Alvimopan RiskMAP

1. Alvimopan RiskMAP Joyce Weaver, Pharm.D., BCPS Office of Surveillance and Epidemiology

2. What is a RiskMAP?* • A RiskMAP is a strategic safety program • Designed to meet specific goals and objectives in minimizing product risks • Uses one or more RiskMAP tools to meet goal(s) • Goes beyond FDA-approved labeling * Guidance for Industry: Development and Use of Risk Minimization Action Plans (RiskMAP); available at http://www.fda.gov/cder/guidance/6358fnl.pdf

3. How do RiskMAPs Work? • Limit use to settings or patients with favorable risk-benefit profile • Prevent use in high-risk settings or patients • Encourage/mandate safety-related monitoring • Start therapy in closely monitored settings • Empower patients to participate in medication-related decisions and safety monitoring • Education • Informed consent • Educate healthcare providers on safety-related medication issues and monitoring

4. RiskMAP Components • Goals & Objectives - Desired end result (with intermediate steps), most often stated in terms of one or more health outcomes to avoid • Tools - processes or systems beyond labeling intended to achieve goals and objectives • Education and outreach • Reminder/prompting systems • Restricted Distribution Systems; aka Performance-linked Access Systems (PLAS) • Evaluation -The performance of the overall RiskMAP and tools in achieving its goals and objectives • Health outcomes or surrogates of health outcomes – numbers or rates of an outcome or event • Compliance with important RiskMAP processes and procedures • Assessment of comprehension, knowledge or desired behavior (e.g., surveys)

5. Targeted Education and Outreach • Purpose: to communicate risks and appropriate safety behaviors to healthcare practitioners and patients • Examples: • DHCP letters • Training programs for HCPs or patients • Continuing Education • Patient labeling such as Medication Guides and Patient Package Inserts • RiskMAP program guides • Videos/DVDs • Limits in marketing or promotion such as no DTC or detailing only certain specialties

6. Reminder/Prompting Systems • Purpose: to assist healthcare providers in following appropriate prescribing practices • Examples: • Limited supply of product per prescription such as dispensing only a 30-day supply • Limits on the number of refills or not allowing refills • Prescription expiration such as requiring a prescription to be filled in a certain period of time • Specialized packaging – • requiring certain warnings • packaging to include MG or PPI • pharmacist checklist • limiting the amount packaged • Prescriber or other HCP attestation of conditions of safe use • MD/patient agreement (e.g., informed consent)

7. Restricted Distribution/ Performance-Linked Access Systems • Purpose: to target the population and conditions of use most likely to confer benefits and to minimize particular risks. Includes prescribing, distribution, dispensing, and/or administering restrictions • Examples: • Prescriptions only by specially certified HCPs • Product dispensing limited to pharmacies or HCPs that elect to be specially certified • Mandatory pharmacy enrollment to dispense • Mandatory enrollment of infusion center or hospital to administer • The drug be dispensed or administered only in certain healthcare settings • Product dispensing only to patients with evidence or other documentation of safe use (e.g., required pregnancy testing) • Wholesaler agreement to distribute product only to registered entities

8. When Should a RiskMAP be Considered? • Products with important benefits should be considered for a RiskMAP in one or more of the following situations: • Risks are serious and preventable • Safe and effective use may call for specialized healthcare skills or settings • When a RiskMAP encourages appropriate use to increase benefits relative to risks • Product is in a class of products with similar risks that require a RiskMAP

9. Proposed Alvimopan RiskMAP • Addresses cardiovascular risk • Sponsor has not made a complete RiskMAP submission • No goals, objectives, supporting documents, detailed implementation plans, evaluation plan, metrics, RiskMAP reporting to FDA • RiskMAP outline based on assumption that cardiovascular safety risks will be minimized by limiting use to inpatient settings

10. Do we understand the risks? • Follow-up in short-term trials not sufficient to ascertain cardiovascular events and other risks (neoplasms, fractures) discovered with long-term testing • Proposed daily dosage is 24 X higher than the dose that produced cardiovascular safety signal in long-term testing

11. Proposed Alvimopan RiskMAP • Agreements with pharmaceutical wholesalers to sell only to hospitals • Targeted education, sales, promotion • Packaging that specifies hospital use • Alert system for outpatient pharmacies not to dispense alvimopan on an outpatient basis

12. Alvimopan RiskMAP Concerns • Current proposal may not prevent longer term use or outpatient use • Pharmaceutical wholesalers do not have a definition of “acute-care hospital” • Many hospital pharmacies dispense for outpatients • Physicians may want patients to finish a course of therapy at home • Extended inpatient stays possible • Alert system for outpatient pharmacies • Available in 50% pharmacies • Pharmacist can override • No collection of medical outcomes to determine if CV events are minimized

13. Alvimopan RiskMAP Tool Considerations • Hospital registration and attestation that a safe-use protocol is in place (dofetilide example) • Sponsor retention of responsibility for who purchases the product (eculizumab example)

14. Alvimopan RiskMAP Conclusions • Much more detail needed about goals, objectives, implementation plans, evaluation plan, metrics, RiskMAP reporting to FDA • Operational changes needed • Sponsor should retain control over supply chain • Need systematic program for hospitals to prevent diversion to outpatient use, longer term IP use • Even with these changes, RiskMAP framework acceptable only if • Short-term use is safe • Process evaluation of RiskMAP sufficient; medical outcomes will not be measured