Friend of the Court Comments

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Friend of the Court Comments
CS-1

• Ronald W. Helms, Ph.D.
• Rho, Inc. and
• Professor Emeritus, Biostatistics, University of
  North Carolina
• Fellow, American Statistical Association

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Why We are Here
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Second Reason for My being Here

• This is a very interesting project.

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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.

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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 Rhos total income this year
  will come from Chiron
• Chiron pays Rho an hourly consulting fee for my
  time travel expenses.
• Rhos 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.

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So, Why am I here?
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This is an interesting project andwe 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?

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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

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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.

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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).

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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
  youve very likely made an important discovery.
• We could use a branch of statistics called
  decision theory for a formal risk-benefit
  analyses.

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Some Obstacles to Approval Potentially
Important Flaws in the Clinical Trial

• Important side note
• FDA and Chiron biostatisticians have confirmed
  each others 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.

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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.

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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.

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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.

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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 studys Data and Safety Monitoring
  Board.
• Would we be ethically bound to terminate this
  study to protect future patients who might be
  assigned to placebo?
• Ive participated in many DSMBs and
• I believe every single one would have stopped
  this study.
• The results of this study are that compelling.

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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.

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What an Interesting Project!