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A L Gould

Publications and source records attributed to A L Gould.

At least 19 recordsLinked to original sources
PubMed2000

A practical approach for evaluating population and individual bioequivalence.

Pharmacokinetic measurements provided by subjects to each of two formulations of a drug have a joint distribution that can be characterized by parameters reflecting scale and correlation as well as location. The bioavailability of the formulations can be expressed in terms of the means of the marginal distributions, their means and variances, or the marginal means and variances and the joint correlation. These expressions correspond, respectively, to 'average', 'population', and 'individual' bioequivalence when the joint distribution of the measurements is bivariate normal. Current proposals for assessing the degree of bioequivalence of two formulations are based on statistics that are composites of variance components and squares of expected mean differences from a mixed linear model. There are technical and practical issues associated with these proposals, particularly that they require more complicated designs than the familiar 2x2 cross-over. This paper describes an alternative approach that can be applied with standard 2x2 cross-over designs, and that provides evaluations of population and individual bioequivalence that should be adequate for all practical clinical purposes. The approach is based on easily computed correlation and regression coefficients whose statistical properties under normality are well known and for which non-parametric and robust alternatives exist when normality cannot be assumed. The approach yields conclusions consistent with those obtained by the current proposals when applied to data sets supplied by the FDA. In the cases where the conclusions do not match, the new approach appears to be more consistent with the data.

Area Under Curve↗
PubMed2000

PhRMA perspective on population and individual bioequivalence.

The Food and Drug Administration (FDA) issued a second-draft guidance in August 1999 on the subject of in vivo bioequivalence, which is based on the concepts of individual and population bioequivalence (IBE and PBE, respectively). The intention of this guidance is to replace the 1992 guidance that requires that in vivo bioequivalence be demonstrated by average bioequivalence (ABE). Although the concepts of population and individual bioequivalence are intuitively reasonable, a detailed review of the literature has not uncovered clinical evidence to justify the additional burden to the innovator and generic companies as well as the consumer that the new guidelines would impose. The criteria for bioequivalence described in the draft guidance employ aggregate statistics that combine information about differences in bioavailability between formulation means and differences in bioavailability variation of formulations between and within subjects. The purely technical aspects of the statistical approach are reasonably sound. However, PhRMA believes that important operational issues remain that need to be resolved before any changes to current practice are implemented. PhRMA believes that the ideals of prescribability and switchability are intuitively reasonable, but it is uncertain of the extent to which the proposed guidance can achieve these goals. It is not clear whether the attainment of such goals is necessary in the evaluation of bioequivalence given the role this plays in drug development, and the lack of clinical evidence argues against a pressing need to change current practice. PhRMA is concerned that the trade-off offered by the aggregate criteria may ultimately represent more harm than good to the public interest. PhRMA recommends more rigorous evaluation of methods based on two-way crossover designs before moving to methods that require more complex designs. One such method is identified herein and contains procedures for estimating prescribability and switchability. The possibility of a phase-in or trial period to collect replicate crossover data to further evaluate IBE and PBE and possibly allow market access based on these criteria as they are being evaluated has been proposed. PhRMA believes this is unprecedented and will offer little additional information beyond that which can be obtained by simulation or has already been collected by the FDA. Simulation studies have the advantage of allowing evaluation of the sensitivity of various procedures to represent the data patterns as created within the simulation. Operating characteristics by which proposed criteria can be adequately judged have not yet been defined. The limitations of ABE for highly variable drugs and narrow therapeutic drugs are well appreciated and may be addressed by means other than a wholesale change in the current criteria.

Humans↗
PubMed1999

Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia.

