Developing a RiskMAP

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Developing a RiskMAP

• Louis A. Morris, Ph.D.
• Philadelphia, July 16, 2004

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Objectives

• The New Era of Risk Management
• FDA and Product Liability
• FDA Draft Guidance RiskMAP
• When will a RiskMAP be needed?
• Selected drugs
• What will be required for a RiskMAP?
• How do I design a RiskMAP for my drug?
• Conclusion

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New FDA Resources and Plans for Risk Management

• Additional FDA resources and enhanced ability to
  monitor safety of new drugs
• PUDFA III authorizes 1.2 billion over five years
• 450 new full-time employees
• Concept paper and Hearings Held
• Draft Guidances Issued May 2004
• To be finalized by end of 2004

More regulators, more things to regulate
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FDAs Refined Concepts

• Risk Management The overall and continuing
  process of minimizing risks throughout a
  products lifecycle to optimize its benefit/risk
  balance.
• Developing Interventions to prevent harm Risk
  Minimization Action Plan (RiskMAP)

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RiskMAP

• A strategic safety program
• designed to minimize known product risks while
  preserving its benefits.
• One or more safety goals and related objectives
• Uses one or more interventions or tools
• extend beyond the package insert and routine
  post marketing surveillance.
• Tools are categorized into three areas
• education and outreach,
• reminder systems
• performance-linked systems.
• Draft Guidance describes
• conditions stimulating the need for a RiskMAP,
• the selection of tools,
• the format for RiskMAPs, and
• the evaluation processes necessary to develop and
  to monitory the success of a risk minimization
  plan.

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When is a RiskMAP Needed?

• FDA
• the nature of risks verses benefits
• risk tolerance issues such as population
  affected, alternative therapy available and
  reversibility of adverse events
• preventability of the adverse event, and
• probability of benefit or success of the risk
  minimization interventions
• Likely Candidates
• Drugs that have serious or life threatening
  contraindications, warnings, precautions or
  adverse effects
• When patient/professional behaviors can mitigate
  risks
• such as pregnancy prevention, blood tests,
  overdose/misuse avoidance, awareness and action
  related to specific safety signals
• When people other than the patient may be at risk
  
• Such as, a child may use the product
  inadvertently
• Schedule II drugs
• Singled out by FDA, with concerns for misuse,
  abuse, addiction, diversion and overdose as
  likely candidates for a RiskMAP.

Look for Benchmarks, Narrow R/B Tolerances,
Preventability, Signals
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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 as Benchmarks
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Practical Guide

• Who should not take Drug?
• Absolute Contraindications, lab test values,
  pregnancy status, etc.
• How should I take Drug?
• Timing, delivery system, unique condition
• What should I avoid while taking Drug?
• Other meds, foods, activities
• What are the possible or reasonably likely side
  effects?
• Unavoidable, rare but serious

Four Medication Guide Questions
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Designing a RiskMAP (1)

• Must clearly specify risk to be managed
• Use PI (or target profile) to select and specify
  problems to be addressed
• Organize and focus on problems needing RiskMAP
• Understand the System
• Processes underlying drug prescribing,
  distribution and use
• Use Root Cause or FMEA analysis to specify
  sources of system failures

Correctly framing the problem points to the
best solution
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Set Goals and Objectives

• Plan must specify
• overall goals of the RiskMAP
• the desired endpoints for safe product use.
• The objectives for each goal
• must be specific and measurable.
• specify the behaviors and processes necessary for
  the stated goals to be achieved.
• For example, if our goal is to prevent pregnancy,
  then an objective may be that all women must have
  a negative pregnancy test performed within seven
  days of initiating therapy.

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Tools FDA Categorization

• Targeted education or outreach.
• health care professionals (e.g., letters
  training programs letters to the editor).
• promotional techniques to publicize risk
  management (e.g., advertisements and sales
  representatives distribution of information).
• consumers and patients (e.g., Medication Guides
  and patient package inserts, limiting sampling or
  direct-to-consumer advertising)
• Reminder systems.
• training or certification programs, physician
  attestation, patient agreements), specialized
  packaging limiting the amount of medication
  dispensed
• Performance-Linked Access Systems.
• acknowledgment, certification, enrollment, or
  records
• Limiting prescribing to certified health care
  practitioners,
• limiting dispensing to certified pharmacies or
  practitioners
• Limiting access to patients with evidence of
  fulfilling certain conditions (e.g., negative
  laboratory test results).

