Review of Tysabri Risk Minimization Action Plan

(RiskMAP) Diane Wysowski, Ph.D.

Division of Drug Risk EvaluationOffice 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 Patient–Physician 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 Tysabri’s 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