Transcript Developing Consumer Marketing Claims within the Clinical

Developing Risk Management
Systems that meet FDA rules --and don’t hurt your product
Judith K. Jones
President, The Degge Group, Ltd.
Louis A. Morris
President , Louis A. Morris & Associates
Gina Ashe
VP Marketing, Infomedics
Objectives
articipants should appreciate strategic and tactical
elements for developing a Risk Management (RM)
Plan:
– Risk Assessment
• Natural History of Disease
– Developing a RM Strategy
• Designing Distribution control
• Developing Communication Objectives
– Designing a RM Program
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Behavioral Goals and Objectives
Selecting and Justifying Tools
PreTesting Communications
Planning Evaluation
FORMAT: PROBLEM SOLVING
EXERCISE
• Introductions, Background & Goals for Today
– (15 minutes)
• Form Groups
– 8:45-10 AM: Developing a RM Strategy
• Problem Identification
• Understand Risk Assessment Issues (by example)
• Defining Desired Behavioral Outcomes, Communications,
Distribution Controls
– 10-10:20 AM: Break
– 10:20-11:20: Developing the FDA RM Plan
• Goals, Objectives, Tools,, Evaluation Planning
– 11:20-12:00 Group Presentations and commentary by
Audience and Faculty
Background
FDA: Need to Develop a RM Plan
Recent Withdrawals
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Seldane (terfenadine)
Posicor  (mibefradil)
Duract  (bromphenac)
Hismanal  (astemizole)
Roxar  (grepafloxacin)
Propulsid  (cisapride)
Rezulin  (troglitazone)
Lotronex  (alosetron HCl)
Raplon  (rapcuronium)
Baycol  (cerivaxtatin)
92 NME’s from 1998-2000
2/98
6/98
6/98
6/99
11/99
3/23/00
3/21/00
8/24/00
3/01
8/8/01
Rezulin Withdrawal
“FDA took this action after its review of recent
safety data…showed that Rezulin is more toxic to
the liver than the other two drugs” [HHS News,
3/21/00]
“And we’ve had to withdraw drugs from the
market that would have been safe if used
according to label instructions” [Janet
Woodcock, Temple University, 4/4/00]
AUG 09, 2001
Anticholesterol Drug Pulled
After Link to 31 Deaths
With Baycol, however, reports of serious
rhabdomyolysis were about 10 times as frequent as
with the other statins, Dr. Jenkins said.
"Baycol really stood out as being different," he
said. "Baycol did not offer any benefits beyond
those of the other statins. But it carried a potential
risk, and that leads to a conclusion that it is no
longer safe to be marketed."
Examples of Drugs with RM
Controls
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Accutane (isotretinoin) Actiq (fentanyl citrate) Clozaril (clozapine)
Lotronex (alosetron
hydrochloride)
Mifiprex (mifepristone
or RU-486)
Thalomid (thalidomide) Tikosyn (dofetilide)
Tracleer (bosentan)
Trovan (trovafloxacin
mesylate or alatrofloxacin
mesylate injection)
Xyrem (sodium oxybate) -
severe recalcitrant nodular acne
severe cancer pain
severe schizophrenia
severe irritable bowel syndrome in women
termination of early intrauterine pregnancy
erythema nodosum leprosum
maintenance of normal sinus rhythm
severe pulmonary arterial hypertension
severe, life-threatening infections
narcolepsy
Import Alerts- drugs with RM plans
Top 20
FDA RM Guidances
• Concept Papers Released March 3, 2003
• Hearings April 9 – 11, 2003
• Three Papers:
– Premarketing Risk Assessment
– Risk Management Programs
– Risk Assessment of Observational Data: Good
Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment
• Guidances To Be Finalized September, 2004
Risk Management Guidance
• Sponsor proposes a Risk Management
Program (RMP)
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Background and rationale for RM approach
Goals, Objectives and RMP Level (4 levels)
Tools and Implementation plan for each tool
Evaluation Plan for each tool and for the
overall RMP
• Analyses to be conducted
• Reporting results to FDA
Risk Management is the process of minimizing risks throughout a
product’s lifecycle to optimize the benefit/risk balance
The Four Levels of Risk Management
• Level 1
Package Insert only
• Level 2
Level 1 + education and outreach to health
professionals and patients/consumers
• Level 3
Level 2 + systems that guide the prescribing,
dispensing, or receipt of a product
• Level 4
Level 3 + Access to product requires
adherence to program elements
Levels may go – concept of progressive interventions will stay
Risk
Management
Unknown
Risks
•Discovering and interpreting
safety signals
•Phase IV Commitments
•Do I need a study/registry?
