Hazard and Risk Management

Hazard and Risk Management

E. Stewart Geary, M.D.

Eisai Co., Ltd.

National Regulatory Conference 2005

Subang Jaya, Selangor, Malaysia

6-7 September, 2005

Risk Management National Regulatory Conference 2005

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Hazard & Risk Management

• Principles of Risk Management

• Risk Management: Clinical Safety of Medical Products– ICH: E2E Guideline– EU– FDA: 3 Guidances

Principles of Risk Management


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Risk

• “Risk can be defined as the combination of the probability of an event and its consequences” (ISO/IEC Guide 73)


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Risk Management

• Process by which organizations methodically address the risks associated with their activities

• Requires identification and “treatment” of risks• Should be a continuous and developing process• Management of safety risks focuses on prevention

and mitigation of harm


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Types of Risks: External

• Financial risks– Interest rates– Foreign exchange

• Strategic Risks– Competition– Industry changes

• Operational Risks– Regulations

• Hazard Risks– Natural disasters– Contracts– Suppliers


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Types of Risks: Internal

• Financial risks– Liquidity & Cash Flow

• Strategic Risks– Research & Development– Intellectual capital

• Operational Risks– Accounting controls– Information systems

• Hazard Risks– Employees– Properties


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Risk Management

• Cycle of Management– Risk Identification

– Risk Assessment

– Plan

– Implement Risk Treatment

– Assess the implemented plan

• Report internally and externally on the identified risk and the progress of its management


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Mitigate/Treat

Identify Assess/Analyze

Plan

Risk Management Cycle

Tra

ck

ReportReport

Risk Management: Clinical Safety of Medical Products


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Background: E2E• E2E: Pharmacovigilance Plans

– The Guideline was released for consultation, under Step 2 of the ICH process, on November 11, 2003.

– EU : Adopted by CPMP, 20 November 2003, issued as CPMP/ICH/5716/03

– MHLW : Released for consultation on April 27, 2004, PFSB/ELD, Deadline for comments July 26, 2004

– FDA : Published in the Federal Register, Vol. 69, No 61, Tuesday, March 30, 2004, pages 16579-80.Comments due by May 19, 2004.


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Background EU

• “Action Plan to Further Progress the European Risk Management Strategy” published 4 May 2005– Risk Detection– Risk Assessment– Risk Minimization– Risk Communication


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Background: RiskMAP• PDUFA III approval June, 2002 included FDA promise

to produce guidance for industry on risk management• 3 Concept Papers issued March 2003

– Public Workshop April 2003

• 3 Draft Guidance Documents issued May, 2004– Development and Use of Risk Minimization Action Plans– Good Pharmacovigilance Practices and

Pharmacoepidemiologic Assessment• Includes guidance on when to develop PVP

– Premarketing Risk Assessment

• 3 Guidances Finalized March 2005

ICH: E2E Guideline

Pharmacovigilance Planning


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E2E

• Pharmacovigilance Specification– Summary of the identified risks of the drug– Potential for important unidentified risks– Populations potentially at-risk– Situations that have not been adequately

studied

• Pharmacovigilance Plan

• Annex of Pharmacovigilance Methods


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Pharmacovigilance Specification

• Summary of the identified risks of the drug

• Potential for important unidentified risks

• Populations potentially at-risk

• Situations that have not been adequately studied

• Can be stand-alone or incorporated in CTD


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Elements of PV Specification

• Non-clinical• Clinical

– Limitations of human safety database• Extent of world-wide exposure• Any new or different safety issues identified• Regulatory actions related to safety

– Populations not studied in pre-approval phase• Children, elderly, pregnancy & lactation, hepatic or

renal disease, genetic polymorphisms, ethnic origin


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Elements of PV Specification

• Clinical– AE/ADR

• Most important identified ADRs (by frequency or seriousness)

• Potential risks (how will they be further identified?)

– Food-drug and drug-drug interactions– Epidemiology of indication and associated AEs– Class effects

• Summary - Ongoing safety issues


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PV Plan

• Summary of Ongoing Safety Issues– Important identified risks– Important potential risks– Important missing information

• Routine PV Practices• Safety Action Plan for specific

issues/missing information• Summary of actions to be done, milestones


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Safety Action Plan for specific issues/missing information

• Risk Issue/Information missing• Objective• Action proposed• Rationale for proposed action• Oversight within company for issue & action• Milestones for evaluation and reporting

– Exposure to product reaching certain levels

– Results of studies becoming available


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E2E-Safety Action Plan

• Safety Action Plan– The objective is to have a more structured and

specific approach to examining pre-defined safety issues

• Is the product safe for elderly patients?

• Is there a risk for cardiac events? How great is that risk?

– Analyses to be performed at each milestone


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E2E-Safety Action Plan

• If a Safety Action Plan results in specific actions there is a need to follow-up and see if those actions improved the risk profile– For instance: Did a Package insert change or

specific education program result in a decrease in the adverse event of concern?


