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FDA Draft Guidance: RiskMAP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Draft Guidance describes: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
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