1. H. Lundbeck A/S16-Apr-151 Perspectives on Non-Inferiority Clinical Trials – based on draft FDA guidance doc DSBS 20 May 2010

2. H. Lundbeck A/S16-Apr-152 Key contents in FDA draft guidance Margins –M1 = effect of active control –M2 = ”clinical” margin (fraction of M1) Analysis methods –Fixed Margin method –Synthesis method

3. H. Lundbeck A/S16-Apr-153 Notation δ CP = effect of active control vs placebo δ TC = effect of test drug vs active control δ TP = effect of test drug vs placebo = δ TC + δ CP NB: A positive figure indicates ”better”

4. H. Lundbeck A/S16-Apr-154 Base logic of NI test If δ CP = M1, then showing that δ TC > -M1 amounts to showing that δ TP > 0, since δ TP = δ TC + δ CP Showing that δ TC is greater than some fraction f of M1, δ TC > -fM1 (=M2), amounts to showing that δ TC + fδ CP > 0 or δ TC + δ CP = δ TP > (1-f)δ CP, i.e. that a fraction (1-f) of the effect of C has been preserved

5. H. Lundbeck A/S16-Apr-155 Inferences based on 95% CI for δ TC M1(δ TP =0) δ TC =0 M2 Preserved:p=0%p=100%0%<p<100% T superior to P demonstrated T superior to C demonstrated Preservation of p % benefit demonstrated

6. H. Lundbeck A/S16-Apr-156 Analysis methods Fixed Margin –Use historical estimate of δ CP and its SE to derive a fixed margin for the test (typically lower limit of 2- sided 95% CI) Synthesis –Treat historical estimate of δ CP as a random variable –Assume independence between historical data and NI trial and use as analysis basis δ TP = δ TC + δ CP V(δ TP ) = V(δ TC )+ V(δ CP )

7. H. Lundbeck A/S16-Apr-157 Fixed Margin versus Synthesis criteria

8. H. Lundbeck A/S16-Apr-158 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

9. H. Lundbeck A/S16-Apr-159 FDA position on margins and methods Fixed Margin M1 Fixed Margin M2 Synthesis M1 Synthesis M2 More conservative margin More conservative method Preferred option

10. H. Lundbeck A/S16-Apr-1510 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 δ TP > 0 Why should an arbitrarily higher standard of evidence (δ TP > 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, δ TP = 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)

11. H. Lundbeck A/S16-Apr-1511 Hypothetical example: 95% CIs relative to P δ TP =0 p % margin 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

12. H. Lundbeck A/S16-Apr-1512 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 –δ TC = log hazard ratio (MVA over Gemzar) –δ CP = log hazard ratio (”no treatment” over MVA) –δ TP = log hazard ratio (”no treatment” over Gemzar) * Von der Masse et al.: JCO, 18:3068-3077 ** Loehrer et al.: JCO, 10:1066-1073

13. H. Lundbeck A/S16-Apr-1513 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)

14. H. Lundbeck A/S16-Apr-1514 Metastatic Bladder Cancer cont’d Assuming constancy of δ CP across 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?

15. H. Lundbeck A/S16-Apr-1515 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