1. 1 Risk Management Programs FDA Experience and Evolving Guidances on Risk Management Practices Anne Trontell, M.D., M.P.H. Deputy Director CDER Office of Drug Safety Anesthetic & Life Support Drugs Advisory Committee September 9, 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 FDA experience with risk managementFocus on 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 Important Concepts Safe means that :Safe means that : –beneficial actions outweigh harmful or undesirable side effects –does not suggest absence of risk 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= Professional package insert or FDA approved product labeling; not an RMP of itself

8. 8 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

9. 9 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.”

10. 10 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

11. 11 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

12. 12 Categorization of Tools in Current Risk Mgt Programs Education & Outreach Education & Outreach “Guiding” Systems “Guiding” Systems Restricted Access Restricted Access

13. 13 Education and Outreach In concept paper, efforts other than professional labeling (also known as “package insert”, PI)In concept paper, efforts other than professional labeling (also known as “package insert”, PI) Healthcare Professional (HCP) letters and other public noticesHealthcare Professional (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)

14. 14 Medication Guides FDA approved patient labelingFDA approved patient labeling Regulated since 1999 (21 CFR Part 208)Regulated since 1999 (21 CFR Part 208) Required dispensing by pharmacists with each prescriptionRequired dispensing by pharmacists 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

15. 15 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 format and contentCFR 208.20 specifies format and content

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 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

18. 18 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

19. 19 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

20. 20 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

21. 21 Systems Guiding Prescribing, Dispensing, Use Patient agreements/informed consentPatient agreements/informed consent Practitioner certification programsPractitioner certification programs Special conditions of dispensingSpecial conditions of dispensing –special packaging –limited supply / no refills –check mechanisms to assure appropriate prescribing

22. 22 Example of Special Packaging Gamma-hexachlorocyclohexane (Lindane ® ) Volume limited to 1 or 2 ounces due to risks of seizures, death with ODVolume limited to 1 or 2 ounces due to risks of seizures, death with OD

23. 23 Example of Product with Multiple Guiding Systems Alosetron Patient agreementPatient agreement Physician attests to knowledge of IBS and product risks to obtain stickers for RxPhysician attests to knowledge of IBS and product risks to obtain stickers for Rx Stickers: indicate M.D. expertise, appropriate patient selection, agreementStickers: indicate M.D. expertise, appropriate patient selection, agreement Pharmacists look for stickers on Rx prior to dispensingPharmacists look for stickers on Rx prior to dispensing

24. 24 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” Often limit prescribing and dispensing to selected HCP and pharmacistsOften limit 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

25. 25 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

26. 26 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 Public comments to FDA: Preserving patient access to benefits of drugs

27. 27 Subpart H Subpart H (CFR 314.500) regulatory approval option for surrogate endpoints or for restrictions to ensure safe useSubpart H (CFR 314.500) regulatory approval option for surrogate endpoints or for restrictions to ensure safe use May include restricted accessMay include restricted access

28. 28 Subpart H Restricted access/distribution can be done without approval under Subpart HRestricted access/distribution can be done without approval under Subpart H Subpart H: affords option of more rapid product withdrawal, FDA review of promotional materials prior to publicationSubpart H: affords option of more rapid product withdrawal, FDA review of promotional materials prior to publication

29. 29 Evaluation of RMP Important to measureImportant to measure –Effectiveness & value-added of tools –Progress towards goal(s) –Changes in health outcomes Allows modification of RMP to meet goalsAllows modification of RMP to meet goals

30. 30 Evaluation of RMP Overlap with concept paper on pharmacovigilance and pharmacoepidemiologyOverlap with concept paper on pharmacovigilance and pharmacoepidemiology Active or targeted surveillance systems may serveActive or targeted surveillance systems may serve –as means of measuring RMP goals, objective –way to determine if RMP is effective

31. 31 Summary: Risk Management Programs Sparingly applied interventions Intended to minimize identified risks Are goal-oriented Use tools commensurate with risks and benefits Merit evaluation

32. 32 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

33. 33 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

34. 34 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

35. 35 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 –show instances of slow product uptake with substitution of alternative products

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38. 38 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

39. 39 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

40. 40 Medication Guide Format -3 What are the possible side effects of (drug)?What are the possible side effects of (drug)? General informationon safe and effective useGeneral informationon 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

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42. 42 Restricted Access System: Sodium Oxybate ( Xyrem ® ) Xyrem ® Success ProgramXyrem ® Success Program –Made available to prescribers through centralized pharmacy Prescribers calls centralized pharmacy which send educational material backPrescribers calls centralized pharmacy which send educational material back Prescriber reviews material and returns enrollment formPrescriber reviews material and returns enrollment form Pharmacy send educational material to patientPharmacy send educational material to patient Patient confirms that read material and drug shipped to patientPatient confirms that read material and drug shipped to patient Receipt of initial drug shipment confirmedReceipt of initial drug shipment confirmed

43. 43 Restricted Access System: Sodium Oxybate ( Xyrem ® ) Xyrem ® Success ProgramXyrem ® Success Program –Detailed surveillance Patients must be seen no less frequently than every 3 monthsPatients must be seen no less frequently than every 3 months Every patient and prescriber registeredEvery patient and prescriber registered –Medication Guide

44. 44 Medication Guide Sodium oxybate (Xyrem®)

45. 45 Sodium oxybate (Xyrem®) - 1 What is the most important information I should know about Xyrem ® ? - 7 items   Xyrem ® is a Schedule III, federally controlled substance. This means that if you sell, distribute, or give your Xyrem ® to anyone else, or if you use your Xyrem ® for purposes other than what it was prescribed for, you may be punished under federal and state law by jail and fines. Your Xyrem ® should be used only by you, as prescribed.

46. 46 Sodium oxybate (Xyrem®) - 2 What is the most important information I should know about Xyrem ® ? It is critical to keep Xyrem ® out of the reach of children. Xyrem ® can cause serious side effects including trouble breathing while asleep, confusion, abnormal thinking, depression, and loss of consciousness. Tell your doctor if you have any of these problems while taking Xyrem ®.

47. 47 Sodium oxybate (Xyrem®) - 3 What is the most important information I should know about Xyrem ® ? The active ingredient in Xyrem ® is gamma-hydroxybutyrate (GHB), a chemical that has been abused (misused). Abuse can cause serious medical problems, including trouble breathing, seizures (convulsions), loss of consciousness, coma, and death. Abuse of Xyrem ® could also lead to dependence, craving for the medicine, and severe withdrawal symptoms.

48. 48 Sodium oxybate (Xyrem®) - 4 What is the most important information I should know about Xyrem ® ? Xyrem ® causes sleep very quickly. Therefore, take Xyrem ® only at bedtime and while in bed. Do not drive a car, operate heavy machinery, or perform any activity that is dangerous or that requires mental alertness for at least 6 hours after taking Xyrem ®. When you first start taking Xyrem ®,until you know whether it makes you sleepy the next day, use extreme care while driving a car, operating heavy machinery or doing anything else that could be dangerous or needs you to be fully mentally alert.

49. 49 Sodium oxybate (Xyrem®) - 5 What is the most important information I should know about Xyrem ® ? You can get Xyrem ® only by prescription. You must get it from one central pharmacy. Before you use Xyrem ®, your doctor should teach you about the safe and effective use of this medicine. You cannot get the medicine until you have read the information the pharmacy will send you about Xyrem ®.

50. 50 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 pyschiatric side effectsmefloquine: adherence, CNS and pyschiatric 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