DSaRM Advisory Committee May 19, 2005 Postmarketing Studies: OND Perspective Julie Beitz MD, Deputy Director, Office of Drug Evaluation III, Office of

DSaRM Advisory Committee DSaRM Advisory Committee May 19, 2005May 19, 2005

Postmarketing Studies:Postmarketing Studies:OND PerspectiveOND Perspective

Postmarketing Studies:Postmarketing Studies:OND PerspectiveOND Perspective

Julie Beitz MD, Deputy Director, Office of Drug Evaluation III,

Office of New Drugs

Julie Beitz MD, Deputy Director, Office of Drug Evaluation III,

Office of New Drugs

2DSaRM Advisory Committee DSaRM Advisory Committee May 19, 2005May 19, 2005

Product Risk AssessmentProduct Risk AssessmentProduct Risk AssessmentProduct Risk Assessment

• Occurs throughout a product’s life cycle

• When embarking on the development plan for a new

product, sponsors and regulators need to consider:– What safety information should be generated pre-approval;

in particular, what specific safety risks should be explored

pre-approval?

– What safety information may be reasonably delayed to

postmarketing studies?

• Occurs throughout a product’s life cycle

• When embarking on the development plan for a new

product, sponsors and regulators need to consider:– What safety information should be generated pre-approval;

in particular, what specific safety risks should be explored

pre-approval?

– What safety information may be reasonably delayed to

postmarketing studies?


Size of the NDA or BLA Safety Database*Size of the NDA or BLA Safety Database*Size of the NDA or BLA Safety Database*Size of the NDA or BLA Safety Database*

• It is not possible to identify all safety concerns pre-approval• After approval, new safety concerns may become apparent

– Large numbers of patients exposed chronically, including those with co-morbid illness or prescribed concomitant medications

• Size of safety database depends upon*:– Product use: chronic or acute?– Intended population: healthy subjects on a large scale, or the

seriously ill?– Are alternative therapies available?

*Guidance for Industry: Premarketing Risk Assessment, March 2005

• It is not possible to identify all safety concerns pre-approval• After approval, new safety concerns may become apparent

– Large numbers of patients exposed chronically, including those with co-morbid illness or prescribed concomitant medications

• Size of safety database depends upon*:– Product use: chronic or acute?– Intended population: healthy subjects on a large scale, or the

seriously ill?– Are alternative therapies available?

*Guidance for Industry: Premarketing Risk Assessment, March 2005


Size of the NDA or BLA Safety Database*Size of the NDA or BLA Safety Database*Size of the NDA or BLA Safety Database*Size of the NDA or BLA Safety Database*

• For acute or short-term use or use in life-threatening illness– Number of exposed subjects should be individualized

• For chronic, long-term use in non-life-threatening illness– 1500 subjects (300-600 for 6 mos and 100 for 1 yr) exposed in

multiple dose studies to relevant doses– >1500 exposed subjects if:

• Concern about late developing adverse events• Need to quantify the rate of a specific low frequency adverse event• Benefits are small• The product may add to existing morbidity in the treated population

*Guidance for Industry: Premarketing Risk Assessment, March 2005; ICH E1A, March 1995

• For acute or short-term use or use in life-threatening illness– Number of exposed subjects should be individualized

• For chronic, long-term use in non-life-threatening illness– 1500 subjects (300-600 for 6 mos and 100 for 1 yr) exposed in

multiple dose studies to relevant doses– >1500 exposed subjects if:

• Concern about late developing adverse events• Need to quantify the rate of a specific low frequency adverse event• Benefits are small• The product may add to existing morbidity in the treated population

*Guidance for Industry: Premarketing Risk Assessment, March 2005; ICH E1A, March 1995


The Fundamental ChallengeThe Fundamental ChallengeThe Fundamental ChallengeThe Fundamental Challenge

Given the limitations of

the premarket safety

assessment, rigorous

postmarketing safety

assessment is critical for

characterizing a product’s

risk profile and for making

informed decisions about

risk minimization

Given the limitations of

the premarket safety

assessment, rigorous

postmarketing safety

assessment is critical for

characterizing a product’s

risk profile and for making

informed decisions about

risk minimization


Presentation OutlinePresentation OutlinePresentation OutlinePresentation Outline

• How are postmarketing studies regulated?

• What can we learn from different types of studies?

• What are some important considerations in designing or reviewing them?

• What are some dilemmas in interpreting them?

• What challenges do regulators face?

• How are postmarketing studies regulated?

• What can we learn from different types of studies?

• What are some important considerations in designing or reviewing them?

• What are some dilemmas in interpreting them?

• What challenges do regulators face?


