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Risk Management ProgramsRisk Management ProgramsFDA Experience and Evolving FDA Experience and Evolving
Guidance on Risk ManagementGuidance on Risk Management
Practices 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
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FDA and Risk Management FDA and Risk Management
• Longstanding role in weighing risk Longstanding role in weighing risk information in context of drug approvalinformation in context of drug approval
• Nomenclature of risk mgt initiated with Nomenclature of risk mgt initiated with 1999 Commissioner’s Report on 1999 Commissioner’s Report on Managing the Risks of Medical Managing the Risks of Medical Products Products
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FDA and Risk Management FDA and Risk Management • PDUFA3 formalized FDA role in risk PDUFA3 formalized FDA role in risk
management management • PDUFA3 calls for FDA to develop three PDUFA3 calls for FDA to develop three
interrelated guidances on risk management interrelated guidances on risk management by Sept 30, 2004by Sept 30, 2004
• Topics Topics – Premarketing Risk Assessment Premarketing Risk Assessment – Pharmacovigilance/ pharmacoepidemiologyPharmacovigilance/ pharmacoepidemiology– Risk Management Risk Management per seper se
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FDA and Risk Management 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
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Presentation Presentation
• Focus on range of FDA experience Focus on range of FDA experience with risk management with risk management
• Draws upon concepts from concept Draws upon concepts from concept paper on “risk management programs” paper on “risk management programs”
• Snapshot of a rapidly evolving Snapshot of a rapidly evolving approach to drug safety approach to drug safety
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““Risk Management Programs” Risk Management Programs” Concept Paper Concept Paper
• Focus on risk minimization effortsFocus on risk minimization efforts
• Efforts termed risk management Efforts termed risk management programs (RMPs) in concept paperprograms (RMPs) in concept paper
• Risks identified using practices Risks identified using practices described in two other PDUFA3 described in two other PDUFA3 documentsdocuments
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Background
SafeSafe means that means that::• beneficial actions outweigh harmful or beneficial actions outweigh harmful or
undesirable side effects undesirable side effects
• does not suggest absence of riskdoes not suggest absence of risk
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Definitions• Risk Management Risk Management Program Program (RMP)(RMP)
– strategic safety effort to reduce risk:strategic safety effort to reduce risk:
>> 1 risk reduction goal1 risk reduction goal
>> 1 intervention (tool) 1 intervention (tool) otherother than PI than PI PI PI
Package insert (professsional oriented) Package insert (professsional oriented) FDA approved product labeling FDA approved product labeling NotNot a Risk Management Program itself a Risk Management Program itself
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RM Program Goal(s)RM Program Goal(s)
• Tailored to product’s specific risk concernsTailored to product’s specific risk concerns• Describe ideal product use scenario or desired Describe ideal product use scenario or desired
end result of RMPend result of RMP• Include “Vision statement” of optimal drug use Include “Vision statement” of optimal drug use
scenario, scenario, – thalidomide: No fetal exposuresthalidomide: No fetal exposures– clozapine: No agranulocytosisclozapine: No agranulocytosis
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When is an RMP Appropriate?When is an RMP Appropriate?
• Whenever risk reduction needs emerge during a Whenever risk reduction needs emerge during a product’s lifecycleproduct’s lifecycle
• Sponsor may volunteer or FDA propose Sponsor may volunteer or FDA propose
• ““When the number or severity of a product’s risks When the number or severity of a product’s risks appears to undermine the magnitude of benefits appears to undermine the magnitude of benefits in an important segment of actual or potential in an important segment of actual or potential users.”users.”
