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FDA guidance for risk evaluation and mitigation strategies - Pharmaceutical products
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DEVELOPING REMS PROFESSOR PEIVAND PIROUZI 2009 GUIDANCE FROM US DEPARTMENT OF HEALTH AND HUMAN SERVICES
September 2009
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FDA and Product Liability FDA Draft Guidance: RiskMAP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
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)
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Draft Guidance describes: conditions stimulating the need for a RiskMAP, the selection of tools, the format for RiskMAPs, and the evaluation processes necessary to develop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
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
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
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
Practical Guide
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
System Analysis Medication Dispensing
Retrieves Name
Writes Prescription
Patient Delivery
Medication used
MD Diagnosis
Retrieve Drug from Shelf
Dispenses Medicine
Error Error
Error Error Error
Error
Error
Failure Mode and Effects Analysis
Develop System Steps (or subsystem) Sources of Failure for each step Probability Severity Likelihood Of Detection
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.
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).
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?
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
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
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
CBC: http://www.cbsnews.com/video/watch/?id=2788489n
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.
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
Behavioral Maintenance Telephone Recurring Interventions (telephone calls)
Persuasion or Emotion Physician or Starter Kit Video Tape or CD Choice of Therapy Physician Decision Aid
Behavioral Commitment Physician Patient Agreement or Contract
Reminder or time sensitive control message
Medication Vial or Prescription
Stickers: Medication Vial or Prescription
Reminder Starter Kit Wallet Card Risk “signal”/compliance Package Warning on Package Acknowledgement of Risks Physician Informed Consent
Risk Communication and Methods of Hazard Avoidance
Package Medication Guide Risk Communication Package/ Pharmacist PPI (Participant Perception Indicator )
General Education Physician Brochure Purpose (strength) Distribution Info. Tools
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
Sample Tactics Matrix Goal Audience
Awareness Motivation Reinforcement
Sales Detail Aid Training manual Leave behinds
CRM Affirmative Scripts, Q&As
Training video Desktop Media
MDs Mailing Sales Rep Material Desktop 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 Reminder
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
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
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
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”?
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
Philou Window
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
Determining Content
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
Distributional Controls
Closed System
Prior Approvals
Certification Special Packaging
Record Keeping
Controlled Substances
Actiq Fosamax
Tikosyn Thalomid Accutane
Clozaril
Varying Levels of Control
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
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
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
Doctor
Patient Multi-platform
Delivered Tests
Safety Assessment
Periodic
MD or Patient Registers
Patient
Com
pilation & R
eporting
Patient Education
& Feedback
Risk Management Evaluation
Patient Experience Feedback
MD Intervention
Multi-Function Registry
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
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
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
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
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
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 re-evaluate these levels?
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”
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
Unintended Consequences
Perception of Risk
Willing-ness to
Use
Safety = Benefits Risks
Beliefs Perceptions
Communications do more than inform, they modify beliefs, may change perceptions
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.
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.
Posted 5/5/2004 1:14 AM
http://www.youtube.com/watch?v=jcEoy9-_5TM&NR=1
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
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