Postmarketing Studies - DefinitionPostmarketing Studies - DefinitionPostmarketing Studies - DefinitionPostmarketing Studies - Definition

“…delineate additional information about the drug’s risks, benefits, and optimal use. These studies could include, but would not be limited to, studying different doses or schedules of administration than were used in phase 2 studies, use of the drug in other patient populations or other stages of the disease, or use of the drug over a longer period of time.” (312.85)

“…delineate additional information about the drug’s risks, benefits, and optimal use. These studies could include, but would not be limited to, studying different doses or schedules of administration than were used in phase 2 studies, use of the drug in other patient populations or other stages of the disease, or use of the drug over a longer period of time.” (312.85)


Required Postmarketing StudiesRequired Postmarketing StudiesRequired Postmarketing StudiesRequired Postmarketing Studies

• Accelerated Approval (1992)– Confirm clinical benefit for products approved based on

surrogate endpoints; safety data are also collected

• Animal Efficacy Rule (2002)– Confirm clinical benefit and assess safety for products

used to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances

• Pediatric Research Equity Rule (2003)– Assess safety and efficacy and support dosing for pediatric

patients

• Accelerated Approval (1992)– Confirm clinical benefit for products approved based on

surrogate endpoints; safety data are also collected

• Animal Efficacy Rule (2002)– Confirm clinical benefit and assess safety for products

used to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances

• Pediatric Research Equity Rule (2003)– Assess safety and efficacy and support dosing for pediatric

patients


Other Postmarketing StudiesOther Postmarketing StudiesOther Postmarketing StudiesOther Postmarketing Studies

• Requested by FDA– Sponsor voluntarily commits to conducting study(ies) after

approval– A schedule for study completion is agreed upon before

approval of the application– FDA tracks status of studies, posts updates on its website,

and reports summary statistics annually in FR • Requested by other regulatory authorities• Conducted at the initiative of the sponsor, NIH or

other investigators– With or without input from FDA

• Requested by FDA– Sponsor voluntarily commits to conducting study(ies) after

approval– A schedule for study completion is agreed upon before

approval of the application– FDA tracks status of studies, posts updates on its website,

and reports summary statistics annually in FR • Requested by other regulatory authorities• Conducted at the initiative of the sponsor, NIH or

other investigators– With or without input from FDA


Categories of Serious Adverse Events*Categories of Serious Adverse Events*Categories of Serious Adverse Events*Categories of Serious Adverse Events*

• Events that are readily attributable to treatment– Hematologic, hepatic, renal, dermatologic or pro-arrhythmic

• Events that are not readily attributable to treatment– Myocardial infarction or stroke in the elderly– Immune defects in AIDS or cancer– Sudden death in schizophrenia

– Large controlled studies are often needed

*Reviewer Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review, February 2005

• Events that are readily attributable to treatment– Hematologic, hepatic, renal, dermatologic or pro-arrhythmic

• Events that are not readily attributable to treatment– Myocardial infarction or stroke in the elderly– Immune defects in AIDS or cancer– Sudden death in schizophrenia

– Large controlled studies are often needed



Investigating Safety Signals*Investigating Safety Signals*Investigating Safety Signals*Investigating Safety Signals*

• Safety signal: a concern about an apparent excess of adverse events compared to what would be expected

• After a safety signal is identified, a careful case level review should be conducted

• If the signal represents a potential safety risk:– Develop a synthesis of all available safety information – Assess the benefit-risk balance of the product for users as a whole

and for at-risk populations– Consider how best to investigate the signal further through

additional studies

*Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, March 2005

• Safety signal: a concern about an apparent excess of adverse events compared to what would be expected

• After a safety signal is identified, a careful case level review should be conducted

• If the signal represents a potential safety risk:– Develop a synthesis of all available safety information – Assess the benefit-risk balance of the product for users as a whole

and for at-risk populations– Consider how best to investigate the signal further through

additional studies



General Advice to Sponsors*General Advice to Sponsors*General Advice to Sponsors*General Advice to Sponsors*

• Consider all available methods to evaluate a particular safety signal

• Choose the method best suited to the particular signal and research question

• Communicate with FDA as plans progress


• Consider all available methods to evaluate a particular safety signal

• Choose the method best suited to the particular signal and research question

• Communicate with FDA as plans progress



Types of StudiesTypes of StudiesTypes of StudiesTypes of Studies

• Preclinical toxicological studies

• Clinical studies– Pharmacokinetic studies

– Pharmacoepidemiologic studies

– Controlled clinical studies• Long-term controlled safety studies

• Each can provide unique information– Mechanistic considerations

– Magnitude, severity, and change in risk over time

– Factors that can enhance or diminish the risk

• Preclinical toxicological studies

• Clinical studies– Pharmacokinetic studies

– Pharmacoepidemiologic studies

– Controlled clinical studies• Long-term controlled safety studies

• Each can provide unique information– Mechanistic considerations

– Magnitude, severity, and change in risk over time

– Factors that can enhance or diminish the risk


Preclinical Toxicological StudiesPreclinical Toxicological StudiesPreclinical Toxicological StudiesPreclinical Toxicological Studies

