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Concept Paper on Risk Concept Paper on Risk Management ProgramsManagement Programs

CDER/CBER CDER/CBER PDUFA3 Risk Management PDUFA3 Risk Management

Working GroupWorking Group

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

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Risk Management Working GroupRisk Management Working Group

• Chair: Anne TrontellChair: Anne Trontell• CDER lead: Florence HounCDER lead: Florence Houn• CBER lead: Mark WeinsteinCBER lead: Mark Weinstein

• OTCOM supportOTCOM support– Nancy SmithNancy Smith– Colleen PritchardColleen Pritchard

• ORP supportORP support– Aileen CiampaAileen Ciampa

• Project ManagerProject Manager– Chris BechtelChris Bechtel

• CDERCDER– Susan AllenSusan Allen– Jonca Bull Jonca Bull – Yuan-Yuan ChiuYuan-Yuan Chiu– Toni Piazza HeppToni Piazza Hepp– Deborah Leiderman Deborah Leiderman – Claudia KarwoskiClaudia Karwoski– Denise ToyerDenise Toyer– Kathleen UhlKathleen Uhl

• CBERCBER– Richard DiamondRichard Diamond– Theresa FinnTheresa Finn– Brian HarveyBrian Harvey– Toni StifanoToni Stifano– Robert WiseRobert Wise

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Overall Context: Overall Context: PDUFA3 GuidancesPDUFA3 Guidances

• PDUFA3 calls for three interrelated PDUFA3 calls for three interrelated guidances on risk management guidances on risk management

• Yesterday’s and tomorrow’s concept Yesterday’s and tomorrow’s concept papers focus on risk assessment papers focus on risk assessment components of risk managementcomponents of risk management– Premarketing Risk Assessment Premarketing Risk Assessment – Pharmacovigilance/pharmacoepidemiologyPharmacovigilance/pharmacoepidemiology

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Context: Context: Today’s Concept Paper Today’s Concept Paper

• Focuses on actions taken to reduce risks in drug Focuses on actions taken to reduce risks in drug product useproduct use– based on assessments described in other two based on assessments described in other two

concept papersconcept papers

• Distinguishes itself from overall efforts by using Distinguishes itself from overall efforts by using the term Risk Management the term Risk Management ProgramsPrograms

• Calls overall process RM planningCalls overall process RM planning

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Process HighlightsProcess Highlights

• CommentsComments --> solicited today and through April 30, 2003--> solicited today and through April 30, 2003

• Draft guidancesDraft guidances--> Fall 2003--> Fall 2003

• Public comment period on draft guidancesPublic comment period on draft guidances• Final guidancesFinal guidances

--> September 30, 2004--> September 30, 2004

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Format of Today’s Meeting Format of Today’s Meeting • No external panelNo external panel

– Workgroup and Steering Committee onlyWorkgroup and Steering Committee only

• Two half-day sessions each including:Two half-day sessions each including:– Two key sections of concept paperTwo key sections of concept paper– Presentation of highlights by WG members Presentation of highlights by WG members – Clarifying questions on presentationsClarifying questions on presentations– Presentations by registered public speakers Presentations by registered public speakers – Qs & As, discussion Qs & As, discussion

• Afternoon concludes with brief wrap-upAfternoon concludes with brief wrap-up

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Scope of Concept PaperScope of Concept Paper

• Considerations for initiating and designing a risk Considerations for initiating and designing a risk management program - management program - definitions and when appropriate definitions and when appropriate

• Selection of tools and levelsSelection of tools and levels

• Evaluation processes and methodsEvaluation processes and methods

• Elements of submissions to FDAElements of submissions to FDA

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AgendaAgendaMorning Workgroup Speakers:Morning Workgroup Speakers:

Concepts, Definitions & When RMPs are Concepts, Definitions & When RMPs are AppropriateAppropriate

Dr. Robert Wise, CBERDr. Robert Wise, CBER

Tools and Levels of RM ProgramsTools and Levels of RM ProgramsDr. Toni Piazza-Hepp, CDERDr. Toni Piazza-Hepp, CDER

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AgendaAgenda

Afternoon Workgroup Speakers:Afternoon Workgroup Speakers:

Evaluation Processes and MethodsEvaluation Processes and MethodsDr. Richard Diamond, CBERDr. Richard Diamond, CBER

Submission ElementsSubmission ElementsDr. Claudia Karwoski, CDERDr. Claudia Karwoski, CDER

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Morning Session: Morning Session: Commentary Invited Commentary Invited

• Definition of an RM Program (RMP)Definition of an RM Program (RMP)• Clarity of RMP goals, objectivesClarity of RMP goals, objectives• Determining when an RMP is needed and Determining when an RMP is needed and

