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

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Risk Management ProgramsRisk Management ProgramsFDA Experience and Evolving FDA Experience and Evolving

Guidances on Risk ManagementGuidances on Risk Management

Practices Practices

Anne Trontell, M.D., M.P.H.Deputy Director

CDER Office of Drug Safety

Anesthetic & Life Support Drugs Advisory Committee September 9, 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 FDA experience with risk Focus on FDA experience with risk management 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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Important Concepts • Safe means thatSafe 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• 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= Professional package insert or FDA approved PI= Professional package insert or FDA approved

product labeling; not an RMP of itself product labeling; not an RMP of 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 other than In concept paper, efforts other than

professional labeling (also known as professional labeling (also known as “package insert”, PI)“package insert”, PI)

• Healthcare Professional (HCP) letters and Healthcare Professional (HCP) letters and other public noticesother 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 dispensing by pharmacists with dispensing by pharmacists with

each prescriptioneach prescription• 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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• 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 format and contentCFR 208.20 specifies format and content

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• 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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Patient Package Insert (PPI)Patient Package Insert (PPI)• FDA approved patient labelingFDA approved patient labeling• Required distribution to patients under Required distribution to patients under

CFR 310.515 for drug products CFR 310.515 for drug products containing estrogens, otherwise optional containing estrogens, otherwise optional

• Subject to CFR 202 when used as brief Subject to CFR 202 when used as brief summary for DTC adssummary 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 agreements/informed consentPatient agreements/informed consent• Practitioner certification programsPractitioner certification programs• Special conditions of dispensingSpecial conditions of dispensing

– special packagingspecial packaging– limited supply / no refillslimited supply / no refills– check mechanisms to assure appropriate check mechanisms to assure appropriate

prescribingprescribing

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Example of Special PackagingExample of Special Packaging

Gamma-hexachlorocyclohexane Gamma-hexachlorocyclohexane (Lindane(Lindane®®))

• Volume limited to 1 or 2 ounces due Volume limited to 1 or 2 ounces due to risks of seizures, death with ODto risks of seizures, death with OD

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Example of Product with Example of Product with Multiple Guiding SystemsMultiple Guiding Systems

Alosetron Alosetron • Patient agreementPatient agreement• Physician attests to knowledge of IBS Physician attests to knowledge of IBS

and product risks to obtain stickers for Rxand product risks to obtain stickers for Rx• Stickers: indicate M.D. expertise, Stickers: indicate M.D. expertise,

appropriate patient selection, agreement appropriate patient selection, agreement • Pharmacists look for stickers on Rx prior Pharmacists look for stickers on Rx prior

to dispensing to dispensing

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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”

• Often limit prescribing and dispensing Often limit prescribing and dispensing to selected HCP and pharmaciststo selected 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

• Public comments to FDA: Preserving patient access to benefits of drugs

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Subpart H

• Subpart H (CFR 314.500) regulatory Subpart H (CFR 314.500) regulatory approval option for surrogate approval option for surrogate endpoints or for restrictions to endpoints or for restrictions to ensure safe use ensure safe use

• May include restricted access May include restricted access

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Subpart H

• Restricted access/distribution can be Restricted access/distribution can be done without approval under done without approval under Subpart HSubpart H

• Subpart H: affords option of more Subpart H: affords option of more rapid product withdrawal, FDA rapid product withdrawal, FDA review of promotional materials prior review of promotional materials prior to publicationto publication

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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 Changes in health outcomes

• Allows modification of RMP to meet Allows modification of RMP to meet goalsgoals

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Evaluation of RMPEvaluation of RMP

• Overlap with concept paper on Overlap with concept paper on pharmacovigilance and pharmacovigilance and pharmacoepidemiologypharmacoepidemiology

• Active or targeted surveillance Active or targeted surveillance systems may servesystems may serve– as means of measuring RMP goals, as means of measuring RMP goals,

objectiveobjective– way to determine if RMP is effectiveway to determine if RMP is effective

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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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““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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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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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– show instances of slow product uptake with show instances of slow product uptake with

substitution of alternative productssubstitution of alternative products

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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 informationon safe and General informationon 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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Restricted Access System:Restricted Access System: Sodium Oxybate ( Sodium Oxybate (XyremXyrem®®))

• XyremXyrem®® Success Program Success Program– Made available to prescribers through Made available to prescribers through

centralized pharmacycentralized pharmacy• Prescribers calls centralized pharmacy which send Prescribers calls centralized pharmacy which send

educational material backeducational 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 Patient confirms that read material and drug shipped to

patientpatient• Receipt of initial drug shipment confirmedReceipt of initial drug shipment confirmed

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Restricted Access System:Restricted Access System: Sodium Oxybate ( Sodium Oxybate (XyremXyrem®®))

• XyremXyrem®® Success Program Success Program– Detailed surveillanceDetailed surveillance

• Patients must be seen no less frequently than every 3 Patients must be seen no less frequently than every 3 monthsmonths

• Every patient and prescriber registeredEvery patient and prescriber registered

– Medication GuideMedication Guide

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Medication GuideMedication Guide

Sodium oxybate (Xyrem®)Sodium oxybate (Xyrem®)

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Sodium oxybate (Xyrem®) - 1Sodium 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.

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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®.

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• 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.

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• 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.

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• 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®.

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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• 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 mefloquine: adherence, CNS and pyschiatricpyschiatric side effects 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 treatment tamoxifen: risk/benefit decision-making outside of cancer treatment

Documents

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