Creating Efficiencies in Clinical Trial Design – Dr. Robert Temple, FDA, CDER

On March 1st, the Boston CMO Network sponsored its second event. Dr. Robert Temple, presented to a group of 80 physician executives from Boston area biotech and pharmaceutical companies on the topic of “Creating Efficiencies in Clinical Trial Design”. Dr. Chris Wright, SVP, Global Medicines Development and Affairs of Vertex Pharmaceuticals was host of the event, which was held at Vertex facilities in Cambridge, MA.

Dr. Robert Temple is Deputy Center Director for Clinical Science of FDA’s Center for Drug Evaluation and Research and is also Acting Director of the Office of Drug Evaluation I. Dr. Temple received his medical degree from the New York University School of Medicine in 1967. In 1972 he joined CDER as a review Medical Officer in the Division of Metabolic and Endocrine Drug Products. He later moved into the position of Director of the Division of Cardio-Renal Drug Products. In his current position, Dr. Temple oversees ODE-1 which is responsible for the regulation of cardio-renal, neuropharmacologic, and psychopharmacologic drug products. Dr. Temple has a long-standing interest in the design and conduct of clinical trials and has written extensively on this subject, especially on choice of control group in clinical trials, evaluation of active control trials, trials to evaluate dose-response, and trials using “enrichment” designs.

Enrichment Designs in Clinical Trials

Dr. Temple discussed the many ways to show drug effect in smaller trials that are encompassed in the concept of enrichment, which is the subject of a future FDA guidance document.

“Enrichment is prospective use of any patient characteristic – demographic, pathophysiologic, historical, genetic, and others – to select patients for study to obtain a study population in which detection of a drug effect is more likely. This occurs to a degree in virtually every trial, although enrichment may not be explicit, and is intended to increase study power by:

• Decreasing heterogeneity; choosing an appropriate population
• Finding a population with many outcome events, i.e., high risk patients or patients with relatively severe diseases – prognostic enrichment
• Identifying a population capable of responding to the treatment – predictive enrichment”

A clear benefit of selecting high-risk patients is the ability to have enough endpoints to demonstrate a possible drug effect, at least in one group of patients. Of course, there is always a question about the benefit/risk equation in patients with lower risk, which usually requires additional study.

Randomized Withdrawal Studies

Dr. Temple also discussed the use of Randomized Withdrawal studies to show long term effectiveness or determine how long patients should be treated. He cited the challenges of showing a benefit vs placebo in a cyclical disease, such as depression, when treating people for only a short period of time. Randomized withdrawal can be used to demonstrate the benefit in prevention of the next episode of depression in these patients.

“Randomized WD trials are carried out in people who appear to have responded. They are regularly used:

• To show long-term effectiveness when long-term placebo cannot be ethically used (hypertension),
• To see how long you should give an adjuvant cancer treatment (tamoxifen) or a bisphosphonate, and
• To demonstrate maintenance effects for anti-depressants and other psychotropic drugs
• Recent discussion (NSF report) of how to handle dropouts (LOCF not liked) suggest another use: make studies short, then show durability with a randomized WD study.
• Illustration of value with anti-depressants, famous for showing small (if any) effects in acute studies.”

Dr. Temple’s presentation was followed by a Q&A session.

About The Boston CMO Network

The Boston CMO Network includes senior physician executives in the greater Boston area who are active in the biotech and pharmaceutical industry. The Network sponsors events for Boston-area physician executives to meet, interact and learn from each other.

A Steering Committee of physician executives plans the group’s events, which are hosted at local biotech companies. The Boston CMO Network expects to hold its next event in June, 2012.

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