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Risk Management Programs

Risk Management Programs

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Risk Management Programs

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  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. FDA and Risk Management • Longstanding 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 Products

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

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

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

  7. Important Concepts • Safe means that: • beneficial actions outweigh harmful or undesirable side effects • does not suggest absence of risk • 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. RM Program Goal(s) • Tailored to product’s specific risk concerns • Describe ideal product use scenario or desired end result of RMP • Include “Vision statement” of optimal drug use scenario, • thalidomide: No fetal exposures • clozapine: No agranulocytosis

  9. When is an RMP Appropriate? • Whenever risk reduction needs emerge during a product’s lifecycle • Sponsor 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.”

  10. How to Assess WhetherRisks 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. RMP Tools • Risk 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 risk

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

  13. Education and Outreach • In concept paper, efforts other than professional labeling (also known as “package insert”, PI) • Healthcare Professional (HCP) letters and other public notices • Training programs and CE for credit • Patient-oriented labeling • Medication Guides (MG) • Patient Package Inserts (PPI)

  14. Medication Guides • FDA approved patient labeling • Regulated since 1999 (21 CFR Part 208) • Required dispensing by pharmacists with each prescription • Primarily for outpatient Rx products with serious & significant public health concerns • planned 5-10 products per year

  15. Medication Guides • Three triggering criteria 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 content

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

  17. Patient Package Insert (PPI) • FDA approved patient labeling • Required 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 ads

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

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

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

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

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

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

  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 registered • central authorization of information from provider and patient of nonpregnant status

  26. Selecting and Developing ToolsConsider: • 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. Subpart H • Subpart H (CFR 314.500) regulatory approval option for surrogate endpoints or for restrictions to ensure safe use • May include restricted access

  28. Subpart H • Restricted 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 publication

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

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

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

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

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

  35. Summary: RMP Tools Restricted Access • Most intrusive on prescribing, dispensing, use • Closed systems, easy to evaluate • Data • support effectiveness in risk minimization • show instances of slow product uptake with substitution of alternative products

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

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

  38. Medication Guide Format -3 • What are the possible side effects of (drug)? • General 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

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

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

  41. Medication Guide Sodium oxybate (Xyrem®)

  42. 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.

  43. 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®.

  44. 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.

  45. 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.

  46. 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®.

  47. Medication Guides • abacavir (2): hypersensitivity reactions • acitretin, isotretinoin : teratogenicity, multiple retinoid toxicities • alosetron: ischemic colitis, serious constipation • bosentan: teratogenicity, hepatotoxicity • interferons (5): depression, hepatotoxicity, pregnancy risks • lindane (2): overdose, seizures, and death • mefloquine: adherence, CNS and pyschiatric side effects • mifepristone: bleeding complications requiring surgery • ribavirin: teratogenicity, anemia, adherence • Na oxybate: scheduling, child protection, abuse/diversion • teraperatide: animal carcinogen • tamoxifen: risk/benefit decision-making outside of cancer treatment