, C=MVA, P=cisplatin • δTC = log hazard ratio (MVA over Gemzar) • δCP = log hazard ratio (”no treatment” over MVA) • δTP = log hazard ratio (”no treatment” over Gemzar) * Von der Masse et al.: JCO, 18:3068-3077 ** Loehrer et al.: JCO, 10:1066-1073 H. Lundbeck A/S24-May-1412

  13. Metastatic Bladder Cancer cont’d • Point estimates • Synthesis method estimated 90.7% preservation of benefit but lower 95% bound was only 11.7% • So ”preservation of 50% benefit” criterion was not met but Gemzar+cisplatin was statistically superior to cisplatin alone (2-sided pvalue=0.035) H. Lundbeck A/S24-May-1413

  14. Metastatic Bladder Cancer cont’d • Assuming constancy of δCPacross trials • Gemzar improves survival when added to cisplatin (p=0.035) • Gemzar+cisplatin was estimated to have similar efficacy as MVA+cisplatin (estimated HR=0.96) • Why do a test for preservation of effect? H. Lundbeck A/S24-May-1414

  15. Conclusions • One standard of evidence for efficacy should be used – superiority to placebo – regardless of the design used (placebo- or active-controlled) • The synthesis method should be used rather than the fixed margin method for better efficiency H. Lundbeck A/S24-May-1415

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