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Goals of a Lotronex® Risk Management Program

Toni Piazza-Hepp, Pharm.D.Deputy Director

Division of Surveillance, Research and Communication Support

Office of Drug Safety

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From: Managing the risks from medical product use; creating a risk management framework, Report to the Commissioner from the FDA Task Force on Risk Management, May 1999

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Options for Drug Access

• No Patient Access– Drug not approved or marketing suspended

• Investigational New Drug (IND) Access– Availability only under study protocol

• Marketing Under Restricted Distribution– Topic of this presentation

• Normal Marketing Conditions– No special restrictions to drug access

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Components of Current Risk Management Programs

• Education– Patients, prescribers, pharmacists

• Registration– Patients, prescribers, pharmacists

• Prescribing and dispensing restrictions• Patient monitoring• Assessment of:

– Compliance with program elements– Ability of program to manage drug risks

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Education: Patients, Prescribers, Pharmacists

• Purpose– Provides description of the program

– Communicates risks and benefits of treatment

– Can be used to:

• Encourage participation in plan assessment activities such as surveys

• Encourage reporting of adverse events

• Considerations– Burdensome, expensive, time-consuming

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Registration: Patients, Prescribers, and/or

Pharmacists• Purpose

– Creates a target population for education, monitoring, and follow-up surveys

– Provides mechanisms to measure plan success• Patient denominator, mandatory surveys associated

with registrations, etc.

• Considerations– Burdensome, expensive, time-consuming– Patient privacy concerns

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Prescibing and Dispensing Restrictions

• Purpose– Limits drug access to targeted patients– Allows pharmacist to verify that prescriptions are written by

authorized prescribers– “No Refills” ensures patients return for follow-up– Drug distribution in special packaging

• can: limit drug supply, include MedGuide, have reinforcing messages on packaging, etc.

• Considerations– Burdensome, expensive, time-consuming– Patient access issues: needy or remotely located – May encourage alternate sourcing

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Patient Monitoring at Regular Intervals

• Purpose– Assures patient follow-up

• Benefit and Safety

– Opportunity for reinforcing safety messages– Opportunity for obtaining and evaluating adverse

event information• Considerations

– Burdensome, expensive, time-consuming– Additional office visits may be necessary

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Assessment of Compliance with Program Elements

• Purpose

– Surveys of patients, prescribers, and/or pharmacists to measure plan compliance, adverse events, etc.

• Considerations

– Burdensome, expensive, time-consuming

– Voluntary surveys: level of participation may be inadequate

• Question whether respondents are representative of all patients receiving drug

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Current Risk Management Programs

• Some (not all) programs are approved under the Subpart H regulation– Provides requirement for postmarketing

restrictions

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21CFR 314 Subpart H: Accelerated approval for serious or life-threatening illnesses

314.520 • FDA will require postmarketing restrictions if it concludes

that a drug product can be safely used only if distribution or use is restricted – e.g. restrictions to certain facilities, physicians with

special training or experience, the performance of specified medical procedures

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21CFR 314 Subpart H: Accelerated approval for serious or life-threatening illnesses

314.530 • FDA may withdraw approval, following a hearing, if

demonstrated that postmarketing restrictions are: – inadequate to assure safe use or – if the applicant fails to adhere to the agreed upon

postmarketing restrictions under Subpart H

314.550 • Promotional materials must be preapproved

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Advantages of Subpart H vs. Voluntary Restriction Program

• Regulatory control by FDA– Rapid withdrawal possible if restrictions not

met or plan fails to accomplish safe use• Auditing needed to assess this

• Review of promotional material (advertising) mandatory

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Drugs with Restricted Distribution

Approved under Subpart H

• Thalidomide (Thalomid): for erythema nodosum leprosum– Teratogenicity

• Fentanyl (Actiq): for breakthrough cancer pain– Child Safety / Abuse and Diversion

• Bosentan (Tracleer): for pulmonary hypertension– hepatotoxicity and teratogencity

• Mifepristone (Mifeprex): for pregnancy termination– appropriate pt management, drug security

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Potential Options for the Design of a Lotronex Risk Management Plan

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GlaxoSmithKline Proposal:

Reintroduce Lotronex to the Market and Restrict Access Under the

Provisions of Subpart H

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GSK Proposed Plan: Strengths

