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FDA and Product Liability FDA Draft Guidance: RiskMAP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Draft Guidance describes: conditions stimulating the need for a RiskMAP, the selection of tools, the format for RiskMAPs, and the evaluation processes necessary to develop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