Selecting Risk Management Tools: FDA Considerations and Experience

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Selecting Risk Management Tools FDA
Considerations and Experience

• Anne Trontell, M.D., M.P.H.
• Deputy Director, Office of Drug Safety
• Joint Advisory Committee of
• DSaRM and Dermatologic Ophthalmic Drugs
• February 26, 2004

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Outline

• Definitions
• General considerations
• Concerns with current isotretinoin RMP
• Candidate tools to address concerns
• Related programs
• Advantages, disadvantages of tool options

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Risk Management Program (RMP) Definitions

• Goals
• ideal product use scenario/vision statement
• tailored to product-specific risk concerns
• may not be fully achievable in practical terms
• example No fetal exposures shall occur

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RMP Definitions

• Tools
• processes or systems intended to enhance safe
  product use by reducing risk
• Choice influenced by severity, reversibility and
  frequency of risk

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Considerations in Selecting RMP Tools

• Each tool should add value in attaining goals
• Seek proven effectiveness, acceptability, low
  burden
• Avoid unnecessary limitations on beneficial
  uses, multiple customized tools, unintended
  consequences

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Broad Categories of Tools

• Product labeling for health professionals
• Education and outreach
• educational materials for HCP and/or patients
• Reminder/Prompting systems
• stickers, informed consent, limited supply
• Limited distribution
• selected groups able to prescribe, dispense, use
• often mandatory use of reminder-like systems

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Experience with Tool Categories

• Product labeling, education and outreach
• extensive use effectiveness limited/unknown
• Reminder systems
• infrequent use effectiveness largely untested
• Limited distribution
• rarely used typically small patient populations
  with limited therapeutic options registration
  allows and has demonstrated effectiveness

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Experience Tool Categories

• Reminder/prompting/limited supply
• alosetron, isotretinoin, lindane
• Limited distribution
• bosentan, clozapine, dofetilide, mifepristone,
  thalidomide, xyrem
• lab testing required

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Areas of Concern with Current Isotretinoin RMP

• Refills dispensed (2.4 of Rx)
• Prescriptions filled without stickers (5-9)
• Stickers without pregnancy testing (9)
• Patients pregnant at initiation of therapy (6 of
  reported pregnancies)
• 2 tests not done, timed incorrectly to menses,
  erroneous or misreported tests

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Areas of Concern with Current Isotretinoin RMP

• Pregnancy exposures occurring during therapy (94
  of total)
• Poor/no use of adequate contraception
• Abstinent patients having unanticipated sexual
  activity without contraceptive use
• Use without medical supervision (?)
• Internet, borrowed, leftover pills

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Areas of Concern with Current Isotretinoin RMP

• Extent of pregnancy exposures unknown
• only voluntary reports and patient surveys
• potential duplication of patients across surveys
• Extent, duration of isotretinoin exposure among
  FCBP poorly estimated

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Prescribing/Dispensing with Stickers Tool
Options

• Better education of pharmacists and physicians
  (? good faith)
• Increase number or types of reminders (
  disease management models)
• Limit prescribing, dispensing by HCPs
• by training, certification, and/or registration
• with systems that obligate compliance and/or
  allow monitoring

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Pregnancy Testing Tool Options for HCP

• More and better education
• More or better reminders
• Limit prescribing, dispensing to selected HCPs
• Require documentation check of negative ?-HCG at
  time of dispensing (e.g. Kaiser)

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Contraception Challenges for Intervention

• Complex and private behavior, sensitive to
  discuss
• with adolescents when parents are present
• assumptions, misinformation common among all ages
• Behavior influenced but not necessarily
  controlled by knowledge
• Attitudinal and behavioral components

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Contraception Tool Options

• Improved education and outreach to patients to
  increase knowledge
• Need for 2 methods
• Effective methods
• Ineffective methods

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Contraception Tool Options

• Use reminders/prompts (such as counseling)
• Reinforce knowledge
• Address attitudes about contraceptive use,
  planned/unplanned sexual activity, partner
  cooperation/resistance to use
• One time or periodic to reinforce behaviors
• Methods could include technologies such as
  interactive voice response (IVR), moderated chat
  rooms, etc

