Temple University - 4/15/031 Practicing “Good Risk Management” Guidance Development Under PDUFA III Paul J. Seligman, MD, MPH Director Office of Pharmacoepidemiology

Temple University - 4/15/03 1

Practicing “Good Risk Practicing “Good Risk Management”Management”

Guidance Development Under PDUFA IIIGuidance Development Under PDUFA III

Paul J. Seligman, MD, MPHPaul J. Seligman, MD, MPHDirectorDirector

Office of Pharmacoepidemiology & Office of Pharmacoepidemiology & Statistical ScienceStatistical Science


Prescription Drug Users Fee Act Prescription Drug Users Fee Act (PDUFA 3) - October 1, 2002(PDUFA 3) - October 1, 2002

• Guidance DevelopmentGuidance Development– Good risk assessmentGood risk assessment– Good risk managementGood risk management– Good pharmacovigilanceGood pharmacovigilance

• Develop interrelated documentsDevelop interrelated documents


Process HighlightsProcess Highlights

• Concept papersConcept papers– Public comments (through April 30, 2003)Public comments (through April 30, 2003)– [Docket 02N-0528][Docket 02N-0528]

– Internet AddressInternet Address http://www.fda.gov/ohrms/docketshttp://www.fda.gov/ohrms/dockets

• Draft guidancesDraft guidances– Fall 2003Fall 2003– Public comment period on draft guidancesPublic comment period on draft guidances

• Final guidancesFinal guidances– September 30, 2004September 30, 2004


Objectives Objectives • Key conceptsKey concepts

– Premarketing Risk AssessmentPremarketing Risk Assessment– Risk Management ProgramsRisk Management Programs– Risk Assessment of Observational Data: Good Risk Assessment of Observational Data: Good

Pharmacovigilance Practices and Pharmacovigilance Practices and Pharmacoepidemiologic AssessmentPharmacoepidemiologic Assessment

• Concept papers available atConcept papers available at– http://www.fda.gov/cder/meeting/riskmanagement.htmhttp://www.fda.gov/cder/meeting/riskmanagement.htm


Premarketing Risk AssessmentPremarketing Risk Assessment



• Generating Risk InformationGenerating Risk Information– General ConsiderationsGeneral Considerations– Special ConsiderationsSpecial Considerations

• Reporting Risk InformationReporting Risk Information– Analyzing and Presenting Risk InformationAnalyzing and Presenting Risk Information



• What is Risk Assessment?What is Risk Assessment?– Risk assessment is the process of identifying, Risk assessment is the process of identifying,

estimating and evaluating the nature and estimating and evaluating the nature and severity of risk from a productseverity of risk from a product

– Good risk assessment underlies good risk Good risk assessment underlies good risk management and pharmacovigilancemanagement and pharmacovigilance



• PremisePremise– Pre-marketing risk assessment relatively Pre-marketing risk assessment relatively

mature, but still evolvingmature, but still evolving– Public health, industry and FDA would all Public health, industry and FDA would all

benefit from optimizing risk assessment benefit from optimizing risk assessment allowing for approval of safe drugs with fully allowing for approval of safe drugs with fully informative labelinginformative labeling


Premarketing Risk AssessmentPremarketing Risk AssessmentGeneral ConsiderationsGeneral Considerations


Key IssuesKey Issues

• Size of the safety data baseSize of the safety data base– characteristics of the drug and its effectscharacteristics of the drug and its effects

– proposed useproposed use

– intended populationintended population

• Characteristics of an ideal safety data baseCharacteristics of an ideal safety data base– adequate durationadequate duration

– diverse populationdiverse population

– better dose-response informationbetter dose-response information• particularly important for drugs with a high rate of drug-particularly important for drugs with a high rate of drug-

induced adverse effects or “biomarkers” of injury (CPK, TA, induced adverse effects or “biomarkers” of injury (CPK, TA, UA, K changes)UA, K changes)


Key Issues (cont.)Key Issues (cont.)

• ““Individualization” factorsIndividualization” factors• drug-drug interactionsdrug-drug interactions

• drug-demographic relationshipsdrug-demographic relationships

• drug-disease relationships, including routine drug-disease relationships, including routine population PKpopulation PK

• Comparative data when it would be particularly Comparative data when it would be particularly importantimportant


Premarketing Risk AssessmentPremarketing Risk AssessmentSpecial ConditionsSpecial Conditions


Special ConsiderationsSpecial Considerations

Evaluation of safetyEvaluation of safety– some general principlessome general principles

– doesn’t mean one size fits alldoesn’t mean one size fits all

– in planning and monitoring development needs to be in planning and monitoring development needs to be constant attention toconstant attention to

• results of animal and human dataresults of animal and human data

• suggestions of problemssuggestions of problems

• population and drug-specific features that raise special population and drug-specific features that raise special concernsconcerns


