The impact of the international guideline entitled Statistical Principles for Clinical Trials (ICH E9).

At the time of writing, the ICH E9 Note for Guidance entitled "Statistical principles for clinical trials" has been in force in Europe, Japan and the U.S.A. for almost a year. The purpose of this paper is to review the initial progress of E9 in terms of its degree of acceptance and also in terms of any early problems which have emerged. A different means of exploring these questions has been adopted in each of the three regions. From Europe there is a regulatory perspective on statistical issues which have been found to be incompletely covered within E9 and which have been important for specific regulatory decisions. From the U.S. there is a report of the results of a survey of U.S. pharmaceutical industry opinion concerning the effect of E9 on statistical practice in drug development. From Japan there is a discussion of the shortage of qualified statisticians in Japan and the difficulties that this causes when trying to implement E9. Some overall conclusions are drawn.

Risk of developing life-threatening ventricular arrhythmia associated with tefenadine in comparison with over-the-counter antihistamines, ibuprofen and clemastine.

An observational, historical cohort evaluation was performed to examine the hypothesis that terfenadine (Seldane) exposure increases the risk of developing life-threatening ventricular arrhythmias. The study population consisted of Medicaid recipients from 4 states that were included in the Computerized On-Line Medical Pharmaceutical Analysis and Surveillance System (COMPASS). The drug exposure period was defined prospectively as 30 days in all treatment cohorts. The primary end point was the development of life-threatening ventricular arrhythmias (ventricular tachycardia, fibrillation and flutter, and cardiac arrest and sudden death). The comparison cohorts included terfenadine (n = 181,672), over-the-counter antihistamines (n = 150,689), ibuprofen (n = 181,672) and clemastine (Tavist; n = 83,156). Over the exposure period, a total of 317 life-threatening ventricular arrhythmic events occurred, 244 of which were cardiac arrests. The incidence of total life-threatening ventricular arrhythmic events and cardiac arrests were more frequent in patients receiving over-the-counter antihistamines (relative risk 0.36) than in those receiving terfenadine, a finding that was consistent across all subgroups. There was no increased risk of life-threatening ventricular arrhythmias in the terfenadine cohort as compared with the ibuprofen cohort (relative risk 0.62), and in some analyses, the ibuprofen cohort had a significantly higher arrhythmic event rate. In all comparisons with the clemastine cohort, the terfenadine cohort had a statistically indistinguishable relative risk (1.08). Age, race, sex and cardiovascular risk were all considered in the adjusted relative-risk analyses. No baseline historical characteristic or imbalance of baseline medications explained the differences between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Demonstration of the reproducibility of treatment efficacy from a single multicenter trial.

According to the Food and Drug Administration's Guidelines for the Format and Content of the Clinical and Statistical Sections of New Drug Applications, approval of a new drug "should be supported by more than one well-controlled trial and carried out by independent investigators. This interpretation is consistent with the general scientific demand for replicability." Nevius has described a four-point proposal for assessing statistical evidence in a single multicenter trial. Briefly, these four points are: (1) combined analysis shows significant results, (2) consistency over centers in terms of direction, (3) consistency over centers in terms of producing nominally significant results in centers with sufficient power, and (4) evidence of efficacy after adjustment for multiple comparisons. What is not clear from Nevius' proposal is how to quantify whether the amount of evidence in a single multicenter trial is equivalent to that from two separate trials. It is proposed that the post hoc subdivision of a multicenter trial may address this issue if the inherent multiple testing problem is accommodated. A minimax statistic is developed to test the hypothesis that the effect of the drug has been reproduced in a single multicenter trial. Monte Carlo simulation is used to generate the distribution of the minimax statistic under the null and several alternative hypotheses. Data from a multicenter trial are used to demonstrate the technique. Bootstrapping is used to determine the null distribution of the minimax statistic.

Risk factors for hepatitis B virus infection among women attending a clinic for sexually transmitted diseases.

Risk factors for and serologic evidence of hepatitis B virus (HBV) infection were analyzed among 557 women. Study subjects were attending a clinic for sexually transmitted diseases and enrolled in a clinical trial of nonoxynol-9 prevention of gonococcal and chlamydial infections. Seventy-eight (14%) showed serologic evidence of past HBV infection. Only age at time of serum collection was significantly associated with HBV marker prevalence (P = 0.04). None of the four measures of sexual activity taken (number of sex partners per month, frequency of sexual intercourse, number of documented episodes of sexually transmitted diseases, and lifetime number of sexual partners) were significantly related to the presence of HBV markers. For each measure, however, differences observed between HBV positive and negative subjects were consistent with what would be expected if these factors did contribute to HBV infection risk. These results support the role of heterosexual transmission of HBV infection in women and are consistent with recommendations for hepatitis B immunization of heterosexually active persons with multiple sexual partners.

