# Presentation: 060909

## 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

## 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

***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***

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## Current Risk Management Programs

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

## 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

## 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

## 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

## 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

## Potential Options for the Design of a Lotronex Risk Management Plan

## GlaxoSmithKline Proposal:

-    Reintroduce Lotronex to the Market and Restrict Access Under the Provisions of Subpart H

## 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

## 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)

## 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

## 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

## 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)

## 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

## 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

## 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)

## Slide 25

## 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

## Slide 27

## 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