Review of Tysabri Risk Minimization Action Plan RiskMAP

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Review of Tysabri Risk Minimization Action Plan
(RiskMAP)

• Diane Wysowski, Ph.D.
• Division of Drug Risk Evaluation
• Office of Drug Safety
• Peripheral and Central Nervous System Drugs
  Advisory Committee Meeting
• March 7-8, 2006

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Presentation Outline

• Briefly review main features of
• -Tysabri RiskMAP goals and methods
• -Tysabri Registry for PML
  surveillance
• -Tysabri Observational Study
• Present issues/questions re above

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Sponsors Tysabri RiskMAP Goals

• To promote informed risk-benefit decisions re
  Tysabri use in treatment of MS pts.
• To minimize risk of PML
• contraindicated in immunocompromised patients
• To minimize health consequences of PML
  (death/disability) thru early diagnosis

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Tysabri Enrollment Process

• Medication Guide provides pt. info. re Tysabri,
  PML (death/disability) risk, other safety
  concerns, instructions to report any new or
  continuously worsening neurological symptoms
• Mandatory enrollment of prescribers and patients
  through Enrollment form

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Tysabri Enrollment Process

• Mandatory PatientPhysician Acknowledgment Form
  (Informed Consent) completed and signed by
  patient and physician
• Tysabri forms and Rx sent to sponsor

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Patient-Physician Acknowledgment Form

• Physician acknowledges / signs
• Has read full prescribing information
• Is aware of PML risk (disability/death)
• Has discussed risk / benefits with pt.
• Is prescribing for relapsing MS
• Confirms pt. has no contraindications
• Has told pt. to report new or worsening
  neurological symptoms
• Is enrolling in Tysabri Registry

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Patient-Physician Acknowledgment Form

• Patient acknowledges / signs
• Has read Medication Guide
• Is aware of PML risk (disability/death)
• Has discussed risks / benefits with M.D.
• Understands need to report to M.D. new or
  worsening neurological symptoms
• Is enrolling in Tysabri Registry

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Tysabri Authorization

• Sponsors plan to
• Enter patient and prescriber M.D. information
  into Tysabri Registry
• Match patient to authorized infusion center
• Notify infusion center of pt. authorization to
  receive Tysabri
• Provide center with Pt. Authorization No.

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Tysabri Distribution

• Tysabri shipped from centralized distribution
  system
• -one distributor
• - 12 specialty pharmacies
• -shipped only after receiving patient
  authorization code from sponsors

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Tysabri Administration

• Tysabri administered only at trained / authorized
  infusion ctrs.
• -hospital clinic
• -stand alone clinic
• -M.D. office
• Sponsors estimate 2,000 authorized infusion
  centers

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Tysabri Administration

• Infusion Center Nurses To Confirm
• M.D. and pt. enrolled in Registry
• Patient has MS (Patient Checklist)
• Patient has Medication Guide and has read it
  (Checklist)
• Pt. is not known to be immunocompromised by HIV,
  hem. cancers, organ transplants, anti-neoplastic
  and immunosuppressive drugs (Checklist)
• Pt. has not experienced any new or continuously
  worsening neurological symptoms lasting over
  several days (Checklist)
• Dose administered is documented (Infusion log)

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Tysabri Administration

• No specific contraindications of Tysabri with
  concomitant/recent use of
• -immune modulator drugs (e.g., interferon beta)
• -systemic corticosteroids (e.g.,
  methylprednisolone)
• -other steroid and immune suppressant drugs
  

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Tysabri Administration

• Patient Checklist gives examples of a few
  diseases and six drugs that induce
  immunocompromise
• Sponsors focus group wanted all drugs and
  diseases that could induce an immunocompromised
  status clearly spelled out

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Education of Prescribers, Infusion Center Nurses

• Sponsors propose to
• Deliver ongoing educational info. via mailings,
  website, toll-free helpline,
• CME programs
• Survey M.D.s and infusion center nurses
• -knowledge of Tysabris PML risk
• -appropriate use conditions

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Tysabri Registry / Pt. Follow-Up

• Sponsors will query prescribing M.D. every 6
  months for
• -pt. continuation of Tysabri
• -any PML cases
• Length of patient f/u not specified

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PML Cases

• Sponsors plan
• Special assessment (questionnaire, MRI, CSF JC
  virus) of suspected PML cases for early diagnosis
  of PML and incidence rate
• Submission of data for uncertain diagnoses to
  external PML expert
• Qualitative analyses of PML risk factors

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Issue Maximizing Benefit, Minimizing Risk of
Tysabri

• Should there be Tysabri restriction
• By MS disability severity?
• By failure on other MS therapies?

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Issue Minimizing PML Risk

• Should there be
• Tysabri contraindication for concomitant and
  recent use of
• -immune modulator drugs,
• -systemic corticosteroids, and
• -immune suppressant drugs?

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Issue Patient Assessment

• Should there be
• Periodic M.D. REassessment and REauthorization of
  patients to receive Tysabri? If so, how
  frequently?
• Assessment by M.D. (vs. nurse) of neurological
  symptoms and immune suppression before Tysabri
  administration?
• Inclusion on Pt. Checklist of all diseases and
  drugs that can induce an immunocompromised state?
  

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Issue Tracking Tysabri Vials

• Should there be
• One to one patient to vial distribution
• (each vial associated with a patient)
• for tight control of Tysabri distribution
• and tracking?

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Issue Patient Follow-up

• Aided by
• Real time collection of Tysabri administration,
  discontinuation, and reasons for discontinuation?
  
• Follow-up of patient deaths thru the National
  Death Index and collection of death certificates?
  

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Tysabri Observational Study

• Tysabri observational study (subset of 3,000
  U.S. Tysabri Registry patients) followed for up
  to 5 years after starting Tysabri for
• -serious non-PML opportunistic
  infections
• -cancer
• -overall safety profile

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Evaluation Re Tysabri Observational Study

• Ascertainment of deaths and causes thru National
  Death Index and death certificate collection
• Inclusion of all patients in Tysabri Registry
• Problems in interpretation of etiology
• -no non-exposed MS controls
• -availability of population control data

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SUMMARY

• Issues presented should be carefully considered
  to maximize Tysabri benefits and minimize PML
  risk.

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Tysabri ODS RiskMAP Review Team

• Mark Avigan, M.D., C.M., Director, DDRE
• Allen Brinker, M.D., M.P.H., Epidemiology TL,
  DDRE
• Jonca Bull, M.D., Acting Deputy Director, ODS-IO
• Gerald Dal Pan, M.D., M.H.S., Director, ODS-IO
• Mary Dempsey, Project Management Office, ODS-IO
• Andrea Feight, D.D.S., M.P.H., Epidemiologist,
  DSRCS
• Charlene Flowers, R.Ph., Safety Evaluator, DDRE
• Laura Governale, Pharm.D.,M.B.A., Drug
  Utilization TL, DSRCS
• Claudia Karwoski, Pharm.D., Scientific
  Coordinator, ODS-IO
• Cindy Kortepeter, Pharm.D. Safety Evaluator TL,
  DDRE
• Toni Piazza-Hepp, Pharm.D., Acting Deputy
  Director, DSRCS
• Judy Staffa, R.Ph., Ph.D., Epidemiologist TL,
  DSRCS
• Diane Wysowski, Ph.D., Epidemiologist, DDRE