Exploratory analyses of clinical trial data used for health technology assessments: a retrospective evaluation.

OBJECTIVES: To examine the validity and statistical limitations of exploratory analyses of clinical trial data commonly requested by agencies responsible for determining which medical products may be financed or reimbursed by a healthcare system. DESIGN: This was a retrospective review of efficacy and safety analyses conducted for German Health Technology Assessment (HTA) evaluations with a decision date between 2015 and 2020, and an illustrative safety-related exploratory analysis of data from two phase III clinical trials of verubecestat (an anti-amyloid drug whose development was stopped for lack of efficacy) as would be mandated by the German HTA agency. RESULTS: We identified 422 HTA evaluations of 404 randomised controlled clinical trials. For 140 trials (34.7%), the evaluation was based on subpopulations of participants in the originating confirmatory trial (175 subpopulations were assessed). In 57% (100 of 175), the subpopulation sample size was 50% or less of the original study population. Detailed analysis of five evaluations based on subpopulations of the original trial is presented. The safety-related exploratory analysis of verubecestat led to 206 statistical analyses for treatments and 812 treatment-by-subgroup interaction tests. Of 31 safety endpoints with an elevated HR (suggesting association with drug treatment), the HR for 81% of these (25 of 31) was not elevated in both trials. Of the 812 treatment-by-subgroup interactions evaluated, 26 had an elevated HR for a subgroup in one trial, but only 1 was elevated in both trials. CONCLUSIONS: Many HTA evaluations rely on subpopulation analyses and numerous post hoc statistical hypothesis tests. Subpopulation analysis may lead to loss of statistical power and uncontrolled influences of random imbalances. Multiple testing may introduce spurious findings. Decisions about benefits of medical products should therefore not rely on exploratory analyses of clinical trial data but rather on prospective clinical studies and careful synthesis of all available evidence based on prespecified criteria.

Influence of structured counseling on women's selection of hormonal contraception in Israel: results of the CHOICE study.

BACKGROUND: The multinational CHOICE (Contraceptive Health Research Of Informed Choice Experience) study evaluated the effects of structured counseling on women's contraceptive decisions, their reasons for making those decisions, and their perceptions of combined hormonal contraceptive (CHC) methods in eleven countries. The aim of this paper to present data from the 1,802 women participating in Israel's CHOICE program. METHODS: Women (aged 17-40 years) who consulted their health care providers about contraception and who would consider a CHC method qualified to participate. After indicating their intended CHC method, the women received counseling about the daily pill, weekly patch, and monthly vaginal ring. After counseling, the women completed a questionnaire about their contraceptive decisions. RESULTS: Before counseling, 67%, 6%, and 5% of women (mean age 27 years) intended to use the pill, patch, or ring, respectively. Counseling significantly influenced the women's CHC choice, with 56%, 12%, and 23% of women selecting the pill, patch, or ring (P<0.0001 for all contraceptive methods versus before counseling). Logistic regression analysis suggested that age significantly increased the probability of switching from the pill to the ring. CONCLUSION: Although the pill was the most popular choice overall, counseling appeared to influence Israeli women's contraceptive decisions, with significantly more women selecting the patch. More than four times as many women selected the ring after counseling than before counseling.

Factors influencing women's selection of combined hormonal contraceptive methods after counselling in 11 countries: results from a subanalysis of the CHOICE study.

OBJECTIVES: To investigate which characteristics of women and healthcare professionals (HCPs) were associated with changing to another combined hormonal contraceptive (CHC) method after contraceptive counselling. METHODS: CHOICE was a cross-sectional survey in which 18,787 women were counselled about combined hormonal contraceptives, during which their contraceptive methods preferred both prior to and after counselling were recorded. In this subanalysis, characteristics associated with changing the method after counselling were determined using logistic regression models. RESULTS: The probability of intending to change from the pill to another method was associated with being older; university-educated; being in a steady relationship; a prior unintended pregnancy; a younger HCP or one who recommended methods other than the pill. Changing to the patch was associated with a female HCP or a HCP who recommended the patch or an injectable. Changing to the ring was associated with being over 21 years; university-educated; being in a relationship; previous hormonal method use; and counselling by a female HCP, a HCP < 60 years old, or a HCP who recommended the ring or an implant. The country of residence influenced these changes in a complex pattern. CONCLUSIONS: Women's choice of CHC methods after contraceptive counselling are influenced by their age, educational background, relationship status, prior unplanned pregnancies and country of residence, as well as age, gender and preferences of their HCP.

Women's perceptions and reasons for choosing the pill, patch, or ring in the CHOICE study: a cross-sectional survey of contraceptive method selection after counseling.

BACKGROUND: The European CHOICE study was a cross-sectional survey that evaluated women's combined hormonal contraceptive choices before and after contraceptive counseling in Austria, Belgium, Czech Republic and Slovakia, the Netherlands, Poland, Sweden, Switzerland, Israel, Russia, and Ukraine. The changes in method selection before and after counseling were reported previously. In this paper we present the reasons given by the 18,787 participating women for selecting their contraceptive method of choice, as well as their perceptions about the contraceptive pill, patch, and ring after counseling. METHODS: Women with an interest in a combined hormonal contraceptive method (pill, patch, or ring) were counseled using a standardized counseling leaflet. The women completed questionnaires, which included questions on why they had selected a particular method of contraception, and the extent to which they agreed with statements about the attributes of the pill, patch, and ring. The results for each country were compared with the percentages for all countries combined by using a binomial regression model. Multiple logistic regression models were used to investigate the extent to which the probability of choosing a method was related to prespecified aspects (i.e. perceptions) of each contraceptive method. RESULTS: 'Easy to use', 'convenience', and 'regular menstrual bleeding' were important selection criteria. 'Nondaily administration' was one of the main reasons women selected the patch or ring. 'Daily use' and 'will forget to take it' were the primary reasons for not selecting the pill, while the main reasons for not choosing the patch included 'not discrete, visible' and 'can fall off'. In a small number of instances, the ring was rejected because some women don't like to use a 'foreign body'. Women's perceptions influenced their contraceptive decisions: positive perceptions about a method increased the likelihood that a woman would select it. After counseling, many women associated the pill with forgetfulness, and many still did not know about the patch or ring's key attributes. Women's knowledge about a particular method was generally greater if they had chosen it. CONCLUSIONS: To support informed contraceptive decision-making, healthcare professionals should realize that a woman's view of a method's ease of use is more important than perceived efficacy, tolerability, health benefits, or risks.

