FDA Guidance for risk evaluation and mitigation strategies - Professor Peivand Pirouzi
DEVELOPING REMSPROFESSOR PEIVAND PIROUZI2009GUIDANCE 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Objectives The New Era of Risk Management FDA and Product Liability FDA Draft Guidance: RiskMAP When will a RiskMAP be needed?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 Tools are categorized into three areas: education and outreach, reminder systems performance-linked systems Draft Guidance describes: conditions stimulating the need for a RiskMAP, the selection of tools, the format for RiskMAPs, and the evaluation processes necessary to develop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
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
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 failuresCorrectly “framing the problem” points to the best solution
System Analysis Medication Dispensing MD Retrieves Writes Diagnosis Name Prescription Error Error Error Patient Delivery ErrorRetrieve Drug Dispenses Medication from Shelf Medicine used 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
CBC: http://www.cbsnews.com/video/watch/?id=2788489nAs Abuse of Painkillers Climbs,OxyContin Gets ReformulatedTo Thwart Improper Use,Pain Therapeutics VersionCant Be Dissolved, CrushedBy DAVID P. HAMILTONStaff Reporter of THE WALL STREET JOURNALJune 29, 2004
New Formulation of Oxycontin– Will it make a difference?2009 September 25Purdue’s current pill is meant to be swallowed whole, but abuserscan easily chew it or crush it and then snort it, smoke it, or dissolve itin liquid and inject it to achieve a heroin-like high.Although there is no proof that the new formulation is safer, thepanel agreed that making the pills harder to crush, chew, or dissolveinto liquid may deter abusers.When the new version of the drug is dissolved into water, it producesa gel, which makes snorting the drug more difficult.
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
Info. Tools Distribution Purpose (strength)Brochure Physician General EducationPPI (Participant Perception Indicator ) Package/ Pharmacist Risk CommunicationMedication Guide Package Risk Communication and Methods of Hazard AvoidanceInformed Consent Physician Acknowledgement of RisksWarning on Package Package Risk “signal”/complianceWallet Card Starter Kit ReminderStickers: Medication Medication Vial or Reminder or time sensitive controlVial or Prescription Prescription messagePatient Agreement or Physician Behavioral CommitmentContractDecision Aid Physician Choice of TherapyVideo Tape or CD Physician or Starter Kit Persuasion or EmotionRecurring Telephone Behavioral MaintenanceInterventions(telephone calls)
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
Sample Tactics Matrix Goal Awareness Motivation ReinforcementAudienceSales Detail Aid Training manual Leave behindsCRM Affirmative Training video Desktop Media Scripts, Q&AsMDs Mailing Sales Rep Material Desktop Media, posterER Sales force Grand Rounds Poster materials TrainingPatients/ Waiting room Brochure/Web site, Materials with logoPartners placard, MD materials pharmacy printouts 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 behaviorHow 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
Determining Content Motivation Willing to Not Willing to Perform Perform SkillsAble to Perform What to Do Persuasion Behavior Not Able to Direction and All Perform Planning BehaviorPhilou Window
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 Varying Levels of Control Certification PriorRecord Special ClosedKeeping Packaging Approvals SystemControlled Actiq Tikosyn Thalomid ClozarilSubstances Fosamax Accutane
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 Additional Self-At- Manufacturer Qualification Training testation sets conditionsMD Limited to CE training Letter of Must use medical Under- sticker specialty standingPharm Limited to Drug Agreement Controlled-acy specialty Admin- Signed Access pharmacy istratinPatient No pre- Qual. check Consent or Must join existing (knowledge Agreement registry condition self-admin) 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
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? Benchmarksor 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 ConsequencesBeliefs Benefits Perceptions Safety = Risks Willing- Perception ness to of Risk Use Communications do more than inform, they modify beliefs, may change perceptions
Black Box as a SignalQUOTE OF THE DAY"Having a black box on the label is a big deal.Its pretty astounding to go from a year agothinking this is one of the most benign drugsto a 180-degree turn in the opposite direction."Dr. Susan Hendrix, a gynecologist, on thegovernment decision to require warning labelson drugs containing estrogen.
http://www.youtube.com/watch?v=jcEoy9-_5TM&NR=1 Posted 5/5/2004 1:14 AMFears cited for IBS drugs lagging salesBy Rita Rubin, USA TODAYSales of Lotronex, a drug to treat irritable bowel syndrome thatwas temporarily taken off the market because of safety concerns,have been far lower than expected since its reintroduction inNovember 2002, its maker says.GlaxoSmithKline attributes Lotronexs disappointing sales to theRisk Management Program required by the Food and DrugAdministration. The program, which is designed to reduce the riskof potentially life-threatening side effects, requires that doctorsattest that they are qualified to prescribe Lotronex. Doctors andpharmacists also are supposed to give patients an FDA-approvedMedication Guide before they start taking Lotronex.
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