1. 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

2. 2 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

3. 3 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

4. 4 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

5. 5 Tysabri Enrollment Process Mandatory Patient–Physician Acknowledgment Form (Informed Consent) completed and signed by patient and physician Tysabri forms and Rx sent to sponsor

6. 6 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

7. 7 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

8. 8 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.

9. 9 Tysabri Distribution Tysabri shipped from “centralized distribution system” -one distributor - ≤12 specialty pharmacies -shipped only after receiving patient authorization code from sponsors

10. 10 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

11. 11 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)

12. 12 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

13. 13 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”

14. 14 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 Tysabri’s PML risk -appropriate use conditions

15. 15 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

16. 16 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

17. 17 Issue: Maximizing Benefit, Minimizing Risk of Tysabri Should there be Tysabri restriction: By MS disability severity? By failure on other MS therapies?

18. 18 Issue: Minimizing PML Risk Should there be: Tysabri contraindication for concomitant and recent use of: -immune modulator drugs, -systemic corticosteroids, and -immune suppressant drugs?

19. 19 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?

20. 20 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?

21. 21 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?

22. 22 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

23. 23 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

24. 24 SUMMARY Issues presented should be carefully considered to maximize Tysabri benefits and minimize PML risk.

25. 25 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