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Contraception Tool Options

• Limit product to patients demonstrating
  appropriate knowledge, skills, and behaviors
• Counselor certification of patient commitment,
  skills with chosen contraceptives
• Periodic IVR or counselor screening for high risk
  behaviors
• DOT for OCP or patches, pill counts, other models
  to track adherence

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Contraceptive Failures

• Contraceptive effectiveness in actual practice ltlt
  efficacy
• Options to limit exposure of FCBP to only with
  the most severe cases of acne
• require documentation, prior authorization, 2nd
  opinion, or other check mechanism for use by
  FCBP

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Medically Unsupervised UseTool Options

• Educate patients about risks
• Alter product packaging
• note risks of unsupervised use, Internet
  purchase, sharing
• limit supply dispensed ltlt 30 days to decrease
  sharing
• Constrain Internet sales

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Relevant RMPs for Comparison

• Clozapine
• multiple manufacturers
• interrelated data systems
• evaluation data used to relax requirements
• Thalidomide
• teratogen with extensive and effective system
• experience with FCBP limited (5)

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Clozapine

• Goal No agranulocytosis
• Weekly to biweekly blood testing assures adequate
  WBC and prevents agran
• Pharmacist must see documented WBC to dispense
• Only registered patients, pharmacists, physicians
  can access drug

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Clozapine Processes

• Central, shared non-rechallenge registry of those
  with history of low WBC
• Independent sponsor programs for weekly, biweekly
  testing
• No patient survey, education

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Thalidomide

• Goal No fetal exposures
• Only registered patients, pharmacists, physicians
  can access drug
• Pregnancy testing done according to pregnancy
  risk category (gender, age, fertility)
• Physician reports negative pregnancy status to
  central authorization database

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Thalidomide

• Patients must report via IVR module on risk
  factors for pregnancy exposure high-risk routed
  directly to person for action
• Pharmacist dispenses product only if check of
  central database assures appropriate physician
  and patient responses
• System tracks pregnancy exposures not lost to f/u
  
• Extensive education, including medication guide,
  informed consent, video

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Comparison of Programs Isotretinoin,
Thalidomide, Clozapine

• Warnings in labeling All
• Patient education materials I, T
• Medication guide I, T
• Patient informed consent I, T

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Comparison of Programs Isotretinoin,
Thalidomide, Clozapine

• Lab testing
• Documentation of results required C
• Physician report of results required T
• Physician uses sticker to attest to
  pregnancy test
  done and negative I

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Comparison of Programs Isotretinoin,
Thalidomide, Clozapine

• Patient Registration
• All patients T
• Nonrechallenge only C
• None I
• Physician registration
• Required to prescribe T, C
• Voluntary to get stickers I

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Comparison of Programs Isotretinoin,
Thalidomide, Clozapine

• Pharmacist Registration
• Required to dispense product T, C
• None I

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Comparison of Programs Isotretinoin,
Thalidomide, Clozapine

• Tracking performance
• patient behaviors T (I)
• patient exposures T (C)
• Direct tracking of outcomes T, C
• Voluntary outcomes, AEs I

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Increasing Education and Outreach Tools
Advantages/Disadvantages

• Advantages
• Acceptable to most
• Feasible
• No change in access
• More time to see if performance improves

• Disadvantages
• Effectiveness limited/unknown, particularly for
  changing behaviors such as contraception

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Increasing Reminder/Prompting Systems
Advantages/Disadvantages

• Advantages
• Physician, pharmacist, patient autonomy
• Ongoing education, reminders re risks and safe
  use
• Less intrusive than limited distribution

• Disadvantages
• Limited experience
• Unknown effectiveness
• Time and costs for counseling, disease mgt

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Limited Distribution Advantages/Disadvantages

• Advantages
• Limits access to those adhering to critical risk
  minimization tools
• Mandatory participation ? registration, better
  data for evaluation
• Likely to limit exposure by FCBP

• Disadvantages
• Unknown effectiveness in young, fertile women
• Time and burdens
• Limits access to drug benefits
• May increase illicit access without any safety
  measures

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Considerations in Modifying or Selecting New RMP
Tools

• Seek evidence for effectiveness and high
  likelihood of added value
• Stay close to familiar tools that work and are
  acceptable
• Avoid unnecessary limitations
• Anticipate time, cost, access impacts of
  constraints, including unintended consequences