Phase 4 Trials (Studies) of Hormonal Contraception Potential for Improving Information on Safety and Effectiveness after Marketing Approval

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Phase 4 Trials (Studies) of Hormonal
ContraceptionPotential for Improving
Information on Safety and Effectivenessafter
Marketing Approval
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Diana Petitti, MDAdjunct ProfessorDepartment of
Preventive MedicineUniversity of Southern
CaliforniaKeck School of Medicine Advisory
Committee for Reproductive Health Drugs, FDA,
January 23/24, 2007
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Phase 4 The period after a drug is approved for
marketing

• Hormonal contraceptives are approved for
  marketing based on very small number of women
  from the point of view of assessing safety and
  relative safety
• The populations included in studies done to
  obtain marketing approval are not representative
  of the women who will use the drugs in real life
• Age
• Smoking
• Medical history
• Motivation to contracept
• Education

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Phase 4 The period after a drug is approved for
marketing

• Little is known about the effectiveness of use of
  hormonal contraceptives in real-life settings and
  in populations different from the ones that
  participate in clinical trials
• Since the overwhelmingly most common reason for
  using contraceptives is to prevent pregnancy,
  this deficiency in post-marketing information is
  noteworthy

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Phase 4 Specific issues in study of safety of
hormonal contraceptives

• We know a lot about what to expect from hormonal
  contraceptives based on the vast amount of
  research done over the last 5 decades
• Vascular events are the most important major
  adverse event caused by combined
  estrogen/progestin contraceptives (ischemic
  stroke, venous thromboembolism, myocardial
  infarction)

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Phase 4 Specific issues in study of safety of
hormonal contraceptives (continued)

• Vascular events
• These are rare (xx per 100,000)
• There are interactions (risk in women with
  certain characteristics puts them at particularly
  high risk)
• Hypertension for stroke
• Obesity for venous thromboembolism
• Smoking for myocardial infarction

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Phase 4 Specific issues in study of safety of
hormonal contraceptives (continued)

• Vascular events
• We do not understand the pathophysiology of
  vascular events caused by combined
  estrogen/progestin hormonal contraceptives and
  thus cannot predict whether or in what direction
  a change will affect these events
• The inability to predict extends to changes in
  estrogen dose, estrogen type, progestin dose,
  progestin type, route of administration,
  cumulative dose, maximum dose, etc., etc., etc.

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Phase 4 SurveillanceUnsystematic Activities

• Surveillance assessing spontaneous reports of
  adverse effects to the FDA
• Waiting for the astute clinician
• Waiting for an interested researcher responding
  to report of an adverse effect from the FDA or
  from the astute clinician

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Phase 4 SurveillanceUnsystematic Activities

• Continuation of the unsystematic approach invites
  trouble false alarms based on faulty data
• Waiting for alarms invites panic in response
• Alarms, whether ultimately false or true,
  undermine the publics confidence in the
  regulatory system and in the industry
• Doing nothing in hopes there will be no alarms
  flies in the face of experience with hormonal
  contraception

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Phase 4 Specific issues in study of the
effectiveness of hormonal contraceptives

• Old products are as poorly studied as new ones
• There may be population trends that would affect
  use-effectiveness (obesity) both in old and in
  new products

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Planned Phase 4 Studies
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Phase 4 Studies

• DESIGN
• Experimental
• Case-control
• Cohort
• Case-control nested within a cohort

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Phase 4 RCTs

• IDEAL IN THEORY BUT
• Extremely costly if large enough to address
  vascular event differences
• Difficult to choose appropriate comparator
• No such thing as a simple randomized trial (???)

