Risk Evaluation and Mitigation Strategies (REMS) Rachel Bohard, PharmD Candidate

Risk Evaluation and Mitigation Strategies (REMS) Rachel Bohard, PharmD Candidate

Objectives Define REMS. Understand the evolution of REMS. Describe components of REMS. List the factors considered by the FDA when assessing the need for REMS. Describe an example of a REMS program. Identify problems with assessing the cost and outcomes of REMS. Identify opportunities for pharmacist leadership in REMS programs.

History of Risk Management Most basic tools: product labeling and drug approval 1,2 1976: 1 st mandatory PPI required for oral contraceptives 1,2 1999: Medication Guides introduced 3 2005: Risk Minimization Action Plans (RiskMAPs) Used to meet product-specific risk-related goals/objectives to minimize risk while sustaining benefits 1,2 For products that pose a clinically important or unusual level of risk 5 Different goals for different products Issues concerning implementation due to lack of enforcement authority

Risk Evaluation and Mitigation Strategies (REMS) Food and Drug Administration Amendments Act (FDAA) Title IX of 2007 authorized FDA to require and enforce (REMS) when necessary 7 Based off of RiskMAPs, but is well defined, assessed over time, and legally enforceable 1 Applies to prescription drugs and biologic products when necessary 1 Primary Goal: keeping patients safe 5 Ensures benefits outweigh risks 5 Aids in management of known risk or potential serious ADEs associated with a particular medication 5

Components of REMS 5 Patient Package Insert Elements to Assure Safe Use (ETASU) Communication Plan Medication Guide Figure 1 Figure 1: David KD. Food and Drug Administration. REMS Evaluations: What Have We Learned? Available at http://www.fdanews.com/ext/files/conference/rmdss10presentations/davis-rems%20evaluations.pdf.

Components of REMS (cont d) 5 Implementation System Monitoring, evaluating, and working to improve implementation of ETASU by pharmacists, providers, and other persons affiliated with the healthcare system Timetable for REMS Assessments (required) 18 months 3 years 7 years

Factors assessed by FDA when considering need for REMS 5 Population size of users Seriousness of disease Benefit expected from drug Expected treatment duration Severity of known/potential adverse events (ADEs) Whether or not the drug is a new molecular entity

Outcomes: Accutane (isotrentinoin) 11 Challenging to Measure Evolution of ipledge program 1 st generation risk management approach PPI and patient brochure 2 nd generation risk management approach: Pregnancy Prevention Program (PPP) Labeling changes, educational materials for counseling, 3 mandatory risk management procedures prior to prescribing Still 2.8-3.4 exposed pregnancies per 1,000 patients

3rd generation risk management approach: System to Manage Accutane Related Teratogenicity (SMART) Improved patient education, required negative pregnancy test, qualification stickers Pregnancy rate did not decline 4th generation risk management approach: ipledge Prescribers, pharmacies, wholesaler distributers, and patients must register in database 0.012% fetal exposures versus previous 0.28% with PPP and SMART

Advantages of REMS Promote safe and appropriate use of drugs Provide opportunities for systematic data collection, reporting, and feedback on medication safety Allow drugs to be approved that would not otherwise have been approved because of risks Allow drugs that might have been withdrawn from the market because of risks to remain on the market Provide opportunities for expanded clinical and leadership roles and collaboration among pharmacists, physicians, and other healthcare practitioners Taken from Clinical Considerations of Risk Evaluation and Mitgivation Strategies in Health Care Systems. Risk Evaluation and Mitigation Strategies Discussion Guide.Available at http://www.remsupdates.org/activities/.

Disadvantages of REMS Lack of standardization Potential for Confusion among healthcare practitioners Time-consuming, labor-intensive nature Lack of reimbursement for extra work involved Insufficient healthcare practitioner input in FDA in premarketing development of REMS Potential for disruption in continuity of patient care

Challenges with REMS Implementation of REMS requirements Study by Childs et al. implemented qualityimprovement initiatives to increase compliance with REMS requirements 14 staff education, incorporation of REMS requirements into existing policy, development of an electronic resource, and creation of a separate storage section for drugs subject to REMS No standardization

Costs of REMS Challenging to quantify costs 15 Hard vs. soft costs Costs to manufacturer 15 $5,000-$500,000 20-120 days of development time Drug approval rates, timeline, setup and monthly maintenance 15,16 Sales impact Costs to distributers 15 $5,000- $1,000,000

Cost to providers 16 Offices/hospitals Policies, procedures, personnel, time, information technology Registration/certification Record keeping Reporting to manufacturer Cost to patients Accessability Time Inconvenience

