Phase 4 The period after a drug is approved for marketing

1. Phase 4 Trials (Studies) of Hormonal ContraceptionPotential for Improving Information on Safety and Effectivenessafter Marketing Approval

2. Diana Petitti, MDAdjunct ProfessorDepartment of Preventive MedicineUniversity of Southern CaliforniaKeck School of Medicine Advisory Committee for Reproductive Health Drugs, FDA, January 23/24, 2007

3. 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

4. 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

5. 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)

6. 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

7. 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.

8. 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

9. 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 public’s 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

10. 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

11. Planned Phase 4 Studies

12. Phase 4 Studies DESIGN • Experimental • Case-control • Cohort • Case-control nested within a cohort

13. 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 (???)

14. Phase 4 Studies DESIGN • Case-control • Cohort • Case-control nested within a cohort

15. 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

16. Phase 4 Studies DESIGN • The main disadvantage of the classical case-control design that it is subject to recall bias—the tendency of the diseased to selectively over-report or under-report past exposure

17. 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

18. 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

19. 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 Prospective Cohort with Direct Enrollmentand Active Follow-up(A New “Vessey” Study)

20. Phase 4 Cohort Studies DATA • Computer stored only • Computer and physicians/records • Computer and physicians/records plus direct patient contact

21. 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 Using Computer-Stored Data Only

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

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

24. Phase 4 Studies ORGANIZATION • Single source (e.g., on Health Plan) • Multiple sources

25. Advantages Efficient Time to information potentially short Greater ability to trust study planners assertions Disadvantages Non-representative Can have limitations due to formulary Single Source of Data

26. Phase 4 Studies COMPARATOR • Historical • Active

27. Advantages Cheaper Disadvantages Cannot be relied on the yield the correct answer about anything Comparison for New Contraceptive:Historical Compared with Active

28. 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

29. 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

30. Advantages Cheaper than full cohort contact Ability to focus on maximizing response rates Disadvantages Can’t be used to study effectiveness Case-Control Study with Patient Contact Nested in a Computer-assembled Cohort Derived from Multiple Sources

31. 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 interest—vascular 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

32. 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