1. 1 Risk Management Programs FDA Experience and Evolving Guidance on Risk Management Practices Anne Trontell, M.D., M.P.H. Deputy Director CDER Office of Drug Safety Pediatric Advisory Subcommittee of the Anti-Infective Drugs Advisory Committee October 29, 2003

2. 2 FDA and Risk Management Longstanding role in weighing risk information in context of drug approvalLongstanding role in weighing risk information in context of drug approval Nomenclature of risk mgt initiated with 1999 Commissioner’s Report on Managing the Risks of Medical ProductsNomenclature of risk mgt initiated with 1999 Commissioner’s Report on Managing the Risks of Medical Products

3. 3 FDA and Risk Management PDUFA3 formalized FDA role in risk managementPDUFA3 formalized FDA role in risk management PDUFA3 calls for FDA to develop three interrelated guidances on risk management by Sept 30, 2004PDUFA3 calls for FDA to develop three interrelated guidances on risk management by Sept 30, 2004 TopicsTopics –Premarketing Risk Assessment –Pharmacovigilance/ pharmacoepidemiology –Risk Management per se

4. 4 FDA and Risk Management Preliminary thinking published and presented April 2003 as “Concept Papers” to solicit public input Draft guidances based on concept papers and commentary are anticipated for release this fall

5. 5 Presentation Focus on range of FDA experience with risk managementFocus on range of FDA experience with risk management Draws upon concepts from concept paper on “risk management programs”Draws upon concepts from concept paper on “risk management programs” Snapshot of a rapidly evolving approach to drug safetySnapshot of a rapidly evolving approach to drug safety

6. 6 “Risk Management Programs” Concept Paper Focus on risk minimization effortsFocus on risk minimization efforts Efforts termed risk management programs (RMPs) in concept paperEfforts termed risk management programs (RMPs) in concept paper Risks identified using practices described in two other PDUFA3 documentsRisks identified using practices described in two other PDUFA3 documents

7. 7 Background Safe means that : beneficial actions outweigh harmful or undesirable side effectsbeneficial actions outweigh harmful or undesirable side effects does not suggest absence of riskdoes not suggest absence of risk

8. 8 Definitions Risk Management Program (RMP)Risk Management Program (RMP) –strategic safety effort to reduce risk: > 1 risk reduction goal > 1 intervention (tool) other than PI !PI !Package insert (professsional oriented) !FDA approved product labeling !Not a Risk Management Program itself

9. 9 RM Program Goal(s) Tailored to product’s specific risk concernsTailored to product’s specific risk concerns Describe ideal product use scenario or desired end result of RMPDescribe ideal product use scenario or desired end result of RMP Include “Vision statement” of optimal drug use scenario,Include “Vision statement” of optimal drug use scenario, –thalidomide: No fetal exposures –clozapine: No agranulocytosis

10. 10 When is an RMP Appropriate? Whenever risk reduction needs emerge during a product’s lifecycleWhenever risk reduction needs emerge during a product’s lifecycle Sponsor may volunteer or FDA proposeSponsor may volunteer or FDA propose “When the number or severity of a product’s risks appears to undermine the magnitude of benefits in an important segment of actual or potential users.”“When the number or severity of a product’s risks appears to undermine the magnitude of benefits in an important segment of actual or potential users.”

11. 11 How to Assess Whether Risks Undermine Benefits? No simple formula compares risks to benefits Risks and benefits vary in types, measurements Case-by-case judgments required by sponsor and/or FDA on whether to develop, submit, and implement an RMP FDA expects most products will be handled by package insert (PI), without formal RMP

12. 12 RMP Tools Risk management tool (intervention): a process or system intended to enhance safe product use by reducing riskRisk management tool (intervention): a process or system intended to enhance safe product use by reducing risk Choice of tools influenced by severity, reversibility and rate of riskChoice of tools influenced by severity, reversibility and rate of risk

13. 13 Categorization of Tools in Current Risk Mgt Programs Education & Outreach Education & Outreach “Guiding” Systems “Guiding” Systems Restricted Access Restricted Access

14. 14 Education and Outreach In concept paper, efforts going “beyond” the package insert or PIIn concept paper, efforts going “beyond” the package insert or PI Healthcare Practitioner (HCP) letters and other public noticesHealthcare Practitioner (HCP) letters and other public notices Training programs and CE for creditTraining programs and CE for credit Patient-oriented labelingPatient-oriented labeling –Medication Guides (MG) –Patient Package Inserts (PPI)

15. 15 Medication Guides FDA approved patient labelingFDA approved patient labeling Regulated since 1999 (21 CFR Part 208)Regulated since 1999 (21 CFR Part 208) Required to be dispensed with each prescriptionRequired to be dispensed with each prescription Primarily for outpatient Rx products with serious & significant public health concernsPrimarily for outpatient Rx products with serious & significant public health concerns –planned 5-10 products per year