• Educational Component• Enhanced Labeling• Medication Guide• Special Packaging

– Provides for limited supply

– MedGuide included

• Dose titration phase– 1mg per day for first 4 weeks

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GSK Proposed Plan: Strengths

• Expedited reporting of targeted adverse events• Pre-approval of promotional materials• Program evaluation component

– Patient survey (Slone Epidemiology Unit)

– Prescribing practices (UnitedHealthcare)

• Continued study• (no refills)

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GSK Proposed Plan: Weaknesses

• Patient selection: – “failed conventional therapy” not adequate to describe severe or

debilitating disease

• Qualified prescribers: attestation of qualifications only is proposed– In current plan, prescribers do not receive education, certification,

or registration with GSK prior to receiving kit with stickers– Program does not limit prescribing to gastroenterologists or

similarly trained MDs

• Monitoring of patients by prescribers on a regular basis: not in current plan– Patient burden to identify problems and contact MD

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GSK Proposed Plan: Weaknesses

• Program submitted did not include “no sticker-no drug” concept – sticker only on initial prescription; refills allowed

without new prescription

– GSK planning to add this concept to plan

• Utility of stickers as an authorized prescriber check is an untested method

• Program assessment not designed to measure compliance with use of stickers

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GSK Proposed Plan: Weaknesses

• Program assessment includes voluntary survey using Eckerd Pharmacy patients– No assurance that survey will be representative

of all Lotronex patients– Program does not include other means to more

widely distribute survey (via prescriber or special packaging) or mandatory survey (via registration of all patients)

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Considerations in Developing Goals for a Lotronex Risk Management Plan:

• Goals stated in Letter Regarding Lotronex from CDER to IBS patients December 18, 2000– Safer use of Lotronex in appropriately informed

patients– Continued access to Lotronex by severely affected

IBS patients under closely monitored conditions– Continued clinical studies of the benefits and risks,

and safe use of Lotronex

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Additional Considerations in Developing Goals for a Lotronex Risk Management Plan:

• Risk factors for ischemic colitis not known– continued IC events must be expected

• Complications of constipation may be prevented by recognizing constipation– but some patients did not report constipation before

complications occurred

• Subpart H considerations– serious/life-threatening disease

– ability to determine success of plan

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Proposed FDA Goals for a Lotronex Risk Management Plan

1) Provide access to severely affected IBS patients

2) Limit prescribers to qualified physicians

3) Identify IC and SCC symptoms early through close medical monitoring (regular follow-up)

4) Measure success of plan (auditing)

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D GSK PROPOSED

PLANEDUCATION MD REGISTRATIONPT REGISTRATIONPHARMACISTREGISTRATIONLIMIT TOGASTROENTER-OLOGISTSLIMIT TOSEVERE IBSREGULAR PTFOLLOWUPBY PHYSICIANAUTHORIZEDPRESCRIBERCHECK MECHANISM

NO REFILLS SPECIAL PACKAGING AUDITING MECHANISM

GOAL 1- severe IBS ?GOAL 2 - qualified MDGOAL 3 - follow-upGOAL 4 - auditing ?

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Plan Design Considerations

• GSK plan does not appear to meet FDA goals

• Alternate plan designs should be considered in order to better meet FDA goals

• Consider incorporation of additional components from other risk management programs

• Seek advice from the Advisory Committee

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A B C D GSK PROPOSED

PLANEDUCATION

MD REGISTRATION

PT REGISTRATION

PHARMACISTREGISTRATION

LIMIT TOGASTROENTER-OLOGISTS

LIMIT TOSEVERE IBS

REGULAR PTFOLLOWUPBY PHYSICIAN

AUTHORIZEDPRESCRIBERCHECK MECHANISM

NO REFILLS

SPECIAL PACKAGING

AUDITING MECHANISM

GOAL 1- severe IBS ?GOAL 2 - qualified MD ?GOAL 3 - follow-up

GOAL 4 - auditing ? ?

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Conclusion

• The full range of drug access options needs to be considered

• If approach is to market under Subpart H, begin with a more restrictive plan than that proposed by GSK in order to meet the proposed FDA goals

• Re-evaluate the program at a specified time (e.g., at one year post-implementation) for:– Compliance with program elements – Ability of program to manage risks

• Modify program at that time if appropriate