On the estimation of the binomial probability in multistage clinical trials

Due to the optional sampling effect in a sequential design, the maximum likelihood estimator (MLE) following sequential tests is generally biased. In a typical two-stage design employed in a phase II clinical trial in cancer drug screening, a fixed number of patients are enrolled initially. The trial may be terminated for lack of clinical efficacy of treatment if the observed number of treatment responses after the first stage is too small. Otherwise, an additional fixed number of patients are enrolled to accumulate additional information on efficacy as well as on safety. There have been numerous suggestions for design of such two-stage studies. Here we establish that under the two-stage design the sufficient statistic, i.e. stopping stage and the number of treatment responses, for the parameter of the binomial distribution is also complete. Then, based on the Rao-Blackwell theorem, we derive the uniformly minimum variance unbiased estimator (UMVUE) as the conditional expectation of an unbiased estimator, which in this case is simply the maximum likelihood estimator based only on the first stage data, given the complete sufficient statistic. Our results generalize to a multistage design. We will illustrate features of the UMVUE based on two-stage phase II clinical trial design examples and present results of numerical studies on the properties of the UMVUE in comparison to the usual MLE.     

Introductory study of the once-a-month, injectable contraceptive cyclofem in Brazil, Chile, Colombia, and Peru

An introductory trial with the injectable contraceptive Cyclofem^® was carried out in Brazil, Chile, Columbia, and Peru, with participation by 3,183 women. Women were follewed-up for up to 2 years of use and the data were evaluated by life table analysis. A total of 29.676 women-months were accumulated for up to 2 years. No pregnancies were observed in the 2 years. The discontinuation rates for amenorrhea in the first year ranged from 3.4 in Brazil to 8.1 in Colombia, and for menstrual disturbances from 5.1 in Chile to 9.2 in Brazil. The discontinuation rates for other medical reasons ranged from 7.8 in Brazil to 26.3 in Colombia, and for personal reasons from 17.2 in Chile to 23.5 in Brazil. Continuation rates ranged from 42.3 in Colombia to 52 in Chile. In the second year of observation the rates of discontinuation were lower than those observed in the first year, with the exception of personal reasons in Brazil, which were the same as those observed in the first year. Continuation rates ranged from 19.4 in Brazil to 36.8 in Chile. The comparison of reasons for discontinuation in selected clinics showed that the rate for amenorrhea in one clinic in Chile was more than three times that in others and in Peru was seven times more in one clinic than in another. Regarding menstrual disturbances, in Peru one clinic presented a rate three times higher than the others. The main reasons for discontinuation due to other medical reasons were headache and weight gain. In conclusion, Cyclofem presented a high contraceptive efficacy and an acceptable rate of continuation and discontinuation for up to 2 years in the four countries.     

Psychological distress and post-abortion contraceptive method effectiveness level chosen at an urban clinic

Objective

We investigated whether more psychological distress before an abortion is associated with the effectiveness of contraception selected (low, moderate, or high effectiveness) at an abortion clinic visit.

Method

Using data from 253 women attending an urban abortion clinic that primarily serves low-income women, we tested the association between pre-abortion psychological distress and the effectiveness level of post-abortion contraceptive choice. Based on typical use failure rates, we classified effectiveness of contraceptive choice into three levels—low, moderate, and high effectiveness. We measured psychological distress with four validated measures of depressive, anxious, and stress symptoms, and negative affect, as well as with a global measure comprising these four measures. We used multivariable ordinal logistic regression to measure the association of each psychological distress measure with post-abortion contraceptive method effectiveness level, adjusting for sociodemographic factors, pregnancy history, trimester of abortion, and importance of avoiding pregnancy in the next year.

Results

We found that compared to women experiencing less stress symptoms, negative affect and global psychological distress, women experiencing more stress symptoms [AOR=1.028, 95% CI: 1.001–1.050], negative affect [AOR=1.05, 95% CI: 1.01–1.09] and global psychological distress [AOR=1.46, 95% CI: 1.09–1.95] were more likely to choose more effective versus less effective methods, p<.05, in adjusted models. Using dichotomous psychological measures we found similar results.

Conclusions

Women experiencing more psychological distress before an abortion selected more effective contraceptive methods after their abortion. Future research should examine whether this distress is associated with subsequent contraceptive use or continuation.

Implications

The current study suggests that contraceptive providers should not assume that women experiencing more psychological distress prefer to use less effective contraceptive methods.     

