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Developing Risk Management Systems that meet FDA rules ---and don’t hurt your product. Judith K. Jones President, The Degge Group, Ltd. Louis A. Morris President , Louis A. Morris & Associates Gina Ashe VP Marketing, Infomedics. Objectives. P.

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Developing risk management systems that meet fda rules and don t hurt your product

Developing Risk Management Systems that meet FDA rules ---and don’t hurt your product

Judith K. Jones

President, The Degge Group, Ltd.

Louis A. Morris

President , Louis A. Morris & Associates

Gina Ashe

VP Marketing, Infomedics

Developing risk management systems that meet fda rules and don t hurt your product

Objectives ---and don’t hurt your product


articipants should appreciate strategic and tactical elements for developing a Risk Management (RM) Plan:

  • Risk Assessment

    • Natural History of Disease

  • Developing a RM Strategy

    • Designing Distribution control

    • Developing Communication Objectives

  • Designing a RM Program

    • Behavioral Goals and Objectives

    • Selecting and Justifying Tools

    • PreTesting Communications

    • Planning Evaluation

Format problem solving exercise
FORMAT: PROBLEM SOLVING EXERCISE ---and don’t hurt your product

  • Introductions, Background & Goals for Today

    • (15 minutes)

  • Form Groups

    • 8:45-10 AM: Developing a RM Strategy

      • Problem Identification

      • Understand Risk Assessment Issues (by example)

      • Defining Desired Behavioral Outcomes, Communications, Distribution Controls

    • 10-10:20 AM: Break

    • 10:20-11:20: Developing the FDA RM Plan

      • Goals, Objectives, Tools,, Evaluation Planning

    • 11:20-12:00 Group Presentations and commentary by Audience and Faculty

Background fda need to develop a rm plan
Background ---and don’t hurt your productFDA: Need to Develop a RM Plan

Recent withdrawals
Recent Withdrawals ---and don’t hurt your product

  • Seldane (terfenadine) 2/98

  • Posicor  (mibefradil) 6/98

  • Duract  (bromphenac) 6/98

  • Hismanal  (astemizole) 6/99

  • Roxar  (grepafloxacin) 11/99

  • Propulsid  (cisapride) 3/23/00

  • Rezulin  (troglitazone) 3/21/00

  • Lotronex  (alosetron HCl) 8/24/00

  • Raplon  (rapcuronium) 3/01

  • Baycol  (cerivaxtatin) 8/8/01

92 NME’s from 1998-2000

Rezulin withdrawal
Rezulin Withdrawal ---and don’t hurt your product

“FDA took this action after its review of recent safety data…showed that Rezulin is more toxic to the liver than the other two drugs” [HHS News, 3/21/00]

“And we’ve had to withdraw drugs from the market that would have been safe if used according to label instructions” [Janet Woodcock, Temple University, 4/4/00]

Developing risk management systems that meet fda rules and don t hurt your product

AUG 09, 2001 ---and don’t hurt your product

Anticholesterol Drug Pulled After Link to 31 Deaths

With Baycol, however, reports of serious rhabdomyolysis were about 10 times as frequent as with the other statins, Dr. Jenkins said.

"Baycol really stood out as being different," he said. "Baycol did not offer any benefits beyond those of the other statins. But it carried a potential risk, and that leads to a conclusion that it is no longer safe to be marketed."

Examples of drugs with rm controls
Examples of Drugs with RM Controls ---and don’t hurt your product

  • Accutane (isotretinoin) - severe recalcitrant nodular acne

  • Actiq (fentanyl citrate) - severe cancer pain

  • Clozaril (clozapine) - severe schizophrenia

  • Lotronex (alosetron hydrochloride) - severe irritable bowel syndrome in women

  • Mifiprex (mifepristone or RU-486) - termination of early intrauterine pregnancy

