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FDA: Tortoise, hare, or something else?

Editor's note: This is part I of a two-part column on the Food and Drug Administration approval process.

Last year, this column highlighted the debate around drug and device safety. At that time, I expected that the controversy would continue to grow.

Indeed, the Avandia issue splashed across the headlines this past month. One consequence was the congressional hearings lambasting the Food and Drug Administration and its Commissioner, Andrew von Eschenbach, for what Rep. Henry Waxman, chairman of the Committee on Oversight and Government Reform, called “a major failure of our system.”

It is human nature to blame individuals rather than the system. Indeed, CNN reported Rep. Waxman's exchange with the Commissioner as a “tongue-lashing.” However, when there are apparent system failures in succession, such as we saw with Vioxx and now with Avandia, it may be evidence of what the statisticians called “systematic error.” In seeking the source for such difficulties, the system itself deserves a closer look.

The Avandia “Failure”
Avandia is a drug that controls blood-sugar levels in non-insulin dependent diabetic patients. For GlaxoSmithKline, its manufacturer, it is a blockbuster drug with 2006 sales exceeding $3 billion.

The current debate was ignited by a May 21 New England Journal of Medicine article in which Dr. Steven Nissen of the Cleveland Clinic published a meta-analysis study reporting that Avandia, also known as rosiglitazone, increased heart attack risk by 43 percent. At the June 6 congressional hearing, Waxman stated, “The FDA never required the manufacturer to [conduct] a thorough post-market study of Avandia's heart risks,” noting that the FDA requires such safety studies after drugs are approved.

Safety takes a back seat

As pointed out in previous columns, safety has always been a concern ever since Hippocrates laid out the dictum of “First, Do No Harm.” Ironically, however, as modern medicine began to deliver an ever increasing supply of “medical miracles” during the last century, the increasing numbers of lives saved encouraged even bolder approaches to therapy.

For example, radical surgery such as organ transplants were not only imagined but became routine. Ever more powerful drugs, including cancer chemotherapeutics that previously were weapons for chemical warfare, became standard pharmacopeia. Emboldened by these successes, and to some extent encouraged by the system, safety became secondary in the race to bring drugs to market.

However, my previous columns (in May 2006 and later in August 2006) pointed out how safety has become increasingly important for patients and society. Some of the reasons for this apparent shift include:

Greater efficacy of medicine: As treatments become more effective, the “blemishes” become more evident. In technical terms, the risk-benefit profile gets shifted towards a higher awareness of risk (e.g. safety).

Baby boomer culture: This is a major population force as this group characteristically holds high expectations and little tolerance for failure.

Chronic diseases: When people take drugs or use devices for extended periods of time, what might have been a mere side effect can turn into a significant safety risk.

Preventive medicine: Likewise, in using drugs or devices for preventive purposes, safety becomes that much more important. It's hard to justify a safety risk in the context of a condition with no symptoms.

As the Avandia story reached the front pages, a number of related side stories also appeared. One recent report in the New York Times described the travails of University of North Carolina medical researcher Dr. John Buse. He testified at the Avandia hearing about being threatened by top GlaxoSmithKline officials and being called a “liar” and “scoundrel” after he had criticized the drug at a medical conference.

Another New York Times report, citing the example of former FDA deputy division director Dr. Rosemary Johann-Liang, highlighted how “an increasing number of [the agency's] drug-safety officers have been punished or ignored after uncovering dangers of popular medicines.”

While society may be putting a premium on safety, this message has not completely reached government and industry. Those who are serious about safety apparently suffer more than just a lack of scientific glamour but also potentially risk their careers and reputations.

Efficacy is the "King of Drug Approval"

Anyone from Wall Street to Main Street who follows drug stocks knows that FDA approval has the power to move billions of dollars. FDA approval is a huge event, not only for fledgling start ups but also for the largest of pharmaceutical companies. Indeed, the ImClone case (e.g. Martha Stewart and Sam Waksal) brought the ordinarily secretive process of FDA approval out into public consciousness. As many know, both Stewart and Waksal went to jail for insider-trading related transgressions. Drug approval is serious business.

At present, the gold standard for drug approval is demonstrated efficacy - namely that the drug works. Safety also is a part of the process and ordinarily there are fairly extensive preclinical and animal studies designed to ferret out unsafe drugs. Most of these studies are fairly routine safety tests that simply set the backdrop to the “real” clinical trials that are of large enough size, or are of clever enough design, to reach the efficacy endpoint.

We have demonstrated that the efficacy endpoint is music to the ears of pharmaceutical executives because achieving that - more than anything else - is what it takes to gain FDA approval. After that, post-marketing safety studies take place, but Avandia showed they may or may not be executed to everyone's satisfaction.

Given the high stakes - billions of dollars - that are involved, this means that the best minds, the most money, and the most effort is and indeed must be expended in an all-out effort to achieve the efficacy endpoint.

However, we live in a world of limited resources. When efficacy is a priority, other concerns - such as safety - must logically fall in priority.

Harsh critique

By no means am I implying that anything fraudulent or criminal is going on. Rather, this is a natural consequence of system bias, one which some senior FDA officials have confirmed to me in private discussions. What is especially troubling, other than the intrinsic bias, is when scientists and officials who take up safety concerns suffer harsh critique.

Ironically, they suffer double jeopardy because the unglamorous business of safety studies is not known for being a fast track to career success.

Previous articles by Ogan Gurel

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.

WTN accepts no legal liability or responsibility for any claims made or opinions expressed herein.

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