Special ConsiderationsSpecial Considerations• DosingDosing

– maintenance dose same as acute dosemaintenance dose same as acute dose– titrationtitration

• Subtle adverse effectsSubtle adverse effects• Pediatrics (dosing, AEs)Pediatrics (dosing, AEs)• Database expansionDatabase expansion• PharmacogeneticsPharmacogenetics

– storing samplesstoring samples


Always EvaluatedAlways EvaluatedSome matters always need assessment, notablySome matters always need assessment, notably

• QTc effectsQTc effects• Evidence of hepatotoxicityEvidence of hepatotoxicity• Polymorphic metabolismPolymorphic metabolism• Drug-drug interactions, including new ones (inducers, Drug-drug interactions, including new ones (inducers,

inhibitors of glucuronidation, P-glycoprotein inhibitors)inhibitors of glucuronidation, P-glycoprotein inhibitors)

And, for biologicsAnd, for biologics• Immunogenicity, neutralizing antibodiesImmunogenicity, neutralizing antibodies• For live agents - virulence, transmissibility, genetic stabilityFor live agents - virulence, transmissibility, genetic stability• Transplantation therapies - survival, function, host Transplantation therapies - survival, function, host

immunocompetenceimmunocompetence


Medication Error Prevention Medication Error Prevention Analysis (MEPA)Analysis (MEPA)

• Pre-marketing assessment Pre-marketing assessment

• Increase “safe use” of products by:Increase “safe use” of products by:– minimizing medication errors related tominimizing medication errors related to

• namingnaming

• labeling, and/orlabeling, and/or

• packaging of the productpackaging of the product


Premarketing Risk Assessment:Premarketing Risk Assessment:Considerations for Data Analysis and Considerations for Data Analysis and

Data PresentationData Presentation


Data analysis issuesData analysis issues

• Grouping of adverse eventsGrouping of adverse events– coding/MedDRAcoding/MedDRA

• Temporal relations between adverse events andTemporal relations between adverse events and product exposureproduct exposure

time-to-eventtime-to-event• Analyses of dose effectsAnalyses of dose effects• Data poolingData pooling• Subgroup analysisSubgroup analysis• Missing safety dataMissing safety data• Data presentationData presentation


Risk Management ProgramsRisk Management Programs


Risk Management Programs Risk Management Programs

• 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


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


Key elements (1) Key elements (1)

• 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


Key elements (2)Key elements (2)

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

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


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


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 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 201.57, 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 approved product labeling which my incorporate RMP materials such as Medication Guides and patient agreements in addition to the PI.patient agreements in addition to the PI.


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.”


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

• No simple formula compares risks to benefits.No 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 RMP.PI revision will not automatically imply a need for RMP.


Risk Management ToolsRisk Management Tools


DefinitionsDefinitions

• Risk management intervention (tool): a Risk management intervention (tool): a process or system intended to enhance safe process or system intended to enhance safe product use by reducing riskproduct use by 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


Types of Tools in Current Types of Tools in Current ProgramsPrograms

• Education & outreachEducation & outreach• Systems Guiding Prescribing, Dispensing, Systems Guiding Prescribing, Dispensing,

Use Use • Restricted Access Systems Restricted Access Systems • Suspension of MarketingSuspension of Marketing


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


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


Evaluation Processes Evaluation Processes and Methodsand Methods


Value of Risk Management Value of Risk Management Program (RMP) EvaluationProgram (RMP) Evaluation

• Assess effectiveness of RMP & its toolsAssess effectiveness of RMP & its tools

— — Before implementation (pretesting)Before implementation (pretesting)

— — Periodically after implementationPeriodically after implementation

• Ensure efforts are expended on effective Ensure efforts are expended on effective interventionsinterventions

• Guide modifications of RMPGuide modifications of RMP


Pretesting RMP Tools Pretesting RMP Tools AllowsAllows::

• Stakeholder inputStakeholder input

• Comprehension testingComprehension testing

• Pilot testing of feasibility, Pilot testing of feasibility, acceptance, other factorsacceptance, other factors


Approaches To EvaluationApproaches To Evaluation

• Select what outcomes should Select what outcomes should be/can be measuredbe/can be measured

• Seek representative and Seek representative and quantitative dataquantitative data

• Use qualitative data as appropriate Use qualitative data as appropriate (e.g. risk communication)(e.g. risk communication)


Approaches To EvaluationApproaches To Evaluation

Consider using 2 complementary Consider using 2 complementary methods methods

– especially for key goals or objectives especially for key goals or objectives

– offset limitations of any single offset limitations of any single methodmethod


Evaluation MethodsEvaluation Methods

Consider limitationsConsider limitations ValidityValidity AccuracyAccuracy TimelinessTimeliness RepresentativenessRepresentativeness BiasesBiases Social burdensSocial burdens CostsCosts


