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Thinking about Life Sciences

http://blog.aesisgroup.com

Sunday, July 22, 2007

Avandia, the Drug Safety Debate and How to Get a Nobel Prize

Drug (and device) safety has been one of this blog’s recurring themes. Last year’s article “Drug /Device
Safety Debate to Yield Big Changes, Grow More Controversial” highlighted why safety is a growing issue
and, very pointedly, forecast that this controversy would continue. Indeed this prediction has been correct.
Throughout the medicine’s history, safety has always been important. Hippocrates’ most famous dictum (not
in his oath but rather an attributed aphorism) is that of primum non nocere - “First, Do No Harm” which has
been a guiding principle for physicians for several millennia.
For anyone reading the headlines, safety has recently gained in importance and the reasons for this trend can
be summarized as follows:
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 (or convenience) 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.
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.
Safety: Who’s to Blame?
The vast majority of recent safety problems (Vioxx, defibrillators, Fen-Phen and most proximally Avandia)
are not, in my opinion, necessarily the result of a malevolent medical-industrial complex or lax physician-
scientists or an ineffective FDA. While apportioning blame is not the purpose of this blog, two points are
important to consider: industry denial and system bias.
Industry denial: The pharmaceutical (and by extension biotechnology and medical technology) industries
are not acutely aware (and perhaps in denial) of this societal change towards safety. Twenty or thirty years
ago, these wouldn’t have been issues and senior executives of these firms who were brought up through the
ranks during the 1960s and 1970s are frankly surprised at the unprecedented response they’ve experienced
over the past half-decade or so. The world is different now.
System bias: Second, there may also be certain system biases that prevent individuals and organizations for
fully focusing on this safety issue. My article in response to the Avandia headlines “FDA: Tortoise, Hare or
Something Else” pointed out how changes in the FDA regulatory emphasis (e.g. more on safety and less on
efficacy) could potentially avert such safety failures in the future. To summarize that FDA reform proposal:

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The requirement to demonstrate efficacy as mandated by the Kefauver-Harris amendment of 1962 is a major
contributor to the complexity and duration of new drug approvals. In addition, an unintended consequence of the
efficacy requirement may be a compromise in the priority for safety. Because efficacy is so important for approval,
priority goes to proving efficacy in large, statistically significant clinical trials which is a long, arduous and costly
process. In a world of limited resources, the emphasis on efficacy means that, despite good intentions, less thought and
effort is necessarily given to evaluating safety – ending up being largely relegated to post-market surveillance. In order
to speed up drug approval as well as devote more resources to comprehensive as well as pre-market safety studies, it is
proposed that the Kefauver-Harris efficacy requirement be scrapped or at least significantly reduced in importance. In
fact, with the advent of personalized medicine whereby large, randomized, double-blind and controlled clinical trials
become increasingly more difficult to meaningfully design and with our present internet age, in which it is much easier
for the market to determine and share information about efficacy, the efficacy requirement has, indeed, become less
relevant. Finally, it should be recognized that with the rapidity by which new technologies are developed, efficacy
results may, in fact, often be obsolete and irrelevant by the time they are obtained. Efficacy is a relative truth; safety is
a durable truth.
Sunday’s New York Times has an article by Stephanie Saul “Drug Safety Critic Hurls Darts From the
Inside” commenting on the personal and professional backdrop behind Dr. Steven Nissen’s questioning of
the safety of Avandia and his “shaking up of the nation’s pharmaceutical industry.” Clearly, Dr. Nissen is
on a mission – an important one – but the NY Times article highlights how this has not been without
controversy; delving deeper into the issue may help us to understand what drives medical science and
ultimately impacts patients.
Do you want to get a Nobel Prize?
Many scientists – especially medical scientists – are strongly driven by a desire to benefit society, to find
that cure that will eliminate disease and suffering for thousands, if not millions of patients. What greater
goal is there? The great Harvard surgeon, Dr. Francis Moore wrote a marvelous book “A Miracle and a
Privilege: Recounting a Half Century of Surgical Advance” where he weaves the story of his personal
history and professional glories. The glorious successes of Dr. Moore and surgery in general put him on
the cover of Time magazine back in 1963 – the apogee and heyday of academic medicine.

Curing disease, however, is just one of the values upheld by science. There are other reasons – perfectly

