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Biomedical subjects

A Lawrence Gould

Publications and source records attributed to A Lawrence Gould.

13 recordsLinked to original sources
PubMed2006

How practical are adaptive designs likely to be for confirmatory trials?

This is a discussion of the following papers appearing in this special issue on adaptive designs: 'Confirmatory Seamless Phase II/III Clinical trials with Hypotheses Selection at Interim: General Concepts' by Frank Bretz, Heinz Schmidli, Franz König, Amy Racine and Willi Maurer; and 'Confirmatory Seamless Phase II/III Clinical Trials with Hypotheses Selection at Interim: Applications and Practical Considerations' by Heinz Schmidli, Frank Bretz, Amy Racine and Willi Maurer.

Biometry↗
PubMed2005

Timing of futility analyses for 'proof of concept' trials.

'Proof of concept' (PoC) trials often are carried out to determine if a treatment is biologically active or inactive. If the predictive probability of rejecting a null hypothesis of no treatment effect on completion of the trial calculated using information accumulated before trial completion is sufficiently low, then the trial could be terminated and resources redirected more productively. If the predictive probability is high, some time might be gained by proceeding with further steps in drug development without affecting the course of the PoC trial in any way. We describe how the interim evaluation timing affects the ability to reach a decision to stop or continue as a function of various assumptions about the true parameters and about the interim outcomes. An important practical finding is that there is no point to carrying out an evaluation before accumulating about 40 per cent of the planned observations. Consequently, if trial costs are mostly at startup or for recruitment of subjects for extended periods of observation, it is unlikely that much benefit will be realized by considering the possibility of early termination for futility except possibly for administrative efficiencies with respect to resource and staff allocation.

Bayes Theorem↗
PubMed2005

Treatment comparisons for a partially categorical outcome applied to a biomarker with assay limit.

The plasma level of HIV-RNA has been shown to be a strong prognostic biomarker for clinical progression and death in HIV infected patients and is widely used as the primary outcome in clinical trials to evaluate antiretroviral treatments. Currently approved assays to measure HIV-RNA levels have a lower limit of reliable quantification (LoQ). Current regulatory guidelines recommend using the proportion of patients achieving HIV-RNA levels below the assay limit at a certain time point (e.g. 24 or 48 weeks) as the primary endpoint for regulatory approval. However, a substantial decrease in HIV-RNA that does not go below the LoQ still is considered clinically beneficial for patients with advanced diseases who have failed many other therapies and are unlikely to maximally suppress the virus and achieve HIV-RNA levels below the LoQ. An experimental treatment may not be distinguishable from a control solely in terms of the proportions of patients whose HIV-RNA levels fall below the LoQ. The sensitivity of the comparison between the experimental treatment and the control could be increased by considering as well the difference between the treatments with respect to the HIV-RNA reductions of patients not achieving HIV-RNA levels below the LoQ. In this paper, we introduce a best-rank analysis which assigns the best rank to patients who achieve the HIV-RNA levels below the LoQ and applies the Mann-Whitney-Wilcoxon rank test to compare the two treatment groups. The Mann-Whitney-Wilcoxon statistic is shown to be a weighted sum of two statistics: one to compare the proportions of patients achieving the HIV-RNA levels below the LoQ and one to compare the viral reductions in patients with HIV-RNA levels above the LoQ. The corresponding statistical null and alternative hypotheses and the clinical interpretations of this best-rank test procedure are also discussed. An example is used to illustrate this approach and a simulation study is used to compare this approach with other methods.

Anti-HIV Agents↗
PubMed2005

Bayesian analysis of multicentre trial outcomes.

Bayesian methods provide flexibility in the analysis of data from multicentre trials that would be difficult to achieve by other means. This paper illustrates some useful applications of Bayesian methods to the analysis of multicentre trials, with emphasis on insights that would be difficult to obtain using conventional frequentist methods. Two trials provide data for illustration: a large multicentre trial comparing two doses of a drug with placebo with respect to an essentially continuous measurement for which the original analysis revealed a significant treatment by centre effect, and a large multicentre trial with intraclass correlation induced by a categorical outcome of up to four episodes of heartburn reported by individual patients. The data from both trials had been analysed previously using conventional frequentist methods. Both sets of data were reanalysed using Bayesian and empirical Bayesian methods; all of the analyses provided the same conclusions for the key questions regarding treatment differences. The Bayesian methods provided some insights useful for model checking and also provided a way to explore some important quantitative aspects about the magnitude of treatment effects.

Antacids↗
PubMed2005

Perspectives on the use of data mining in pharmaco-vigilance.

