Developing Risk Management Systems that meet FDA rules and dont hurt your product

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Developing Risk Management Systems that meet FDA
rules ---and dont hurt your product

• Judith K. Jones
• President, The Degge Group, Ltd.
• Louis A. Morris
• President , Louis A. Morris Associates
• Gina Ashe
• VP Marketing, Infomedics

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Objectives

• 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

P

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FORMAT PROBLEM SOLVING EXERCISE

• Introductions, Background Goals for Today
• (15 minutes)
• Form Groups
• 845-10 AM Developing a RM Strategy
• Problem Identification
• Understand Risk Assessment Issues (by example)
• Defining Desired Behavioral Outcomes,
  Communications, Distribution Controls
• 10-1020 AM Break
• 1020-1120 Developing the FDA RM Plan
• Goals, Objectives, Tools,, Evaluation Planning
• 1120-1200 Group Presentations and commentary by
  Audience and Faculty

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BackgroundFDA Need to Develop a RM Plan
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(No Transcript)
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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 NMEs from 1998-2000
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Rezulin Withdrawal

• FDA took this action after its review of recent
  safety datashowed that Rezulin is more toxic to
  the liver than the other two drugs HHS News,
  3/21/00
• And weve 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

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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."
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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

Import Alerts- drugs with RM plans
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Top 20
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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

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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 products lifecycle to
optimize the benefit/risk balance
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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
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Risk Management
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

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Risk Management Irony
Benefits
Perceptions
Beliefs
Safety
Risks
Willing-ness to Use
Perception of Risk
Unintended Consequences
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Four Pillars ofRisk Management

• Risk Assessment
• Signal Evaluation
• Risk Communication
• System Controls

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Forming GroupsFair Distribution of Disciplines
Reseat if necessaryAppoint Leader/Recorder/Repor
ter
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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 drugs profile is otherwise benign

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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.

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Tasks for Groups

• 845-1000
• 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)

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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?

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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?
• 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?

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BackgroundRisk Communications and
Behavioral/Distribution Controls
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Part ICommunications
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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

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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

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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

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Communications Process
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
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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)

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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

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Part IIImplementing and Evaluating An RM
Program
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RM System Design
B/RM Planning Design
Message Development
Research/ Testing
Systems Design
B/RM Implementation
Evaluation
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Distributional Controls
How do we slot the risk-control level for any
drug?
Closed System
Prior Approvals
Special Packaging
Record Keeping
Certification
Clozaril
Controlled Substances
Actiq Fosamax
Tikosyn
Thalomid Accutane
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Multi-Function Registry
MD Intervention
Doctor
MD or Patient Registers Patient
Safety Assessment
Periodic
Multiplatform Delivered Tests
RM Evaluation
Patient
Compilation Reporting
Patient Education Feedback
Iterative
Patient Experience Feedback
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Part IIIBehavioral Outcomes
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Sample of Desired Behaviors

• MDs
• Select appropriate patients
• Provide RM counseling patients
• Oversee compliance with necessary behaviors (lab
  tests)
• Side Effect monitoring
• Patients
• Understand medications 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

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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)

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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

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The MD Comfort Zone
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
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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

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Patient Compliance Insight 1 Information is
Not Learning
Example of Cholesterol-Lowering Medication
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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.
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Patient Compliance Insight 2Physicians 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

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Patient Compliance Insight 3Each 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

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Tasks for Groups-2

• 1020-1130
• 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
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BackgroundFDA Concept Paper
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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

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RM Program

• RM Goals and Objectives
• RM Program should have one or more safety related
  goalstailored 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

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Part IITool Selection
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Sample Tactics Matrix
Theme Risk Avoidance Involvement Logo
as Reminder
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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
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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
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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 initiativemay exempt or defer any MG
content or format requirement on the basis that
it is inapplicable, unnecessary or contrary to
patients best interest
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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

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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

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How Many/What Type of Tools?

• Just Enough
• Too Little RM
• FDA perception that company doesnt 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)

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Part IIIPre-Testing and Evaluation
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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

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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

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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

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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)

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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?

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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.

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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

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Bi-Directional Evaluation
Measure Behavioral Impacts
Survey
RMP
Database
Measure, knowledge, beliefs, intentions, reported
behavior
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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

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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