  • Thalomid (thalidomide) - erythema nodosum leprosum

  • Tikosyn (dofetilide) - maintenance of normal sinus rhythm

  • Tracleer (bosentan) - severe pulmonary arterial hypertension

  • Trovan (trovafloxacin mesylate or alatrofloxacin mesylate injection) - severe, life-threatening infections

  • Xyrem (sodium oxybate) - narcolepsy

Import Alerts- drugs with RM plans

Developing risk management systems that meet fda rules and don t hurt your product

Top 20 ---and don’t hurt your product

Fda rm guidances
FDA RM Guidances ---and don’t hurt your product

  • Concept Papers Released March 3, 2003

  • Hearings April 9 – 11, 2003

  • Three Papers:

    • Premarketing Risk Assessment

    • Risk Management Programs

    • Risk Assessment of Observational Data: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment

  • Guidances To Be Finalized September, 2004

Risk management guidance
Risk Management Guidance ---and don’t hurt your product

  • Sponsor proposes a Risk Management Program (RMP)

    • Background and rationale for RM approach

    • Goals, Objectives and RMP Level (4 levels)

    • Tools and Implementation plan for each tool

    • Evaluation Plan for each tool and for the overall RMP

      • Analyses to be conducted

      • Reporting results to FDA

Risk Management is the process of minimizing risks throughout a product’s lifecycle to optimize the benefit/risk balance

The four levels of risk management
The Four Levels of Risk Management ---and don’t hurt your product

  • Level 1 Package Insert only

  • Level 2 Level 1 + education and outreach to health professionals and patients/consumers

  • Level 3 Level 2 + systems that guide the prescribing, dispensing, or receipt of a product

  • Level 4 Level 3 + Access to product requires

    adherence to program elements

Levels may go – concept of progressive interventions will stay

Developing risk management systems that meet fda rules and don t hurt your product

Risk Management ---and don’t hurt your product

Unknown Risks

Known Risks

  • Discovering and interpreting safety signals

  • Phase IV Commitments

  • Do I need a study/registry?

  • Designing interventions (tools)

  • Justifying choice of interventions

  • Pre-testing Interventions

  • Implementing interventions

  • Evaluating interventions

  • Revising interventions

Risk management irony
Risk Management Irony ---and don’t hurt your product




Safety =


Willing-ness to Use

Perception of Risk

Unintended Consequences

Four pillars of risk management
Four Pillars of ---and don’t hurt your productRisk Management

  • Risk Assessment

  • Signal Evaluation

  • Risk Communication

  • System Controls

Developing risk management systems that meet fda rules and don t hurt your product
Forming Groups: ---and don’t hurt your productFair Distribution of Disciplines Reseat if necessaryAppoint Leader/Recorder/Reporter

Product 1
Product #1 ---and don’t hurt your product

  • A product for diabetic neuropathy shown to be very effective causes severe tachycardia (rapid heart rate) with excess caffeine in a genetically sensitive group.

  • This group can be identified by a genetic test which is costly (~$3000/person)

  • The drug’s profile is otherwise benign

Product 2
Product # 2 ---and don’t hurt your product

  • An antibiotic product indicated for upper respiratory infections is highly effective with most pathogens, including resistant organisms-likely to be used widely.

  • Its risk is similar to other antibiotics except that if used more than twice in a three month period, it causes severe diarrhea and colitis, particularly toxic to the elderly and children.

Tasks for groups
Tasks for Groups ---and don’t hurt your product

  • 8:45-10:00

  • Identify and Define

    1. Additional Study

    • Conduct a phase IV study to help identify and characterize the risk (30 min)

  • Developing a RM Strategy

    • Who, What, How, When, Where and Why? (20 min)

      3. How to manage Risks?

    • List Key Messages (selected) for each audience (10 min)

    • Assume that FDA believes that communications by themselves will be insufficient. What distribution system controls will be necessary to influence desired behaviors? (15 min)

Phase iv study
Phase IV Study ---and don’t hurt your product

  • Who will we recruit?

    • Types of people (assume statisticians estimate that at least 2000 people are needed)

  • How will we recruit them?

  • What will we measure?

