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Biomedical subjects

Robert Temple

Publications and source records attributed to Robert Temple.

13 recordsLinked to original sources
PubMed2007

BiDil for heart failure in black patients: The U.S. Food and Drug Administration perspective.

Critics of the U.S. Food and Drug Administration (FDA) approval of the fixed combination of hydralazine hydrochloride, 37.5 mg, and isosorbide dinitrate, 20 mg, for treating heart failure in black patients have suggested that data were insufficient to distinguish treatment effects in black and white people; that distinctions based on race, rather than pathophysiology, were scientifically unreasonable; and that a "race-based" approval could be a commercial ploy to avoid a more expensive and prolonged full evaluation of a drug. The criticisms acknowledge that data supporting the approval came from a well-designed clinical trial in which self-identified black patients with heart failure who took hydralazine hydrochloride-isosorbide dinitrate with standard therapy experienced a statistically significant 43% (95% CI, 11% to 63%) reduction in mortality compared with those who took only the standard therapy. The criticisms do not always recognize that the decision to conduct the trial in only black patients reflected careful analyses of 2 previous trials in racially mixed patient populations that compared hydralazine hydrochloride-isosorbide dinitrate with placebo or with enalapril. Both trials showed little or no overall effect of hydralazine hydrochloride-isosorbide dinitrate in the mostly white patient population but hinted at a substantial effect in subsets of black patients. Perhaps most critically, the criticisms do not appreciate the urgency of strong scientific evidence of a substantial survival benefit in black patients. A serious attempt to avoid race-based approval by mandating study of a mixed population to identify a possible white patient-responder subset, particularly without a plausible hypothesis as to what that subset might be, would have required years of work, many thousands of patients, and wholly unreasonable delay in approval of a treatment whose effectiveness had been well-documented in the group for which it was intended.

Black People↗
PubMed2006

FDA perspective on trials with interim efficacy evaluations.

Over the years FDA has seen a variety of 'adaptive' approaches, including repeated calculation of p-values. More recently there has been interest in adjusting sample sizes based on event rates, easy if the treatment group rates remain blinded but possible even with unblinded analysis. In large trials, group sequential analytic approaches are routine. Early stopping however, can reduce available data and in cardiac trials we have generally urged use of only survival as the basis for stopping, even if the primary endpoint is a composite (death, new AMI, etc). Other possibilities include adaptive randomization and starting additional dose groups. Enrichment designs focus on populations with a higher event rate or on populations more likely to respond. They can reduce sample sizes and target therapy toward people most likely to benefit.

Clinical Trials as Topic↗
PubMed2006

Blood pressure as an example of a biomarker that functions as a surrogate.

There are many important uses of biomarkers in drug development. An area of particular interest is the use of biomarkers as surrogate end points. Only a small minority of biomarkers are established surrogate end points. Blood pressure is an example of a surrogate end point accepted by both clinicians and regulators. It was a plausible surrogate because of the large epidemiologic databases demonstrating a correlation between elevated blood pressures and adverse cardiovascular outcomes. That plausibility has been supported, however, by the numerous placebo-controlled outcome studies evaluating several pharmacologically distinct agents that showed an effect on stroke and coronary heart disease outcomes from lowering blood pressure.

Animals↗
PubMed2004

Independence of the statistician who analyses unblinded data.

This discussion considers arguments for and against separating responsibility for the unblinded interim analysis of a clinical trial from responsibility for trial management and modifications to the ongoing trial. The degree to which one or different statisticians carry out these responsibilities and thus the degree of statistician independence for the two activities can vary, but a sponsor should recognize that giving a single statistician both responsibilities might limit flexibility in managing the trial, particularly with respect to modifying an ongoing trial.

Clinical Trials Data Monitoring Committees↗
PubMed2004

Assessing tumor-related signs and symptoms to support cancer drug approval.

Cancer causes premature death and significant, often devastating, symptoms. While prolongation of survival is an obvious end point for new cancer drug approval, the US Food and Drug Administration (FDA) has also utilized end points that evaluate patient symptoms. In this article we discuss the end points, evidence, and analyses supporting cancer drug approvals based on evaluations of tumor-related signs and symptoms. With advice from the Oncologic Drug Advisory Committee (ODAC) in the late 1970s and early 1980s, FDA determined that acceptable end points for cancer drug approval were survival or an improvement in the quality of a patient's life, e.g., an improvement in tumor-related symptoms. This article summarizes 15 FDA cancer drug approvals based on patient symptom assessments and/or physical signs (thought to represent symptomatic improvement) as the primary evidence of effectiveness. These include painful bone events (three cases), cosmetic improvement in Kaposi's sarcoma and cutaneous T-cell lymphoma (six cases), the consequences (decreased transfusions, etc.) of long-duration responses in leukemias and lymphomas (two cases), relief of pulmonary or esophageal obstruction (two cases), and one case each of symptom benefit in pancreatic cancer (also associated with survival benefit) and pulmonary symptom benefit in lung cancer. An instructive example of an individual patient benefit end point is discussed, though it did not lead to a drug approval (the cisplatin-epinephrine gel application). Improved trial designs and analysis plans may allow greater reliance on morbidity assessments to support future cancer drug approvals. Drug sponsors are encouraged to include symptom assessments in cancer clinical trials and to perform further research to improve symptom-assessment methods. The FDA routinely meets with sponsors at End of Phase 2 Meetings to discuss drug development plans and the design of phase 3 trials. We encourage sponsors to request special protocol assessments (SPA) after meeting with the FDA to get written confirmation of the adequacy of plans for assessing cancer morbidity and quality of life, including protocols, end points, statistical analysis plans, and draft case report forms.

