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Reforming FDA: Focus on safety, let market judge efficacy

Editor's note: This is part II of a two-part column on the Food and Drug Administration approval process. Part I focused on the recent controversy over Avandia, GlaxoSmithKline's diabetes drug.

The primacy of efficacy over safety seems to be so deeply integral to the system that it might be helpful to realize that this has not always been the case. For much of its history, the Food and Drug Administration's primary mandate was to protect the public's safety.

The original 1906 Food and Drugs Act, which created the FDA, prohibited the interstate transport of food and drugs that had been adulterated (formulated with additives), injurious to health, or otherwise “misbranded.” The Chinese toothpaste problem, for example, would have been priority No. 1 for an FDA of 1906.

In a decisive change for the agency, the Kefauver-Harris Amendment radically transformed the FDA. This legislation mandated that all new drug applications had to demonstrate “substantial evidence” of the drug's efficacy on top of the existing requirement for safety studies.

Times were simpler back in 1962. Academic medicine was in its heyday and new, efficacious drugs seemed to drop from the heavens. The population was considerably younger, as the baby boomers were mostly in their teens. Chronic diseases were much less common as many conditions such as cancer were effectively death sentences. “Living with Cancer” is largely a phrase of our present time.
Of course, nobody at that time would have desired unsafe medicines. The thalidomide tragedy was, in fact, what sparked the 1962 legislation.

However, 2007 is a very different time from 1962. Since then, it has since become enormously costly (both in terms of money and time) to generate the “substantial evidence” of drug efficacy.

Drug development now takes much longer. And in shifting priority from safety to efficacy, the Kefauver-Harris amendment has had the unintended consequence of slowing down drug approvals in the present era.

FDA: Tortoise or hare?

The article “Potentially Incompatible Goals at FDA” said the following: “Patients want immediate access to breakthrough medicines but also want to believe the drugs are safe... These goals can be incompatible.” While incompatibility shouldn't necessarily be a foregone conclusion, the article does highlight an extraordinary tension that may radically reshape FDA over the coming years.

Should the FDA be a tortoise and take more time in approving drugs, or should it be a hare and allow drugs to hop quickly to market? Baby boomers, who are used to getting what they want, desire both.

The key to achieving both speed and safety will be to restore FDA's primary emphasis on safety and allow the market (which is not just the commercial market but also the medical, academic, and scientific communities as well) to work out the efficacy of drugs. While some may call this heresy, in reality such a situation already exists in at least three forms.

• Regulatory approval in Europe is less dependent on demonstrating efficacy than FDA. The main concern is safety and that is one reason why Europeans receive breakthrough drugs and devices earlier than Americans.

• Off-label use in the United States has created a situation in which drugs and devices ostensibly deemed safe and approved for a single indication can, indeed, be used without approval for other uses.

• FDA monitors the vitamin and nutraceutical markets for safety only, and does not allow efficacy claims.

Interestingly, the loophole of off-label use raises particular dangers because the safety and efficacy studies used in obtaining initial approval are generally pertinent only to very defined and limited indications. Indeed, as efficacy endpoints become even more of a challenge to achieve, limiting the scope of primary indications becomes increasingly necessary. Thus, safety information obtained as part of an application may not be relevant for unregulated off-label uses.

It is also important to recognize another important trend, that of personalized medicine, that further complicates efficacy determinations. As personalized medicine becomes more prevalent, designing and implementing large double-blind, randomized clinical trials becomes increasingly difficult, as well as moot. And lastly, with the increasingly rapid pace of technology advancement, results from large and lengthy efficacy trial may be obsolete by the time their results are available.

In short, the efficacy standard, while it has laudably served us well during simpler times, may very well be getting the way of bringing drugs safely and quickly to patients.

Speeding drugs (safely) to market

In a CNBC special on June 4, the following question was asked: “Should the FDA be speeding cancer drugs to market?” The president of FasterCures, an organization founded by Mike Milken and funded by the Gates Foundation and the Sumner Redstone Foundation, gave a rather unimaginative answer - “YES if they work, NO if they don't!”

In terms of bringing more drugs to market, we should realize that the true rate-limiting step is more likely to be the innovation gap highlighted in my previous Memorial Day column. While the protracted drug approval process is indeed a problem, there's a plethora of innovative potential therapies being held up at earlier stages in the product development process.

Indeed, the simplistic exhortation to place more drugs on fast-track status is less likely to be a construed as a desire for faster cures than a plea by proxy from drug companies for laxer regulation. The latter is certainly against the tide of public opinion in light of the recent controversies.

A proposal for FDA reform

The FDA doesn't need to choose between being a tortoise or a hare. Rather, the agency should redefine itself outside of the terms that device companies want, and end-users think they need.

I propose that FDA refocus its primary mission to ensure drug and device safety (both in development as well as formulation and manufacturing). To do so, FDA must make safety the primary endpoint for approval. Once safety is central to the approval process (and therefore receives billions in market capitalization), the best and the brightest will be set to this task. This also would be more detailed and comprehensive in its scope, rather than the relatively routine tests currently conducted. Safety shouldn't be just a matter of going through a checklist but should also inspire the same ingenuity has been applied to achieving efficacy endpoints.

Efficacy would be determined in the market, as it is in the European, off-label, and vitamin world. Some may argue that we need a strong, efficacy-driven FDA, but remember that in 1962 communication among and between clinicians, scientists, and the broader market was much less open and transparent than it is now in today's Google and YouTube era.

It is unlikely that blatantly ineffective treatments will gain significant traction in such a market, especially because academic peer review and market-driven judgments can be more efficiently transmitted to all providers. Truth-in-advertising laws would need to be upheld (and indeed enforced aggressively) and just as with off-label use, manufacturers would be prohibited from making any specific efficacy claims.

When it comes to accelerating new drugs to market and filling up the pipeline with new compounds, we should focus less on the last steps of the pipeline (speeding up FDA approval) and more on the beginning of the pipeline, which suffers now from an innovation gap. Bridging the innovation gap will require us to encourage government and private institutions to further accelerate the transition of university-level science to the initial stages of clinical and commercial development.

Obviously, all these ideas require much more space to develop so I'll leave further details to later columns. For now, the take-home message is that while we need a strong FDA even more than ever, we need one that's different from what it is today.

Previous articles by Ogan Gurel

Dr. Ogan Gurel: FDA: Tortoise, hare, or something else?

Dr. Ogan Gurel: Who is minding the Innovation Gap?

Barriers will not stop convergence of medical technologies

Ogan Gurel: Abbott vs. Thailand has implications for innovation and access

Ogan Gurel: Personalized medicine and technology convergence

Of private equity, research, and drug development

Dr. Ogan Gurel is chairman of the Aesis Group, which provides consulting services to companies and investment firms in the life sciences and healthcare sectors. He is also Chief Medical Officer of BlueBob Analytics and an Adjunct Associate Professor of Bioengineering at the University of Illinois – Chicago. Gurel was previously CEO of Duravest, a publicly traded Chicago investment company that initiates and develops next-generation medical technologies. Previous to Duravest, he was a vice president and medical director at Sg2, a healthcare intelligence think tank and consultancy serving hospitals and health systems, and an associate at Booz Allen Hamilton. He can be e-mailed at

This article previously appeared in, and was reprinted with its permission.

The opinions expressed herein or statements made in the above column are solely those of the author, and do not necessarily reflect the views of Wisconsin Technology Network, LLC.

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