Lets not spend too much time here
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Designing a RiskMAP (2)

• Develop a behaviorally predictive model
• the set of beliefs underlying behavioral
  intentions,
• the motivations that support or stand in the way
  of exhibiting desired behavior and
• the environmental conditions that facilitate or
  place barriers to compliance.

What do you want people to do?
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Behavioral Models

• Attitude Change
• Understanding Beliefs and Persuasion
• Improving Involvement (personal relevance) or
  Competency (self-efficacy)
• Decision making (mental models)
• Think and act like experts
• Field Theory (barriers and facilitators)
• Stages of Change or Precaution Adoption
• Emotional Models (fear appeals or positive affect)

Choose the Model that best fits the problem
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Designing a RiskMAP (3)

• Developing Interventions
• Selecting Tools
• FDA three classes are descriptive but not
  predictive
• Suggest two class categorization
• Informational Tools
• Use Communication Model to select tools
• Distribution Controls
• Additional classes of tools available
• Economic Controls (incentives for compliance)
• Product Modifications (reformulations, system
  delivery)
• Combinations and systems improvements

Personal view Tools fit the 4 Ps of Marketing
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As Abuse of Painkillers Climbs,OxyContin Gets
Reformulated To Thwart Improper Use,Pain
Therapeutics' VersionCan't Be Dissolved,
Crushed By DAVID P. HAMILTON Staff Reporter of
THE WALL STREET JOURNALJune 29, 2004
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Tools Selection (FDA)

• Necessary And Sufficient for Influencing Behavior
• FDA Selecting Tools
• Input from stakeholders
• Consistency with existing tools
• Documented evidence
• Degree of validity and reproducibility

Needed A Rationale Communications Model
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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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How to Select Tools

• Select tool(s) to meet communication challenge(s)
• What is purpose of intervention, RiskMAP goal
• Message is more important than media
• Pay attention to content
• Distinguish between repetition and redundancy
• Mere repetition can wear out, increase cognitive
  load
• Repeat message in new ways to improve likelihood
  of memory and behavior
• Point of influence cues
• Timing and situation stimulates behavior

How many tools just enough 10 is too much, 1 is
not enough
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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 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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Communications Planning

• What 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)
• How to communicate it?
• Develop Communication Objectives
• What are the key primary and secondary messages?
• Select media based on how people use drug and
  communication goals
• How do I know if it is working?
• Pretesting
• Evaluation Planning

Will information be sufficient?
Do we need a distribution control system?
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Phrasing of Warning Messages

• Complete warning
• Signal this is important
• Risk what is the hazard
• Behavior advocated what to do to avoid risk
• Consequence of failure to heed warning

Some parts may be implicit and understood, no
need to make explicit
Tradeoffs Comprehensive vs Comprehensible
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Philou Window
Determining Content
Willing to Perform Not Willing to Perform
Able to Perform Behavior What to Do Persuasion
Not Able to Perform Behavior Direction and Planning All
Motivation
Skills
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Designing Risk Communications

• Reducing Cognitive Load
• Use of Communication Objectives
• Design with Goal in Mind
• Stay On Point
• Simple Language
• But get the point across
• Avoid Seductive Details
• Selective Use of Graphic Signals
• What is really important, not everything

Build a schema consistent with risk avoidance
behavior
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Distributional Controls
Varying Levels of Control
Closed System
Prior Approvals
Special Packaging
Record Keeping
Certification
Clozaril
Controlled Substances
Actiq Fosamax
Tikosyn
Thalomid Accutane
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Controlled Distribution

• MD always Controls Distribution
• Additional Limitations by controlling
• Who prescribes, dispenses, uses
• Conditions of Use
• MD with enhanced limitations
• Necessary testing
• Necessary knowledge qualifications
• Necessary evaluation

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Distribution Limitations
Existing Qualification Additional Training Self-At-testation Manufacturer sets conditions
MD Limited to medical specialty CE training Letter of Under-standing Must use sticker
Pharm-acy Limited to specialty pharmacy Drug Admin-istratin Agreement Signed Controlled Access
Patient No pre-existing condition Qual. check (knowledge self-admin) Consent or Agreement Must join registry
Mandatory vs. Voluntary Debate
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System Enhancements