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How to Assess WhetherHow to Assess WhetherRisks Undermine Benefits?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
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RMP ToolsRMP Tools
• Risk management tool (intervention): a Risk management tool (intervention): a process or system intended to enhance safe process or system intended to enhance safe product use by reducing riskproduct use by reducing risk
• Choice of tools influenced by severity, Choice of tools influenced by severity, reversibility and rate of riskreversibility and rate of risk
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Categorization of Tools in Categorization of Tools in Current Risk Mgt ProgramsCurrent Risk Mgt Programs
• Education & OutreachEducation & Outreach
• “ “Guiding” SystemsGuiding” Systems
• Restricted Access Restricted Access
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Education and OutreachEducation and Outreach• In concept paper, efforts going “beyond” In concept paper, efforts going “beyond”
the package insert or PI the package insert or PI• Healthcare Practitioner (HCP) letters Healthcare Practitioner (HCP) letters
and other public noticesand other public notices• Training programs and CE for creditTraining programs and CE for credit• Patient-oriented labelingPatient-oriented labeling
– Medication Guides (MG)Medication Guides (MG)– Patient Package Inserts (PPI)Patient Package Inserts (PPI)
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Medication GuidesMedication Guides
• FDA approved patient labeling FDA approved patient labeling • Regulated since 1999 (21 CFR Part 208)Regulated since 1999 (21 CFR Part 208)• RequiredRequired to be dispensed with each to be dispensed with each
prescriptionprescription• Primarily for outpatient Rx products with Primarily for outpatient Rx products with
serious & significant public health serious & significant public health concernsconcerns– planned 5-10 products per yearplanned 5-10 products per year
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Medication GuidesMedication Guides
• Now 13 Medication Guide texts covering Now 13 Medication Guide texts covering 22 different products 22 different products
• Cover diverse risks: include but not Cover diverse risks: include but not limited to hepatotoxicity, teratogenicity, limited to hepatotoxicity, teratogenicity, abuse and diversion, overdoseabuse and diversion, overdose
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Medication GuidesMedication 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• interferonsinterferons (5): depression, hepatotoxicity, pregnancy risks(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, adherence ribavirin: teratogenicity, anemia, adherence • Na oxybate: scheduling, child protection, abuse/diversion Na oxybate: scheduling, child protection, abuse/diversion • teraperatide: animal carcinogenteraperatide: animal carcinogen• tamoxifen: risk/benefit decision-making outside of cancer tamoxifen: risk/benefit decision-making outside of cancer
treatment treatment
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Medication GuidesMedication GuidesPediatric Safety or Exposure ConcernsPediatric Safety or Exposure Concerns • abacavir (2): hypersensitivity reactionsabacavir (2): hypersensitivity reactions• isotretinoin : teratogenicity, multiple retinoid toxicitiesisotretinoin : teratogenicity, multiple retinoid toxicities• interferonsinterferons (5): depression, hepatotoxicity, pregnancy risks(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, adherence ribavirin: teratogenicity, anemia, adherence • Na oxybate: scheduling, child protection, abuse/diversion Na oxybate: scheduling, child protection, abuse/diversion
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Medication GuidesMedication 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 AEspt labeling could help prevent serious AEs– serious risks: could affect pt decision to useserious risks: could affect pt decision to use– pt adherence to directions crucial to pt adherence to directions crucial to
effectivenesseffectiveness
• CFR 208.20 specifies content areas and CFR 208.20 specifies content areas and format, including font sizeformat, including font size
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Medication Guide Format - 1Medication 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 MGhealth concern that prompted MG
• What is (drug)? What is (drug)? – Indications, disease stateIndications, disease state
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Medication Guide Format - 2Medication Guide Format - 2
• Who should not take (drug)? Who should not take (drug)? – contraindicationscontraindications
• How should I take (drug)?How should I take (drug)?– dosing instructionsdosing instructions
• What should I avoid while What should I avoid while taking(drug)?taking(drug)?– Precautions, special populationsPrecautions, special populations
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Medication Guide Format -3Medication Guide Format -3
• What are the possible side effects of What are the possible side effects of (drug)? (drug)?
• General information on safe and General information on safe and effective use effective use – Rx occurs for reasons not in MG, ask Rx occurs for reasons not in MG, ask
HCP if concerns, do not use for other HCP if concerns, do not use for other than prescribed condition or give to than prescribed condition or give to other people, names of product, mfgother people, names of product, mfg
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Patient Package Insert (PPI)Patient Package Insert (PPI)• FDA approved patient labelingFDA approved patient labeling• Required distribution to patients Required distribution to patients
under CFR 310.515 for drug under CFR 310.515 for drug products containing estrogens, products containing estrogens, otherwise optional otherwise optional
• Subject to CFR 202 when used as Subject to CFR 202 when used as brief summary for DTC adsbrief summary for DTC ads
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Patient Package Insert (PPI)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
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PPI vs. Medication GuidePPI vs. Medication Guide
• Medication guides required to be Medication guides required to be dispensed with medications to dispensed with medications to patientspatients
• PPIs other than estrogens: optionalPPIs other than estrogens: optional
• Generic products have same Generic products have same Medication Guide requirements as Medication Guide requirements as innovator innovator
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Systems Guiding Prescribing, Systems Guiding Prescribing, Dispensing, UseDispensing, Use
• Purpose is to assist individuals in Purpose is to assist individuals in following appropriate prescribing following appropriate prescribing practicespractices