Outcome Measures for Tools, Outcome Measures for Tools, Objectives, or GoalsObjectives, or Goals

Changes in or absolute levels of:Changes in or absolute levels of:

• Patient health outcomesPatient health outcomes

• Surrogates of health outcomesSurrogates of health outcomes

• Process measures or behaviorsProcess measures or behaviors

• Behavioral components - Behavioral components - Comprehension, Knowledge, AttitudesComprehension, Knowledge, Attitudes


Limitations of Current Limitations of Current Evaluation MethodsEvaluation Methods

Spontaneous adverse event reporting: Spontaneous adverse event reporting: – Decrease may reflect change in reporting, Decrease may reflect change in reporting,

notnot change in frequency of event change in frequency of event – – Continuing reports Continuing reports maymay signal persistent signal persistent

safety problem safety problem

Administrative data:Administrative data: – – May not be representative of general May not be representative of general

population population

– – Often exclude high risk populationsOften exclude high risk populations


Limitations of Current Limitations of Current Evaluation MethodsEvaluation Methods

SurveysSurveys or other a or other active surveillance ctive surveillance systems:systems:

– – Reporting biasesReporting biases

– – Sampling errorsSampling errors


Elements of RMP Elements of RMP Submission to FDASubmission to FDA

• Sections of RMP SubmissionSections of RMP Submission– BackgroundBackground– Goals, objectives, and levelGoals, objectives, and level– ToolsTools– Evaluation planEvaluation plan

• Reporting RMP to FDAReporting RMP to FDA


Risk Assessment of Observational Data: Risk Assessment of Observational Data: Good Pharmacovigilance Practices Good Pharmacovigilance Practices

andand Pharmacoepidemiologic AssessmentPharmacoepidemiologic Assessment



• Important pharmacovigilance conceptsImportant pharmacovigilance concepts• Safety signal identificationSafety signal identification• Pharmacoepidemiologic assessment and Pharmacoepidemiologic assessment and

interpretation of safety signalsinterpretation of safety signals• Development of pharmacovigilance plansDevelopment of pharmacovigilance plans



• Focus solely on observational data sourcesFocus solely on observational data sources– Case Reports, Case SeriesCase Reports, Case Series– Pharmacoepidemiologic StudiesPharmacoepidemiologic Studies

• RegistriesRegistries• SurveysSurveys


What is Pharmacovigilance?What is Pharmacovigilance?

All post-approval scientific and data All post-approval scientific and data gathering activities relating to the detection, gathering activities relating to the detection, assessment, understanding, and prevention assessment, understanding, and prevention of adverse effects or any other product- of adverse effects or any other product- related problems related problems

This includes the use of This includes the use of pharmacoepidemiological studiespharmacoepidemiological studies


Pharmacovigilance: Why?Pharmacovigilance: Why?

• At the time of approval, clinical trial data are At the time of approval, clinical trial data are available on limited numbers of patients available on limited numbers of patients treated for relatively short periodstreated for relatively short periods

• Once a product is marketed, large numbers Once a product is marketed, large numbers of patients may be exposed, including:of patients may be exposed, including:– Patients with co-morbid illnessesPatients with co-morbid illnesses– Patients using concomitant medicationsPatients using concomitant medications– Patients with chronic exposurePatients with chronic exposure


Pharmacovigilance: Why?Pharmacovigilance: Why?

• After marketing, new safety information After marketing, new safety information may become available:may become available:– Through use of the product domestically or in Through use of the product domestically or in

other countriesother countries– Through use of other drugs in the same classThrough use of other drugs in the same class– From preclinical studiesFrom preclinical studies– From pharmacologic studiesFrom pharmacologic studies– From controlled clinical trialsFrom controlled clinical trials


What is a Pharmacovigilance Plan?What is a Pharmacovigilance Plan?

• A plan proposed by a sponsor for the A plan proposed by a sponsor for the ongoing evaluation of safety signals ongoing evaluation of safety signals identified with the use of a productidentified with the use of a product

• May be developed at the time of product May be developed at the time of product launch or after a signal is identifiedlaunch or after a signal is identified



• A sponsor’s plan may involve:A sponsor’s plan may involve:– Expedited reporting of certain serious adverse Expedited reporting of certain serious adverse

eventsevents– Implementation of active surveillance activities to Implementation of active surveillance activities to

identify as yet unreported adverse eventsidentify as yet unreported adverse events– Conduct of additional observational studies or Conduct of additional observational studies or

clinical trialsclinical trials

• A pharmacovigilance plan might be a A pharmacovigilance plan might be a component of a larger risk management component of a larger risk management programprogram


Good Pharmacovigilance PracticesGood Pharmacovigilance Practices


Good Pharmacovigilance Practice Good Pharmacovigilance Practice starts by acquiring complete data from starts by acquiring complete data from

spontaneous adverse event reports.spontaneous adverse event reports.