OBJECTIVES: To assess the utility of prostate-specific antigen (PSA) as a predictor of prostate volume by characterizing the relationship between prostate volume and serum PSA in men with symptomatic benign prostatic hyperplasia (BPH) and no evidence of prostate cancer, stratified by decade of life. METHODS: Placebo-controlled multicenter trials in patients with BPH and a safety study in normal young men provided baseline measurements of serum PSA and prostate volume. The analyses included patients with a baseline prostate volume measured by either transrectal ultrasound (TRUS) or magnetic resonance imaging and baseline serum PSA. A common central laboratory was used for all but one of the individual studies; both laboratories used the Hybritech method. Patients 80 years of age or older were excluded. Patients with a baseline serum PSA greater than 10 ng/mL were excluded to reduce the likelihood of including occult prostate cancer cases. The patients in the BPH trials were screened at baseline by digital rectal examination (DRE) and serum PSA. Those with suspicious findings underwent TRUS-guided biopsy; only patients with negative biopsies are included in these analyses. RESULTS: The analyses included 4627 patients, 4448 from the BPH trials and 179 from the safety study. The men in the BPH trials were older (mean age+SE, 63.7+0.10 years) than the men in the safety study (mean age + SE, 30.8+/-0.43), had larger prostates (mean volume+/-SE, 43.7+/-0.38 mL versus 26.3+/-0.49 mL in the safety study), and had higher serum PSA values (mean+/-SE, 2.6+/-0.03 ng/mL versus 0.7+/-0.39 ng/mL in the safety study). The relationship between prostate volume and serum PSA was evaluated using only the BPH trial data. Prostate volume and serum PSA have an age-dependent log-linear relationship (ie, their logarithms are linearly related, and the parameters of the relationship depend on age). Older men tend to have a steeper rate of increase in prostate volume with increasing serum PSA (P < 0.00 for differences between slopes), and there was a slight tendency for PSA density to increase with age. Receiver operating characteristic (ROC) curves were constructed to evaluate the ability of serum PSA to predict threshold prostate sizes in men with BPH. The ROC curve analyses revealed that PSA had good predictive value for assessing prostate volume, with areas under the curve ranging from 0.76 to 0.78 for various prostate volume cutoff points (30, 40, and 50 mL). Conclusions. Prostate volume is strongly related to serum PSA in men with BPH and no evidence of prostate cancer, and the relationship depends on age. Since treatment outcome or risk of long-term complications depend on baseline prostate volume, serum PSA can estimate the degree of prostate enlargement sufficiently accurately to be useful for therapeutic decision making. To achieve a specificity of 70% while maintaining a sensitivity between 65% and 70%, approximate age-specific criteria for detecting men with prostate glands exceeding 40 mL are PSA > 1.6 ng/mL, >2.0 ng/mL, and >2.3 ng/mL for men with BPH in their 50s, 60s, and 70s, respectively.

Adult↗
PubMed1998

Cholesterol reduction yields clinical benefit: impact of statin trials.

BACKGROUND: We determined the effect of incorporating the results of eight recently published trials of Hmg CoA reductase inhibitors ("statins") on the conclusions from our previously published meta-analysis regarding the clinical benefit of cholesterol lowering. METHODS AND RESULTS: We used the same analytic approach as in our previous investigation, separating the specific effects of cholesterol lowering from the effects attributable to the different types of intervention studied. The reductions in coronary heart disease (CHD) and total mortality risk observed for the statins fell near the predictions from our earlier meta-analysis. Including the statin trial findings into the calculations led to a prediction that for every 10 percentage points of cholesterol lowering, CHD mortality risk would be reduced by 15% (P<.001), and total mortality risk would be reduced by 11% (P<.001), as opposed to the values of 13% and 10%, respectively, reported previously. Cholesterol lowering in general and by the statins in particular does not increase non-CHD mortality risk. CONCLUSIONS: Adding the results from the statin trials confirmed our original conclusion that lowering cholesterol is clinically beneficial. The relationships (slope) between cholesterol lowering and reduction in CHD and total mortality risk became stronger, and the standard error of the estimated slopes decreased by about half. Use of statins does not increase non-CHD mortality risk. The effect of the statins on CHD and total mortality risk can be explained by their lipid-lowering ability and appears to be directly proportional to the degree to which they lower lipids.

Cholesterol↗
PubMed1998

Modifying the design of ongoing trials without unblinding.

Conventional group sequential designs provide an objective basis for reducing the sample size of a trial if the difference between the treatments is much more or much less than anticipated. The flexibility of group sequential designs can be enhanced by allowing the sample size to increase when the variability turns out greater than expected. This can be accomplished by examining the variability before unblinding the data at the first stage of the trial. Depending on the result of this examination, the trial may continue as planned, or the design may change in various ways, for example, by increasing the sample size or by changing the number of stages or the scheduling of the interim analyses. The effect of this adaptive flexibility on the error rates turns out as one would expect from the findings for fixed-sample designs: no material impact on the type I error rate and an effect on the power that depends on the final total sample size.

Clinical Trials as Topic↗
PubMed1997

Discussion of individual bioequivalence by M.-L. Chen.

