FDA guidance for risk evaluation and mitigation strategies - Pharmaceutical products

1. DEVELOPING REMS
PROFESSOR PEIVAND PIROUZI
2009
GUIDANCE FROM US DEPARTMENT OF HEALTH AND HUMAN SERVICES
September 2009

2. 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 FDA Draft Guidance: RiskMAP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

3. FDA’s Refined Concepts
 Risk Management: “The overall and
continuing process of minimizing risks
throughout a product’s lifecycle to optimize
its benefit/risk balance.”
 Developing Interventions to prevent harm:
Risk Minimization Action Plan (RiskMAP)

4. 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 Draft Guidance describes: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 monitor the
success of a risk minimization plan

5. When is a RiskMAP Needed?
 FDA
 the nature of risks versus benefits
 risk tolerance issues such as population affected, alternative therapy available
and reversibility of adverse events
 preventability of the adverse event
 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

6. Examples of Drugs with RM Controls
• Accutane (isotretinoin) - severe recalcitrant nodular acne
• Actiq (fentanyl citrate) - severe cancer pain
• Clozaril (clozapine) - severe schizophrenia
• Mifiprex (mifepristone
or RU-486) - termination of early intrauterine pregnancy
• Thalomid (thalidomide) - erythema nodosum leprosum
• Tikosyn (dofetilide) - maintenance of normal sinus rhythm
• Trovan (trovafloxacin
mesylate or alatrofloxacin
mesylate injection) - severe, life-threatening infections

7. 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

8. Designing a RiskMAP (1)
 Must clearly specify risk to be managed
 Use 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 to specify sources of system failures
Correctly “framing the problem” points to the best solution

9. System Analysis
Medication Dispensing
MD Retrieves Writes
Diagnosis Name Prescription
Error Error Error
Patient
Delivery
Error
Retrieve Drug Dispenses Medication
from Shelf Medicine used
Error Error Error

10. Failure Mode and Effects Analysis
 Develop System Steps (or subsystem)
 Sources of Failure for each step
 Probability
 Severity
 Likelihood Of Detection

11. 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.

12. Tools: FDA Categorization
(3 classes)
 “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).

13. 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
 the environmental conditions that facilitate or place
barriers to compliance.
What do you want people to do?

14. 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

15. Designing a RiskMAP (3)
 Developing Interventions
 Selecting Tools
 FDA three classes are descriptive but not predictive
(Education, Reminder, Access)
 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
Tools fit the 4 Ps of Marketing: product, price, place (distribution), and promotion

16. CBC: http://www.cbsnews.com/video/watch/?id=2788489n
As Abuse of Painkillers Climbs,
OxyContin Gets Reformulated
To Thwart Improper Use,
Pain Therapeutics' Version
Can't Be Dissolved, Crushed
By DAVID P. HAMILTON
Staff Reporter of THE WALL STREET JOURNAL
June 29, 2004

17. New Formulation of Oxycontin– Will it make a difference?
2009 September 25
Purdue’s current pill is meant to be swallowed whole, but abusers
can easily chew it or crush it and then snort it, smoke it, or dissolve it
in liquid and inject it to achieve a heroin-like high.
Although there is no proof that the new formulation is safer, the
panel agreed that making the pills harder to crush, chew, or dissolve
into liquid may deter abusers.
When the new version of the drug is dissolved into water, it produces
a gel, which makes snorting the drug more difficult.

18. Tools Selection (FDA)
 Necessary And Sufficient for Influencing Behavior
 FDA: Selecting Tools
 Inputfrom stakeholders
 Consistency with existing tools
 Documented evidence
 Degree of validity and reproducibility
Needed: A Rationale Communications Model

19. Info. Tools Distribution Purpose (strength)
Brochure Physician General Education
PPI (Participant Perception Indicator ) Package/ Pharmacist Risk Communication
Medication Guide Package Risk Communication and Methods
of Hazard Avoidance
Informed Consent Physician Acknowledgement of Risks
Warning on Package Package Risk “signal”/compliance
Wallet Card Starter Kit Reminder
Stickers: Medication Medication Vial or Reminder or time sensitive control
Vial or Prescription Prescription message
Patient Agreement or Physician Behavioral Commitment
Contract
Decision Aid Physician Choice of Therapy
Video Tape or CD Physician or Starter Kit Persuasion or Emotion
Recurring Telephone Behavioral Maintenance
Interventions
(telephone calls)

20. 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

21. Sample Tactics Matrix
Goal Awareness Motivation Reinforcement
Audience
Sales Detail Aid Training manual Leave behinds
CRM Affirmative Training video Desktop Media
Scripts, Q&As
MDs Mailing Sales Rep Material Desktop Media, poster
ER Sales force Grand Rounds Poster
materials Training
Patients/ Waiting room Brochure/Web site, Materials with logo
Partners placard, MD materials
pharmacy
printouts
Theme: Risk Avoidance Involvement Logo as Reminder

22. 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

23. 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
Adapted from Ostrove, 2001

24. 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

25. 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”?

26. 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

27. Determining Content
Motivation Willing to Not Willing to
Perform Perform
Skills
Able to Perform What to Do Persuasion
Behavior
Not Able to Direction and All
Perform Planning
Behavior
Philou Window

28. 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

29. Distributional Controls
Varying Levels of Control
Certification Prior
Record Special Closed
Keeping Packaging Approvals System
Controlled Actiq Tikosyn Thalomid Clozaril
Substances Fosamax Accutane

30. 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

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

32. 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

33. Multi-Function Registry
MD
Doctor Intervention
MD or Patient
Registers Safety
Compilation & Reporting
Patient Assessment
Multi-platform Risk Management
Patient Delivered Evaluation
Tests
Periodic Patient
Education
& Feedback
Patient
Experience
Feedback

34. Multifunction Registry
 Survey Risk Knowledge, Attitudes, Intentions
 Provide Individual Feedback to MD/Patient
 Survey to Evaluate Risk Management 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

35. FDA on Evaluation
 Select well-defined, validated metrics
 Use at least 2 different evaluation methods for key
objectives or goals
 Compensate for each method’s weaknesses
 Pre test and periodically evaluate tools
 Make Evaluations Public

36. Evaluation
 PreTesting
 Testing the comprehension of tools
 Pilot Testing
 “real world” assessment in phase III or IV (actual use study)
 Multiple Program Evaluation
 Database results
 Survey results

37. 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

38. Large Simple Safety Study
 Prospectively Designed Phase III
 Actual Use Study
 Best way to predict outcomes
 Limitations
 Consent
 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

39. 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?
 Benchmarksor evaluation criteria
 Do we need to re-evaluate these levels?

40. 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”

41. 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 indicators (Searching predefined terms)
 Consider combinations to compensate for individual
weaknesses
 Limits on explanatory variables

42. Unintended Consequences
Beliefs Benefits Perceptions
Safety =
Risks
Willing-
Perception ness to
of Risk Use
Communications do more than inform, they modify
beliefs, may change perceptions

43. 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.

44. http://www.youtube.com/watch?v=jcEoy9-_5TM&NR=1
Posted 5/5/2004 1:14 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.

45. 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
Seek to improve over time

46. 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 company’s 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