Transcript Explanation of Additional Resource Needs at the Close of PDUFA-II

Practicing “Good Risk
Management”
Guidance Development Under PDUFA III
Paul J. Seligman, MD, MPH
Director
Office of Pharmacoepidemiology &
Statistical Science
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Prescription Drug Users Fee Act
(PDUFA 3) - October 1, 2002
• Guidance Development
– Good risk assessment
– Good risk management
– Good pharmacovigilance
• Develop interrelated documents
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Process Highlights
• Concept papers
– Public comments (through April 30, 2003)
– [Docket 02N-0528]
– Internet Address
http://www.fda.gov/ohrms/dockets
• Draft guidances
– Fall 2003
– Public comment period on draft guidances
• Final guidances
– September 30, 2004
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Objectives
• Key concepts
– Premarketing Risk Assessment
– Risk Management Programs
– Risk Assessment of Observational Data: Good
Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment
• Concept papers available at
– http://www.fda.gov/cder/meeting/riskmanagement.htm
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Premarketing Risk Assessment
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Premarketing Risk Assessment
• Generating Risk Information
– General Considerations
– Special Considerations
• Reporting Risk Information
– Analyzing and Presenting Risk Information
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Premarketing Risk Assessment
• What is Risk Assessment?
– Risk assessment is the process of identifying,
estimating and evaluating the nature and
severity of risk from a product
– Good risk assessment underlies good risk
management and pharmacovigilance
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Premarketing Risk Assessment
• Premise
– Pre-marketing risk assessment relatively
mature, but still evolving
– Public health, industry and FDA would all
benefit from optimizing risk assessment
allowing for approval of safe drugs with fully
informative labeling
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Premarketing Risk Assessment
General Considerations
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Key Issues
• Size of the safety data base
– characteristics of the drug and its effects
– proposed use
– intended population
• Characteristics of an ideal safety data base
– adequate duration
– diverse population
– better dose-response information
• particularly important for drugs with a high rate of druginduced adverse effects or “biomarkers” of injury (CPK, TA,
UA, K changes)
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Key Issues (cont.)
• “Individualization” factors
• drug-drug interactions
• drug-demographic relationships
• drug-disease relationships, including routine
population PK
• Comparative data when it would be particularly
important
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Premarketing Risk Assessment
Special Conditions
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Special Considerations
Evaluation of safety
– some general principles
– doesn’t mean one size fits all
– in planning and monitoring development needs to be
constant attention to
• results of animal and human data
• suggestions of problems
• population and drug-specific features that raise special
concerns
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Special Considerations
• Dosing
– maintenance dose same as acute dose
– titration
• Subtle adverse effects
• Pediatrics (dosing, AEs)
• Database expansion
• Pharmacogenetics
– storing samples
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Always Evaluated
Some matters always need assessment, notably
• QTc effects
• Evidence of hepatotoxicity
• Polymorphic metabolism
• Drug-drug interactions, including new ones (inducers,
inhibitors of glucuronidation, P-glycoprotein inhibitors)
And, for biologics
• Immunogenicity, neutralizing antibodies
• For live agents - virulence, transmissibility, genetic
stability
• Transplantation therapies - survival, function, host
immunocompetence
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Medication Error Prevention
Analysis (MEPA)
• Pre-marketing assessment
• Increase “safe use” of products by:
– minimizing medication errors related to
• naming
• labeling, and/or
• packaging of the product
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Premarketing Risk Assessment:
Considerations for Data Analysis and
Data Presentation
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Data analysis issues
• Grouping of adverse events
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– coding/MedDRA
Temporal relations between adverse events and
product exposure
time-to-event
Analyses of dose effects
Data pooling
Subgroup analysis
Missing safety data
Data presentation
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Risk Management Programs
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Risk Management Programs
• Focuses on actions taken to reduce risks in drug
product use
– based on assessments described in other two
concept papers
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Scope of Concept Paper
• Considerations for initiating and designing a risk
management program - definitions and when appropriate
• Selection of tools and levels
• Evaluation processes and methods
• Elements of submissions to FDA
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Key elements (1)
• Definition of an RM Program (RMP)
• Clarity of RMP goals, objectives
• Determining when an RMP is needed and
Sponsor/FDA roles in decision-making
• Best ways for tools to be in guidance
• Classification of RMP tools into Levels
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Key elements (2)
• Pretesting of RMP tools
• Recommended evaluation of all RMPs
• Recommendation for 2 independent methods
to evaluate key RMP goal(s)
• Role of qualitative data in evaluation
• Elements of RMP submissions & reports
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Definition: Risk Management (RM)
Methods used throughout
a product’s lifecycle to:
• minimize risks
• optimize benefit/risk balance
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Risk Management Program (RMP)
• Strategic safety effort to reduce risk:
> 1 risk reduction goal
> 1 intervention (tool) in addition to PI
• Tool examples: education, forms, processes, and
other methods to influence or control a product’s:
– prescribing
– dispensing
– use
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 labeling which my incorporate RMP materials such as Medication Guides and
patient agreements in addition to the PI.
