Boola! Boola! Boolean.

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  • 01/22/2014

Sometimes statements of the obvious are useful. Here’s one from Yale University’s Nicholas Downing, a third year medical student at Yale University School of Medicine and lead author of a new study, which examined nearly 200 new drug approvals between 2005 and 2012:

“Not all FDA approvals are created equally.”

According to the Washington Post, “Downing and his team found broad differences in the data it took to get a thumbs up from FDA. For instance, the agency required that many new drugs prove themselves in large, high-quality clinical trials. But about a third won approval on the basis of a single clinical trial, and many other trials involved small groups of patients and shorter durations. Only about 40 percent of approvals included trials in which the new drug was compared with existing drugs on the market.”

“There was a lack of uniformity in the level of evidence the FDA used,” Joseph Ross, assistant professor of internal medicine at Yale and a senior author of the study, said in announcing the findings.

Well, duh.

The Yale study, funded by the Pew Charitable Trusts and published Tuesday in JAMA, acknowledges that the FDA has valid reasons for its varied requirements.

“Such regulatory flexibility allows for a customized approach to approval,” it states, “including the ability to rapidly approve potentially effective therapies for life-threatening diseases, such as certain cancers, or those diseases for which there is no existing effective treatment, such as orphan diseases.”

Downing, the study’s lead author, said the analysis is not intended to suggest that the FDA should use a one-size-fits-all approval process or that it somehow has approved the wrong drugs. Rather, he said, it was meant to educate people who assume that all new drugs have cleared the same amount of safety testing before ending up on the market.

“It’s very understandable that regulators have a flexible standard for approval, but patients and doctors need to be aware the standard is flexible,” he said. “It’s important for doctors and patients to have a discussion about how much we know about the potential benefits or risks of taking a drug before they take it . . . [and] it underscores the need to continue to study these drugs after approval.”

Yep. Not new – but worth repeating.

Missing from the Yale study is the relevant fact that, per PDUFA V, the FDA is designing a five-item grid as a management tool to explain its risk-benefit decisions in a more concise format. The model that it has created as a working template confirms a truism about its drug approval tendencies that industry has suspected for years: the baseline for FDA approval is a high rating of the severity of the disease being treated and the medical need for the product.

The agency is developing a grid of the five basic factors that need to be addressed in any decision on the commercial availability of a drug. The top two are the seriousness of the condition addressed and the need for a new treatment of the condition. Then comes the traditional heart of the NDA package: analyses of clinical data on the benefits of the drug and the risks associated with its use.

The fifth fundamental factor is explicitly the level of risk management associated with the product. The FDA is going to take it into consideration in every decision; sponsors who ignore or underplay the identification of who should use the product and who might use it will have a gap in their filings.

The grid proposal does not call for a fixed mathematical formula behind each approval. The agency has not tried to reduce the judgments in an approval decision to a rigid calculation.

Judgment? You mean FDA decisions aren’t black and white?

In the words of John Jenkins, director of the Office of New Drugs at the Center for Drug Evaluation and Research, disagreement “happens a lot in the decisions that we have to make. Very few of the decisions that we make on drugs are easy. Very few of the drugs we see have a dramatic overwhelming benefit with relatively no risk. We see that most drugs have marginal to moderate benefits on a population basis and they have general safety but they have the risks of serious toxicities at some low levels." In other words, every decision is very complex.

The unspoken danger is that regulators love ambiguity because ambiguity is power. That’s different than regulatory flexibility – which is a good thing. But it’s a fine line and the distinction is often in the eyes of the beholder. But it is certainly a distinction with a difference.


Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.

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