• Focus on Outcomes, not Process
• Measure knowledge and provide feedback where
  needed
• Immediate programmed learning
• Personalized form to patient
• Customized form to MD (patient experience model)
• Integration of safety assessment and risk
  minimization

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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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Multifunction Registry

• Survey Risk Knowledge, Attitudes, Intentions
• Provide Individual Feedback to MD/Patient
• Survey to Evaluate RM Intervention
• Combine data to evaluate Impact
• Measure Hypothesized ADEs in Registry
• Survey forms carefully designed to avoid
  question-asking biases

Create Specialized Benefit-Risk Database
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FDA on Evaluation

• Select well-defined, validated metrics
• Use at least 2 different evaluation methods for
  key objectives or goals
• Compensate for each methods weaknesses
• Pre test and periodically evaluate tools
• Make Evaluations Public

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Evaluation

• PreTesting
• Comprehension Testing of Tools
• Pilot Testing
• LSSS real world assessment in phase IIIb or IV
  (actual use study)
• Multiple Program Evaluation
• Database results
• Survey results
• CQI Review

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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 study in clinics 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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Large Simple Safety Study

• Prospectively Designed Phase IIIb
• Actual Use Study
• Best way to predict outcomes
• Limitations
• Consent as a possible confounder
• MD as an investigator,
• Opportunities
• Randomly Vary Risk Minimization Interventions
• Evaluation reasons for success vs. failure
• Learn about many aspects of RiskMAP implementation

Wonderful Opportunity
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Post-Implementation 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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Evaluation of Goals Objectives

• Evaluation must match specific goals/objectives
• Education measure comprehension, opinions, etc.
• Behavior Change measure by observation
  self-report
• Limited Use - drug use data base
• Reduce ADRs collect ADR experience
• Data Collection Methods
• Questionnaires (multiple sampling methods)
• Move toward representative sample, not an audit
  with low response rates
• Existing database (administrative, prescribing)
• Evaluate Tools pre and/or post launch
• Evaluate unintended consequences

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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
• Consider combinations to compensate for
  individual weaknesses
• 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

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Risk Management Irony
Benefits
Perceptions
Beliefs
Safety
Risks
Willing-ness to Use
Perception of Risk
Communications do more than inform, they modify
modify beliefs, may change perceptions
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Black Box as a Signal
QUOTE OF THE DAY"Having a black box on the label
is a big deal. It's pretty astounding to go from
a year ago thinking this is one of the most
benign drugs to a 180-degree turn in the opposite
direction." Dr. Susan Hendrix, a gynecologist,
on the government decision to require warning
labels on drugs containing estrogen.
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Posted 5/5/2004 114 AM
                                         

Fears cited for IBS drug's lagging sales By Rita Rubin, USA TODAY Sales of Lotronex, a drug to treat irritable bowel syndrome that was temporarily taken off the market because of safety concerns, have been far lower than expected since its reintroduction in November 2002, its maker says. GlaxoSmithKline attributes Lotronex's disappointing sales to the Risk Management Program required by the Food and Drug Administration. The program, which is designed to reduce the risk of potentially life-threatening side effects, requires that doctors attest that they are qualified to prescribe Lotronex. Doctors and pharmacists also are supposed to give patients an FDA-approved Medication Guide before they start taking Lotronex.

   
                                  


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Continuous Quality Improvements

• Seek to avoid All or None Reactions
• Add more/redesign tools if current ones not
  working
• Seek to diagnose cause for failures
• Redesign interventions based on data
• Form Committees
• Working Committee
• Oversight and Review
• Periodic Meetings
• Each 6 months

Benchmarking Success Seek to improve over time,
avoid setting an a priori level
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Conclusion

• FDA draft guidance is reasonable and responsive
  to public input
• Companies must begin to adapt their thinking to
  incorporate risk minimization
• Ball is in pharma companys court
• FDA will design Risk Minimization Plans if
  pharmaceutical companies do not
• Still in a period of learning, not a lot of
  successes
• Innovation and evaluation is needed