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When is an RM Program
Appropriate?
• Whenever risk reduction needs emerge
(throughout product lifecycle)
• Sponsor may volunteer or FDA propose
• “When the number or severity of a product’s risks
appears to undermine the magnitude of benefits in
an important segment of actual or potential users.”
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How to Assess Whether
Risks Undermine Benefits?
• No simple formula compares risks to benefits.
• Risk and benefit numbers, types, measures vary.
• 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 PI.
– PI revision will not automatically imply a need for RMP.
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Risk Management Tools
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Definitions
• Risk management intervention (tool): a
process or system intended to enhance safe
product use by reducing risk
• Risk management programs use one or more
tools
• Choice of tools influenced by severity,
reversibility and rate of risk
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Types of Tools in Current
Programs
• Education & outreach
• Systems Guiding Prescribing, Dispensing,
Use
• Restricted Access Systems
• Suspension of Marketing
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Selecting and Developing Tools
Consider:
• Stakeholder input: feasibility, acceptance
• Consistency: with existing/accepted tools
• Evidence of success in achieving desired objective
based on other RMP
• Evidence of success in ability of novel tool to achieve
desired objectives
– based on application in non-RMP settings
• Variability, validity, reproducibility
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Proposed “Levels” for RMP
Classification
Level 1: Package insert only
Level 2: Adds education and outreach tools
Level 3: Level 2 plus systems guiding
prescribing, dispensing and/or use
Level 4: Access to product requires
adherence to specific program elements
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Evaluation Processes
and Methods
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Value of Risk Management
Program (RMP) Evaluation
• Assess effectiveness of RMP & its tools
— Before implementation (pretesting)
— Periodically after implementation
• Ensure efforts are expended on effective
interventions
• Guide modifications of RMP
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Pretesting RMP Tools
Allows:
• Stakeholder input
• Comprehension testing
• Pilot testing of feasibility,
acceptance, other factors
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Approaches To Evaluation
• Select what outcomes should
be/can be measured
• Seek representative and
quantitative data
• Use qualitative data as appropriate
(e.g. risk communication)
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Approaches To Evaluation
Consider using 2 complementary
methods
– especially for key goals or objectives
– offset limitations of any single
method
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Evaluation Methods
Consider limitations
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Validity
Accuracy
Timeliness
Representativeness
Biases
Social burdens
Costs
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Outcome Measures for Tools,
Objectives, or Goals
Changes in or absolute levels of:
• Patient health outcomes
• Surrogates of health outcomes
• Process measures or behaviors
• Behavioral components Comprehension, Knowledge, Attitudes
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Limitations of Current
Evaluation Methods
Spontaneous adverse event reporting:
– Decrease may reflect change in reporting,
not change in frequency of event
– Continuing reports may signal persistent
safety problem
Administrative data:
– May not be representative of general
population
– Often exclude high risk populations
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Limitations of Current
Evaluation Methods
Surveys or other active surveillance
systems:
– Reporting biases
– Sampling errors
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Elements of RMP
Submission to FDA
• Sections of RMP Submission
– Background
– Goals, objectives, and level
– Tools
– Evaluation plan
• Reporting RMP to FDA
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Risk Assessment of Observational Data:
Good Pharmacovigilance Practices
and
Pharmacoepidemiologic Assessment
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Scope of Concept Paper
• Important pharmacovigilance concepts
• Safety signal identification
• Pharmacoepidemiologic assessment and
interpretation of safety signals
• Development of pharmacovigilance plans
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Scope of Concept Paper
• Focus solely on observational data sources
– Case Reports, Case Series
– Pharmacoepidemiologic Studies
• Registries
• Surveys
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What is Pharmacovigilance?
