Certican

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Certican (everolimus) TabletsProphylaxis of
rejection in heart transplantation

• Renata Albrecht, M.D.
• Steve Gitterman, M.D., Ph.D.
• Division of Special Pathogen and Transplant
  Products
• Office of Antimicrobial Products
• OND/CDER/FDA

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Cardiovascular and Renal Drugs Advisory
CommitteeNovember 16, 2005

• Standing committee
• Experts and consultants
• Cardiology, nephrology, transplantation,
  statistics, clinical pharmacology
• Approvable action previously taken
• Novartis interested in a public discussion of
  Certican application and unmet medical need in
  heart transplantation

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Agenda

• Novartis presentation
• Overview of cardiac transplantation
• FDA presentation
• Questions for committee discussion and vote

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Certican NDA 21-628

• Phase 3 comparative studies
• Heart study B253
• Renal studies B201, B251
• Regimen
• Fixed-dose everolimus, full dose
  cyclosporine, and steroids
• Protocol amended at 12 months due to toxicity

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Certican withfull dose cyclosporine

• Approvable letters (see Novartis backgrounder)
• Risk outweighs benefit
• Novartis proposed labeling
• Certican should not be used long-term together
  with full doses of cyclosporine.

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Question 1

• Fixed-dose everolimus and full-dose
  cyclosporine
• Novartis has presented the results and
  extensively discussed the use of a fixed-dose
  everolimus regimen with full-dose cyclosporine
  in study B253. Both FDA and Novartis agree that
  this exact fixed-dose regimen should not be used
  for the prophylaxis of organ rejection in cardiac
  transplantation. Do committee members agree with
  this conclusion?

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Therapeutic Drug Monitoring (TDM)

• Novartis will present proposed dosing regimen in
  heart transplantation
• Everolimus dosing
• Cyclosporine dosing
• No prospective randomized study of TDM in heart
  transplantation conducted
• Other sources of information
• Analyses from full dose cyclosporine heart
  study
• Proposed extrapolation from noncomparative kidney
  TDM studies
• Clinical Pharmacology Modeling

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Question 2

• Therapeutic Drug Monitoring
• Novartis has proposed an alternative TDM-based
  regimen for the use of everolimus in combination
  with cyclosporine. The proposed regimen has not
  been prospectively tested in a cardiac
  transplantation study. In the absence of a
  prospective study of this regimen, do committee
  members believe there is sufficient information
  available to conclude that the regimen as
  proposed by Novartis has been demonstrated to be
  safe and effective for use in heart
  transplantation?

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Question 2 (continued)

• In your discussion, please be specific regarding
  what information supports the proposed TDM-based
  regimen.
• Please discuss in your answer whether you believe
  that everolimus has been shown safe and effective
  for all cardiac transplant recipients.
• Alternatively, please discuss whether you believe
  there are certain subgroups where use should be
  specifically indicated or specifically
  restricted.

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Question 3

• Are Additional Data Needed?
• If your answer to question 2 is YES, that the
  proposed TDM-regimen is safe and effective,
  please comment on what additional information
  should be obtained regarding everolimus
  post-approval. Additionally, do you have any
  recommendations regarding labeling (package
  insert).

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Question 4

• What Additional Data Are Needed?
• If your answer to question 2 is NO, please
  comment what additional information would be
  necessary for approval. For example, please
  comment whether the currently-ongoing European
  study and/or the planned US cardiac
  transplantation study would be adequate to
  demonstrate safety and efficacy. Also comment
  whether additional data or studies would be
  necessary.