Abortions in relation to age,coital frequency,and fecundity

Abortion rates show variations by age in the United States. This article addresses the question of age variations in abortions. Since the probability of pregancy is increased in direct proportion to increased coital frequency, age and coitus-specific abortion rates are calculated. Since the probability of pregnancy is related to fecundity, age and fecundity abortion rates are also calculated. When combining coital frequency and fecundity with the agespecific abortion rates, the variation by age disappears for all women except teen-agers.     

基于倾向性评分匹配方法的孕前使用避孕药和妊娠天数的相关性分析

目的 探讨孕前使用避孕药对妊娠天数的影响。 方法 采用倾向性匹配评分方法,以基础资料为匹配条件,将使用避孕药者设为观察组,按照1∶4匹配未使用者为对照组。随访获取妊娠天数资料,进而探讨孕前使用避孕药和妊娠天数的关系。 结果 共匹配避孕药组241例,对照组964例,匹配以后各项资料均未见显著性差异(P＞0.05)。Cox回归分析发现,在调整基础资料后,使用避孕药可使妊娠天数缩短,危害比(hazard ratio,HR)为0.85(95%CI:0.74~0.98)。亚组分析发现,年龄≥31岁、体质指数≥24、无妊娠史三个亚组,孕前服用避孕药使妊娠天数缩短,HR(95%CI)分别为0.76(0.59,0.97)、0.67 (0.46,0.98)、0.78(0.63,0.96)。 结论 孕前服用避孕药可能缩短妊娠天数,特别是高龄、肥胖、初次妊娠女性,更应注意避孕药的使用。     

Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive

This open-label, randomized study compared the pharmacokinetics of ethinylestradiol (EE) from the contraceptive vaginal ring NuvaRing (15 microg EE/day), the transdermal patch (20 microg EE/day) and a combined oral contraceptive (COC) containing 30 microg EE. After 2-8 weeks of synchronization by COC treatment, subjects were randomized to 21 days of treatment with NuvaRing, patch or COC. Analysis of area under the EE concentration-versus-time curve (AUC) during 21 days of treatment showed that exposure to EE in the NuvaRing group was 3.4 times lower than in the patch group (p < .05) and 2.1 times lower than in the pill group (p < .05). Serum EE levels of subjects showed much lower variation with NuvaRing than with the patch or the COC. Thus, exposure to EE was significantly lower with NuvaRing than with the patch and pill methods, demonstrating that NuvaRing is a low-estrogen-dose contraceptive method that also results in low estrogen exposure.     

Lea''s Shield®: A study of the safety and efficacy of a new vaginal barrier contraceptive used with and without spermicide

The purpose of this study was to evaluate the safety, efficacy and acceptability of Lea's Shield^®, a new vaginal contraceptive barrier device, when used with either spermicidal or non-spermicidal lubricant.

One-hundred-eighty-five (185) women enrolled at six centers. Half were randomized to use the device with spermicide and half with a non-spermicidal lubricant. To be eligible, volunteers had to be 18–40 years old (inclusive), in good health with regular menses, sexually active in an ongoing relationship and at risk for pregnancy, and willing to use Lea's Shield^® as their sole means of contraception for six months. Participants were seen at admission, one week, one month, three months and six months. Gross cumulative life table rates were calculated for pregnancy and others reasons for discontinuation. Adverse experiences and responses to an acceptability questionnaire were evaluated.

One-hundred-eighty-two (182) volunteers contributed data to the analysis of safety and 146 to that of contraceptive efficacy. The unadjusted six-month life table pregnancy rate was 8.7 per 100 women for spermicide users and 12.9 for non-spermicide users (p = 0.287). After controlling for age, center, and frequent prior use of barrier methods, the adjusted six-month life table pregnancy rate was 5.6 for spermicide users and 9.3 for non-spermicide users (p = 0.086), indicating that use of spermicide lowered pregnancy rates, although not significantly, during typical use.

For purposes of comparison, it is important to note that this study differed from the cap/diaphragm and sponge/diaphragm studies in that a high percentage (84%) of volunteers were parous. For reasons that are unclear, pregnancy rates among parous women using barrier contraceptives tend to be higher than among nulliparous women. Indeed, in this study there were no pregnancies among nulliparous users of Lea's Shield^®. Standardization of parity of this study population on those of the cap/diaphragm and sponge/diaphragm studies suggests that unadjusted pregnancy rates for this device would have been considerably lower (2.2 and 2.9 per 100 users of spermicide and nonspermicide, respectively) had the study been done using the populations of earlier studies. Since no directly comparative study has been done, these figures provide a tentative estimate of the relative efficacy of Lea's Shield^® compared with the sponge, cap, and diaphragm.