Opportunities for pharmacist leadership 17 Actively participate in development & implementation of strategies Managing clinical & distributive therapeutic areas requiring REMS Pharmacists are uniquely qualitified Comprehension of clinical care, systems of drug distribution, attention to detail P&T Committees Continuing-education seminars

Publications Inservice education Professional meeting presentations Provider, resident, and student education Insight on program design and advocacy to improve program design Technician opportunities as well Record keeping

References 1. Choe LY. Food and Drug Administration. Risk Evaluation and Mitigation Strategies (REMS). Available at http://www.fda.gov/downloads/aboutfda/workingatfda/fellowshipinternshipgraduatefac ultyprograms/pharmacystudentexperientialprogramcder/ucm276838.pdf. Accessed May 10, 2012. 2. Leiderman DB. Risk management of drug products and the U.S. Food and Drug Administration Evolution and context. Drug Alcohol Depend. 2009:105;S9-S13. 3. Food and Drug Administration. Code of Federal Regulations: Title 21 Part 208: Medication Guides for Prescription Drug Products. 4. Trontell A. FDA Experience and Evolving Guidance on Risk Management Practices. Food and Drug Administration. Available at: www.fda.gov/ohrms/dockets/ac/03/slides/3978s1_11_trontell.ppt. Accessed May 16, 2012. 5. Dal Pan GJ. A Short Tutorial on REMS: The FDA Perspective. Medscape. Available at http://www.medscape.com/viewarticle/762240. Accessed May 10, 2012. 6. Food and Drug Administration, 2005a. Guidance for Industry on the Development and Use of Risk Minimization Action Plans. Available at http://www.fda.gov/cder/guidance/6358fnl.htm. Accessed May 16, 2012.

7. Food and Drug Administration. Food and Drug Administration Amendments Act of 2007. Available at http://www.fda.gov/. Accessed May 10, 2012. 8. Eli Lilly and Company. Risk Evaluation and Mitigation Strategy (REMS): Zyprexa Relprevv Patient Care Program. Available at http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandpro viders/ucm111350.htm?utm_campaign=google2&utm_source=fdasearch&utm_medium=w ebsite&utm_term=rems&utm_content=1. Accessed May 16, 2012. 9. Food and Drug Administration. ipledge March 2006 Update. Available at http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandpro viders/ucm094310.htm?utm_campaign=google2&utm_source=fdasearch&utm_medium=w ebsite&utm_term=accutane ipledge update 2006&utm_content=1. Accessed May 16, 2012. 10. AstraZeneca Pharmaceuticals. Risk Evaluation and Mitigation Strategy (REMS): Caprelsa (vandetanib). Available at http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandpro viders/ucm111350.htm?utm_campaign=google2&utm_source=fdasearch&utm_medium=w ebsite&utm_term=rems&utm_content=1. Accessed May 16, 2012. 11. Abroms L, Maibach E, Lyon-Daniel K, et al. What is the Best Approach to Reducing Birth Control Defects? PLoS Med. 2006:3(11):e483.

12. Traynor K. American Society of Health-System Pharmacists. RENS Review Explores Programs Burdens. Available at http://www.ashp.org/menu/news/pharmacynews/newsarticle.aspx?source=news&type=r ss&id=3651. Accessed May 16, 2012. 13. Chung R. Tufts Center for the Study of Drug Development. U.S. Healthcare Stakeholders Uncertain about Benefits of Risk Evaluation Program. Available at http://csdd.tufts.edu/news/complete_story/pr_ir_jan-feb_2011. Accessed May 22, 2012. 14. Childs L, Alexander E, Duong M. Risk evaluation and mitigation strategies: Assessment of a medical center s policies and procedures. Am J Health-Syst Pharm. 2012:69;885-9. 15. Miller G. Fierce Pharma Manufacturing. REMS costs calculated in study. Available at http://www.fiercepharmamanufacturing.com/story/rems-costs-calculated-study/2011-06- 27. Accessed May 16, 2012. 16. Decisive Bio-Insight. Risk Evaluation and Mitigation Strategies (REMS) Trends and Implications for Bio-Pharma. Available at http://www.decibio.com/rems. Accessed May 11, 2012. 17. Clinical Considerations of Risk Evaluation and Mitgivation Strategies in Health Care Systems. Risk Evaluation and Mitigation Strategies Discussion Guide. Available at http://www.remsupdates.org/activities/ Accessed May 22, 2012. 18. Stubbing J, Joshi RA, Hoffman JM. Risk evaluation and mitigation strategies: Challenges and opportunities for health-system pharmacists. Am J Health-Syst Pharm. 2010:67;1547-54.