All post-approval scientific and data
gathering activities relating to the detection,
assessment, understanding, and prevention
of adverse effects or any other productrelated problems
This includes the use of
pharmacoepidemiological studies
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Pharmacovigilance: Why?
• At the time of approval, clinical trial data are
available on limited numbers of patients
treated for relatively short periods
• Once a product is marketed, large numbers
of patients may be exposed, including:
– Patients with co-morbid illnesses
– Patients using concomitant medications
– Patients with chronic exposure
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Pharmacovigilance: Why?
• After marketing, new safety information
may become available:
– Through use of the product domestically or in
other countries
– Through use of other drugs in the same class
– From preclinical studies
– From pharmacologic studies
– From controlled clinical trials
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What is a Pharmacovigilance Plan?
• A plan proposed by a sponsor for the
ongoing evaluation of safety signals
identified with the use of a product
• May be developed at the time of product
launch or after a signal is identified
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What is a Pharmacovigilance Plan?
• A sponsor’s plan may involve:
– Expedited reporting of certain serious adverse
events
– Implementation of active surveillance activities to
identify as yet unreported adverse events
– Conduct of additional observational studies or
clinical trials
• A pharmacovigilance plan might be a
component of a larger risk management
program
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Good Pharmacovigilance Practices
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Good Pharmacovigilance Practice
starts by acquiring complete data from
spontaneous adverse event reports.
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Characteristics of a Good
Case Report
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Adverse event(s) details
Baseline patient characteristics
Therapy details
Time to onset of signs or symptoms
Diagnosis of the event
Clinical course of the event and outcomes
Laboratory data
• Any other relevant information
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Good Medication Error Report
• Product
• Sequence of events leading to the error
• Work environment in which the error
occurred
• Types of personnel involved with the error
• Narratives- follow NCC MERP taxonomy
(National Coordinating Council for Medication
Error Reporting and Prevention)
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Assessing Causality
• It is rarely certain whether the event was product
induced.
• Features supportive of an association
– event occurred in the expected timeframe
– absence of symptoms prior to exposure
– absence of co-morbid conditions or use of
concomitant medications
– (+) dechallenge, (+) rechallenge
– event consistent with the established mechanism
of action of product
• Grouping case reports into “probable,” “possible,”
and “unlikely” when appropriate
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Pharmacoepidemiologic Assessment
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When and why are pharmacoepidemiologic
studies recommended?
• To further characterize potential safety
signals from controlled clinical trials
– chronic exposures
– patients with comorbid conditions
• To further evaluate and quantify a safety
signal identified after approval
– incidence rate vs. reporting rate
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Minimal Requirements
• Pharmacoepidemiologic study
protocols
• Registries
• Surveys
• Reporting and assessing safety
signals
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Reporting Safety Signals to FDA
• Submit a synthesis of all available safety
information
• Provide an assessment of the risk/benefit
profile of the product
• Propose steps to further investigate
through additional studies
• Propose risk management strategies as
appropriate
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What is a Pharmacovigilance Plan?
• An enhanced pharmacovigilance plan
proposed by a sponsor for
– the ongoing evaluation of identified signals
pre- or post-approval, or
– to monitor at risk populations which have not
been adequately studied
• FDA may request the plan at the time of
launch or when a signal is identified
• Efforts may be above and beyond routine
postmarketing spontaneous reporting
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Pharmacovigilance Plans May
Involve...
• Expedited reporting of certain serious
adverse events
• Periodic summary reporting at more
frequent intervals
• Perform active surveillance to identify
unreported adverse events
• Conduct of additional observational
studies or controlled clinical trials,
registry, surveys
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Challenges Ahead
• How can the quality of adverse event
reports be improved?
• What conclusions can be drawn from
observational data sources given inherent
limitations of such data?
• What more can be done to enhance our
knowledge about safety signals once they
are identified?
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