Sponsor/FDA roles in decision-makingSponsor/FDA roles in decision-making• Best ways for tools to be in guidanceBest ways for tools to be in guidance• Classification of RMP tools into LevelsClassification of RMP tools into Levels

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Afternoon: Invited Afternoon: Invited CommentaryCommentary

• Pretesting of RMP toolsPretesting of RMP tools• Recommended evaluation of all RMPsRecommended evaluation of all RMPs• Recommendation for 2 independent Recommendation for 2 independent

methods to evaluate key RMP goal(s)methods to evaluate key RMP goal(s)• Role of qualitative data in evaluationRole of qualitative data in evaluation• Elements of RMP submissions & Elements of RMP submissions &

reportsreports

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RISK MANAGEMENT RISK MANAGEMENT PROGRAM CONCEPTSPROGRAM CONCEPTS

Robert P. Wise MD, MPHRobert P. Wise MD, MPHCBERCBER

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OVERVIEWOVERVIEW

• Definitions Definitions

• Risk Management Program (RMP)Risk Management Program (RMP)– component goals and objectivescomponent goals and objectives– when appropriatewhen appropriate

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DefinitionsDefinitions • ProductProduct: : drug or biological regulated by CDER or CBERdrug or biological regulated by CDER or CBER

– Includes vaccines and plasma derivativesIncludes vaccines and plasma derivatives– Excludes other blood productsExcludes other blood products

• FDA FDA approval (or licensure)approval (or licensure) means a product is : means a product is :– safe and effective safe and effective – for labeled indicationsfor labeled indications– under labeled conditions of use under labeled conditions of use

• SafeSafe means that beneficial actions: means that beneficial actions:– outweigh harmful or undesirable side effects;outweigh harmful or undesirable side effects;– does not suggest absence of risk.does not suggest absence of risk.

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Definition: Risk Management (RM)Definition: Risk Management (RM)

Methods used throughout Methods used throughout a product’s lifecycle to: a product’s lifecycle to:

• minimize risksminimize risks• optimize benefit/risk balanceoptimize benefit/risk balance

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What is Risk Management?What is Risk Management?

• Use of risk information from investigational and Use of risk information from investigational and marketing phases marketing phases

• Identification and interpretation of risks and Identification and interpretation of risks and benefits in actual usebenefits in actual use

• Interventions to minimize risks as necessaryInterventions to minimize risks as necessary• Intervention phases:Intervention phases:

– DesignDesign– ImplementationImplementation– Evaluation Evaluation – Revision as appropriateRevision as appropriate

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Risk Management Risk Management PlanningPlanning • All sponsor efforts to minimize product risks: All sponsor efforts to minimize product risks:

– Risk assessment Risk assessment – Pharmacovigilance/pharmacoepidemiology Pharmacovigilance/pharmacoepidemiology – Special studies or interventionsSpecial studies or interventions– Professional product labeling (PI)Professional product labeling (PI)

• All products have risk management planningAll products have risk management planning– Traditional: PI and postmarketing surveillance (PMS)Traditional: PI and postmarketing surveillance (PMS)– Risk management Risk management programprogram when PI and PMS are not when PI and PMS are not

sufficient to minimize riskssufficient to minimize risks

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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) in addition to PI1 intervention (tool) in addition to PI

• Tool examples: education, forms, processes, and other Tool examples: education, forms, processes, and other methods to influence or control a product’s:methods to influence or control a product’s:– prescribingprescribing– dispensingdispensing– useuse

Note: the package insert (PI) is that portion of the approved product labeling described in 21 CFR 201.57, Note: the package insert (PI) is that portion of the approved product labeling described in 21 CFR 201.57, that is directed primarily to health professionals. The PI should not be confused with approved product that is directed primarily to health professionals. The PI should not be confused with approved product labeling which my incorporate RMP materials such as Medication Guides and patient agreements in labeling which my incorporate RMP materials such as Medication Guides and patient agreements in addition to the PI.addition to the PI.

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Definition: RMP Goal(s)Definition: RMP Goal(s)

• Tailored to specific risk concernsTailored to specific risk concerns• Describe desired end result of RMPDescribe desired end result of RMP• Include “Vision statement” of optimal drug Include “Vision statement” of optimal drug

use scenario, e.g:use scenario, e.g:

““No patient with condition A (e.g. pregnancy)No patient with condition A (e.g. pregnancy) should receive product B (e.g. teratogen).”should receive product B (e.g. teratogen).”

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Definition: Definition: RM Program ObjectivesRM Program Objectives

• Intermediate steps to an RMP goal Intermediate steps to an RMP goal

• Affect processes, behaviors, or outcomes Affect processes, behaviors, or outcomes

• Multiple objectives can serve one goal Multiple objectives can serve one goal (e.g. MD training, pharmacy practice)(e.g. MD training, pharmacy practice)

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When is an RM Program When is an RM Program Appropriate?Appropriate?