There were no serious adverse experiences attributed to the use of Lea's Shield^®. Acceptability was very good. Seventy-five percent (75%) of women responded to an end-of-study questionnaire; 87% of these reported that they would recommend Lea's Shield^® to a friend.

Lea's Shield^® is a new vaginal contraceptive that does not require clinician fitting. Pregnancy rates in this study compare favorably with other studies of barrier contraceptive methods including the cervical cap, diaphragm, and sponge, even though this study was done with greater rigor and with a greater percentage of parous women than previous barrier studies. Lea's Shield^® appears to be safe and very acceptable to study volunteers.     

Inverse probability weighted estimating equations for randomized trials in transfusion medicine

Thrombocytopenia is a condition characterized by extremely low platelet counts, which puts patients at elevated risk of morbidity and mortality because of bleeding. Trials in transfusion medicine are routinely designed to assess the effect of experimental platelet products on patients’ platelet counts. In such trials, patients may receive multiple platelet transfusions over a predefined period of treatment, and a response is available from each such administration. The resulting data comprised multiple responses per patient, and although it is natural to want to use this data in testing for treatment effects, naive analyses of the multiple responses can yield biased estimates of the probability of response and associated treatment effects. These biases arise because only subsets of the patients randomized contribute response data on the second and subsequent administrations of therapy and the balance between treatment groups with respect to potential confounding factors is lost. We discuss the design and analysis issues involved in this setting and make recommendations for the design of future platelet transfusion trials. Copyright © 2013 John Wiley & Sons, Ltd.     

Once-a-month contraceptive pills in China: a review of available evidence

OBJECTIVE: A review of evidence was conducted to assess the safety, effectiveness and continuation of once-a-month contraceptive pills. METHODS: Papers were identified by electronic searches in Chinese and international databases and manual searches of Chinese journals and index of family planning literature. Data on pharmacokinetics, clinical performance and laboratory examinations were extracted from 17 papers of mixed quality on pills containing quinestrol 3 mg and norgestrel 12 mg (Quin-Ng) or levonorgestrel 6 mg (Quin-Lng) used by women in China. RESULTS: Quin-Lng pills gave steady-state serum levels of ethinylestradiol between 0.20-0.25 and 0.15 ng/mL. The 1-year perfect use pregnancy rate was 1.1 per 100 women-years. Nausea and increased leukorrhea were common; bleeding control was good. Hypertension developed in 5.8% of Quin-Ng pill users during the first year of use. For Quin-Ng and Quin-Lng once-a-month pills, 1 year continuation rates were 73.6 and 82.1 per 100, respectively. CONCLUSIONS: Lack of good quality data prevents confident assessment of the safety and efficacy of once-a-month pills. Short-term safety information indicates a high incidence of bothersome side effects and hypertension. The high monthly estrogen and progestogen doses raise questions about the safety of the once-a-month pills.     

关爱服务对女性流产后避孕方法选择的影响

目的 研究流产后关爱服务(PAC)对患者流产后避孕方法选择的影响.方法 采用方便抽样法抽取2015年4月至2016年2月于西安交通大学第一附属医院接受人工流产的患者154例,对进行人工流产的患者按来院顺序编号并按奇偶数分为干预组和对照组各77例.在流产前,对干预组患者提供流产后关爱服务,为对照组患者实施常规健康教育;两组患者接受人工流产后,通过返院咨询和电话咨询等形式,对其避孕方法和是否再次意外妊娠情况于流产后1、3、6、9个月共进行4次随访.结果 干预前,两组患者采用的避孕方法主要是不安全避孕法(干预组占71.4%,对照组占61.0%)及常规避孕法(干预组占27.3%,对照组占39.0%),差异均无统计学意义(均P>0.05).干预后1、3、6、9个月时,干预组患者的常规避孕率由干预前的27.3%迅速降低到2.6%,并在之后的随访中逐渐提高;而对照组患者的常规避孕率由干预前的39.0%增加到81.8%,并维持较高水平.干预组患者的高效避孕率由干预前的1.3%显著增长到97.4%,并保持较高水平;对照组患者的高效避孕率缓慢增长到5.2%.干预组患者的不安全避孕率由干预前的71.4%显著降低到1.3%,并保持较低水平,而对照组患者的不安全避孕率由干预前的61.0%缓慢降低到15.6%.两组患者的3种避孕方法在1、3、6、9个月随访时差异均有统计学意义(χ2=12.48~138.45,均P<0.05).结论 流产后关爱服务能提高患者的高效避孕率.经过流产后关爱服务咨询,在后续的随访中,需要巩固女性的科学避孕知识和强化其意识,维持避孕效果.     