    • Conceptually, what do we need to know?

    • How will we measure it?

Task rm strategy
Task: RM Strategy ---and don’t hurt your product

1. Define the problem

  • What are the specific risk we are facing in terms of what can happen to which patients under what conditions?

  • Develop the overall RM Strategy:

    • Who do we need to influence?

    • What do we want them to do? (Be specific, define for each audience)

    • When/Where do they need to exhibit this behavior (conditions)

    • How will we get them to do it?

      What messages will be necessary to influence behavior

      Will “information” be sufficient? Do we need “behavioral control systems”?

  • Background risk communications and behavioral distribution controls
    Background ---and don’t hurt your productRisk Communications and Behavioral/Distribution Controls

    Part i communications

    Part I ---and don’t hurt your productCommunications

    Communications planning
    Communications Planning ---and don’t hurt your product

    • What to do people need to know?

      • Message must be sufficient to influence behavior

        • Must affect Knowledge

          • Be Understood

          • May need to motivate audience (personal susceptibility, willingness to overcome barriers to resistance, motivate behavior)

        • Will “information” be sufficient? Do we need “behavioral control systems”?

    • How to communicate it?

      • What are the key primary and secondary messages? (Communication Objectives)

      • What media will reach intended audience (how much redundancy)?

      • Will we need a Medication Guide?

    • How do I know it is working? (next session)

      • Pretesting

      • Evaluation Planning

    Developing communication objectives cos
    Developing Communication Objectives (COs) ---and don’t hurt your product

    • What is the most important information for people to know about using this drug?

      • List in descending order of importance

      • Assume must provide information relevant to six headers for MedGuides if preparing most patient information documents

    • What do we need to say to influence advocated behavior?

    • List for each audience

    Information options
    Information Options ---and don’t hurt your product

    • HCPs

      • PI, Label Changes (black box), Dear Doctor letters, Advertisements (medication errors), Fair Balance in ads, MedEd, brochures, etc.

    • Patients

      • PPIs, Medication Guide, Informed Consent, Multiple options (Accutane, Thalidomide), refrain from DTC.

    • Public (PR)

      • FDA public announcements (talk papers, press releases), website posting, advisory committee meetings

    Communications process
    Communications Process ---and don’t hurt your product

    Goal/Barrier Measure

    • Exposure Distribution

    • Attention Readership

    • Interest Willingness to Read

    • Understand Comprehension

    • Accept Attitude Change

    • Memory Recall/Recognition Tests

    • Decide Decision Making Scenarios

    • Behave Intention to Heed/Behavior

    • Learn Behavior Maintenance

    Select Vehicles to Maximize Communication Goal May need a combination of Vehicles

    Risk communications 1
    Risk Communications (1) ---and don’t hurt your product

    • Seek Intervention that will force exposure

      • PPI – voluntary distribution (7% for Darvon)

      • MG – required by law (39% for Estrogen PPI)

      • Packaging – systems (93% for OCs)

    • Risk Messages break through clutter

      • Clearly identify as risk message (not marketing in disguise)

    • Redundancy for backup and reminder purpose (not as primary communication purpose)

    Risk communications 2
    Risk Communications (2) ---and don’t hurt your product

    • Assure Understanding of Key Objectives

      • Will not get sufficient repetition

      • Test for COs in Comprehension Tests

    • Understand Factors Controlling Behavior Change

      • Attitude-Behavior Consistency

      • Barriers as well as Facilitators

    • Evaluation Specific Enough to Understand Failures and Recommend Changes

    Part ii implementing and evaluating an rm program

    Part II ---and don’t hurt your productImplementing and Evaluating An RM Program

    Developing risk management systems that meet fda rules and don t hurt your product

    RM System Design ---and don’t hurt your product

    B/RM Planning & Design







    B/RM Implementation


    Distributional controls
    Distributional Controls ---and don’t hurt your product

    How do we slot the risk-control level for any drug?