A follow-up study of methods of contraception, sexual activity, and rates of trichomoniasis, candidiasis, and bacterial vaginosis.

A randomized, clinical trial was conducted to evaluate the spermicidal agent nonoxynol 9 as prophylaxis for sexually transmitted diseases. Eight hundred eighteen women using birth control who attended a sexually transmitted disease clinic were evaluated monthly for trichomoniasis, candidiasis, and bacterial vaginosis for 6 months. Women using the active spermicide experienced a somewhat lower incidence rate of trichomoniasis (relative rate 0.83; 95% confidence interval 0.61 to 1.12) and bacterial vaginosis (relative rate 0.86; 95% confidence interval 0.69 to 1.12) as compared with placebo users. The rate of candidiasis was nearly identical for spermicide and placebo users (relative rate 1.02; 95% confidence interval 0.77 to 1.35). The number of sexual partners during the preceding month was related directly to the occurrence of trichomoniasis (p = 0.047) and bacterial vaginosis (p = 0.009) but not candidiasis (p = 0.99). Subjects using oral contraceptives experienced a statistically significant lower rate of trichomoniasis than did women using an intrauterine contraceptive device or who had had a tubal ligation (relative rate 0.56; 95% confidence interval 0.39 to 0.81).

Oral contraceptive use and the risk of chlamydial and gonococcal infections.

Oral contraceptive users were compared with nonusers with respect to the rate of cervical infections by Chlamydia trachomatis and Neisseria gonorrhoeae. The comparison was adjusted for differences in demographic and behavioral characteristics between the two groups. The rates of infection among oral contraceptive users were increased by approximately 70% (statistically significant) for both pathogens. Cervical ectopy was implicated in the increased rate of chlamydia but not gonorrhea. Rates of gonorrheal infection differed significantly among oral contraceptive formulations; rates were higher for formulations containing more androgenic progestins.

PIP: The rate of cervical infections by Chlamydia trachomatis and Neisseria gonorrhoeae was compared in 617 oral contraceptive (OC) users and 101 controls who were either IUD users or were sterilized. Study subjects were drawn from an Alabama sexually transmitted diseases clinic; 89% were black and the average age was 23 years. OC use was associated with a 73% increase in chlamydial risk and a 70% increase in the risk of gonococcal infection. The number of sexual partners was positively correlated with the rates of both infections, while age was negatively related. 46% of the OC users compared with 19% of nonusers had cervical ectopy. However, the difference of the effect of ectopy on chlamydia and gonorrhea was not statistically significant between OC users and nonusers. The amount of estrogen in the OC was not associated with ectopy, chlamydia, or gonorrhea. In contrast, gonorrhea rates were higher for women taking OCs that contained norethindrone and norgestrel. Formulations containing the less androgenic progestin, norethindrone acetate, were not associated with increased gonococcal risk. These findings suggest that women using OCs, especially OCs that contain norgestrel, should be screened more aggressively than nonusers of OCs for both gonorrhea and chlamydia.

A clinical trial of nonoxynol-9 for preventing gonococcal and chlamydial infections.

A randomized, double-blind, placebo-controlled trial was conducted to evaluate the spermicidal agent nonoxynol-9 as prophylaxis for cervical infections caused by Chlamydia trachomatis and Neisseria gonorrhoeae. Eight hundred eighteen women were recruited from a sexually transmitted disease clinic. Only subjects who were using reliable birth control methods (oral contraceptives, intrauterine device, or sterilization) were eligible. Subjects were randomly assigned to use either a commercially available spermicidal agent containing nonoxynol-9 or a placebo preparation. Subjects were followed up for six months; specimens were collected monthly for culture of the two pathogens. Women assigned to the nonoxynol-9 group were less likely to become infected with N. gonorrhoeae (relative rate, 0.75; 90% confidence limits, 0.58 and 0.96) and C. trachomatis (relative rate, 0.79; 90% confidence limits, 0.64 and 0.97). Among women who used their assigned gel for the majority of coital episodes, a stronger protective effect was observed.

Detection of diabetic retinopathy by optometrists.

Optometrists examined 25 eyes with varying severity of diabetic retinopathy. No history or clinical information was provided to the optometrists who performed fundus examinations on dilated eyes using direct or indirect ophthalmoscopes. Color stereoscopic fundus photographs were independently graded and used as the standard. Optometrists made a correct diagnosis of whether retinopathy was present in 77% of the eyes (95% confidence interval (CI): 73%, 82%). They made a correct diagnosis of the type and degree of diabetic retinopathy in 57% of the eyes (95% CI: 39%, 75%). This diagnosis rate exceeded the rate reported for physician examiners (39%) and equaled that of general ophthalmologists (52%) in the only other similar study. Sensitivity for diagnosis of diabetic retinopathy in eyes of diabetic patients using only ophthalmoscopy was 74% (95% CI: 67%, 81%), while specificity for diagnosis of the absence of retinopathy was 84% (95% CI: 73%, 96%). 100% of these optometrists would have referred the eye with preproliferative retinopathy. 53% would have referred the eye classified as proliferative retinopathy without high risk characteristics, and 79% would have referred the eye with macular edema.