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Phase 4 Studies

• DESIGN
• Case-control
• Cohort
• Case-control nested within a cohort

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Phase 4 Studies

• DESIGN
• Case-control studies as a stand-alone design are
  used most often to study exposures that occurred
  in the distant past for which exposure
  information cannot be reliably retrieved from
  records or computer-stored information sources

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Phase 4 Studies

• DESIGN
• The main disadvantage of the classical
  case-control design that it is subject to recall
  biasthe tendency of the diseased to selectively
  over-report or under-report past exposure

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Phase 4 Studies Hybrid

• DESIGN
• The increasing availability of computer stored
  information on drug exposures makes it possible
  to combine the best features of cohort and
  case-control designs

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Phase 4 StudiesCohort

• DATA
• Prospective cohort with direct enrollment and
  active follow-up
• Computer stored only
• Computer and physicians/records
• Computer and physicians/records plus direct
  patient contact

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Prospective Cohort with Direct Enrollmentand
Active Follow-up(A New Vessey Study)

• Advantages
• Comprehensive information
• Good data on confounders
• Ability to include diverse populations

• Disadvantages
• Costly
• Time to results is long
• Power for rare events is low

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Phase 4 Cohort Studies

• DATA
• Computer stored only
• Computer and physicians/records
• Computer and physicians/records plus direct
  patient contact

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Using Computer-Stored Data Only

• Advantages
• Cheap
• Potential to yield information quickly

• Disadvantages
• Events cannot be confirmed
• Patients are poorly characterized
• Information on important confounders is poor if
  it exists at all
• Difficult to study effectiveness

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Supplementing Computer Stored Data With
Physicians/Records but Not Patient Contact

• Advantages
• Events can be confirmed or disconfirmed using
  standard criteria
• Information is available on some confounders and
  effect-modifiers lacking in computer data

• Disadvantages
• Lack (or inconsistent availability) of
  information on some important confounders (family
  history past medical history)
• Uncertain accuracy of information on confounders
• Difficult to study effectiveness

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Supplementing Computer Stored Data and
Physicians/Records With Direct Patient Contact

• Advantages
• Potential to characterize patients well
• Good information on confounders and
  effect-modifiers
• Accurate and complete information potentially
  available on effectiveness

• Disadvantages
• Expensive
• Time to information is long
• Subject to response bias

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Phase 4 Studies

• ORGANIZATION
• Single source (e.g., on Health Plan)
• Multiple sources

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Single Source of Data

• Advantages
• Efficient
• Time to information potentially short
• Greater ability to trust study planners
  assertions

• Disadvantages
• Non-representative
• Can have limitations due to formulary

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Phase 4 Studies

• COMPARATOR
• Historical
• Active

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Comparison for New ContraceptiveHistorical
Compared with Active

• Advantages
• Cheaper

• Disadvantages
• Cannot be relied on the yield the correct answer
  about anything

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Recommended Design for Phase 4 Study of New
Contraceptive Safety Hybrid

• Computer-based prospective cohort
• New product compared with old products newly
  initiated
• Data from multiple sources
• Increases diversity of population of users
• Assures mix of hormonal contraceptives
• Confirmation using physician/hospital records
  and experts working based on specified criteria
  blinded to use

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Recommended Design for Phase 4 Study of New
Contraceptive

• Collection of information on confounders by
  direct patient contact using a nested unmatched
  case-control design with oversampling of controls
  by a large fraction
• Nesting decreases cost
• Lack of matching and oversampling make it
  possible to post-stratify

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Case-Control Study with Patient Contact Nested in
a Computer-assembled Cohort Derived from Multiple
Sources

• Advantages
• Cheaper than full cohort contact
• Ability to focus on maximizing response rates

• Disadvantages
• Cant be used to study effectiveness

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Some Final Comments

• It is very difficult to mount a study that will
  definitively show the equivalence of a new
  product compared with something else because the
  events of greatest interestvascular events--are
  rare and the power of feasible study designs is
  low except unless there are large differences
• The ability of any feasible study with a cohort
  design and patient data collection to assess
  whether there are interactions (effect
  modification) between the new product and one or
  another of the factors known to increase the risk
  of vascular disease, such as obesity, smoking,
  family history) is very, very limited
• Because the main reason for using these products
  in pregnancy prevention, more information about
  the comparative effects of the new products with
  old ones is very important

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Some Final Comments

• Collecting information about comparative
  effectiveness would require small numbers
  compared with collecting information about safety
• Collecting information about comparative
  effectiveness could require a cohort design with
  regular direct patient contact since pregnancies
  are not reliably recorded in any computer-stored
  data source (no matter what they tell you)
• High response rates would be essential to valid
  conclusions about comparative effectivenss

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