In the last 5 years, regulatory agencies and drug monitoring centres have been developing computerised data-mining methods to better identify reporting relationships in spontaneous reporting databases that could signal possible adverse drug reactions. At present, there are no guidelines or standards for the use of these methods in routine pharmaco-vigilance. In 2003, a group of statisticians, pharmaco-epidemiologists and pharmaco-vigilance professionals from the pharmaceutical industry and the US FDA formed the Pharmaceutical Research and Manufacturers of America-FDA Collaborative Working Group on Safety Evaluation Tools to review best practices for the use of these methods.In this paper, we provide an overview of: (i) the statistical and operational attributes of several currently used methods and their strengths and limitations; (ii) information about the characteristics of various postmarketing safety databases with which these tools can be deployed; (iii) analytical considerations for using safety data-mining methods and interpreting the results; and (iv) points to consider in integration of safety data mining with traditional pharmaco-vigilance methods. Perspectives from both the FDA and the industry are provided. Data mining is a potentially useful adjunct to traditional pharmaco-vigilance methods. The results of data mining should be viewed as hypothesis generating and should be evaluated in the context of other relevant data. The availability of a publicly accessible global safety database, which is updated on a frequent basis, would further enhance detection and communication about safety issues.

Adverse Drug Reaction Reporting Systems↗
PubMed2003

Effect of within-household reinfestation on design sensitivity.

The effect of within-household reinfestation on design sensitivity is investigated through statistical modeling of the reinfestation process. When reinfestation is present, household randomization tends to magnify treatment differences when compared with individual randomization or a randomized blocking design in the simple setting of two patients per household. The effect of reinfestation under more general household randomization settings is investigated by determining the relationship between the treatment effect and the number of patients per household. In an actual clinical study of treatment for head lice infestation, household randomization with proper stratification was adopted. The results from the study were consistent with theoretical expectations. This seeming contradiction to the blocking principle demonstrates the need to check whether all conditions are met before applying standard design principles.

Animals↗
PubMed2003

Industry, government, and academic panel discussion on multiple comparisons in a "real" phase three clinical trial.

A Food and Drug Administration (FDA)/Industry/Academic Panel Discussion on multiplicity aspects of a real Phase III clinical trial was held at the Third International Conference on Multiple Comparisons, August 6, 2002, in Bethesda, Maryland. The goal was to develop some consensus among industry, government, and academic statisticians concerning requirements and methods for multiplicity management in typical clinical trials. The session was tape-recorded; this article mostly comes from an edited transcript.

Clinical Trials, Phase III as Topic↗
PubMed2002

A meta-analysis of the dose-response relationship of inhaled corticosteroids in adolescents and adults with mild to moderate persistent asthma.

BACKGROUND: Although inhaled corticosteroids (ICS) are commonly used in the treatment of persistent asthma, the relationship between dose and clinical response remains unclear. OBJECTIVE: This study investigated whether ICS exhibit a dose-response relationship in the treatment of mild to moderate persistent asthma. METHODS: This was a meta-analysis of published randomized clinical trials concerning the relationship between ICS dose and response in asthma. Relevant studies were identified through a search of PubMed and MEDLINE for articles on asthma and ICS published between January 1996 and January 2001. The search was limited to publications classified as clinical trials that included the text words asthma and corticosteroids, glucocorticoids, beclomethasone, budesonide, fluticasone, flunisolide, mometasone, or triamcinolone acetonide. Five clinical measures were considered: morning peak expiratory flow rate (AM PEFR), evening PEFR (PM PEFR), forced expiratory volume in 1 second (FEV(1)), beta-agonist use, and asthma symptom score (severity of symptoms on a given day, as evaluated by patients). RESULTS: Forty-three studies were identified, of which 16 met the criteria for inclusion in the meta-analysis. These studies involved 4 agents: fluticasone propionate, triamcinolone acetonide, budesonide, and mometasone furoate. A statistically significant dose response in AM PEFR was observed with fluticasone propionate, triamcinolone acetonide, and budesonide (respective 95% CIs, 4.9 to 11.5, 4.7 to 18.0, and 5.8 to 24.9). A statistically significant dose response to fluticasone propionate and triamcinolone acetonide was also observed in PM PEFR (95% CIs, 2.0 to 8.7 and 2.4 to 13.7) and asthma symptom score (95% CI, -0.069 to -0.002 and -0.60 to -0.10). In terms of FEV(1), the dose response was statistically significant only with budesonide (95% CI, 0.025 to 0.17). Dose-response relationships were not disproportionately driven by the highest doses, and the greatest effects on response were seen at doses below or at the low end of the recommended range, suggesting that use of high doses of ICS may contribute only marginally to efficacy. CONCLUSIONS: Dose-response relationships were not uniformly observed with all drugs or for all measures of response. Use of higher doses of ICS in patients with mild to moderate persistent asthma does not appear to increase the efficacy of these drugs.