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Summary: E2E-Safety Action Plan

• Created on the basis of conscious assessment of current safety information

• Targeted plan to address a specific question– Usually involves gathering more information to better

define a specific risk

• Requires re-assessment and modification at pre-determined milestones

• Submitted to a regulatory authority for comment and approval

FDA

FDA: Premarketing Risk Assessment


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Premarketing Risk Assessment• Depends on

– Quantity of patients studied– Quality of data analysis

• Size of database– Smaller for life-threatening diseases– Difficult to offer guidance for products used for short-term, a

cute use– Long-term treatment of non-life-threatening Dz (E1A)

• 1500 patients exposed of which• 300-600 for 6 months• 100 for 1 year• Reasonable exposure to highest proposed dose


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Premarketing Risk Assessment

• Larger databases needed for– Safety concern from animal studies,

pharmacological class, etc.– Small benefit– Preventive therapies (few of exposed benefit)– Uncertain magnitude of benefit– Use in healthy population– Safe and effective alternative already available


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Premarketing Risk Assessment• Examine terminology, assessment methods, use of

standard terms– MedDRA

• Consider long-term controlled studies– Most extensions are single-arm or otherwise uncontrolled– For comparison group for evaluation of events common

in that background population

• Diverse population in safety database– Old, young, women, minorities, limit exclusion criteria

• Multiple doses in phase III


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Premarketing Risk Assessment• Detecting Unanticipated Interactions

– Drug-drug interactions in addition to those predicted by metabolic pathway

• For likely concomitant medications used in that population

– Product-dietary supplement interactions

• Comparative Safety Data– Especially when background rate of AEs is

high or other drugs in class have same ADRs


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Premarketing Risk Assessment: Data Analysis

• Essentially the same tools currently used for the Integrated Safety Summary

• Similar to E2E “PV Specification”

FDA: Risk Minimization Action Plans (RiskMAP)


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Role of RiskMAPs

• Necessary for only some products– “For most products routine risk management

will be sufficient and a RiskMAP need not be considered.”

• RiskMAP: a strategic safety program designed to meet specific goals and objectives in minimizing known risks while preserving benefits


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RiskMAP

• State a specific goal– “fetal exposure to drug X should not occur”– “lower incidence of liver failure on drug X”

• Translate into pragmatic, specific and measurable objectives– Targeted education to physicians, patients– Reminder systems– Access systems


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RiskMAP Tools

• Targeted education & outreach– Health care practitioner letters– Training programs– Continuing education– Professional/public notifications– Medication guides– Patient package inserts– Focused or limited promotion techniques


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RiskMAP Tools

• Reminder systems– Patient agreement forms– Certification programs for practitioners– Limit amount in single prescription– Specialized product packaging– Systems to attest safety measures are satisfied

(stickers, etc.)


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RiskMAP Tools

• Performance-linked access systems– Link product access to lab test results or other

documentation– Compulsory reminder systems (no product

without acknowledgment)– Prescription only by specified practitioners– Dispensing only by specially certified

pharmacies


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FDA’s Tools

• Product recalls

• Warning letters

• Safety alerts

• Guidance documents

• Seizures and injunctions


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RiskMAP

• Every RiskMAP should contain a plan to periodically evaluate its effectiveness– Test tools before implementation if possible (e.g.

during phase III)– RiskMAP plan should describe when periodic

evaluation results will be sent to FDA– Eliminate ineffective tools

• RiskMAP evaluations will involve analysis of observational/descriptive data rather than statistical hypothesis testing


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RiskMAP

• Select evidence-based performance measures– Number, percentage or rate of an outcome– Whenever possible use at least two different

measures/methods for each goal

• Submit RiskMAP to IND/NDA/BLA


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RiskMAP Contents

• Background

• Goals & Objectives

• Strategy & Tools

• Evaluation Plan– Including potential unintended and untoward

consequences of the RiskMAP


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RiskMAP Progress Report

• Summary of the RiskMAP

• Methodology

• Data

• Results

• Discussion & Conclusions


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RiskMAP Data Analysis• Emphasis is on selecting a quantitative “performance

measure”– Number, percentage or rate of outcome

• Careful consideration at the time of choosing a performance measure– Adapting to increasing exposure to drug as use expands– New population exposures as new indications or new countries get

marketing approval

• Data analysis to demonstrate the performance measure is being met

• If performance measure is not met, need to consider new actions/additions to RiskMAP


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Summary: Safety Action Plan vs RiskMAP

• Broadly defined, all products have always had a PVP– Package insert, CCDS, ADR collection & reporting

• Some but not all products will require a PVP Safety Action Plan or RiskMAP

• FDA’s RiskMAP is similar to the Safety Action Plan in E2E but is targeted to reduce a specific risk


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Summary: Safety Action Plan vs RiskMAP

• Both PVP and RiskMAP’s are marked by– Moving from a reactive to proactive model of PV– Moving from “one size fits all” PV to tailored programs specific

for each drug– Setting measurable targets for drug safety and periodically

assessing whether or not they have been met

• RiskMAP takes a specific risk and creates a plan to minimize it

• Pharmacovigilance Plan gathers more information to identify risks

Thank you for your kind attention!