Developing Risk Management Systems that meet FDA rules ---

and don’t hurt your product

Judith K. JonesPresident, The Degge Group, Ltd.

Louis A. Morris President , Louis A. Morris & Associates

Gina AsheVP Marketing, Infomedics

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

Objectives

FORMAT: PROBLEM SOLVING EXERCISE

• 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

BackgroundFDA: Need to Develop a RM Plan

Recent Withdrawals• 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

“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]

AUG 09, 2001

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."

Import Alerts- drugs with RM plans

Examples of Drugs with RM Controls

• 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

Top 20

FDA RM Guidances

• 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

• 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

• 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

Risk Management

Known RisksUnknown 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

Perception of Risk

Willing-ness to

Use

Safety =Benefits

RisksBeliefs Perceptions

Unintended Consequences

Four Pillars ofRisk Management

•Risk Assessment

•Signal Evaluation

•Risk Communication

•System Controls

Forming Groups:Fair Distribution of Disciplines

Reseat if necessaryAppoint Leader/Recorder/Reporter

Product #1• 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

• 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• 8:45-10:00• Identify and Define

1. Additional Study• Conduct a phase IV study to help identify and characterize

the risk (30 min)

2. 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

• 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

1. Define the problem– What are the specific risk we are facing in terms of what

can happen to which patients under what conditions?2. Develop the overall RM Strategy:

1. Who do we need to influence?2. What do we want them to do? (Be specific, define for each

audience)3. When/Where do they need to exhibit this behavior

(conditions)4. 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”?

BackgroundRisk Communications and

Behavioral/Distribution Controls

Part ICommunications

Communications Planning

• 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)

• 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

• 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

• 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

Goal/Barrier Measure

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

Risk Communications (1)

• 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)

• 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 IIImplementing and Evaluating An

RM Program

Message Development

Message Development

B/RM Planning & DesignB/RM Planning & Design

Research/ Testing

Research/ Testing

SystemsDesign

SystemsDesign

B/RM ImplementationB/RM Implementation

RM System Design

EvaluationEvaluation

Distributional Controls

Closed System

Prior Approvals

CertificationSpecial Packaging

Record Keeping

Controlled Substances

Actiq Fosamax

Tikosyn Thalomid Accutane

Clozaril

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

Doctor

PatientMultiplatform

Delivered Tests

SafetyAssessmentPeriodic

MD or PatientRegistersPatient

Co

mp

ilatio

n &

Re

po

rting

Patient Education

& Feedback

RM Evaluation

Patient Experience Feedback

MD Intervention

Iterative

Multi-Function Registry

Part IIIBehavioral Outcomes

Sample of Desired Behaviors• 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

• 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

• 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

Will benefit and protect patient,Willing to try

Too Much RM

Too Little RM

Comfort Zone

Personal Liability

Too much work to use

Drug may hurt patient

Too risky to try

Consider Providing Patient Feedback to 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

0%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4 5 6

Months Since Starting Therapy

% S

till

on

Th

erap

y Baseline*

Breakeven**

Statin+

Program++

Patient Compliance Insight #1: Information is Not Learning

*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.

71%

Example of Cholesterol-Lowering Medication

Patient Compliance Insight #2:Physicians’ 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”• 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• 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

BackgroundFDA Concept Paper

RM Concept Paper

• 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 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 IITool Selection

Form (tools) Distribution PurposeBrochure Physician General Education

PPI Package or Pharmacist Broad Risk Communication

Medication Guide Package Risk Communication and Methods of Avoidance

Informed Consent Physician Acknowledgement of Risks

Warning on Package Package Risk “signal”/compliance reminder

Wallet Card Starter Kit Reminder

Stickers: Medication Vial or Prescription

Medication Vial or Prescription

Reminder or time sensitive controls

Patient Agreement or Contract

Physician Behavioral Commitment

Decision Aid Physician Choice of Therapy

Video Tape or CD Physician or Starter Kit Persuasion or Choice of Therapy

Recurring Interventions (telephone calls)

Telephone Behavioral Maintenance

Sample Tactics Matrix GoalAudience

Awareness Motivation Reinforcement

Sales Detail Aid Training manual Leave behinds

CRM Affirmative Scripts, Q&As

Training video Desk Top Media

MDs Mailing Sales Rep Material Desk Top Media, poster

ER Sales force materials

Grand Rounds Training

Poster

Patients/Partners

Waiting room placard, pharmacy printouts

Brochure/Web site, MD materials

Materials with logo

Theme: Risk Avoidance Involvement Logo as ReminderTheme: Risk Avoidance Involvement Logo as Reminder

When is a Medication Guide Needed?

• 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)

• 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)

• 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

• 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

• 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?

• 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 IIIPre-Testing and Evaluation

Comprehension Tests• 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• 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

• 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)

• 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

• 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

• 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 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

RMP

Survey

Database

Measure Behavioral Impacts

Measure, knowledge, beliefs, intentions, reported behavior

Existing Databases

• 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

• 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