• Purpose– Predict potentially serious toxicity that might occur in

humans– Assess suspected or documented toxicities observed in

humans during development or after approval

• Dilemmas– Not all adverse events in humans are predicted by animal

studies– Not all adverse events in humans are confirmed after the

fact in animals

• Purpose– Predict potentially serious toxicity that might occur in

humans– Assess suspected or documented toxicities observed in

humans during development or after approval

• Dilemmas– Not all adverse events in humans are predicted by animal

studies– Not all adverse events in humans are confirmed after the

fact in animals


Reasons for False Positive/Negative Reasons for False Positive/Negative Animal StudiesAnimal Studies

Reasons for False Positive/Negative Reasons for False Positive/Negative Animal StudiesAnimal Studies

• Very large doses are used• May saturate pharmacological mechanisms• Lead to irrelevant toxicities

• Subjective adverse events are not detectable in animals

• Immunologic effects are difficult to detect in animals• Rare events in humans will rarely be observed in

animals as few animals are evaluated

• Very large doses are used• May saturate pharmacological mechanisms• Lead to irrelevant toxicities

• Subjective adverse events are not detectable in animals

• Immunologic effects are difficult to detect in animals• Rare events in humans will rarely be observed in

animals as few animals are evaluated


Pharmacokinetic StudiesPharmacokinetic StudiesPharmacokinetic StudiesPharmacokinetic Studies

• Purpose– Select optimal dosage strength, form, and regimen– Assess factors that can enhance or diminish absorption,

distribution, metabolism and excretion– Monitor the course of patients experiencing adverse events– Determine bioequivalence of new formulations

• Dilemmas– Timing of studies and populations studied are often debated– It is not possible to assess all factors that may affect blood

or tissue levels

– Not all factors that affect pK parameters can be quantified

• Purpose– Select optimal dosage strength, form, and regimen– Assess factors that can enhance or diminish absorption,

distribution, metabolism and excretion– Monitor the course of patients experiencing adverse events– Determine bioequivalence of new formulations

• Dilemmas– Timing of studies and populations studied are often debated– It is not possible to assess all factors that may affect blood

or tissue levels

– Not all factors that affect pK parameters can be quantified


Pharmacokinetic Studies:Pharmacokinetic Studies:Study Design ConsiderationsStudy Design Considerations

Pharmacokinetic Studies:Pharmacokinetic Studies:Study Design ConsiderationsStudy Design Considerations

• Was a baseline for study subjects established?

• Sufficiently long crossover period to prevent carryover effects?

• Were study subjects compliant with diet?

• Good analytical method to measure product concentrations?

• Appropriate number of samples and optimal timing of collection?

• Degree of protein binding in various clinical situations?

• Differences in activity or receptor binding of optical isomers and

metabolites?

• Dosage strengths/forms studied similar to those to be marketed?

• Was a baseline for study subjects established?

• Sufficiently long crossover period to prevent carryover effects?

• Were study subjects compliant with diet?

• Good analytical method to measure product concentrations?

• Appropriate number of samples and optimal timing of collection?

• Degree of protein binding in various clinical situations?

• Differences in activity or receptor binding of optical isomers and

metabolites?

• Dosage strengths/forms studied similar to those to be marketed?


Pharmacokinetic Studies:Pharmacokinetic Studies:Interpretation IssuesInterpretation Issues

Pharmacokinetic Studies:Pharmacokinetic Studies:Interpretation IssuesInterpretation Issues

• For each study, have the appropriate assumptions

been made? – Pharmacokinetic models used – Rate limiting steps– Presence or absence of metabolites

• When considering several studies, are appropriate studies being compared?– Populations studied– Study conditions (fasted vs. fed)– Formulations studied– Assay methods used

• For each study, have the appropriate assumptions

been made? – Pharmacokinetic models used – Rate limiting steps– Presence or absence of metabolites

• When considering several studies, are appropriate studies being compared?– Populations studied– Study conditions (fasted vs. fed)– Formulations studied– Assay methods used


Pharmacoepidemiologic Studies*Pharmacoepidemiologic Studies*Pharmacoepidemiologic Studies*Pharmacoepidemiologic Studies*

• Purpose– May be the only practical choice to characterize uncommon or

delayed adverse events– Identify important co-morbidities or co-therapies as risk factors– Examine the natural history of a disease– Explore drug use patterns

• Dilemmas– What is the optimal design and size?– How many studies are needed?– How best to minimize bias and account for confounding?