    Prior Approvals

    Closed System

    Special Packaging

    Record Keeping



    Controlled Substances

    Actiq Fosamax


    Thalomid Accutane

    Developing risk management systems that meet fda rules and don t hurt your product

    Multi-Function Registry ---and don’t hurt your product




    MD or Patient












    Compilation & Reporting



    & Feedback





    Part iii behavioral outcomes

    Part III ---and don’t hurt your productBehavioral Outcomes

    Sample of desired behaviors
    Sample of Desired Behaviors ---and don’t hurt your product

    • MDs

      • Select appropriate patients

      • Provide RM counseling patients

      • Oversee compliance with necessary behaviors (lab tests)

      • Side Effect monitoring

    • Patients

      • Understand medication’s risks

      • Understand avoidance behaviors

        • behaviors necessary to prevent risks

      • Behavioral Compliance

        • Initiating and maintaining behaviors with medication taking requirements to avoid adverse events

          May need iterative education and motivation

    Practicalities of engaging mds
    “Practicalities” of Engaging MDs ---and don’t hurt your product

    • MD time constraints

    • The office staff “shield”

    • Limitations of Distribution channels

      • Sales Rep as the RM messenger

      • The clutter of direct mail

      • Technology limitations

    • Attitudes toward adopting new (potentially risky) medications into their practice

    • General risk aversion (on several fronts)

    Avoid one size fits all approach to mds
    Avoid “One Size Fits All” Approach to MDs ---and don’t hurt your product

    • Specialists vs. PCPs

    • Targeting the “right” physicians early in the program (sissy vs. sassy docs)

    • KOL acceptance

    • For those interested in the Medicine:

      • This is an issue of patient safety

      • This may be a particular necessary medicine

      • Prescribers need to know this

    The md comfort zone
    The MD Comfort Zone ---and don’t hurt your product

    Personal Liability

    Too much work to use

    Too Much RM

    Will benefit and protect patient,

    Willing to try

    Comfort Zone

    Drug may hurt patient

    Too risky to try

    Too Little RM

    Consider providing patient feedback to their mds
    Consider Providing Patient Feedback ---and don’t hurt your productto Their MDs

    • Additional knowledge MDs gain about:

      • patient comprehension of product benefits and risks

      • Benefit/Risk Perceptions

      • Barriers to Use

      • Attitudes about Medication

      • Motivations

      • Behavioral Intentions

      • Compliance Measures

    Patient compliance insight 1 information is not learning
    Patient Compliance Insight #1: ---and don’t hurt your productInformation is Not Learning

    Example of Cholesterol-Lowering Medication


    *Scott-Levin data 10/00-3/01 showing 45% of patients continuing on medication each month from prior month.

    **Internal calculations using program costs, expected returns, and Scott-Levin Rx data.

    +Scott-Levin data from 10/00-3/01 for monthly adherence of statin users.

    ++Adherence rates observed among Adhere program participants.

    Patient compliance insight 2 physicians active role is essential
    Patient Compliance Insight #2: ---and don’t hurt your productPhysicians’ Active Role is Essential

    • Driven by physician-patient relationship

    • Deliberate “ask” from MD

    • Patients increasingly turning to their own sources for information, may be unreliable

    • InfoMedics Survey: Why Do Patients Comply with Programs?

    • 73% of patients motivated to participate because of doctor-patient relationship

    • 80% of patients would participate again if asked by physician

    Patient compliance insight 3 each patient conducts their own individual risk assessment
    Patient Compliance Insight #3: ---and don’t hurt your productEach patient conducts their own individual “risk assessment”

    • Medication containing estrogen, topically applied for short periods of time only, shown to not enter blood stream

    • MDs comfortable with remote risk of breast cancer (no documented cases)

    • MDs recognized significant symptom relief and quality of life improvements that medication delivered

    • Patient concerns around “HRT therapies” caused MDs concerns--not willing to prescribe

    Tasks for groups 2
    Tasks for Groups-2 ---and don’t hurt your product

    • 10:20-11:30

    • Design:

      1. RMP Outline

      • Goals, Objectives

      • Choice of Tools and Justification (30 min)

        2. Methods of Evaluation:

      • Individual Tools (Comprehension Test)

        • List Communication Objectives

      • The Risk Management Plan (30 min)

    These tasks should be completed for presentation

    Background fda concept paper
    Background ---and don’t hurt your productFDA Concept Paper

    Rm concept paper
    RM Concept Paper ---and don’t hurt your product

    • Risk Management Program

      • A strategic program designed to decrease product risk by using one or more interventions or tools beyond the PI. For example:

        • Specialized educational materials

        • Processes or forms to increase compliance or reduce risk

        • Systems to modify prescribing, dispensing and use

    Rm program
    RM Program ---and don’t hurt your product

    • RM Goals and Objectives

      • RM Program should have one or more safety related goals…tailored to specific concerns

      • Goals are broad, conceptual statements of desired outcomes

      • Objectives are translation of goals into pragmatic, specific and measurable processes or behavioral outcomes

        • Apply to each audience

    Part ii tool selection

    Part II ---and don’t hurt your productTool Selection

    Sample tactics matrix
    Sample Tactics Matrix ---and don’t hurt your product

    Theme: Risk Avoidance Involvement Logo as Reminder

    When is a medication guide needed
    When is a Medication Guide Needed? ---and don’t hurt your product

    • When product poses a “serious and significant public health concern ...”

    • Translated: when patient information is necessary to safe and effective use

    • To apply to between 5 and 10 products (drugs and biologics) annually

    • Not to be used indiscriminately

    Adapted from Ostrove, 2001

    Triggering circumstances 201 8
    Triggering Circumstances (201.8) ---and don’t hurt your product

    • Could help prevent serious adverse effects

    • When patient needs to know of serious risks, relative to benefits, that might affect decision to use or continue use

    • When drug is important to health, and patient adherence to directions is crucial to effectiveness

    Adapted from Ostrove, 2001

    Six headers that patients need to know adapted slightly
    Six Headers That Patients Need to Know (Adapted Slightly) ---and don’t hurt your product

    • What is the most important information I should know?

    • What does “Drug” do?

    • Who should not take “Drug”?

    • How should I take “Drug”?

    • What should I avoid while taking “Drug”?

    • What are the possible or reasonably likely side effects?

    FDA on its initiative…may exempt or defer any MG content or format requirement on the basis that it is inapplicable, unnecessary or contrary to patients’ best interest

    Tools selection
    Tools Selection ---and don’t hurt your product

    • Necessary And Sufficient for Influencing Behavior

    • FDA: Selecting Tools

      • Input from stakeholders

      • Consistency with existing tools

      • Documented evidence

      • Degree of validity and reproducibility

    Tools selection suggestions
    Tools Selection-Suggestions ---and don’t hurt your product

    • Have a conceptual model

      • What is necessary to influence behavior

        • Type of Behavior (short term or long term)

        • Reliance on Memory (recall or environmental cues)

    • Use Clinical/Marketing Data

      • Describe audience

        • Demographically and psychographically (motivations)

    • Justification

      • Select sufficient/diverse tools to “solve problem”

    How many what type of tools
    How Many/What Type of Tools? ---and don’t hurt your product

    • Just Enough

      • Too Little RM

        • FDA perception that company “doesn’t get it”

        • Physicians unwilling to prescribe (lack of comfort)

      • Too Much RM can cause a “backlash”

        • Unintended Consequences (failure to prescribe because of RM obligations)

    Part iii pre testing and evaluation

    Part III ---and don’t hurt your productPre-Testing and Evaluation

    Comprehension tests
    Comprehension Tests ---and don’t hurt your product

    • Need to Test to Determine Understandability

      • Potential to effect behavioral change

      • May help with Document Simplification

        • but not leave out meaningful details

    • Enhance Liability Protection

      • Defense against failure to warn

    • Common for Rx to OTC Switches

    • Applied to Medication Guides

      • Informed Consent, Brochures, Videos, etc.