16. 16 Medication Guides Now 13 Medication Guide texts covering 22 different productsNow 13 Medication Guide texts covering 22 different products Cover diverse risks: include but not limited to hepatotoxicity, teratogenicity, abuse and diversion, overdoseCover diverse risks: include but not limited to hepatotoxicity, teratogenicity, abuse and diversion, overdose

17. 17 Medication Guides abacavir (2): hypersensitivity reactionsabacavir (2): hypersensitivity reactions acitretin, isotretinoin : teratogenicity, multiple retinoid toxicitiesacitretin, isotretinoin : teratogenicity, multiple retinoid toxicities alosetron: ischemic colitis, serious constipationalosetron: ischemic colitis, serious constipation bosentan: teratogenicity, hepatotoxicitybosentan: teratogenicity, hepatotoxicity interferons (5): depression, hepatotoxicity, pregnancy risksinterferons (5): depression, hepatotoxicity, pregnancy risks lindane (2): overdose, seizures, and deathlindane (2): overdose, seizures, and death mefloquine: adherence, CNS and psychiatric side effectsmefloquine: adherence, CNS and psychiatric side effects mifepristone: bleeding complications requiring surgerymifepristone: bleeding complications requiring surgery ribavirin: teratogenicity, anemia, adherenceribavirin: teratogenicity, anemia, adherence Na oxybate: scheduling, child protection, abuse/diversionNa oxybate: scheduling, child protection, abuse/diversion teraperatide: animal carcinogenteraperatide: animal carcinogen tamoxifen: risk/benefit decision-making outside of cancer treatmenttamoxifen: risk/benefit decision-making outside of cancer treatment

18. 18 Medication Guides Pediatric Safety or Exposure Concerns abacavir (2): hypersensitivity reactionsabacavir (2): hypersensitivity reactions isotretinoin : teratogenicity, multiple retinoid toxicitiesisotretinoin : teratogenicity, multiple retinoid toxicities interferons (5): depression, hepatotoxicity, pregnancy risksinterferons (5): depression, hepatotoxicity, pregnancy risks lindane (2): overdose, seizures, and deathlindane (2): overdose, seizures, and death mefloquine: adherence, CNS and psychiatric side effectsmefloquine: adherence, CNS and psychiatric side effects ribavirin: teratogenicity, anemia, adherenceribavirin: teratogenicity, anemia, adherence Na oxybate: scheduling, child protection, abuse/diversionNa oxybate: scheduling, child protection, abuse/diversion

19. 19 Medication Guides Three triggering criteriaThree triggering criteria At least one criterion must be met At least one criterion must be met –pt labeling could help prevent serious AEs –serious risks: could affect pt decision to use –pt adherence to directions crucial to effectiveness CFR 208.20 specifies content areas and format, including font sizeCFR 208.20 specifies content areas and format, including font size

20. 20 Medication Guide Format - 1 FAQs-like formatFAQs-like format Title, brand name, established nameTitle, brand name, established name What is most important information?What is most important information? –health concern that prompted MG What is (drug)?What is (drug)? –Indications, disease state

21. 21 Medication Guide Format - 2 Who should not take (drug)?Who should not take (drug)? –contraindications How should I take (drug)?How should I take (drug)? –dosing instructions What should I avoid while taking(drug)?What should I avoid while taking(drug)? –Precautions, special populations

22. 22 Medication Guide Format -3 What are the possible side effects of (drug)?What are the possible side effects of (drug)? General information on safe and effective useGeneral information on safe and effective use –Rx occurs for reasons not in MG, ask HCP if concerns, do not use for other than prescribed condition or give to other people, names of product, mfg

23. 23 Patient Package Insert (PPI) FDA approved patient labelingFDA approved patient labeling Required distribution to patients under CFR 310.515 for drug products containing estrogens, otherwise optionalRequired distribution to patients under CFR 310.515 for drug products containing estrogens, otherwise optional Subject to CFR 202 when used as brief summary for DTC adsSubject to CFR 202 when used as brief summary for DTC ads

24. 24 Patient Package Insert (PPI) Many follow Medication Guide format & content to promote consistency in FDA-approved patient labeling Unit-of-use packaging with PPIs can function similarly to Medication guide

25. 25 PPI vs. Medication Guide Medication guides required to be dispensed with medications to patientsMedication guides required to be dispensed with medications to patients PPIs other than estrogens: optionalPPIs other than estrogens: optional Generic products have same Medication Guide requirements as innovatorGeneric products have same Medication Guide requirements as innovator