Antineoplastic Agents↗
PubMed2004

ROBERT TEMPLE: an eye for data. Interview.

Robert Temple has spent more than thirty years of his career at the Food and Drug Administration-and he still likes it! After medical school, internship, and residency, Temple pursued endocrinology research at the NIH before deciding, in the early 70s, to apply his interests in science to consumer advocacy at the FDA. The FDA was undergoing enormous changes at that time, and Temple enjoyed the challenges associated with improving drug development and patient safety. Always relying on a critical evaluation of data, he is comfortable discussing mechanisms of drug action, experimental design, and regulatory policies, as well as the social implications of direct-to-consumer advertising of drugs. Currently, Temple is Director of one of the six Offices of Drug Evaluation and also serves as the Associate Director for Medical Policy.

Drug Approval↗
PubMed2004

Issues in regulatory guidelines for data monitoring committees.

As clinical trials have emerged as the major research method for evaluating new interventions, the process for monitoring intervention safety and benefit has also evolved. The Data Monitoring Committee (DMC) has become the standard approach to implement this responsibility for many Phase III trials. Recent draft guidelines on the operation of DMCs by the Food and Drug Administration (FDA) have raised issues that need further clarification or discussion, especially for industry sponsored trials. These include, the time when DMCs are needed, the role of the independent statistician to support the DMC, and sponsor participation at DMC meetings. This paper provides an overview of these issues, based on the discussions at the January, 2003 workshop sponsored by Duke Clinical Research Institute.

Clinical Trials Data Monitoring Committees↗
PubMed2003

Design and analysis of non-inferiority mortality trials in oncology.

The recent revision of the Declaration of Helsinki and the existence of many new therapies that affect survival or serious morbidity, and that therefore cannot be denied patients, have generated increased interest in active-control trials, particularly those intended to show equivalence or non-inferiority to the active-control. A non-inferiority hypothesis has historically been formulated in terms of a fixed margin. This margin was historically designed to exclude a 'clinically meaningful difference', but has become recognized that the margin must also be no larger than the assured effect of the control in the new study. Depending on how this 'assured effect' is determined or estimated, the selected margin may be very small, leading to very large sample sizes, especially when there is an added requirement that a loss of some specified fraction of the assured effect must be ruled out. In cases where it is appropriate, this paper proposes non-inferiority analyses that do not involve a fixed margin, but can be described as a two confidence interval procedure that compares the 95 per cent two-sided CI for the difference between the treatment and the control to a confidence interval for the control effect (based on a meta-analysis of historical data comparing the control to placebo) that is chosen to preserve a study-wide type I error rate of about 0.025 (similar to the usual standard for a superiority trial) for testing for retention of a prespecified fraction of the control effect. The approach assumes that the estimate of the historical active-control effect size is applicable in the current study. If there is reason to believe that this effect size is diminished (for example, improved concomitant therapies) the estimate of this historical effect could be reduced appropriately. The statistical methodology for testing this non-inferiority hypothesis is developed for a hazard ratio (rather than an absolute difference between treatments, because a hazard ratio seems likely to be less population dependent than the absolute difference). In the case of oncology, the hazard ratio is the usual way of comparing treatments with respect to time to event (time to progression or survival) endpoints. The proportional hazards assumption is regarded as reasonable (approximately holding). The testing procedures proposed are conditionally equivalent to two confidence interval procedures that relax the conservatism of two 95 per cent confidence interval testing procedures and preserve the type I error rate at a one-sided 0.025 level. An application of this methodology to Xeloda, a recently approved drug for the treatment of metastatic colorectal cancers, is illustrated. Other methodologies are also described and assessed - including a point estimate procedure, a Bayesian procedure and two delta-method confidence interval procedures. Published in 2003 by John Wiley & Sons, Ltd.

Antimetabolites, Antineoplastic↗
PubMed2002

Policy developments in regulatory approval.

Although radical changes in drug regulation are rare (e.g., the Federal Food, Drug and Cosmetic Act of 1938 and the 1962 amendment to the Act creating an effectiveness requirement), regulations and guidance do evolve significantly in the face of new problems and accumulating experience. Recent changes have been driven by the Food and Drug Administration Modernization Act (FDAMA), user fee legislation, the International Conference on Harmonization, recent safety related drug withdrawals, and concerns about trial ethics and investigator conflict of interest. FDAMA and guidance developed in response to it has helped circumstances in which FDA would rely on a single study to support effectiveness and the circumstances in which surrogate endpoints could support approval. An ICH Document 'Choice of control group and related design issues in clinical trials' focussed attention on the ethics of placebo controls (acceptable, even if there is existing therapy, when the placebo-treated patient will suffer no irreversible injury) and the design of 'equivalence' or 'non-inferiority' trials. There has been greatly increased attention to obtaining good dose-response information and to assessing need for modifying treatment in demographic (age, gender, race) and concomitant disease (renal or hepatic function abnormalities) subgroups, and in assessing drug-drug interactions. Other important trends are increasing reliance on non-U.S. data, increasing numbers of FDA-industry meetings during drug development, and new focus on risk assessment and risk management.

Dose-Response Relationship, Drug↗