# Presentation: 659451

## Drug Safety at FDA:  A Regulatory Update

**4****th**** Annual Workshop in Japan for Global Pharmacovigilance**

- Paul J. Seligman, M.D., M.P.H.
- Director
- Office of Pharmacoepidemiology and Statistical Science
- Center for Drug Evaluation and Research, FDA

- November 19, 2004

## Slide 2

- November 19, 2004

## FDA and Risk Management 

- Longstanding role in weighing risk information in context of drug approval
- Nomenclature of risk mgt initiated with 1999 Commissioner’s Report on Managing the Risks of Medical Products

- November 19, 2004

## FDA and Risk Management 

- PDUFA3 formalized FDA role in risk management
- PDUFA3 calls for FDA to develop three interrelated guidances on risk management by Sept 30, 2004

- November 19, 2004

## FDA and Risk Management

- Guidances
**Premarketing Risk Assessment ****(“*****Premarketing Risk Assessment”)***
**Risk Management Programs****(“*****Development and Use of risk Minimization Action Plans*****”)**
**Pharmacovigilance/ pharmacoepidemiology****(“*****Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment*****”)**

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## Premarketing Risk AssessmentDraft Guidance

- Risk Assessment Draft Guidance addresses two general topics:
- Generating Risk Information
- Reporting Risk Information

- November 19, 2004

## Premarketing Risk Assessment

- What is Risk Assessment?
- Risk assessment is an iterative process designed to optimize the benefit-risk balance for regulated products. It consists of identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a product.
- Good risk assessment underlies good risk management and pharmacovigilance.

- November 19, 2004

## Premarketing Risk Assessment Draft Guidance Outline

- Appropriate size of safety database
- What are the Characteristics of an _*ideal *_safety database?
- When would comparative safety data be useful?
- Special Risk Assessment considerations

- November 19, 2004

## Special Risk Assessment Considerations

- During Product Development
- Products intended to be used chronically examine whether a lower or less frequent maintenance dose is appropriate
- Products with a proposed titration scheme optimize titration scheme based on specific studies
- AEs unlikely to be detected or readily reported additional testing may be appropriateex) CNS effects assess cognitive function, motor skills, sexual function, and mood

- November 19, 2004

## Special Risk Assessment Considerations

- Minimizing the Potential for Medication Errors
- Document that product’s proprietary name, established name, and labeling do not contribute to medication errors
- Part of medication error prevention analysis (MEPA)
- Mechanisms include Failure Mode and Effects Analysis (FMEA), expert panels, computer assisted analysis, direct observation, clinical trials, and focus groups
- Use of multiple analysis techniques is recommended

- November 19, 2004

## Special Risk Assessment Considerations

- Safety Aspects to Address During Development
- The potential for certain serious AEs:
- QTc prolongation
- Hepatotoxicity
- Nephrotoxicity
- Bone marrow toxicity
- Drug-drug interactions
- Polymorphic metabolism

- November 19, 2004

## Risk Management Programs Draft Guidance 

- Focuses on risk minimization efforts
- Efforts are termed risk minimization action plans (RiskMAPs)
- Risks identified using practices described in two other PDUFA3  documents

- November 19, 2004

## Definitions

- Risk Minimization Action Plan is a strategic safety effort to reduce risk consisting of at least one risk reduction goal and at least one intervention (tool) other than PI
-   PI
- FDA approved product labeling
- Package insert  (professional oriented)
- _Not_ a Risk Management Program itself

- November 19, 2004

## Risk Management Draft Guidance Outline

- When is a RiskMAP appropriate?
- Goals and objectives
- Tools
- Evaluation
- Submissions

- November 19, 2004

## When is an RMP Appropriate?

- Whenever risk reduction needs emerge during a product’s 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.

- November 19, 2004

## RiskMAP Goal(s) 

- Tailored to product’s specific risk concerns
- Describe ideal product use scenario or desired end result of RiskMAP
- Include “Vision statement” of optimal drug use scenario

- November 19, 2004

## How to Assess WhetherRisks Undermine Benefits?

- No simple formula compares risks to benefits
- Risks and benefits vary in types, measurements
- Case-by-case judgments required by sponsor and/or FDA on whether to develop, submit, and implement an RiskMAP
- FDA expects most products will be handled by package insert (PI), without formal RiskMAP

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## RiskMAP Tools

- Risk management tool (intervention): a process or system intended to enhance safe product use by reducing risk
- Choice of tools influenced by severity, reversibility and rate of risk

