Thinking about Life Sciences: FDA: Tortoise, Hare or Something Else Pri... http://blog.aesisgroup.com//2007/07/02/fda-tortoise-hare-or-something-el...

Thinking about Life Sciences

http://blog.aesisgroup.com

Tuesday, June 12, 2007

FDA: Tortoise, Hare or Something Else

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 just this past month. One consequence was the
congressional hearings last week lambasting the Food & Drug Administration (FDA) and its Commissioner
Dr. 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. CNN reported Rep. Waxman’s exchange with
the Commissioner as a “tongue-lashing.” However, when there are failures in succession such as we saw with
Vioxx and now with Avandia, it may be evidence of what the statisticians call a systematic error. In seeking the
source for such problems, the system itself deserves a closer look.
The Avandia Controversy
Avandia is a drug that controls blood-sugar levels in noninsulin dependent diabetic patients. For its
manufacturer (GlaxoSmithKline) it is a blockbuster drug with sales exceeding $3 billion in 2006. The
current debate was ignited by a May 21st New England Journal of Medicine article in which Dr. Steven Nissen
of the Cleveland Clinic published a metaanalysis study reporting that Avandia (also known as
rosiglitazone) increased heart attack risk by 43 percent. At the June 6th congressional hearing, Rep.
Waxman stated that “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 they are approved.
Safety: Takes a Back Seat
As pointed out in previous postings, safety has always been a primary concern. 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—even those such as many cancer chemotherapeutics that previously were weapons for chemical
warfare—became standard pharmacopeia. Emboldened by these successes and to some extent
encouraged by the system, the health care industry put safety second to bringing new therapies 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 more generally. 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 metamorphose into a significant safety risk.

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Preventative medicine. Likewise in using drugs or devices for preventative purposes, safety
becomes that much more important. It’s hard to justify a safety risk in the context of a
condition with no symptoms.
Quality-of-Life Treatments Drugs and devices that provide quality-of-life benefits rather
than being explicitly life-saving are necessarily held to a much higher standard of safety.
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 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 highlighted — citing the specific example of Dr. Rosemary Johann-Liang (a
former deputy division director at FDA) — 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 only incompletely 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 reputation.
Efficacy is King: What that implies
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 startups but also for the
largest of pharmaceutical or device 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 is also 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
optimize reaching the primary efficacy endpoint. “We have demonstrated 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, postmarketing safety studies take place, which, as in the case of Avandia,
may or may not be to everyone’s satisfaction.
We live in a world of limited resources. Given the high stakes involved (billions of dollars), this means that
the best minds, the most money, and the most effort is expended in an all-out effort to achieve the efficacy
endpoint. When efficacy is a priority other concerns , such as safety, are downgraded. By no means am I
implying that anything necessarily 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, of course) is when scientists and officials who do take
up safety concerns suffer harsh critique. Ironically, they suffer double jeopardy because the business of
safety studies is not known as a fast track to career success.
The primacy of efficacy over safety: How did we get there?
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 FDA’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 1962 Kefauver-Harris Amendment radically transformed 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.

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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 New York Times article “Potentially Incompatible Goals at FDA” said that “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.
1. Regulatory approval in Europe by the European Medicines Agency (EMEA) 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.
2. 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.
3. FDA monitors the vitamin and nutraceutical markets for safety only, and does not allow
efficacy claims.
Interestingly, the off-label use loophole 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 and Devices (Safely) to Market
In a CNBC special on June 4th, the 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

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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.
FDA Reform: A Proposal
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..
The proposal would be 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 which would also 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 check-list 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
encouraging 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. 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.
Ogan Gurel, MD MPhil
gurel@aesisgroup.com
http://blog.aesisgroup.com/

Drug safety clinical trials Avandia FDA reform health policy diabetes Aesis Research Group Ogan Gurel MD

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