The exposure odds ratio in nested case-control studies with competing risks.

A nested case-control study, also known as an ambidirectional study, is a case-control study within a cohort study. Although distortion by competing risks is well-recognized in follow-up studies, the problem has not been as widely appreciated in nested case-control studies. This paper extends previous work concerning the bias associated with competing risks for nested case-control studies. Specifically, the distorting effect of competing risks is illustrated for three methods of control selection. Assuming the proportional hazards model, the authors derived formulas for the bias of the odds ratio when competing risks cannot be ignored. Examples illustrate the magnitude of bias that occurs when the exposure of interest is associated with competing causes of death or withdrawal.

Host factors in juvenile periodontitis.

This study was undertaken to determine whether defects in leukocyte function or in genes at the MHC play a role in the etiology of either localized (LJP) or generalized (GJP) juvenile periodontitis. Thirteen LJP and five GJP patients (ranging in age from 13 to 22 years) and their matched controls were compared with respect to selected leukocyte functions and HLA phenotypic frequencies. The results of these studies indicated that there were significant decreases in the phagocytic and chemotactic abilities of polymorphonuclear leukocytes (PMN) in both LJP and GJP. All JP patients displayed intrinsic cell defects in chemotaxis compared with controls; in addition, some patients displayed multiple defects, including those which were serum-associated. Also, there appeared to be a significant association between JP and HLA-DR2 and HLA-A33 phenotypes. Fifty percent of the JP patients were HLA-DR2-positive, whereas only six percent of the matched controls were positive. Thirty-six percent of JP patients were HLA-A33-positive, whereas none of the controls was positive. The association seen with DR2 may be due to sampling, since there were no significant differences between the JP cases and a larger unmatched control sample which was not evaluated for periodontal disease. We conclude from these data that increased susceptibility of some patients to a very aggressive and destructive form of periodontal disease (JP) is based on defects in PMN responsiveness. Further investigations are necessary to determine whether these defects are under genetic control.

In vitro activity of the spermicide nonoxynol-9 against Chlamydia trachomatis.

The in vitro activity of nonoxynol-9 against four serotypes (C, D, H, and K) of Chlamydia trachomatis was investigated. A constant inoculum of each serotype was exposed to serial twofold dilutions (1:100 to 1:800) of Koromex, Conceptrol, or reference preparations (not containing nonoxynol-9) for 4 and 24 h at 37 degrees C. The mixtures of nonoxynal-9 or nonnonoxynol preparations and control inocula were dispensed into triplicate wells containing McCoy cell monolayers. After incubation at 37 degrees C, the monolayers were fixed and stained with iodine and examined for evidence of infection with C. trachomatis. All nonoxynol-9-containing preparations showed marked antichlamydial activity as judged by percent reduction of glycogen-containing intracytoplasmic inclusions. The reference preparations, which did not contain nonoxynol-9, were markedly less active when tested in this in vitro system.

A case-control study of spermicides and gonorrhea.

A case-control study was done to evaluate the effectiveness of vaginal spermicides as a prophylaxis against gonorrhea. The subjects included 735 women with gonorrhea and 958 controls seen in a sexually transmitted disease clinic. The relative risk (RR) of gonorrhea for spermicide users compared with nonusers was 0.67 with 90% confidence limits, 0.44 to 1.0. This RR was 0.47 (90% confidence limits, 0.25 to 0.87) after the exclusion of women using oral contraceptives, an intrauterine device, or with a tubal ligation. The protective effect of spermicides was confined largely to women who had also used diaphragms or whose partners had used condoms. The RR of gonorrhea for spermicide and condom users relative to nonusers of spermicides, condoms, and diaphragms was 0.41 (90% confidence limits, 0.21 to 0.79), while for spermicide and diaphragm users, this RR was 0.45 (90% confidence limits, 0.15 to 1.3). These results suggest that a woman can appreciably decrease her risk of contracting gonorrhea if she uses spermicides in conjunction with either the diaphragm or the condom.

Phenotypes of the fourth complement component (C4) in black Americans from the southeastern United States.

C4 is composed of two tightly linked genes (C4A and C4B) lying within the major histocompatibility complex of chromosome 6 that can be demonstrated by agarose gel electrophoresis. Seven alleles and five alleles at the C4A and C4B loci, respectively, were detected in 169 black individuals from the southeastern United States. Furthermore, the phenotypic frequencies of C4A6, C4A5, C4A4, C4B4, C4B3 and C4BQ0 were significantly different between black and white Americans.