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

2. 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.pdfhttp://www.fda.gov/cder/guidance/6358fnl.pdf

3. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 13 Alvimopan RiskMAP Tool Considerations 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. 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