1. “Friend of the Court” Comments Ronald W. Helms, Ph.D. Rho, Inc. and Professor Emeritus, Biostatistics, University of North Carolina Fellow, American Statistical Association CS-1

2. CS-2 Why We are Here

3. CS-3 Second Reason for My being Here This is a very interesting project.

4. CS-4 Disclaimer The views expressed in this presentation are mine alone and do not represent: –FDA –Chiron –Rho, a contract research organization in Chapel Hill and my current employer. –The University of North Carolina Department of Biostatistics, my employer until I retired. But these views may represent the best interests future lung transplant patients.

5. CS-5 Rho/Helms “Financial Conflict of Interest” Neither Rho nor I have any financial stake in the outcome of this NDA. –Less than 0.5% of Rho’s total income this year will come from Chiron –Chiron pays Rho an hourly consulting fee for my time + travel expenses. –Rho’s Board of Directors told me they prefer that I work on other, more financially rewarding projects. Neither FDA nor Chiron has edited my presentation. I have reviewed the briefing docs from FDA and Chiron, plus other, more comprehensive documentation.

6. CS-6 So, Why am I here?

7. CS-7 This is an interesting project … and we have a problem…. We – the professionals involved in this review – Advisory Panel, FDA staff, Chiron staff – have a problem. The Kaplan-Meier graph tells us this product has the potential to save the lives of a socially significant number of lung transplant patients. This NDA does not meet the usual regulatory requirements for approval. Should it be approved?

8. CS-8 Some Advantages of Approval The results indicate that if approved, widespread use of CyIS would probably save the lives of ~300-350 lung transplant patients per year. In general terms, CyIS appears to improve survival probability about 30-35 percentage points. Placebo ~53%, CyIS ~89%. There are about 1,000 U.S. lung transplants/year. –A product for this indication is “deeply orphan.” –Orphan status: # patients/year < 200,000

9. CS-9 Some Advantages of Approval If CyIS were approved, FDA could require Chiron to conduct the sufficiently large followup study that Chiron has proposed. –If the followup study were negative the approval could be withdrawn. –As a practical matter, without approval the followup study will probably never be run. –Off-label CyIS would ultimately become standard of care; failure to use it will be unethical. Aside: this is true for cyclosporine, which is not approved for lung transplants – the studies have never been done.

10. CS-10 Some Obstacles to Approval We have the results of only one “small” unconfirmed study. –Serious problem. The one study has flaws, as noted by both Chiron and FDA. –One flaw is very important. –Some flaws are potentially important. –Some are inconsequential (my opinion).

11. CS-11 Some Obstacles to Approval – Very Important Flaw in the Clinical Trial The stated primary outcome was acute rejection, not mortality/survival. –Statistical methods routinely used for Phase 3 confirmatory studies are not very helpful with this problem (“switching primary endpoint”). –Good, old-fashioned common sense can be helpful: When you see that big an effect on survival you’ve very likely made an important discovery. –We could use a branch of statistics called “decision theory” for a formal risk-benefit analyses.

12. CS-12 Some Obstacles to Approval – Potentially Important Flaws in the Clinical Trial Important side note: –FDA and Chiron biostatisticians have confirmed each other’s statistical calculations. There is no issue about correctness of calculations. –Opinion: The issues are about how to use and interpret the statistics, not the actual results.

13. CS-13 Some Obstacles to Approval – Potentially Important Flaws in the Clinical Trial Randomization: If done improperly this could be an important flaw. Lack of balance with respect to important baseline characteristics. Unmasking (a.k.a. “unblinding”): The study was conducted in such a manner that investigators could have been unmasked. This study was conducted at a single clinical center, not multiple centers.

14. CS-14 Some Obstacles to Approval – Potentially Important Flaws in the Clinical Trial Bottom line: –I reviewed each of these potentially important flaws. –My conclusions: each “flaw” is either: not a flaw at all, or relatively unimportant. –Example: Randomization “failed” to balance w.r.t. all important baseline factors – it rarely does. –If requested, I will be happy to discuss any of these in somewhat more detail.

15. CS-15 Some Obstacles to Approval – Unimportant Flaws in the Clinical Trial We do not need to address unimportant flaws, such as: –Various relatively minor statistical issues –Lack of a priori, printed CRFs –Study terminated at end of specified time period, before target number of subjects were enrolled.

16. CS-16 An Important Ethical Point What if: –The data before us were the results of an interim analysis halfway through the study. –The members of this Advisory Panel were instead sitting as the study’s Data and Safety Monitoring Board. –Would we be ethically bound to terminate this study to protect future patients who might be assigned to placebo? I’ve participated in many DSMBs and I believe every single one would have stopped this study. The results of this study are that compelling.

17. CS-17 Another Important Ethical Point I think the people in this room – FDA staff, Advisory Panel, Chiron staff – are ethically bound to find a way: –To make this product available – on label – to U.S. lung transplant patients. Without approval, for years CyIS will only be available to people who can afford to pay for it from their own funds – wealthy people. –To make it necessary for Chiron to conduct their proposed post-approval followup study. Realistically, this can only be done as a post-approval study.

18. CS-18 What an Interesting Project!