Standardization of Data Collection and Analysis of Bleeding in Combined Hormone Contraceptive Trials

1. Standardization of Data Collection and Analysis of Bleeding in Combined Hormone Contraceptive Trials James Trussell, PhD Office of Population Research Princeton University

2. Sources Mishell DR, Guillebaud J, Westhoff C, Nelson A, Kaunitz AM, Trussell J, Davis A. Recommendations for standardization of data collection and analysis of bleeding in combined hormone contraceptive trials, and Combined hormonal contraceptive trials: variable data collection and bleeding assessment methodologies influence study outcomes and physician perception. Contraception 2007;75: in press.

3. Background • Decreases in doses of estrogen and progestin • Increased incidence of unscheduled bleeding and spotting • Diverse approaches have been used to assess cycle control in 12 clinical studies • Standardization of methods for collecting and analyzing such data long overdue

4. Diverse Approaches • All studies required subjects to keep a daily diary of bleeding and spotting • In most cases, diary content not described and sample pages not provided • Little information regarding data collection or patient instruction for completing the diaries • Mostly paper diaries collected every three months • No information about validation of methods

5. Diverse Approaches • Interactive Voice Response utilized to confirm contraceptive method adherence in one study (NuvaRing) • Active inquiry regarding incidence of bleeding/spotting and daily electronic data capture with time and date stamping of all entries utilized in one study (Seasonale)

6. Diverse Approaches • Most studies utilized the WHO Belsey criteria: • Vaginal blood loss requiring sanitary protection classified as bleeding • Vaginal blood loss not requiring sanitary protection classified as spotting • Notable exception: several studies classify bleeding as requiring more than one pad or tampon • One study asked women to classify bleeding as light, normal or heavy

7. Diverse Approaches • Current common use of mini-pads and pantyliners further clouds the interpretation of bleeding and spotting data (not an issue in earlier research) • None of the studies addressed the impact of these products when collecting data in bleeding diaries

8. Diverse Approaches • Criteria for inclusion of a cycle for the analysis of bleeding/spotting rarely described and vary significantly among products • If contraceptive method was not used for 3 or more consecutive days, trials of one OC and a contraceptive vaginal ring excluded those cycles from bleeding/spotting analysis • Most studies did not specify the number of cycles excluded from bleeding analysis or delineate the reasons for exclusion

9. Diverse Approaches • Inconsistent criteria used to calculate rates of unscheduled bleeding or spotting • Bleeding/spotting that occurred during the last week of active hormone administration within a cycle not always counted as unscheduled but instead as “early withdrawal bleeding” • Bleeding that was reported during Days 1-4 of active hormone administration not consistently considered unscheduled but instead as scheduled

10. Diverse Approaches • Possible for only bleeding reported on Days 5 to 17 of the 21-day active pill cycle to be defined as unscheduled • Bleeding that occurred in the other 8 days of the cycle may be excluded from calculations; allows significant underreporting

11. Diverse Approaches • Cycle control or bleeding profile of hormonal contraceptives usually presented as an incidence, but “incidence” varied • proportion within a population • incidence within a specified time frame ranging from a single cycle to a year • percentage of patients achieving an “intended bleeding pattern”

12. Diverse Approaches • Amenorrhea variably defined as • absence of withdrawal bleeding • two consecutive cycles without bleeding or spotting • no bleeding or spotting throughout a 90 day reference period

13. Consequence of Diverse Approaches • Based on the same raw data, the percent of cycles in which unscheduled bleeding/spotting occurred in patients who had taken the product ranged • 19.1% to 28.9% in the first cycle • 13.3% to 18.8% in later cycles when evaluated utilizing varying definitions employed in prior regulatory reviews of other combined oral contraceptive products

14. Problem with Belsey Criteria • Not particularly useful for the reporting of cyclic bleeding in women using CHCs without appropriate modification • Recommend use of a predefined reference period (most commonly 90 days) • Do not differentiate bleeding occurring during active hormone therapy from that occurring during the placebo interval; therefore cannot identify unscheduled bleeding

15. Interpretation • Regardless of formulation, method of delivery, or cycle length, unscheduled bleeding and spotting episodes more frequent • in women who do not use the contraceptive method consistently • in first-time users compared with long-term users • during initial cycles of use

16. Interpretation • Beyond these findings, data from existing studies not adequately consistent to permit meaningful comparisons of unscheduled bleeding or spotting to provide clinicians useful information to guide their practices

17. Recommendations: Study Design • Minimum duration of 6 months for studies of cyclic hormonal contraceptives and a longer duration for studies of extended regimens • Duration of the reference period for cycle control should correspond to the longest cycle evaluated in the study • In a controlled comparison of 28-day regimens, reference period should be 28 days • In studies that include an extended regimen, reference period should be as long as the complete cycle (e.g. 49 days, 91 days, 364 days, etc…)

18. Recommendations: Inclusion Criteria • Include all women eligible for CHC (up to age 45) without restriction to body weight • Screen subjects at risk for untreated Chlamydia infection; chlamidial cervicitis often causes abnormal bleeding and spotting

19. Recommendations: Terminology • Bleeding: evidence of blood loss that requires use of a tampon, pad or pantyliner • Spotting: evidence of blood loss not requiring new use of sanitary protection (including pantyliners) • Episode of bleeding/spotting: bleeding/spotting days bounded on either end by 2 days of no bleeding or spotting

20. Recommendations: Terminology • Abandon use of “period” or “menses” with regard to CHC use • Replace with “scheduled” or “withdrawal” bleeding • Any bleeding or spotting that occurs during the hormone-free intervals, regardless of the duration of the regimen. May continue into Days 1-4 of the subsequent CHC cycle • Term “scheduled bleeding” emphasizes that withdrawal bleeding is not the same as menstruation

21. Recommendations: Terminology • Abandon use of “breakthrough” bleeding or spotting • Replace with “unscheduled” bleeding or spotting • Any bleeding or spotting that occurs while taking active hormones • Two exceptions: • Bleeding/spotting that begins during a hormone-free interval and continues to Days 1-4 of the next active cycle not considered “unscheduled” • Bleeding/spotting reported during Days 1-7 of the first cycle of any study medication not considered “unscheduled”

22. Recommendations: Terminology • Abandon use of “amenorrhea” • Replace with “absence of all bleeding and spotting”

23. Recommendations: Data Collection • Ask subjects to document use of combined hormonal contraceptives and incidents of bleeding and spotting in a consistent manner every 24 hours • Encourage recording data at the same time within each 24-hour time period

24. Recommendations: Data Collection • Daily real-time electronic collection is preferred • Daily phone call (interactive phone response) • Electronic diaries • Text messaging • Other validated systems • Prospective comparative studies needed to assess accuracy of electronic data collection versus traditional paper diaries

25. Recommendations: Data Analysis • Present observed bleeding patterns within a reference period as: • Total days • Unscheduled days (active hormone) • Scheduled days (hormone free) For bleeding and/or spotting, bleeding only and spotting only • Present incidence (percentage of subjects) of absence of bleeding or spotting

26. Recommendations: Data Analysis • Structure trials to allow analysis of cycle control stratified according to: • Body mass index (BMI) • Weight • Age • Parity • Smoking • Hormonal contraceptive use history • Untreated Chlamydia infection

27. Recommendations: Data Analysis • To evaluate of bleeding patterns over time, analyze data from: • Subjects who complete the trial • Intent-to-treat population • Subpopulation of subjects who discontinue prematurely due to unacceptable bleeding

28. Recommendations: Data Reporting • Analyze the incidence of unscheduled bleeding/spotting on a daily basis • Present in graphical form