Known
Risks
•Designing interventions (tools)
•Justifying choice of interventions
•Pre-testing Interventions
•Implementing interventions
•Evaluating interventions
•Revising interventions
Risk Management Irony
Beliefs
Safety =
Perception
of Risk
Benefits
Risks
Perceptions
Willingness to
Use
Unintended Consequences
Four Pillars of
Risk Management
•Risk Assessment
•Signal Evaluation
•Risk
Communication
•System Controls
Forming Groups:
Fair Distribution of Disciplines
Reseat if necessary
Appoint Leader/Recorder/Reporter
Product #1
• A product for diabetic neuropathy shown to
be very effective causes severe tachycardia
(rapid heart rate) with excess caffeine in a
genetically sensitive group.
• This group can be identified by a genetic
test which is costly (~$3000/person)
• The drug’s profile is otherwise benign
Product # 2
• An antibiotic product indicated for upper
respiratory infections is highly effective
with most pathogens, including resistant
organisms-likely to be used widely.
• Its risk is similar to other antibiotics except
that if used more than twice in a three
month period, it causes severe diarrhea and
colitis, particularly toxic to the elderly and
children.
Tasks for Groups
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8:45-10:00
Identify and Define
1. Additional Study
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Conduct a phase IV study to help identify and characterize
the risk (30 min)
2. Developing a RM Strategy
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Who, What, How, When, Where and Why? (20 min)
3. How to manage Risks?
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List Key Messages (selected) for each audience (10 min)
Assume that FDA believes that communications by
themselves will be insufficient. What distribution system
controls will be necessary to influence desired behaviors?
(15 min)
Phase IV Study
• Who will we recruit?
– Types of people (assume statisticians
estimate that at least 2000 people are
needed)
• How will we recruit them?
• What will we measure?
– Conceptually, what do we need to know?
– How will we measure it?
Task: RM Strategy
1. Define the problem
– What are the specific risk we are facing in terms of what
can happen to which patients under what conditions?
2. Develop the overall RM Strategy:
1. Who do we need to influence?
2. What do we want them to do? (Be specific, define for each
audience)
3. When/Where do they need to exhibit this behavior
(conditions)
4. How will we get them to do it?
What messages will be necessary to influence behavior
Will “information” be sufficient? Do we need “behavioral
control systems”?
Background
Risk Communications and
Behavioral/Distribution Controls
Part I
Communications
Communications Planning
• What to 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)
• Will “information” be sufficient? Do we need “behavioral control
systems”?
• How to communicate it?
– What are the key primary and secondary messages? (Communication
Objectives)
– What media will reach intended audience (how much redundancy)?
– Will we need a Medication Guide?
• How do I know it is working? (next session)
– Pretesting
– Evaluation Planning
Developing Communication
Objectives (COs)
• What is the most important information for people to
know about using this drug?
– List in descending order of importance
– Assume must provide information relevant to six headers
for MedGuides if preparing most patient information
documents
• What do we need to say to influence advocated
behavior?
• List for each audience
Information Options
• HCPs
– PI, Label Changes (black box), Dear Doctor letters,
Advertisements (medication errors), Fair Balance in
ads, MedEd, brochures, etc.
• Patients
– PPIs, Medication Guide, Informed Consent, Multiple
options (Accutane, Thalidomide), refrain from DTC.
• Public (PR)
– FDA public announcements (talk papers, press
releases), website posting, advisory committee
meetings
Communications Process
Goal/Barrier
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Exposure
Attention
Interest
Understand
Accept
Memory
Decide
Behave
Learn
Measure
Distribution
Readership
Willingness to Read
Comprehension
Attitude Change
Recall/Recognition Tests
Decision Making Scenarios
Intention to Heed/Behavior
Behavior Maintenance
Select Vehicles to Maximize Communication Goal
May need a combination of Vehicles
Risk Communications (1)
• Seek Intervention that will force exposure
– PPI – voluntary distribution (7% for Darvon)
– MG – required by law (39% for Estrogen PPI)
– Packaging – systems (93% for OCs)
• Risk Messages break through clutter
– Clearly identify as risk message (not marketing in
disguise)
• Redundancy for backup and reminder purpose (not
as primary communication purpose)
Risk Communications (2)
• Assure Understanding of Key Objectives
– Will not get sufficient repetition
– Test for COs in Comprehension Tests
• Understand Factors Controlling Behavior Change
– Attitude-Behavior Consistency
– Barriers as well as Facilitators
• Evaluation Specific Enough to Understand
Failures and Recommend Changes
Part II
Implementing and Evaluating An
RM Program
RM System Design
B/RM Planning & Design
Message
Development
Systems
Design
B/RM Implementation
Evaluation
Research/
Testing
Distributional Controls
How do we slot the risk-control level for any drug?