We review and discuss some technical statistical issues and practical implementation issues associated with the use of individual as opposed to population average bioequivalence to express the relative bioavailabilities of alternative formulations of a drug. A number of promising methods for addressing individual bioequivalence have been described. Individual bioequivalence calculations can be done using standard crossover designs, although more sophisticated assessments that compare test-reference variability to reference-reference variability require more complex designs. However, more experience about the clinical implications of various degrees of individual bioinequivalence as expressed by various metrics should be accumulated before definitive regulations are set forth mandating the use of individual bioequivalence for expressing relative bioavailabilities.

Chemistry, Pharmaceutical↗
PubMed1996

Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials.

OBJECTIVES: Six randomized clinical trials have compared at least 1 year of 5 mg finasteride to placebo in the treatment of clinical benign prostatic hyperplasia (BPH). The findings for the 2601 men in these trials provide an opportunity to investigate the heterogeneity of the effects seen in the individual studies and to identify pretreatment predictors of outcomes as expressed by symptoms or peak urinary flow rates. METHODS: A formal meta-analysis using an Empirical Bayes approach employed data from all finasteride studies which included the Phase III trials in North America and Internationally, the Prospect, Early Intervention, and SCARP trials, and the Veterans Administration Cooperative Study which compared terazosin, finasteride, and the combination of these two drugs. A pooled analysis was also undertaken on the combined dataset. RESULTS: The effect of finasteride treatment on improvements in total symptom severity, frequency score, and peak urinary flow rate was consistent across all six trials and similar among men with similar prostate volumes at baseline. Symptom severity improved by 1.8 points (95% confidence interval [CI], 0.7 to 2.9) in men with prostate volumes less than 20 cc (n = 72), while the improvement was 2.8 points (95% CI, 2.1 to 3.5) for men with volumes greater than 60 cc (n = 272) on the Quasi-IPSS Scale (range 0 to 30). Similarly, improvements in peak urinary flow rate ranged from 0.89 mL/s (95% CI, -0.05 to 1.83) for men with prostate volumes less than 20 cc to 1.84 mL/s (95% CI, 1.37 to 2.30) in men with volumes greater than 60 cc. The difference in the magnitude of improvement between finasteride and placebo becomes significant (that is, no overlap in 95% CI) for men with a baseline prostate volume assessed by either transrectal ultrasonography or magnetic resonance imaging of greater than 40 cc, which encompasses approximately 50% of the entire population. Baseline prostate volume is a key predictor of treatment outcomes: approximately 80% of the variation in the treatment effects noted between studies could be attributed to differences in mean prostate volumes at baseline. Variation in entry criteria results in large differences in baseline symptom severity status, prostate volume, and consequently apparent inconsistencies in the overall outcomes of these trials. CONCLUSIONS: This meta-analysis suggests that finasteride is most effective in men with large prostates. Men with small prostates may not be suitable candidates for finasteride therapy for BPH. The need for a careful reevaluation of the definitions and terminology used when discussing urination problems is apparent.

Enzyme Inhibitors↗
PubMed1995

Re-evaluating design specifications of longitudinal clinical trials without unblinding when the key response is rate of change.

The design of clinical trials often requires knowledge of quantities such as between- and within subject variances about which only imprecise information exists. To provide assurance that the study has the desired power to detect a minimum clinically meaningful difference between treatment groups. Gould, Gould and Shih, and Shih have recommended obtaining relevant information from the trial at an interim stage without unblinding. Wittes and Brittain provided a similar recommendation, but viewed the portion up to the interim stage as an (internal) pilot study and required unblinding. This paper considers the problem of re-evaluating the design specifications in longitudinal clinical trials when the key response is the rate of change (slope). The proposed method aims to re-evaluate the sample size and study duration in a way that maintains the trial's blinding, using an EM algorithm. Simulation results show that the effect on type I error rate in negligible, but the potential gain in power can be substantial. The procedure is simple to use in practice, as it does not unblind patients' treatment identifications, and, since it does not unveil the relative efficacy of treatments, it fulfils the requirement of a valid 'administrative' (interim) analysis.

Algorithms↗
PubMed1995

Cholesterol reduction yields clinical benefit. A new look at old data.