• Whenever risk reduction needs emerge Whenever risk reduction needs emerge (throughout product lifecycle)(throughout product 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 in appears to undermine the magnitude of benefits in an important segment of actual or potential users.”an important segment of actual or potential users.”

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How to Assess WhetherHow to Assess WhetherRisks Undermine Benefits?Risks Undermine Benefits?

• No simple formula compares risks to benefitsNo simple formula compares risks to benefits

• Risk and benefit numbers, types, measures vary Risk and benefit numbers, types, measures vary

• Case-by-case judgments required by sponsor Case-by-case judgments required by sponsor and/or FDA on whether to develop, submit, and and/or FDA on whether to develop, submit, and implement an RMP implement an RMP

• FDA expects:FDA expects:– Most products will be handled by PI.Most products will be handled by PI.– PI revision will not automatically imply a need for RMPPI revision will not automatically imply a need for RMP

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Risk Management ToolsRisk Management Tools

Toni Piazza-Hepp, Pharm. D.Toni Piazza-Hepp, Pharm. D.CDERCDER

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DefinitionsDefinitions• Risk management intervention (tool): a process Risk management intervention (tool): a process

or system intended to enhance safe product use or system intended to enhance safe product use by reducing riskby reducing risk

• Risk management programs use one or more Risk management programs use one or more toolstools

• 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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Types of Tools in Current Types of Tools in Current ProgramsPrograms

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Education and OutreachEducation and Outreach• Beyond professional labeling (“package insert”, PI)Beyond professional labeling (“package insert”, PI)

• HCP letters and other public noticesHCP letters and 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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Systems Guiding Prescribing, Systems Guiding Prescribing, Dispensing, UseDispensing, Use

• Patient agreements/informed consentPatient agreements/informed consent

• Enrollment of one or more stakeholders in special programEnrollment of one or more stakeholders in special program

• Practitioner certification programsPractitioner certification programs

• Special conditions of dispensingSpecial conditions of dispensing– special packagingspecial packaging– limited supply / no refilllimited supply / no refill– check mechanisms to assure appropriate prescribingcheck mechanisms to assure appropriate prescribing

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Restricted Access SystemsRestricted Access Systems• Designed to enforce compliance with program Designed to enforce compliance with program

elementselements

• May include registration/enrollment of May include registration/enrollment of physicians/pharmacists/patientsphysicians/pharmacists/patients

• May include documentation of safe use May include documentation of safe use conditions (such as lab tests) before dispensing conditions (such as lab tests) before dispensing to patientsto patients

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Suspension of MarketingSuspension of Marketing

With or without application withdrawalWith or without application withdrawal

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Selecting and Developing ToolsSelecting and Developing ToolsConsider:Consider:

• Stakeholder input: feasibility, acceptanceStakeholder input: feasibility, acceptance• Consistency: with existing/accepted toolsConsistency: with existing/accepted tools• Evidence of success in achieving desired objective Evidence of success in achieving desired objective

based on other RMPbased on other RMP• Evidence of success in ability of novel tool to achieve Evidence of success in ability of novel tool to achieve

desired objectivesdesired objectives– based on application in non-RMP settingsbased on application in non-RMP settings

• Variability, validity, reproducibilityVariability, validity, reproducibility

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Proposed “Levels” for RMP Proposed “Levels” for RMP ClassificationClassification

• Broad categorization; a continuumBroad categorization; a continuum• Risk management Risk management planningplanning considers all considers all

levels; basis is product risklevels; basis is product risk• Risk management Risk management program (RMP)program (RMP)

– begins at Level 2begins at Level 2– beyond the “package insert”beyond the “package insert”

• Increased level - increased divergence from Increased level - increased divergence from conventional prescribing and dispensingconventional prescribing and dispensing

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Proposed “Levels” for RMP Proposed “Levels” for RMP ClassificationClassification

Level 1: Package insert onlyLevel 1: Package insert only

Level 2: Adds education and outreach tools Level 2: Adds education and outreach tools

Level 3: Level 2 plus systems guiding Level 3: Level 2 plus systems guiding prescribing, dispensing and/or useprescribing, dispensing and/or use

Level 4: Access to product requires Level 4: Access to product requires adherence to specific program elementsadherence to specific program elements

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Morning Session: Morning Session: Commentary Invited Commentary Invited

• Definition of an RM Program (RMP)Definition of an RM Program (RMP)• Clarity of RMP goals, objectivesClarity of RMP goals, objectives• Determining when an RMP is needed and Determining when an RMP is needed and

Sponsor/FDA roles in decision-makingSponsor/FDA roles in decision-making• Best ways for tools to be in guidanceBest ways for tools to be in guidance• Classification of RMP tools into LevelsClassification of RMP tools into Levels