- November 19, 2004

## Categorization of Tools in Current Risk Mgt Programs

-  Education & Outreach
-  Reminder Systems
-  Restricted (performance-linked) Access

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## Education and Outreach

- Specific, targeted education and outreach efforts to increase appropriate knowledge of key people or groups (e.g., health care professionals).  Examples include,
- “Dear Health Care Professional” letters
- Training programs for health care professionals or patients
- Patient labeling

- November 19, 2004

## Reminder Systems

- Systems that prompt or otherwise guide health care professionals and/or patients in prescribing, dispensing, or receiving a product in ways that minimize risk.  Examples include,
- Patient agreement or acknowledgement forms
- Limited amount in any single prescription or refill of product
- Specialized product packaging to enhance safety

- November 19, 2004

## Restricted (Performance-Linked) Access

- Systems that link product access to laboratory testing results or other documentation.  Examples include,
- Prescription only by specially certified health care professionals
- Product dispensing only by specially certified pharmacies or practitioners
- Product dispensing only to patients with evidence or other documentation of safe-use conditions (e.g., lab test results)

- November 19, 2004

## Selecting and Developing ToolsConsider:

- Stakeholder input on feasibility, acceptance
- prescribers, pharmacists, pts, payors
- Consistency: with existing/accepted tools
- Evidence: past effectiveness in similar product or related  objective

- November 19, 2004

## Evaluation of RiskMAP

- Important to measure
- Effectiveness & value-added of tools
- Progress towards goal(s)
- Changes in health outcomes or best  available surrogate outcome
- Allows modification of RiskMAP to meet goals

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## Evaluation of RiskMAP

- May include active surveillance systems for outcomes, AEs
- Discussed in draft guidance on  pharmacovigilance and pharmacoepidemiology

- November 19, 2004

## Summary: Risk Minimization Action Plans

- Sparingly applied interventions
- Intended to minimize identified risks
- Are goal-oriented
- Use tools commensurate with risks and benefits
- Merit evaluation

- November 19, 2004

## Risk Management Plan Review

- For FY ’04, the CDER Office of Drug Safety (ODS) was involved in the review of 22 Risk Management Plans (RMPs)
- Five of these plans concerned NMEs
- Eleven of these plans were submitted after PDUFA3 went into effect
- ODS was involved in the review of two periapproval RMPs
- ODS evaluated/validated four active RMPs

- November 19, 2004

## Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment Draft Guidance

- Focuses on:
- Identifying, Describing, Investigating, and Interpreting Safety Signals
- Developing a Pharmacovigilance Plan

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## The Role of Pharmacovigilance in Risk Management

- Definition of Pharmacovigilance:
- “All observational (nonrandomized) postapproval scientific and data gathering activities relating to the detection, assessment, and understanding of adverse events”

- November 19, 2004

## Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment Draft Guidance Outline

- Identifying and Describing Safety Signals: From Case Reports to Case Series
- Beyond Case Review: Investigating a Signal Through Observational Studies
- Interpreting Safety Signals: From Signal to Potential Safety Risk
- Beyond routine Pharmacovigilance: Developing a Pharmacovigilance Plan

- November 19, 2004

## Safety Reporting Requirements for Human Drug and Biological Products; Proposed Rule(aka: SADR Rule)

- November 19, 2004

## Background

- 68 FR 12405-12497, March 14, 2003
- FR Doc. 03-05204
- Docket No. 00N-1484
- Comment period extended until October 14, 2003

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## Rationale

- Further worldwide consistency
- Collection of safety information
- Submission of safety reports
- Increase quality of safety reports
- Expedite FDA review of critical safety information
- Protect and promote the public health

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## Consistency in Safety Reporting

- Greater worldwide consistency in content, format, reporting frequency, and standardization of terminology
- Harmonize with safety reporting standards developed by CIOMS and ICH
- ICH E2A:  Expedited Reporting
- ICH E2C:  Periodic Safety Update Reports
- ICH M1: Postmarketing coding with MedDRA

- November 19, 2004

## New Postmarketing Expedited Safety Reports

- Already capture *serious and unexpected* adverse drug experiences in an expedited way
- Formally capture Medication Errors as expedited reports
- Submit unexpected SADRs with unknown outcome as expedited reports
- Define a new category of *Always Expedited *reports

- November 19, 2004

## Always Expedited Reports

- Congenital Anomalies
- Acute Respiratory Failure
- Ventricular Fibrillation
- Torsades de Pointe
- Malignant Hypertension
- Seizure
- Agranulocytosis
- Aplastic Anemia
- Toxic Epidermal Necrolysis
- Liver Necrosis

