Healthy Skepticism Library item: 12329

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Publication type: news

Mansell P.
Tougher scrutiny needed to weed out CV effects, says FDA advisor
PharmaTimes 2008 Jan 2
http://www.pharmatimes.com/clinicalnews/article.aspx?id=12536&src=EWorldNews

Full text:

Earlier assessment in the drug development process and mandatory post-marketing surveillance should be part of a more determined regulatory push to root out potential cardiovascular safety problems in drugs geared mainly to non-cardiovascular indications, says a US authority in the field.

Speaking at the recent annual meeting of the European Society of Cardiology in Vienna, Austria, Dr Jeffrey Borer, professor of cardiovascular medicine and director of the Howard Gilman Institute for Vascular Heart Diseases at NewYork-Presbyterian Hospital/Weill Cornell Medical Center in New York City, noted that recent drug withdrawals – including Merck & Co’s painkiller Vioxx (rofecoxib) – had underlined the importance of evaluating new drugs for unacceptable cardiovascular risks.

“It is clear that drugs intended for non-cardiovascular problems must be more fully scrutinised than in the past in order to allow doctors and patients to be assured that risks are well defined and that they do not outweigh the benefits provided by the drugs for the individual patient,” Dr Borer told the meeting. “The primary strategy to achieve this goal is increasing formal observations in both pre- and post-approval studies.”

More specifically, Dr Borer recommended that:

• Cardiovascular safety assessment should be incorporated into drug development from the preclinical stage, with animal studies to determine a compound’s effects on cardiac physiology/pharmacology, even if the drug is not intended for cardiovascular indications. Evaluation of cardiovascular effects should also begin in the earliest phases of clinical testing in humans.
• Definitions of adverse cardiovascular events such as heart attacks and strokes should be standardised for all observers before the drug candidate is administered to patients. At present, Dr Borer pointed out, the cardiovascular potential of compounds not intended for heart problems is often assessed only minimally, and generally in the later phases of development. Moreover, the definition of adverse events is left to each observer individually, limiting the strength of any conclusions about cardiovascular safety.
• Regulatory bodies should have the authority to mandate the continuing evaluation of drug effects, even after approval. This would allow drug labelling updates to sharpen the precision with which doctors and patients can determine a product’s risk-benefit ratio and select treatment strategies, Dr Borer said.

• Regulators should also be empowered to withdraw approval if mandated post-marketing studies are not conducted – an authority FDA, for example, does not currently possess.
• If a drug is likely to be used by people at relatively high cardiovascular risk, at least one study of the drug’s beneficial effects should be performed in these types of patient, rather than just in low-risk patients as is commonly the case.

• Analysis plans should be drawn up to incorporate all data gathered during drug development, including the results of non-randomised, uncontrolled observational studies, with a view to boosting the statistical power to find problems if they exist.

Dr Borer’s presentation was based partly on an article published in the August 2007 issue of the European Heart Journal. This summarised the conclusions of a group of cardiologists, biostatisticians, US and European regulators as well as representatives from the US National Institutes of Health and the pharmaceutical industry who had discussed the above issues at a Cardiovascular Clinical Trialists round table in Paris.

An advisor to the US Food and Drug Administration since 1977, Dr Borer served three terms as chair of the agency’s Cardio-Renal Drugs Advisory Committee between 1982 and 2004.