• Purpose– May be the only practical choice to characterize uncommon or

delayed adverse events– Identify important co-morbidities or co-therapies as risk factors– Examine the natural history of a disease– Explore drug use patterns

• Dilemmas– What is the optimal design and size?– How many studies are needed?– How best to minimize bias and account for confounding?



Controlled Clinical StudiesControlled Clinical StudiesControlled Clinical StudiesControlled Clinical Studies

• Purpose

– Phase 2: Assess effectiveness and “determine the common short-term side effects and risks associated with the drug.” [312.21(b)]

– Phase 3: Assess safety and effectiveness needed to “evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labelling.” [312.21(c)]

– Postmarketing: Assess safety and effectiveness: • In populations not previously studied (new uses)• New dosing regimens• Longer treatment durations

• Purpose

– Phase 2: Assess effectiveness and “determine the common short-term side effects and risks associated with the drug.” [312.21(b)]

– Phase 3: Assess safety and effectiveness needed to “evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labelling.” [312.21(c)]

– Postmarketing: Assess safety and effectiveness: • In populations not previously studied (new uses)• New dosing regimens• Longer treatment durations


Controlled Clinical StudiesControlled Clinical StudiesControlled Clinical StudiesControlled Clinical Studies

• Dilemmas

– A large number of patients - representing appropriate demographic subsets and risk groups - needs to be enrolled to observe a relatively uncommon adverse event

– If inclusion criteria are set too narrowly, study findings may not be relevant to general clinical settings

– Studies in phases 2/3 typically do not test specified hypotheses about safety

• Dilemmas

– A large number of patients - representing appropriate demographic subsets and risk groups - needs to be enrolled to observe a relatively uncommon adverse event

– If inclusion criteria are set too narrowly, study findings may not be relevant to general clinical settings

– Studies in phases 2/3 typically do not test specified hypotheses about safety


NDA/BLA Materials for Clinical ReviewNDA/BLA Materials for Clinical ReviewNDA/BLA Materials for Clinical ReviewNDA/BLA Materials for Clinical Review

• Integrated Summary/Analysis of Safety• Adverse event tables• Case report forms for dropouts or patients who experienced

serious adverse events• Individual patient adverse event data and laboratory listings • Narrative summaries of deaths, serious adverse events, and

events leading to dropout• Other documents

– Reports of specific safety studies– Coding dictionaries– Source documents for auditing purposes

• Integrated Summary/Analysis of Safety• Adverse event tables• Case report forms for dropouts or patients who experienced

serious adverse events• Individual patient adverse event data and laboratory listings • Narrative summaries of deaths, serious adverse events, and

events leading to dropout• Other documents

– Reports of specific safety studies– Coding dictionaries– Source documents for auditing purposes


Controlled Clinical Studies:Controlled Clinical Studies:Adverse Events*Adverse Events*

Controlled Clinical Studies:Controlled Clinical Studies:Adverse Events*Adverse Events*

• Assess drug-relatedness– For common events, compare rates for product vs. placebo– For rare events, the expected rate = 0, so even a few cases could

represent a safety signal

• For events that seem drug-related, explore:– Dose-dependency– Time to onset, severity of events– Time course of events– Demographic interactions– Drug-drug, drug-disease interactions


• Assess drug-relatedness– For common events, compare rates for product vs. placebo– For rare events, the expected rate = 0, so even a few cases could

represent a safety signal

• For events that seem drug-related, explore:– Dose-dependency– Time to onset, severity of events– Time course of events– Demographic interactions– Drug-drug, drug-disease interactions



Controlled Clinical Studies:Controlled Clinical Studies:Adverse Event ReportingAdverse Event Reporting

Controlled Clinical Studies:Controlled Clinical Studies:Adverse Event ReportingAdverse Event Reporting

• Over-reporting – Study design: excessive dosing, frequent assessments, study

duration long enough to introduce other factors– Overzealous investigators or patients’ awareness heightened– Improper coding

• Under-reporting– Study design: infrequent or poorly timed assessments,

inappropriate parameters monitored, follow-up too short– Investigators attribute event to underlying disease– Event not recognized by investigators or patients– Improper coding

• Over-reporting – Study design: excessive dosing, frequent assessments, study

duration long enough to introduce other factors– Overzealous investigators or patients’ awareness heightened– Improper coding

