Developing Risk Management Systems that meet FDA rules ---and don’t hurt your product

1. 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

2. Objectives P 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 • Behavioral Goals and Objectives • Selecting and Justifying Tools • PreTesting Communications • Planning Evaluation

3. 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

4. BackgroundFDA: Need to Develop a RM Plan

6. Recent Withdrawals • Seldane (terfenadine) 2/98 • Posicor  (mibefradil) 6/98 • Duract  (bromphenac) 6/98 • Hismanal  (astemizole) 6/99 • Roxar  (grepafloxacin) 11/99 • Propulsid  (cisapride) 3/23/00 • Rezulin  (troglitazone) 3/21/00 • Lotronex  (alosetron HCl) 8/24/00 • Raplon  (rapcuronium) 3/01 • Baycol  (cerivaxtatin) 8/8/01 92 NME’s from 1998-2000

7. 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]

8. 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."

9. Examples of Drugs with RM Controls • Accutane (isotretinoin) - severe recalcitrant nodular acne • Actiq (fentanyl citrate) - severe cancer pain • Clozaril (clozapine) - severe schizophrenia • Lotronex (alosetron hydrochloride) - severe irritable bowel syndrome in women • Mifiprex (mifepristone or RU-486) - termination of early intrauterine pregnancy • Thalomid (thalidomide) - erythema nodosum leprosum • Tikosyn (dofetilide) - maintenance of normal sinus rhythm • Tracleer (bosentan) - severe pulmonary arterial hypertension • Trovan (trovafloxacin mesylate or alatrofloxacin mesylate injection) - severe, life-threatening infections • Xyrem (sodium oxybate) - narcolepsy Import Alerts- drugs with RM plans

10. Top 20

11. 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

12. Risk Management Guidance • Sponsor proposes a Risk Management Program (RMP) • 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

13. 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

14. Risk Management Unknown Risks Known Risks • Discovering and interpreting safety signals • Phase IV Commitments • Do I need a study/registry? • Designing interventions (tools) • Justifying choice of interventions • Pre-testing Interventions • Implementing interventions • Evaluating interventions • Revising interventions

15. Risk Management Irony Benefits Perceptions Beliefs Safety = Risks Willing-ness to Use Perception of Risk Unintended Consequences

16. Four Pillars ofRisk Management • Risk Assessment • Signal Evaluation • Risk Communication • System Controls

17. Forming Groups:Fair Distribution of Disciplines Reseat if necessaryAppoint Leader/Recorder/Reporter

18. 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

19. 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.

20. Tasks for Groups • 8:45-10:00 • Identify and Define 1. Additional Study • Conduct a phase IV study to help identify and characterize the risk (30 min) • Developing a RM Strategy • Who, What, How, When, Where and Why? (20 min) 3. How to manage Risks? • 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)

21. 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?

22. 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? • Develop the overall RM Strategy: • Who do we need to influence? • What do we want them to do? (Be specific, define for each audience) • When/Where do they need to exhibit this behavior (conditions) • 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”?

23. BackgroundRisk Communications and Behavioral/Distribution Controls

24. Part ICommunications

25. 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

26. 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

27. 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

28. 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

29. 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)

30. 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

31. Part IIImplementing and Evaluating An RM Program

32. RM System Design B/RM Planning & Design Message Development Systems Design Research/ Testing B/RM Implementation Evaluation

33. Distributional Controls How do we slot the risk-control level for any drug? Prior Approvals Closed System Special Packaging Record Keeping Certification Clozaril Controlled Substances Actiq Fosamax Tikosyn Thalomid Accutane

34. Multi-Function Registry MD Intervention Doctor MD or Patient Registers Patient Safety Assessment Periodic Multiplatform Delivered Tests RM Evaluation Patient Compilation & Reporting Patient Education & Feedback Iterative Patient Experience Feedback

35. Part IIIBehavioral Outcomes

36. 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

37. “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)

38. 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

39. The MD Comfort Zone Personal Liability Too much work to use Too Much RM Will benefit and protect patient, Willing to try Comfort Zone Drug may hurt patient Too risky to try Too Little RM

40. Consider Providing Patient Feedback to Their MDs • Additional knowledge MDs gain about: • patient comprehension of product benefits and risks • Benefit/Risk Perceptions • Barriers to Use • Attitudes about Medication • Motivations • Behavioral Intentions • Compliance Measures

41. Patient Compliance Insight #1: Information is Not Learning Example of Cholesterol-Lowering Medication 71% *Scott-Levin data 10/00-3/01 showing 45% of patients continuing on medication each month from prior month. **Internal 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.

42. 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

43. 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

44. 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

45. BackgroundFDA Concept Paper

46. 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

47. 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

48. Part IITool Selection

50. Sample Tactics Matrix Theme: Risk Avoidance Involvement Logo as Reminder