Administration, Inhalation↗
PubMed2002

Substantial evidence of effect.

Pressures for rapid drug development, especially for treatments that may affect public health significantly, drive a need to reconsider what is necessary to establish the "substantial evidence" of efficacy and safety required for regulatory approval. The concept of substantial evidence of effect can be stated fairly simply in principle, but its application to the evaluation of findings from real clinical drug development programs can be quite complicated and depend on circumstances relating to the population studied and the condition being treated. This paper discusses a number of considerations that arise in attempting to address this issue. These include confirmation of efficacy/safety as opposed to replication of results, the use of surrogates for the clinical outcome, ethical considerations, the use of trials aimed at demonstrating equivalence or noninferiority instead of superiority of a new drug, and the balance between benefits and risks. Recent developments such as the International Conference on Harmonization (ICH) guidelines dealing with statistical principles and choice of control group, and Food and Drug Administration (FDA) guidances interpreting the 1998 Modernization Act identify useful alternative definitions of substantial evidence and also identify when a single study can be enough to demonstrate a clinically important effect. The primary difficulty with the use of noninferiority trials is the need to demonstrate assay sensitivity or validity, i.e., that the trial would have demonstrated the superiority of the active control treatment to placebo had the trial included a placebo group. Failure to demonstrate a significant difference between the presumed active treatments and an inactive control precludes a definitive conclusion of assay validity, but external evidence, e.g., from trials demonstrating the activity of the active control, may yet justify concluding that the trial was assay valid. Issues of interpretation of important unexpected findings are illustrated in the recent experience with the alpha- and beta-blocker carvedilol, where there was a significant reduction in mortality among patients on carvedilol relative to placebo, but a treatment effect could not be demonstrated for the primary outcome. Experience with trials of thrombolytic agents illustrates alternative strategies for demonstrating substantial evidence of effect. Finally, meta-analyses can contribute to the substantial evidence by synthesizing the findings from separate trials to provide a perspective on drug performance in a heterogeneous population of patients that no single trial could provide.

Carbazoles↗
PubMed2002

Comparison of alternative strategies for analysis of longitudinal trials with dropouts.

PROBLEM: Patients may withdraw from longitudinal clinical trials for many reasons. Methods for handling the problem presented by missing data of patients who withdraw before reaching the time point of the primary measurement include carrying the last observation forward (LOCF), data as observed analysis (DAO), mixed model approaches, and pattern mixture models. METHOD: We evaluate a multiple imputation (MI) approach that has the flexibility to adjust inferences about the treatment effect for the withdrawn patients relative to currently used alternatives. Sensitivity analyses are performed under a collection of scenarios that include many circumstances that may arise in practice, including different assumptions about treatment effects post-withdrawal and about the missing data mechanism. Simulations are used to compare the results of analyses based on the MI approach with those based on the LOCF, DAO, and the mixed model approaches. RESULTS: The LOCF and DAO approaches cannot be recommended as strategies for handling missing responses, at least for these scenarios, because they provide biased estimates of treatment effects and biased tests of the null hypothesis of no treatment effect. Application of the various approaches to the analysis of clinical data from a longitudinal trial confirms the underestimation of the variability when the LOCF approach is used.

Analysis of Variance↗
PubMedDate not supplied

Practical pharmacovigilance analysis strategies.

PURPOSE: To compare two recently proposed Bayesian methods for quantitative pharmacovigilance with respect to assumptions and results, and to describe some practical strategies for their use. METHODS: The two methods were expressed in common terms to simplify identifying similarities and differences, some extensions to both methods were provided, and the empirical Bayes method was applied to accumulated experience on a new antihypertensive drug to elucidate the pattern of adverse-event reporting. Both methods use the logarithm of the proportional risk ratio as the basic metric for association. RESULTS: The two methods provide similar numerical results for frequently reported events, but not necessarily when few events are reported. Using a lower 5% quantile of the posterior distribution gives some assurance that potential signals are unlikely to be noise. The calculations indicated that most potential adverse event-drug associations that were well-recognized after 6 years of use could be identified within the first year, that most of the associations identified in the first year persisted over time. Other insights into the pattern of event reporting were also noted. CONCLUSION: Both methods can provide useful early signals of potential drug-event associations that subsequently can be the focus of detailed evaluation by skilled clinicians and epidemiologists.

Adverse Drug Reaction Reporting Systems↗