Record
Keeping
Controlled
Substances
Closed
Special
Certification Prior
Approvals System
Packaging
Actiq
Fosamax
Tikosyn
Thalomid
Accutane
Clozaril
Multi-Function Registry
Doctor
MD
Intervention
Patient
Safety
Assessment
Multiplatform
Delivered
Tests
RM
Evaluation
Patient
Education
& Feedback
Patient
Experience
Feedback
Compilation & Reporting
MD or Patient
Registers
Patient
Part III
Behavioral Outcomes
Sample of Desired Behaviors
• MDs
– Select appropriate patients
– Provide RM counseling patients
– Oversee compliance with necessary behaviors (lab
tests)
– Side Effect monitoring
• Patients
– Understand medication’s risks
– Understand avoidance behaviors
• behaviors necessary to prevent risks
– Behavioral Compliance
• Initiating and maintaining behaviors with medication taking
requirements to avoid adverse events
May need iterative education and motivation
“Practicalities” of Engaging MDs
• MD time constraints
• The office staff “shield”
• Limitations of Distribution channels
– Sales Rep as the RM messenger
– The clutter of direct mail
– Technology limitations
• Attitudes toward adopting new (potentially risky)
medications into their practice
• General risk aversion (on several fronts)
Avoid “One Size Fits All”
Approach to MDs
• Specialists vs. PCPs
• Targeting the “right” physicians early in the
program (sissy vs. sassy docs)
• KOL acceptance
• For those interested in the Medicine:
– This is an issue of patient safety
– This may be a particular necessary medicine
– Prescribers need to know this
The MD Comfort Zone
Too Much RM
Personal Liability
Too much work to use
Comfort
Zone
Too Little RM
Will benefit and protect patient,
Willing to try
Drug may hurt patient
Too risky to try
Consider Providing Patient Feedback
to Their MDs
• Additional knowledge MDs gain about:
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patient comprehension of product benefits and risks
Benefit/Risk Perceptions
Barriers to Use
Attitudes about Medication
Motivations
Behavioral Intentions
Compliance Measures
Patient Compliance Insight #1:
Information is Not Learning
% Still on Therapy
Example of Cholesterol-Lowering Medication
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Baseline*
Breakeven**
71%
Statin+
Program++
0
1
2
3
4
5
6
Months Since Starting Therapy
*Scott-Levin
data 10/00-3/01 showing 45% of patients continuing on medication each month from prior month.
calculations using program costs, expected returns, and Scott-Levin Rx data.
+Scott-Levin data from 10/00-3/01 for monthly adherence of statin users.
++Adherence rates observed among Adhere program participants.
**Internal
Patient Compliance Insight #2:
Physicians’ Active Role is Essential
• Driven by physician-patient relationship
• Deliberate “ask” from MD
• Patients increasingly turning to their own
sources for information, may be unreliable
InfoMedics Survey: Why Do Patients Comply with Programs?
• 73% of patients motivated to participate because of doctor-patient
relationship
• 80% of patients would participate again if asked by physician
Patient Compliance Insight #3:
Each patient conducts their own
individual “risk assessment”
• Medication containing estrogen, topically applied
for short periods of time only, shown to not enter
blood stream
• MDs comfortable with remote risk of breast
cancer (no documented cases)
• MDs recognized significant symptom relief and
quality of life improvements that medication
delivered
• Patient concerns around “HRT therapies” caused
MDs concerns--not willing to prescribe
Tasks for Groups-2
• 10:20-11:30
• Design:
1. RMP Outline
• Goals, Objectives
• Choice of Tools and Justification (30 min)
2. Methods of Evaluation:
• Individual Tools (Comprehension Test)
– List Communication Objectives
• The Risk Management Plan (30 min)
These tasks should be completed for presentation
Background
FDA Concept Paper
RM Concept Paper
• Risk Management Program
– A strategic program designed to decrease
product risk by using one or more interventions
or tools beyond the PI. For example:
• Specialized educational materials
• Processes or forms to increase compliance or reduce
risk
• Systems to modify prescribing, dispensing and use
RM Program
• RM Goals and Objectives
– RM Program should have one or more safety
related goals…tailored to specific concerns
– Goals are broad, conceptual statements of
desired outcomes
– Objectives are translation of goals into
pragmatic, specific and measurable processes or
behavioral outcomes
• Apply to each audience
Part II
Tool Selection
Form (tools)
Distribution
Purpose
Brochure
Physician
General Education
PPI
Package or Pharmacist
Broad Risk Communication
Medication Guide
Package
Risk Communication and Methods
of Avoidance
Informed Consent
Physician
Acknowledgement of Risks
Warning on Package
Package
Risk “signal”/compliance reminder
Wallet Card
Starter Kit
Reminder
Stickers: Medication
Vial or Prescription
Medication Vial or
Prescription
Reminder or time sensitive controls
Patient Agreement or
Contract
Physician
Behavioral Commitment
Decision Aid
Physician
Choice of Therapy
Video Tape or CD
Physician or Starter Kit Persuasion or Choice of Therapy
Recurring
Interventions
(telephone calls)
Telephone
Behavioral Maintenance
Sample Tactics Matrix
Goal
Audience
Awareness
Motivation
Reinforcement
Sales
Detail Aid
Training manual
Leave behinds
CRM
Affirmative
Scripts, Q&As
Training video
Desk Top Media
MDs
Mailing
Sales Rep Material
Desk Top 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
When 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
(drugs and biologics) annually
• Not to be used indiscriminately
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
Six Headers That Patients Need
to Know (Adapted Slightly)
• What is the most important information I
should know?