BACKGROUND: There has been a continuing debate about the overall benefit of cholesterol lowering. We performed a novel meta-analysis of all randomized trials of more than 2 years' duration (n = 35 trials) to describe how coronary-heart-disease (CHD), non-CHD, and total mortality are related to cholesterol lowering and to type of intervention. METHODS AND RESULTS: The analytic approach was designed to separate the effects of cholesterol lowering itself from the other effects of the different types of intervention used. For every 10 percentage points of cholesterol lowering, CHD mortality was reduced by 13% (P < .002) and total mortality by 10% (P < .03). Cholesterol lowering had no effect on non-CHD mortality. Certain types of intervention had specific effects independent of cholesterol lowering. Fibrates (clofibrates, 7 trials; gemfibrozil, 2 trials) increased non-CHD mortality by about 30% (P < .01) and total mortality by about 17% (P < .02). Hormones (estrogen, 2 trials; dextrothyroxin, 2 trials) increased CHD mortality in men by about 27% (P < .04), non-CHD mortality by about 55% (P < .03), and total mortality by about 33% (P < .01). No specific effects independent of cholesterol lowering were found due to diet (n = 11) or other interventions (resins, 5; niacin, 3; statins, 2; partial ileal bypass, 1). CONCLUSIONS: The results suggest that cholesterol lowering itself is beneficial but that specific adverse effects of fibrates and hormones increase the risk of CHD (hormones only), non-CHD, and total mortality.

Cholesterol↗
PubMed1995

Group sequential extensions of a standard bioequivalence testing procedure.

Bioequivalence trials compare the relative bioavailability of different formulations of a drug. Regulatory requirements for demonstrating average bioequivalence of two formulations generally include showing that a (say) 90% confidence interval for the ratio of expected pharmacologic end point values of the formulations lies between specified end points, e.g., 0.8-1.25. The likelihood of demonstrating bioequivalence when the formulations truly are equivalent depends on the sample size and on the variability of the pharmacologic end point. Group sequential bioequivalence testing provides a statistically valid way to accommodate misspecification of the variability in designing the trial by allowing for additional observations if a clear decision to accept or reject bioequivalence cannot be reached with the initial set of observations. This paper describes group sequential bioequivalence designs applicable in most practical situations that allow a decision to be reached with fewer observations than fixed-sample designs about 60% of the time at approximately the same average cost. The designs can be used in trials where the formulations are expected to have equal bioavailability and in trials where the formulations are expected to differ slightly. Data analyses are carried out exactly as for fixed-sample designs. Providing the capability of sequential decisions modestly affects the nominal significance levels, e.g., the required confidence level may be 93-94% instead of 90%.

Biological Availability↗
PubMed1993

Sample sizes for event rate equivalence trials using prior information.

Trials for demonstrating the 'equivalence' of active standard and test treatments generally require large sample sizes that depend on the definition of 'equivalence' and the overall event rate when the outcome is incidence of an event such as mortality. The planning of sample sizes for such trials requires specification of a value for the overall event rate. This value often will reflect the outcomes of previous trials of the standard treatment, and is subject to uncertainty that needs some accommodation, to protect against an inadequate sample. Bayes and Empirical Bayes methods can be used to incorporate information from one or more previous trials into the sample size calculation when equivalence means high confidence that the event rate ratio is less than some specified value.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Monitoring of clinical trials and interim analyses from a drug sponsor's point of view.

This paper illustrates aspects of data monitoring of clinical trials in the pharmaceutical industry. Formal interim analyses are performed at least in part to address the question of whether the trial should proceed or whether there should be an early termination of the trial. For formal interim analyses, frequently independent data and safety monitoring committees are utilized for monitoring clinical trials, and adjustments to nominal significance levels for test statistics are required. Various statistical methods developed during the last fifteen years are utilized. Administrative interim analyses are those analyses that are performed without any intention to stop the trial as a consequence of those analyses. For administrative interim analyses, adjustments to significance levels may not be required, but results must still be carefully interpreted. Regardless of the interim analyses performed, it is critical that the plans for interim analyses be identified in the study protocol, and the dissemination of interim results be carefully restricted. The following clinical trials sponsored by Merck Sharp and Dohme Research Laboratories (MSDRL) will illustrate these points: CONSENSUS; CONSENSUS II; 4S; Haemophilus influenza type b efficacy trial; famotidine in upper gastrointestinal haemorrhage, and a phase II analgesic study. It is anticipated that data monitoring and interim analysis activities will increase for future clinical trials due to the availability of appropriate statistical methods and improved data management systems.

Clinical Trials as Topic↗
PubMed1992

Interim analyses for monitoring clinical trials that do not materially affect the type I error rate.