• Alternatively stated, make it difficult to Alternatively stated, make it difficult to forget important safety processesforget important safety processes
• May use a variety of reminders, May use a variety of reminders, promptsprompts
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Systems Guiding Prescribing, Systems Guiding Prescribing, Dispensing, UseDispensing, Use
• Patient agreementsPatient agreements• Practitioner certification programsPractitioner certification programs• Special conditions of dispensingSpecial conditions of dispensing
– special packagingspecial packaging– limited supply / no refillslimited supply / no refills– pharmacy checking mechanisms to pharmacy checking mechanisms to
assure appropriate prescribingassure appropriate prescribing
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Example of Special PackagingExample of Special Packaging
LindaneLindane ( (-hexachlorocyclohexane-hexachlorocyclohexane))
• Volume limited to 1 or 2 ounces due Volume limited to 1 or 2 ounces due to risks of seizures, death with to risks of seizures, death with excessive use or reapplicationexcessive use or reapplication
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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
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Example of Products with Example of Products with Multiple Guiding SystemsMultiple Guiding Systems
Alosetron/Isotretinoin Alosetron/Isotretinoin • Patient agreementPatient agreement• Physician attests to necessary knowledge Physician attests to necessary knowledge
to obtain special stickers to affix to Rx to obtain special stickers to affix to Rx• Stickers: indicate M.D. expertise, Stickers: indicate M.D. expertise,
appropriate patient selection/testing appropriate patient selection/testing • Pharmacists look for stickers on Rx prior Pharmacists look for stickers on Rx prior
to dispensing to assure safe use to dispensing to assure safe use conditions have been addressedconditions have been addressed
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Restricted Access SystemsRestricted Access Systems
• Link drug product access to Link drug product access to compliance with RMP elements compliance with RMP elements – e.g. clozapine: “no blood, no drug” e.g. clozapine: “no blood, no drug”
• Limit prescribing and dispensing to Limit prescribing and dispensing to selected HCP and pharmacistsselected HCP and pharmacists
• May require documentation of safe use May require documentation of safe use conditions (such as lab tests) before conditions (such as lab tests) before dispensing to patientsdispensing to patients
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Example of Restricted Access:Example of Restricted Access: Thalidomide Thalidomide
System for Thalidomide Education and System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.)Prescribing Safety (S.T.E.P.S.)– Product shipped only to registered Product shipped only to registered
pharmacists pharmacists – Pharmacists dispense thalidomide Rx only ifPharmacists dispense thalidomide Rx only if
• patient & prescriber are both registeredpatient & prescriber are both registered• central authorization of information from central authorization of information from
provider and patient of nonpregnant statusprovider and patient of nonpregnant status
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Selecting and Developing ToolsSelecting and Developing ToolsConsider:Consider:
• Stakeholder input on feasibility, acceptance– prescribers, pharmacists, pts, payors
• Consistency: with existing/accepted tools
• Evidence: past effectiveness in similar product or related objective
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Public Comments to FDA
• Preserve patient access to benefits of drugs
• Avoid confusion/burden for medical and pharmacy practice
• Avoid multiple customized programs
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Evaluation of RMPEvaluation of RMP
• Important to measure Important to measure – Effectiveness & value-added of toolsEffectiveness & value-added of tools– Progress towards goal(s) Progress towards goal(s) – Changes in health outcomes or best Changes in health outcomes or best
available surrogate outcomeavailable surrogate outcome
• Allows modification of RMP to meet Allows modification of RMP to meet goalsgoals
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Evaluation of RMPEvaluation of RMP
• May include active surveillance May include active surveillance systems for outcomes, AEssystems for outcomes, AEs
• Discussed in concept paper on Discussed in concept paper on pharmacovigilance and pharmacovigilance and pharmacoepidemiologypharmacoepidemiology
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Summary: Summary: Risk Management ProgramsRisk Management Programs• Sparingly applied interventions
• Intended to minimize identified risks
• Are goal-oriented
• Use tools commensurate with risks and benefits
• Merit evaluation
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Summary: RMP ToolsSummary: RMP Tools
Category: Education & OutreachCategory: Education & Outreach
• Many types, can be general or targeted Many types, can be general or targeted • Applied to many drugs Applied to many drugs • Limited intrusion on conventional Limited intrusion on conventional
prescribing, dispensing, and use prescribing, dispensing, and use processesprocesses
• Data on effectiveness are limited and Data on effectiveness are limited and mixed mixed
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Summary: RMP ToolsSummary: RMP Tools
““Guiding” Systems Guiding” Systems • Limited number of systems in useLimited number of systems in use• Moderate intrusion on conventional Moderate intrusion on conventional
prescribing, dispensing, and use prescribing, dispensing, and use processesprocesses
• As yet, no evidence on effectiveness but As yet, no evidence on effectiveness but evaluations are planned for several evaluations are planned for several programsprograms
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Summary: RMP ToolsSummary: RMP Tools
Restricted AccessRestricted Access
• Limited number of systems in useLimited number of systems in use• Applied to date for products with limited Applied to date for products with limited
therapeutic alternatives, significant riskstherapeutic alternatives, significant risks• User populations typically smallUser populations typically small
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Summary: RMP ToolsSummary: RMP Tools
Restricted AccessRestricted Access
• Most intrusive on prescribing, dispensing, Most intrusive on prescribing, dispensing, use use
• Closed systems, easy to evaluateClosed systems, easy to evaluate• Data Data
– support effectiveness in risk minimizationsupport effectiveness in risk minimization– suggest slow product uptake, substitution of suggest slow product uptake, substitution of
alternative products, unintended alternative products, unintended consequencesconsequences