- Acute Liver Failure
- Anaphylaxis
- Acute Renal Failure
- Sclerosing Syndromes
- Pulmonary Hypertension
- Pulmonary Fibrosis
- Confirmed or Suspected Transmission of Infectious Agent by Marketed Product
- Confirmed or Suspected Endotoxin Shock

- November 19, 2004

## Conclusions

- Goal of proposed rule is to improve consistency, quality, timely reporting, and analysis of important safety information
- Final rule pending FDA review and action on public comments

- November 19, 2004

## Institute of Medicine (IOM) study

- FDA will sponsor an IOM-conducted study of US drug safety
- Goal:  study effectiveness of current pharmacovigilance system
- Emphasis on postmarketing phase
- Examine FDA’s role within the health care delivery system
- Recommend measures to enhance the confidence of Americans in the safety and effectiveness of their drugs

- November 19, 2004

## Summary

- Ensuring the safety of drug products marketed in the US remains a priority for FDA
- FDA will put increased emphasis on understanding how to evaluate safety _throughout_ a product’s life cycle
- How to assess and weigh a product’s risks relative to its benefits remains an extremely challenging area
- These complex issues are of concern to patients and health care professionals, not just regulators and drug developers

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## Slide 40

- November 19, 2004

## Placeholder/Transition to Backup slides

- November 19, 2004

## Changes based on ICH E2A 

*Adverse drug experience*
*+*
*Associated with the use of the drug*
**changed to**
*Suspected adverse drug reaction (SADR)*
- and
*Suspected adverse reaction (SAR)*

- November 19, 2004

## ReplaceAdverse Drug Experience

**Any adverse event (AE) associated with the use of a drug in humans, whether or not considered drug related, including AEs occurring:****  ****• during use of a drug in professional practice;****  • from drug overdose whether accidental or intentional; ****  • from drug abuse; ****  • from drug withdrawal; and ****  • Any failure of expected pharmacological action.**
**With **
_**Suspected Adverse Drug Reaction (SADR)**_
**A noxious and unintended response to any dose of a drug product for which there is a reasonable possibility that the product caused the response.  In this definition, the phrase “a reasonable possibility” means that the relationship cannot be ruled out.**

- November 19, 2004

## Changes based on ICH E2A

- For individual case safety reports (ICSRs):
- Minimum data set required for all ICSRs of SADRs
- Causality of ICSRs in clinical trials (either in IND or while marketing) based on opinion of either sponsor/applicant or investigator
- Determination of life-threatening SADR in an IND study based on opinion of either sponsor or investigator

- November 19, 2004

## Changes based on ICH E2A and ICH E2C

- Reporting requirements for spontaneous reports codified
- definition of *spontaneous* consistent with ICH E2C
- SADR info from class action law suits neither *spontaneous* nor *study* information

- November 19, 2004

## Changes based on ICH E2C

- Standardize submission date (month, day) for PSURs
- Company Core Safety Information (CCSI) used to determine whether an SADR is “listed” or “unlisted”
- “Listed SADR” is an SADR whose nature, specificity, severity, and outcome are consistent with the information in the CCSI

- November 19, 2004

## Frequency for Submission of Postmarketing Periodic Safety Reports

- Current
- Quarterly for 3 years after U.S. approval
- Annually thereafter
- Proposed
- Descriptive information
- Semiannually for 2 years after U.S. approval
- Annually for the next 3 years
- Every 2.5 years for the next 10 years
- Every 5 years thereafter
- Individual Case Safety Reports
- Semiannually after U.S. approval

- November 19, 2004

## Changes based on ICH M1

- ICSRs arising in marketing use of a product would be required to be coded using MedDRA

- November 19, 2004

## Quality

- Risk-based approach: greater emphasis, effort, and information for serious SADRs than on nonserious SADRs
- For postmarketing reports:
- Direct (active) contact with initial reporter by a health care professional at the company
- Licensed physician at company is responsible for the content of postmarketing safety reports

- November 19, 2004

## Proposal for PostmarketingExpedited and Periodic Safety Reporting

- Active query required if additional information needed
- For nonserious SADRs, no information required to be collected other than minimum data set
- Contractors must submit all safety reports of SADRs and medication errors to applicant within 5 calendar days

- November 19, 2004

## New Postmarketing Expedited Safety Reports (continued)

- Blood and blood component safety reports: Submit all serious SADRs, not just fatalities, within 45 days
- Bioavailability and Bioequivalence Studies not Subject to an IND: Submit all serious and unexpected SADRs as expedited reports

- November 19, 2004