Douglas C. Throckmorton

Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety Testing Consortium

The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortiums (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts.

Expanded Access to Opioid Overdose Intervention: Research, Practice, and Policy Needs

In this issue, Coffin and Sullivans analysis suggests that distribution of naloxone to heroin users is likely to be a cost-effective strategy for treating overdose. The editorialists discuss the a...

Developing microphysiological systems for use as regulatory tools--challenges and opportunities.

In the last few years, scientists have made important progress in developing systems using human cells to test the effects of drugs and other substances. These systems have the potential to improve toxicity testing beyond currently available tools. The innovative new tools, which are known as microsystems, microphysiological systems, or organs on a chip, can aid in the development of medical products so that toxicity may be identified earlier in product development. This may lower costs and speed new treatments to patients. Experts believe that these systems may eventually enable scientists to test more environmental compounds more efficiently.

Is Randomization to Placebo Safe? Risk in Placebo-Controlled Angina Trials: Angina Risk Meta-Analysis

Objective: It was the aim of this study to document the risks of symptomatic patients with angina in placebo-controlled, anti-anginal drug development trials in which symptom-limited exercise testing was used as the primary endpoint. Patients and Methods: The original case report forms submitted to the United States Food and Drug Administration in support of approval of new or supplemental new drug applications between 1973 and 2001 were identified and subjected to a by-patient meta-analysis, utilizing both a maximum likelihood analysis and classical Mantel-Haenszel methods. Results: There were 63 placebo-controlled, clinical trials that randomized 10,865 patients, with 1,047 patient-years of observation time. The trials involved 21 different chemical entities from 4 different drug classes. The relative risk (RR) for withdrawal (placebo compared to drug-treated patients) was not increased [RR = 0.92, 95% confidence interval (CI) 0.78–1.08; p = 0.28]. Of interest, a RR of 0.54 (95% CI 0.26–1.04; p < 0.068) for irreversible harm (a combination of cerebrovascular accidents, myocardial infarction and death) and a RR of 0.89 (95% CI 0.61–1.30; p = 0.56) for serious cardiovascular events (myocardial infarction, congestive heart failure, cerebrovascular accidents) both non-statistically significantly favored being randomized to placebo. Conclusions: For the development of current or future drugs for the treatment of angina, there is no obvious contraindication to the use of placebo controls and exercise tolerance testing.

The FDA and the Next Wave of Drug Abuse — Proactive Pharmacovigilance

The FDA and the Next Wave of Drug Abuse In responding to the opioid crisis, the FDA needs to recognize shifting trends in the addiction landscape. Taking a systematic approach to monitoring such trends should allow the agency to intervene promptly and appropriately to protect the public from associated risks.

Medication development in opioid addiction: Meaningful clinical end points

The FDA’s “abstinence” outcome measure for approval of new medications to treat opioid-use disorders has been difficult to achieve; developing and validating alternative meaningful outcomes could facilitate drug development. The FDA’s “abstinence” outcome measure for approval of new medications to treat opioid-use disorders has been difficult to achieve; developing and validating alternative meaningful outcomes could facilitate drug development.

Proceedings of the Nineteenth Annual Symposium: Advances in Cardiovascular Pharmacology: Protocol Design and Methodology. The U.S. Regulatory Process: May 3, 4, 5, 2000, Washington, D.C.

The purpose of this symposium is to try to involve people from the three main areas involved in drug development—academic, regulatory, and the pharmaceutical industry. Our aim is to have an open and free discussion of ideas in cardiovascular drug development. As we see from this year’s symposium we have actually expanded into the treatment of vasculopathy and will try to emphasize some of these aspects, which I think is an appropriate contribution to a cardiovascular therapeutic meeting. Hyperlipidemia and hypertension are major factors contributing to stroke or cardiovascular disease. These are important conditions, and we need to focus on their therapy and prevention. A lot of people say, “Why hold this type of symposium?” There are many different forms. There is the American Heart Association, the American College of Cardiology—both excellent meetings given every year—but they are totally different. They are researchbased meetings and certainly do not involve discussing aspects of protocol design and evolving approaches to drug development. There are certainly many advisory committee meetings and many excellent interactive sessions with the Food and Drug Administration. These are more on a formal basis, and they are not open to discussion for all to take part. So I think that this course is unique. I am not sure if we have ever had the symposium work exactly as we hoped. I hope [that during] this year’s session and in the future we will be able to come closer to our goal in having an open forum for a “give-and-take” between regulators, members of the academic community, and those who design and run clinical trials for the pharmaceutical industry. Today’s first mini symposium is going to deal with the topic of congestive heart failure. This is an important area of great interest and an area with many compounds under development. This is certainly an area with controversy and a difficult one for drug development. There have been several special meetings this past year to try to develop a consensus to guide drug development. I would like to discuss some of the proceedings and how the developing consensus directly relates to trial design. For this symposium session my colleague, Dr. Borer, is going to chair the meeting. I am going to introduce Dr. Borer now, who I might add has coauthored a book on CV drug development with me. Because people always ask us if we have the minutes to the symposium and is it going to be published, we have put together a publication stemming from the symposium. We have pulled together a number of symposium sessions, synthesized them, and put them together as a book, entitled Cardiovascular Drug Development, published by Marcell–Decker.