Monitoring clinical trials often requires examining the interim findings to see if the sample size originally specified in the protocol will provide the required power against the null hypothesis when the alternative hypothesis is true, and to increase the sample size if necessary. This paper presents a new method, based on the overall response rate, for carrying out interim power evaluations when the observations have binomial distributions, without unblinding the treatment assignments or materially affecting the type I error rate. Simulation study results confirm the performance of the method.

Bias↗
PubMed1991

Expanded clinical evaluation of lovastatin (EXCEL) study results. II. Assessment of the human lens after 48 weeks of treatment with lovastatin.

The crystalline lenses of hypercholesterolemic patients were assessed before and after 48 weeks of treatment with lovastatin or placebo to determine the effect of lovastatin on the human lens. Patients were given a biomicroscopic (slit-lamp) examination of the lens, and a previously validated, standardized classification system was used to describe the findings. A total of 8,245 patients were randomly assigned in equal numbers to treatment with placebo or lovastatin 20 or 40 mg once or twice daily in this double-blind, parallel-group study. Statistical analyses of the distribution of cortical, nuclear and subcapsular opacities at 48 weeks, adjusted for age and presence of an opacity at baseline, showed no significant differences (p less than 0.01) between the placebo and lovastatin-treated groups. Visual acuity assessments at week 48 were also not found to have significantly different distributions among treatment groups. Moreover, no significant differences were found among the groups in the frequencies of greater than or equal to 2-line worsening in visual acuity with concurrent progression in lenticular opacity, cataract extraction, or any spontaneously reported adverse ophthalmologic experience. No evidence was found for an effect of lovastatin on the human lens after 48 weeks of treatment.

Adolescent↗
PubMed1991

Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia.

In the Expanded Clinical Evaluation of Lovastatin (EXCEL) Study, a multicenter, double-blind, diet- and placebo-controlled trial, we evaluated the efficacy and safety of lovastatin in 8245 patients with moderate hypercholesterolemia. Patients were randomly assigned to receive placebo or lovastatin at a dosage of 20 mg once daily, 40 mg once daily, 20 mg twice daily, or 40 mg twice daily for 48 weeks. Lovastatin produced sustained, dose-related (P less than .001) changes as follows (for dosages of 20 to 80 mg/d): decreased low-density lipoprotein-cholesterol level (24% to 40%), increased high-density lipoprotein-cholesterol level (6.6% to 9.5%), decreased total cholesterol level (17% to 29%), and decreased triglyceride level (10% to 19%). The National Cholesterol Education Program's low-density lipoprotein-cholesterol level goal of less than 4.14 mmol/L (160 mg/dL) was achieved by 80% to 96% of patients, while the less than 3.36 mmol/L (130 mg/dL) goal was achieved by 38% to 83% of patients. The difference between lovastatin and placebo in the incidence of clinical adverse experiences requiring discontinuation was small, ranging from 1.2% at 20 mg twice daily to 1.9% at 80 mg/d. Successive transaminase level elevations greater than three times the upper limit of normal were observed in 0.1% of patients receiving placebo and 20 mg/d of lovastatin, increasing to 0.9% in those receiving 40 mg/d and 1.5% in those receiving 80 mg/d of lovastatin (P less than .001 for trend). Myopathy, defined as muscle symptoms with a creatine kinase elevation greater than 10 times the upper limit of normal, was found in only one patient (0.1%) receiving 40 mg once daily and four patients (0.2%) receiving 80 mg/d of lovastatin. Thus, lovastatin, when added after an adequate trial of a prudent diet, is a highly effective and generally well-tolerated treatment for patients with moderate hypercholesterolemia.

Adult↗
PubMed1991

Another view of active-controlled trials.

Placebo-controlled efficacy trials may become more difficult to carry out with the increasing availability of effective therapies, especially for serious illnesses where denial of effective therapy may be objectionable ethically. Active-controlled trials aimed at establishing efficacy by demonstration of "equivalence" to "standard" therapy have potentially serious interpretational problems, and do not necessarily encourage good experimental practice. This article describes an alternative approach to the analysis of data from active-controlled trials using the information that makes an active-controlled trial necessary or desirable, namely a large, valid body of information about the consequence of using placebo. The approach uses information about placebo responses and also active agent responses from prior placebo-controlled trials to determine the likelihood of a significant active-placebo difference in an active-controlled trial, or in a trial with a vestigial placebo group. The sensitivity of the treatment comparisons depends directly on the quality of the design and execution of the active-controlled trial. The method is illustrated with data from trials of an H2-receptor antagonist in the treatment of acute duodenal ulcer.

Bayes Theorem↗