Characteristics of a Good Characteristics of a Good Case ReportCase Report

• Adverse event(s) detailsAdverse event(s) details• Baseline patient characteristicsBaseline patient characteristics• Therapy detailsTherapy details• Time to onset of signs or symptomsTime to onset of signs or symptoms• Diagnosis of the eventDiagnosis of the event• Clinical course of the event and outcomesClinical course of the event and outcomes• Laboratory dataLaboratory data

• Any other relevant informationAny other relevant information


Good Medication Error ReportGood Medication Error Report

• ProductProduct• Sequence of events leading to the errorSequence of events leading to the error• Work environment in which the error Work environment in which the error

occurredoccurred• Types of personnel involved with the errorTypes of personnel involved with the error• Narratives- follow NCC MERP taxonomy Narratives- follow NCC MERP taxonomy

(National Coordinating Council for Medication (National Coordinating Council for Medication Error Reporting and Prevention)Error Reporting and Prevention)


Assessing CausalityAssessing Causality

• It is rarely certain whether the event was product It is rarely certain whether the event was product induced.induced.

• Features supportive of an associationFeatures supportive of an association– event occurred in the expected timeframe event occurred in the expected timeframe – absence of symptoms prior to exposureabsence of symptoms prior to exposure– absence of co-morbid conditions or use of absence of co-morbid conditions or use of

concomitant medications concomitant medications – (+) dechallenge, (+) rechallenge(+) dechallenge, (+) rechallenge– event consistent with the established mechanism event consistent with the established mechanism

of action of product of action of product • Grouping case reports into “probable,” “possible,” Grouping case reports into “probable,” “possible,”

and “unlikely” when appropriateand “unlikely” when appropriate


Pharmacoepidemiologic AssessmentPharmacoepidemiologic Assessment


When and why are pharmacoepidemiologic When and why are pharmacoepidemiologic studies recommended?studies recommended?

• To further characterize potential safety To further characterize potential safety signals from controlled clinical trialssignals from controlled clinical trials– chronic exposureschronic exposures– patients with comorbid conditionspatients with comorbid conditions

• To further evaluate and quantify a safety To further evaluate and quantify a safety signal identified after approvalsignal identified after approval– incidence rate vs. reporting rateincidence rate vs. reporting rate


Minimal Requirements Minimal Requirements

• Pharmacoepidemiologic study Pharmacoepidemiologic study protocolsprotocols

• RegistriesRegistries

• SurveysSurveys

• Reporting and assessing safety Reporting and assessing safety signalssignals


Reporting Safety Signals to FDAReporting Safety Signals to FDA

• Submit a synthesis of all available safety Submit a synthesis of all available safety informationinformation

• Provide an assessment of the risk/benefit Provide an assessment of the risk/benefit profile of the product profile of the product

• Propose steps to further investigate Propose steps to further investigate through additional studiesthrough additional studies

• Propose risk management strategies as Propose risk management strategies as appropriateappropriate



• An enhanced pharmacovigilance plan An enhanced pharmacovigilance plan proposed by a sponsor for proposed by a sponsor for – the ongoing evaluation of identified signals the ongoing evaluation of identified signals

pre- or post-approval, or pre- or post-approval, or – to monitor at risk populations which have not to monitor at risk populations which have not

been adequately studiedbeen adequately studied

• FDA may request the plan at the time of FDA may request the plan at the time of launch or when a signal is identifiedlaunch or when a signal is identified

• Efforts may be above and beyond routine Efforts may be above and beyond routine postmarketing spontaneous reportingpostmarketing spontaneous reporting


Pharmacovigilance Plans May Pharmacovigilance Plans May Involve...Involve...

• Expedited reporting of certain serious Expedited reporting of certain serious adverse eventsadverse events

• Periodic summary reporting at more Periodic summary reporting at more frequent intervalsfrequent intervals

• Perform active surveillance to identify Perform active surveillance to identify unreported adverse eventsunreported adverse events

• Conduct of additional observational Conduct of additional observational studies or controlled clinical trials, studies or controlled clinical trials, registry, surveysregistry, surveys


Challenges AheadChallenges Ahead

• How can the quality of adverse event How can the quality of adverse event reports be improved?reports be improved?

• What conclusions can be drawn from What conclusions can be drawn from observational data sources given inherent observational data sources given inherent limitations of such data?limitations of such data?

• What more can be done to enhance our What more can be done to enhance our knowledge about safety signals once they knowledge about safety signals once they are identified?are identified?


Documents

Temple University - 4/15/031 Practicing “Good Risk Management” Guidance Development Under PDUFA III Paul J. Seligman, MD, MPH Director Office of Pharmacoepidemiology