    • Applied to Physician Labels

    • Evolving to test decision making, attitudes, intentions

    Testing considerations
    Testing Considerations ---and don’t hurt your product

    • Do we need actual patients?

      • May require Clinic Study or screening?

        • Can we generalize from non-patients?

        • Are experienced patients too knowledgeable?

      • Important subpopulations (low literacy, younger)

    • What documents need to be tested?

      • Key (Core) Communication Vehicles

      • Testing in what combination – may need field test

    • What do we want to know from the tests?

      • Document diagnostics

        • Suggestions for improvements

      • Meet Benchmarks – 80% to 85% for primary COs

      • RM document longer and more complex, need secondary COs

    General procedure
    General Procedure ---and don’t hurt your product

    • Recruit (n= 400 to 1,200)

      • Use Shopping Malls/Clinical Trials/Patients

      • Screen for at-risk population

        • Disease characteristics

        • Low Literacy (pronunciation tests)

    • Design

      • One Cell Survey

      • Multi-Cell Comparisons

    General procedure 2
    General Procedure (2) ---and don’t hurt your product

    • Procedure

      • Screening

      • Document Exposure – read as normally would

        • Interviewer Leaves Room

    • Questionnaire

      • Develop Communication Objectives

      • Funnel Approach

        • Open ends

        • Specific Communication Objectives

        • Follow-up Questions

    • Document usually present (may be taken away for initial open ends)

    Evaluation ---and don’t hurt your product

    • How can we know the impact of our RM interventions?

      • Seek behavior change/adherence

    • If we do not get “sufficient” adherence:

      • Can we “diagnose” the failure?

      • Will we be able to revise the plan?

      • What do we mean by “sufficient” anyway?

        • Benchmarks or evaluation criteria

        • Do we need to set these levels a priori?

    Risk management concept paper
    Risk Management Concept Paper ---and don’t hurt your product

    • Evaluation of RM Tools

      • Select well-defined, validated metrics

      • Use at least 2 different evaluation methods for key objectives or goals

      • Use qualitative data … when quantitative data are not available or not applicable

      • Consider using evaluation methods for each RM tool.

    Evaluation of goals objectives
    Evaluation of Goals & Objectives ---and don’t hurt your product

    • Evaluation must match specific goals/objectives

      • Education – measure comprehension, opinions, etc.

        • Education encompasses knowledge, persuasion, decision making, etc

        • For example: Detect occurrence of MAADO

      • Behavior Change – measure by observation & self-report

      • Limited Use - drug use data base

      • Reduce ADRs – collect ADR experience

        • Can we use spontaneous reports?

    • Data Collection Methods

      • Questionnaires (multiple sampling methods)

      • Existing database (administrative, prescribing)

    • Evaluate Tools pre and/or post launch

    • Evaluate “unintended consequences”

    Bi directional evaluation
    Bi-Directional Evaluation ---and don’t hurt your product

    Measure Behavioral Impacts




    Measure, knowledge, beliefs, intentions, reported behavior

    Existing databases
    Existing Databases ---and don’t hurt your product

    • Numerous Available

      • Each has strengths and weaknesses

        • Some focus on claims (have diagnosis and outcomes)

        • Some focus on prescribing

        • Some focus ER visits

      • May be able to use surrogate indicators

    • Limits on explanatory variables

    Rm survey sampling methodology
    RM Survey Sampling Methodology ---and don’t hurt your product

    • Registry

      • Theoretically an audit, in reality – low response rate

      • Time Series (surveys)

        • Concern about prior surveys biasing response

        • Concern about running out of sample

    • Consider

      • Probability sampling (smaller but scientific sample)

        • Response rates are in the basement toilet

      • Bell-Weather (Sentinel Cites) or Quota sampling

        • smaller, incentivized sample

      • Multifunction Registry

        • integrate marketing and safety purposes

      • Geographical Testing

        • Base program for all, add-ons tested for impact