Randomized trial of the effect of tailored versus standard use of the combined oral contraceptive pill on continuation rates at 1 year

Background

There is growing interest from women and clinicians in extended or tailored use of the combined oral contraceptive (COC) pill. Potential advantages include less bleeding, greater contraceptive efficacy and user satisfaction. We examined the effect of a tailored pill regimen, compared with the standard regimen, on continuation and satisfaction rates at 1 year and associated bleeding patterns.

Study Design

This was a randomized controlled trial with 503 women aged 18–45 years. Women were randomized to either the standard regimen (21 daily pills followed by a 7-day pill-free interval) or tailored regimen (daily pills until three consecutive days bleeding triggers a 3-day pill-free interval) of Microgynon 30® (ethinyl oestradiol 30 mcg, levonorgestrel 150 mcg). Primary outcome was COC continuation at 12 months; secondary outcomes included satisfaction with pill regimen regarding contraception and bleeding pattern. Daily electronic diaries were used to record women's pill use, switching to other contraceptive methods, menstrual bleeding patterns and satisfaction levels.

Results

Eighty-three percent of women were already taking the COC at recruitment, 13% were restarting the COC and 4% were first time COC users. Seventy-one percent of all women were followed up at 12 months. Continuation rates at 1 year were 82% in the tailored arm versus 80% in the standard arm [odds ratio (OR)=1.13; 95% confidence interval (CI)=0.67–1.91]. Satisfaction with contraceptive regimen was 86% (tailored) versus 94% (standard) (OR=0.37; 95% CI=0.17–0.79), and satisfaction with bleeding pattern was 79% versus 87%, respectively (OR=0.53; 95% CI=0.30–0.93). Median number of bleeding days per month was 2.4 (tailored) and 4.9 (standard). Incidence, duration and intensity of bleeding episodes were significantly lower in the tailored arm.

Conclusions

In women familiar with standard use of the COC, switching to tailored COC use or continuing with standard use were both associated with high COC continuation rates and high satisfaction with contraceptive regimen and bleeding pattern. While significant differences tended to favor the standard group, tailored COC use was associated with significantly less bleeding, suited some women very well and can provide a suitable alternative to standard use.     

Stopping rules and estimation problems in clinical trials

Stopping rules in clinical trials can lead to bias in point estimation of the magnitude of treatment difference. A simulation exercise, based on estimation of the risk ratio in a typical post-myocardial infarction trial, examines the nature of this exaggeration of treatment effect under various group sequential plans and also under continuous naive monitoring for statistical significance. For a fixed treatment effect the median bias in group sequential design is small, but it is greatest for effects that the trial has reasonable power to detect. Bias is evidently greater in trials that stop early and is dramatic under naive monitoring for significance. Group sequential plans lead to a multimodal sampling distribution of treatment effect, which poses problems for incorporating their estimates into meta-analyses. By simulating a population of trials with treatment effects modelled by an underlying distribution of true risk ratios, a Bayesian method is proposed for assessing the plausible range of true treatment effect for any trial based on interim results. This approach is particularly useful for producing shrinkage of the unexpectedly large and imprecise observed treatment effects that arise in clinical trials that stop early. Its implications for trial design are discussed.     

Power in college students' contraceptive decisions

Excluding Hollerbach (1980), previous fertility researchers have paid little attention to contraceptive power bases, relationships that become the source of changes in birth control values and behavior. Eight contraceptive power bases, each evaluated as a direct or obvious strategy, were identified in a pilot study involving 25 college students as participants and 10 undergraduate raters. Two-hundred college students completed a questionnaire which included the Bem Sex Role Inventory, inquired into their sexual and contraceptive behavior, and asked about contraceptive power bases. There were highly significant main effects for both students' personal experiences with contraceptive power bases and for their opinions about the comfort and effectiveness of same. Coercion was the most popular and legitimate power was the least popular power base. Women were more likely than men to be the targets of contraceptive power bases, the majority of which were stereotyped as feminine by women in particular. Sex role identification was unrelated to students' experiences with contraceptive power bases. The implications of these findings for family-planning researchers and practioners are addressed.Data presented in this article were collected in 1983 by Patricia Soja-Perrin for a master's thesis executed under the authors' strict direction and intensive supervision.     

