Postmarketing Studies: OND Perspective

1
Postmarketing StudiesOND Perspective

• Julie Beitz MD, Deputy Director,
• Office of Drug Evaluation III,
• Office of New Drugs

2
Product Risk Assessment

• Occurs throughout a products 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?

3
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

4
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
• gt1500 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

5
The Fundamental Challenge

• Given the limitations of the premarket safety
  assessment, rigorous postmarketing safety
  assessment is critical for characterizing a
  products risk profile and for making informed
  decisions about risk minimization

6
Presentation 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?

7
Postmarketing Studies - Definition

• delineate additional information about the
  drugs 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)

8
Required 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

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Other 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

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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

11
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

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

13
Types 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

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Preclinical 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

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Reasons for False Positive/Negative Animal 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

16
Pharmacokinetic 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

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Pharmacokinetic StudiesStudy 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?

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Pharmacokinetic StudiesInterpretation 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

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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?
• Guidance for Industry Good Pharmacovigilance
  Practices and Pharmacoepidemiologic Assessment,
  March 2005

20
Controlled 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

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Controlled 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

22
NDA/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

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Controlled Clinical StudiesAdverse 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
• Reviewer Guidance Conducting a Clinical Safety
  Review of a New Product Application and Preparing
  a Report on the Review, February 2005

24
Controlled Clinical StudiesAdverse 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

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Controlled Clinical StudiesLaboratory
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
• Reviewer Guidance Conducting a Clinical Safety
  Review of a New Product Application and Preparing
  a Report on the Review, February 2005
• ICH E14 Draft, June 2004

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Controlled Clinical StudiesSpecial 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?

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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

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Controlled Clinical Studies
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
• Reviewer Guidance Conducting a Clinical Safety
  Review of a New Product Application and
  Preparing a Report on the Review, February 2005

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Summary 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