• What does “Drug” do?
• Who should not take “Drug”?
• How should I take “Drug”?
• What should I avoid while taking “Drug”?
• What are the possible or reasonably likely
side effects?
FDA on its initiative…may exempt or defer any MG content or
format requirement on the basis that it is inapplicable, unnecessary
or contrary to patients’ best interest
Tools Selection
• Necessary And Sufficient for Influencing
Behavior
• FDA: Selecting Tools
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Input from stakeholders
Consistency with existing tools
Documented evidence
Degree of validity and reproducibility
Tools Selection-Suggestions
• Have a conceptual model
– What is necessary to influence behavior
• Type of Behavior (short term or long term)
• Reliance on Memory (recall or environmental cues)
• Use Clinical/Marketing Data
– Describe audience
• Demographically and psychographically (motivations)
• Justification
– Select sufficient/diverse tools to “solve problem”
How Many/What Type of Tools?
• Just Enough
– Too Little RM
• FDA perception that company “doesn’t get it”
• Physicians unwilling to prescribe (lack of comfort)
– Too Much RM can cause a “backlash”
• Unintended Consequences (failure to prescribe
because of RM obligations)
Part III
Pre-Testing and Evaluation
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
Testing Considerations
• Do we need actual patients?
– May require Clinic Study or screening?
• Can we generalize from non-patients?
• Are experienced patients too knowledgeable?
– Important subpopulations (low literacy, younger)
• What documents need to be tested?
– Key (Core) Communication Vehicles
– Testing in what combination – may need field test
• What do we want to know from the tests?
• Document diagnostics
– Suggestions for improvements
• Meet Benchmarks – 80% to 85% for primary COs
• RM document longer and more complex, need secondary COs
General Procedure
• Recruit (n= 400 to 1,200)
– Use Shopping Malls/Clinical Trials/Patients
– Screen for at-risk population
• Disease characteristics
• Low Literacy (pronunciation tests)
• Design
– One Cell Survey
– Multi-Cell Comparisons
General Procedure (2)
• Procedure
– Screening
– Document Exposure – read as normally would
• Interviewer Leaves Room
• Questionnaire
– Develop Communication Objectives
– Funnel Approach
– Open ends
– Specific Communication Objectives
– Follow-up Questions
– Document usually present (may be taken away for
initial open ends)
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 set these levels a priori?
Risk Management Concept Paper
• Evaluation of RM Tools
– Select well-defined, validated metrics
– Use at least 2 different evaluation methods for
key objectives or goals
– Use qualitative data … when quantitative data
are not available or not applicable
– Consider using evaluation methods for each
RM tool.
Evaluation of Goals & Objectives
• Evaluation must match specific goals/objectives
– Education – measure comprehension, opinions, etc.
• Education encompasses knowledge, persuasion, decision making, etc
• For example: Detect occurrence of MAADO
– Behavior Change – measure by observation & self-report
– Limited Use - drug use data base
– Reduce ADRs – collect ADR experience
• Can we use spontaneous reports?
• Data Collection Methods
– Questionnaires (multiple sampling methods)
– Existing database (administrative, prescribing)
• Evaluate Tools pre and/or post launch
• Evaluate “unintended consequences”
Bi-Directional Evaluation
Measure Behavioral Impacts
Survey
RMP
Database
Measure, knowledge, beliefs,
intentions, reported behavior
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 surrogate indicators
• Limits on explanatory variables
RM Survey Sampling Methodology
• Registry
– Theoretically an audit, in reality – low response rate
– Time Series (surveys)
• Concern about prior surveys biasing response
• Concern about running out of sample
• Consider
– Probability sampling (smaller but scientific sample)
• Response rates are in the basement toilet
– Bell-Weather (Sentinel Cites) or Quota sampling
• smaller, incentivized sample
– Multifunction Registry
• integrate marketing and safety purposes
– Geographical Testing
• Base program for all, add-ons tested for impact