Monthly injectable contraceptive use by adolescents in Brazil: evaluation of clinical aspects

PURPOSE: This prospective noncomparative observational study evaluated the clinical symptoms, body weight and blood pressure of 38 adolescents receiving a monthly injectable contraceptive containing estradiol valerate 5 mg and norethisterone 50 mg. METHODS: The volunteers, aged 16-19 years, were examined monthly during 1 year and asked about the following symptoms at baseline: dysmenorrhea, headache, breast tenderness, leg pain and irritability. RESULTS: There was a constant and gradual decline in each of the above symptoms over time, and there was a statistically significant difference between symptoms reported at the first visit and subsequent appointments. Body weight and blood pressure did not change significantly during the 1-year period. No pregnancies were observed. CONCLUSION: These findings suggest that monthly injectable contraception with estradiol valerate 5 mg/norethisterone 50 mg represents a highly effective and well-tolerated contraceptive for teens.     

Impact of common contraceptive methods on quality of life and sexual function in Hong Kong Chinese women

The combined oral contraceptive (COC) pills, injectables, intrauterine contraceptive device (IUCD) and female sterilization are the most common contraceptive methods used by women. Women's choice, compliance and satisfaction with specific contraceptive methods are influenced by any impact of the method on their quality of life and sexual function. Anxiety regarding possible adverse effects of the contraceptive methods on their quality of life and sexual function is one of the common concerns. The aim of this prospective observational study was to determine the impact of the abovementioned contraceptive methods on the quality of life and sexual function of the users. A sample of 361 Hong Kong Chinese women who were first-time users of the following contraceptive methods completed the study: COC pills (n=87), injectables (n=67), IUCD (n=96) and female sterilization (n=111). Quality of life and sexual function of the subjects were assessed before and 3–4 months after use of the method by a standardized questionnaire. The questions were adopted from the validated Chinese versions of the World Health Organization Quality of Life (WHOQOL) questionnaire and the Derogatis Sexual Functioning Inventory (DSFI). In the female sterilization group, we found a significantly higher score for sexual satisfaction (p=.004) and sexual drive (p=.003) 3–4 months after sterilization, as well as an improved WHOQOL social domain score (p=.009). However, the other DSFI subscale scores and WHOQOL domain scores were not significantly different (p>.05). No significant difference was demonstrated in all the WHOQOL domain scores and DSFI subscale scores after use of COC pills, injectables and IUCD (p>.05). We conclude that the COC pills, injectables, IUCD and female sterilization all do not have significant adverse impact on quality of life and sexual function. After female sterilization, there is a significant improvement in sexual satisfaction and sexual drive.     

Reproducibility probability in clinical trials

For marketing approval of a new drug product, the United States Food and Drug Administration (FDA) requires that substantial evidence of the effectiveness of the drug product be provided through the conduct of at least two adequate and well-controlled clinical trials. The purpose of conducting the second clinical trial is to study whether the clinical result from the first trial is reproducible in the second trial with the same study protocol. Under certain circumstance, the FDA Modernization Act of 1997 includes a provision to allow data from one adequate and well-controlled clinical trial investigation and confirmatory evidence to establish effectiveness for risk/benefit assessment of drug and biological candidates for approval. In this paper, we introduce the concept of reproducibility probability for a given clinical trial, which is useful in providing important information for regulatory agencies in deciding whether a single clinical trial is sufficient and for pharmaceutical companies in adjusting the sample size in a future clinical trial. Three approaches, the estimated power approach, the method of confidence bounds and the Bayesian approach, are studied in evaluating reproducibility probabilities under several study designs commonly used in clinical trials.     

绝经后宫内节育器取出74例临床观察

目的探讨绝经后妇女宫内节育器(intrauterine contraceptive device,IUD)取出困难的原因及应对措施。方法回顾分析荥阳市人民医院74例绝经后妇女行IUD取器术情况。结果 28例顺利取出,45例取器困难,1例金属环残端严重嵌入宫颈壁。结论绝经后妇女IUD的取出首选常规取器术。对患者术前进行综合评价及宫颈软化处理是成功施术的关键。