• Under-reporting– Study design: infrequent or poorly timed assessments,

inappropriate parameters monitored, follow-up too short– Investigators attribute event to underlying disease– Event not recognized by investigators or patients– Improper coding


Controlled Clinical Studies:Controlled Clinical Studies:Laboratory Abnormalities*Laboratory Abnormalities*

Controlled Clinical Studies:Controlled Clinical Studies:Laboratory Abnormalities*Laboratory Abnormalities*

• Analysis of central tendency• Outliers• Dropouts or dose reductions for laboratory abnormalities• Dose-dependency, time to onset, time course• Potential for severe hepatotoxicity• Potential for QT/QTc prolongation

– Thorough QT/QTc study**


**ICH E14 Draft, June 2004

• Analysis of central tendency• Outliers• Dropouts or dose reductions for laboratory abnormalities• Dose-dependency, time to onset, time course• Potential for severe hepatotoxicity• Potential for QT/QTc prolongation

– Thorough QT/QTc study**


**ICH E14 Draft, June 2004


Controlled Clinical Studies:Controlled Clinical Studies:Special PopulationsSpecial Populations

Controlled Clinical Studies:Controlled Clinical Studies:Special PopulationsSpecial Populations

• Neonates and young pediatric patients– Were doses adequately adjusted for weight?– Was the stage of development of physiologic functions,

metabolic pathways considered?– Were potential adverse effects on growth, neurocognitive

development considered?– Was the frequency of testing, imaging, or blood sampling

adequate?

• Geriatrics– Were renal function, muscle mass considered?– Was the impact of altered homeostatic mechanisms

considered?

• Neonates and young pediatric patients– Were doses adequately adjusted for weight?– Was the stage of development of physiologic functions,

metabolic pathways considered?– Were potential adverse effects on growth, neurocognitive

development considered?– Was the frequency of testing, imaging, or blood sampling

adequate?

• Geriatrics– Were renal function, muscle mass considered?– Was the impact of altered homeostatic mechanisms

considered?


Long-Term Controlled Safety Studies*Long-Term Controlled Safety Studies*Long-Term Controlled Safety Studies*Long-Term Controlled Safety Studies*

• Purpose– Assess/compare rates of adverse event rates across groups

• Helpful when event is more common with cumulative exposure

– Facilitate attribution of adverse events to the product• Helpful when the event occurs relatively commonly in the

treated population, or could be part of the disease being treated

• Dilemmas– Timing of studies relative to product approval

– Sample size, study duration and “simple” safety endpoints *Guidance for Industry: Premarketing Risk Assessment, March 2005

• Purpose– Assess/compare rates of adverse event rates across groups

• Helpful when event is more common with cumulative exposure

– Facilitate attribution of adverse events to the product• Helpful when the event occurs relatively commonly in the

treated population, or could be part of the disease being treated

• Dilemmas– Timing of studies relative to product approval

– Sample size, study duration and “simple” safety endpoints *Guidance for Industry: Premarketing Risk Assessment, March 2005


Controlled Clinical Studies: Controlled Clinical Studies: Pooling Safety Data*Pooling Safety Data*

Controlled Clinical Studies: Controlled Clinical Studies: Pooling Safety Data*Pooling Safety Data*

• Pooling safety data from different studies can improve the precision of an incidence estimate– Good for low frequency events– Permits exploration of effects within subgroups– Can obscure important differences between studies

• Most appropriate to pool data from studies with similar designs

• Still important to explore the range of incidences across the studies being pooled


• Pooling safety data from different studies can improve the precision of an incidence estimate– Good for low frequency events– Permits exploration of effects within subgroups– Can obscure important differences between studies

• Most appropriate to pool data from studies with similar designs

• Still important to explore the range of incidences across the studies being pooled



Summary of ChallengesSummary of ChallengesSummary of ChallengesSummary of Challenges

• It is not possible to identify all safety concerns prior to

product approval

• Studies of approved or new uses may generate

safety information that:– Needs to be placed in context with what is already known

– May impact the benefit-risk balance for labeled indications

– May need to be applied to:• Other members of a product class

• Other dosage forms

• It is not possible to identify all safety concerns prior to

product approval

• Studies of approved or new uses may generate

safety information that:– Needs to be placed in context with what is already known

– May impact the benefit-risk balance for labeled indications

– May need to be applied to:• Other members of a product class

• Other dosage forms

Documents

DSaRM Advisory Committee May 19, 2005 Postmarketing Studies: OND Perspective Julie Beitz MD, Deputy Director, Office of Drug Evaluation III, Office of