26. 26 Systems Guiding Prescribing, Dispensing, Use Purpose is to assist individuals in following appropriate prescribing practicesPurpose is to assist individuals in following appropriate prescribing practices Alternatively stated, make it difficult to forget important safety processesAlternatively stated, make it difficult to forget important safety processes May use a variety of reminders, promptsMay use a variety of reminders, prompts

27. 27 Systems Guiding Prescribing, Dispensing, Use Patient agreementsPatient agreements Practitioner certification programsPractitioner certification programs Special conditions of dispensingSpecial conditions of dispensing –special packaging –limited supply / no refills –pharmacy checking mechanisms to assure appropriate prescribing

28. 28 Example of Special Packaging Lindane (  -hexachlorocyclohexane ) Volume limited to 1 or 2 ounces due to risks of seizures, death with excessive use or reapplicationVolume limited to 1 or 2 ounces due to risks of seizures, death with excessive use or reapplication

29. 29 Additional Risk Management Tools Used for Lindane PI revised: boxed warning re 2nd line use, reuse, risk in children and in adults<50 kg Medication guide to inform about risks and instruct on appropriate use FDA Public Health Advisory issued

30. 30 Example of Products with Multiple Guiding Systems Alosetron/Isotretinoin Patient agreementPatient agreement Physician attests to necessary knowledge to obtain special stickers to affix to RxPhysician attests to necessary knowledge to obtain special stickers to affix to Rx Stickers: indicate M.D. expertise, appropriate patient selection/testingStickers: indicate M.D. expertise, appropriate patient selection/testing Pharmacists look for stickers on Rx prior to dispensing to assure safe use conditions have been addressedPharmacists look for stickers on Rx prior to dispensing to assure safe use conditions have been addressed

31. 31 Restricted Access Systems Link drug product access to compliance with RMP elementsLink drug product access to compliance with RMP elements –e.g. clozapine: “no blood, no drug” Limit prescribing and dispensing to selected HCP and pharmacistsLimit prescribing and dispensing to selected HCP and pharmacists May require documentation of safe use conditions (such as lab tests) before dispensing to patientsMay require documentation of safe use conditions (such as lab tests) before dispensing to patients

32. 32 Example of Restricted Access: Thalidomide System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) –Product shipped only to registered pharmacists –Pharmacists dispense thalidomide Rx only if patient & prescriber are both registeredpatient & prescriber are both registered central authorization of information from provider and patient of nonpregnant statuscentral authorization of information from provider and patient of nonpregnant status

33. 33 Selecting and Developing Tools Consider: Stakeholder input on feasibility, acceptance – –prescribers, pharmacists, pts, payors Consistency: with existing/accepted tools Evidence: past effectiveness in similar product or related objective

34. 34 Public Comments to FDA Preserve patient access to benefits of drugs Avoid confusion/burden for medical and pharmacy practice Avoid multiple customized programs

35. 35 Evaluation of RMP Important to measureImportant to measure –Effectiveness & value-added of tools –Progress towards goal(s) –Changes in health outcomes or best available surrogate outcome Allows modification of RMP to meet goalsAllows modification of RMP to meet goals

36. 36 Evaluation of RMP May include active surveillance systems for outcomes, AEsMay include active surveillance systems for outcomes, AEs Discussed in concept paper on pharmacovigilance and pharmacoepidemiologyDiscussed in concept paper on pharmacovigilance and pharmacoepidemiology

37. 37 Summary: Risk Management Programs Sparingly applied interventions Intended to minimize identified risks Are goal-oriented Use tools commensurate with risks and benefits Merit evaluation

38. 38 Summary: RMP Tools Category: Education & Outreach Many types, can be general or targetedMany types, can be general or targeted Applied to many drugsApplied to many drugs Limited intrusion on conventional prescribing, dispensing, and use processesLimited intrusion on conventional prescribing, dispensing, and use processes Data on effectiveness are limited and mixedData on effectiveness are limited and mixed

39. 39 Summary: RMP Tools “Guiding” Systems Limited number of systems in useLimited number of systems in use Moderate intrusion on conventional prescribing, dispensing, and use processesModerate intrusion on conventional prescribing, dispensing, and use processes As yet, no evidence on effectiveness but evaluations are planned for several programsAs yet, no evidence on effectiveness but evaluations are planned for several programs

40. 40 Summary: RMP Tools Restricted Access Limited number of systems in useLimited number of systems in use Applied to date for products with limited therapeutic alternatives, significant risksApplied to date for products with limited therapeutic alternatives, significant risks User populations typically smallUser populations typically small

41. 41 Summary: RMP Tools Restricted Access Most intrusive on prescribing, dispensing, useMost intrusive on prescribing, dispensing, use Closed systems, easy to evaluateClosed systems, easy to evaluate DataData –support effectiveness in risk minimization –suggest slow product uptake, substitution of alternative products, unintended consequences