The CHOICE study: effect of counselling on the selection of combined hormonal contraceptive methods in 11 countries.

OBJECTIVES: To encourage healthcare professionals to counsel women seeking combined hormonal contraceptives (CHCs) about alternative CHCs and to study the influence of counselling on women's selection of CHCs. METHODS: Women (15-40 years old) in 11 countries who consulted HCPs about CHCs were counselled about the pill, transdermal patch, and vaginal ring. Both the HCPs and the women completed questionnaires. RESULTS: Of women who were counselled (n = 18,787), 47% selected another CHC method than originally planned. One in four who intended to use the pill chose another method (16% chose the patch; 65% chose the ring). In total, patch use increased from 5% -8% (difference = 3.7% [97.5% CI: 3.3-4.2]; p < 0.0001). Ring use nearly quadrupled from 8% -30% (difference = 21.7% [97.5% CI: 21.0-22.5]; p < 0.0001). Nearly all women who were undecided prior to counselling selected a method after counselling. Selection of the pill increased most in Russia (+ 11%) and Sweden (+ 5%); patch selection was greatest in Russia (+ 7%) and Israel (+ 6%); ring use increased most in Ukraine and in the Czech Republic and Slovakia (+ 36%). CONCLUSIONS: Counselling increases use of alternative CHCs, such as the patch and the ring. Considerable differences between countries were noted.

Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis.

BACKGROUND & AIMS: In the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, patients with ulcerative colitis treated with infliximab were more likely than those given placebo to have a clinical response, undergo remission, and have mucosal healing. We investigated the association between early improvement (based on endoscopy) and subsequent clinical outcome. METHODS: Patients underwent endoscopic evaluations at weeks 0, 8, 30, and 54 (ACT-1 only), and were categorized into 4 subgroups by week 8 (Mayo endoscopy subscore, 0-3). The association of week 8 endoscopy subscores, subsequent colectomy risk, symptoms and corticosteroid use outcomes were analyzed. Mucosal healing was defined as a Mayo endoscopy subscore of 0 (normal) or 1 (mild). RESULTS: Infliximab-treated patients with lower week 8 endoscopy subscores were less likely to progress to colectomy through 54 weeks of follow-up evaluation (P=.0004). This trend was not observed among patients given placebo (P=.47). Patients with lower endoscopy subscores achieved better symptomatic and corticosteroid use outcomes at weeks 30 and 54 (P<.0001, infliximab; P<.01, placebo). Among patients who achieved clinical response at week 8, trends in subsequent clinical outcomes by week 8 endoscopy subscores were generally consistent with that for the overall patient population; no trends were observed among patients who achieved clinical remission. CONCLUSIONS: The degree of mucosal healing after 8 weeks of infliximab was correlated with improved clinical outcomes including colectomy. Similar trends were observed for all outcomes except colectomy among the subgroup with clinical response at week 8. The degree of mucosal healing at week 8 among those in clinical remission did not predict subsequent disease course.

Comprehensive counseling about combined hormonal contraceptives changes the choice of contraceptive methods: results of the CHOICE program in Sweden.

OBJECTIVE: To study the influence of counseling on women's contraceptive decisions. DESIGN: A cross-sectional multicenter study. SETTING: Seventy Swedish family planning clinics. POPULATION: Women aged 15-40 years attending for a contraceptive consultation who expressed interest in a combined hormonal contraceptive (CHC) method. METHODS: Structured counseling about three CHCs and questionnaires completed after counseling from the healthcare professional. MAIN OUTCOME MEASURES: Method originally requested, perceptions of CHC attributes, method chosen and reasons for the choice. RESULTS: In all, 173 healthcare professionals and 1,944 women participated. The mean standard deviation (SD) age of the women was 22.6(6.1) years. After structured counseling, a majority of women (56.0%; n=1 069; 95% confidence interval (CI) 53.1-58.9) chose the daily pill, 6.2% (n=118; 95% CI 4.9-7.8) chose the weekly patch, and 22.5% (n=430; 95% CI 20.2-25.1) chose the monthly ring. The weekly patch was chosen more often after counseling (6.2 vs 2.4% before counseling; p<0.0001). The greatest change was in the proportion of women who chose the contraceptive ring after counseling (22.5% vs. 8.5% before counseling; p<0.0001). The proportion of undecided women after counseling was reduced considerably (3.9% vs. 27.8% before counseling). Among the 523 women who were undecided before counseling, 50.6% chose the pill, 10.2% the patch and 24.6% the ring, while 20.9% of women who initially requested the pill changed to another method. CONCLUSIONS: Structured counseling facilitated choice of contraceptive method for most women, leading to changes in women's selection of a CHC method.