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legitimate and perfectly human – why scientists do what they do. A sense of aesthetic, a desire for fame,
the need for money all enter into the equation. The ancient Latin phrase pulchritudo splendor varitatis
(“beauty is the splendor of truth”) indeed suggests that beauty and truth are interrelated. Einstein was
once noted to have said that he gave his highest praise for a good theory on the basis not that it was
correct but that it was beautiful. There are other biases in the practice of science of a more mundane, if
not even more important sort. They are:
The Bias Towards Cures: I wrote about this in the article “What’s More Important in Medicine:
Diagnostics, Therapeutics or Prognosis?” whereby our medical system and our research establishment
have put therapeutics (as compared to diagnostics or prognostics) on a pedestal. Therapeutics is where all
the talent, money and resources go. Indeed, if you wish to obtain venture capital (VC) funding for an idea,
you would benefit from using some buzz words that excite the imagination of your would-be financier.
One of these VC hot buttons is “unmet need” which implies that your idea is addressing a disease which is
awaiting a cure.
The Bias Towards the Positive: This was likewise addressed in the article “Subtle But Powerful,
Publication Bias Goes Beyond Financial Incentives” which highlighted how negative results such as a
drug study that fails or an unsuccessful experiment typically do not find their way into the scientific
literature. What scientist wants to advertise to the world that their experiment or their wonderful
compound ultimately did not succeed? There are few exceptions yet those “negative results” that do make
it to press – such as the famous Michelson and Morley experiment can actually have a strong impact on
the field.
The Bias Towards Efficacy: Safety is a rather pedestrian, unglamorous topic and the brightest minds (in
academia, industry and the FDA) do well by focusing on figuring out how and why drugs work rather than
understanding what makes them safe. Again, this topic was discussed in the article: “FDA: Tortoise, Hare
or Something Else” and explains why, in a world of limited resources, safety studies can unintentionally
get less emphasis than would otherwise be preferred.
The Bias Towards Beauty: Simple, elegant and beautiful experiments are held in highest regard by the
scientific community. Meticulous, vast number crunching such as that done in the sort of meta-analysis
that Dr. Nissen conducted perform a valuable service but are not necessarily upheld as paragons of great
science. There are technical reasons for that relating, for example, to the statistical challenges involved but
ultimately such value judgments fall to a matter of style than necessarily a better avenue towards the truth.
In summary then, if you want to get a Nobel Prize in today’s world (or at least get published), here’s what
you do.
Find a problem that cures a disease, make sure your experiments come out positively, don’t get hung up too much on
safety and make sure your experiments are elegantly beautiful.
Publish or Perish
Many are familiar with the phrase “publish or perish,” It is the mantra of academic success. Therein lies,
however, the dilemma. Some ideas, such as those that don’t have to do with necessarily curing a disease,
or that highlight a negative result, or that are concerned more with safety than efficacy or that are
downright ugly carry a risk of not being well-received by the scientific community – whether or not they
are true. Some of the controversy around the Avandia affair has, indeed, been backlash against what are
perceived by some to be Dr. Nissen’s unconventional methods reaching out, for example, directly to the
media rather than allowing the process to make its way entirely through the scientific community. As the
NY Times article wrote: “Dr. Nissen also has critics, who say he seeks the spotlight as much as the safety
of medicine.”
If I were to put myself in Dr. Nissen’s position, however, I could very well imagine that going through the
regular channels would ultimately compromise the impact and significance of the message. Nissen did
controversially point out on the ABC program Nightline that the “deaths caused by Avandia could ‘dwarf’
the carnage of Sept. 11, 2001” and thus one could understand that relying exclusively on the conventional
channels could potentially compromise patient lives. Sometimes to the chagrin of others, doctors flout

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societal constraints for the benefit of their patients and this can sometimes be similarly expressed in a
broader, more public health context. People may chafe at that but ultimately, wouldn’t you want your
doctor to have that view when it came to your health?
[This is why, incidentally, the Surgeon General position must be as unpoliticized as the Attorney
General role … but more on that in another posting]
Bottom line then: you may or may not agree with Dr. Nissen’s approach - considered unorthodox by
some - but I do believe it is certainly understandable.
Erythropoeitin in 1989
Some of you who have read the article “Subtle But Powerful, Publication Bias Goes Beyond Financial
Incentives” may see parallels in my experience (as a medical student) writing about erythropoietin back in
1989 and these themes of scientific bias.

Back then I wrote a letter to the Annals of Internal Medicine commenting on what was then one of the
first reported studies evaluating the use of erythropoietin (EPO) in pre-dialysis patients. By the way, if
you read that early EPO article you’ll see that it is very much aligned along those scientific virtues of cure,
positivity and efficacy.
In any case, to paraphrase my basic points:
That 1989 letter – which you can find here –acknowledged that EPO “clearly ameliorated the anemia”. I also
pointed out that “it is important to consider the possibility of two significant side effects: systemic hypertension as well
as an acceleration in the progression of chronic renal failure”. I based my conclusion on the fact that while the original
paper stated in both the abstract and its summary that there were no changes in mean blood pressure, careful reading of
the methods section revealed that three of the 11 treated patients required an increase in their anti-hypertensive
medications. I interpreted this to mean that this dangerous, hypertensive side effect was in fact masked by the change in
anti-hypertensive regimen and that the conclusions of the paper could – to put it graciously – be misinterpreted. To put
it less graciously, the authors were covering up a “negative result” (e.g. a potential adverse effect) by medicating it away
and not forthrightly presenting that in the conclusions to their paper.
At that time, I actually did elicit the input of two quite prominent renal professors at the Columbia
University College of Physicians & Surgeons where I was a medical student. They indeed provided me
with some assistance and in return for their help I offered to also put their names on the letter. I had
thought they would gladly take me up on the offer but curiously (at least to me at the time) they declined.
They were likely being gracious to the extent that the core ideas of the letter were mine but in retrospect, I
also suspect that despite their belief in the validity of these points they did not want to be associated
publicly with something that was not curative, was not positive and not focused on efficacy.
The famous lines “the thrill of victory and the agony of defeat” from ABC’s “Wide World of Sports”
highlight the stakes involved in intense competition. It’s certainly fine and to be expected that scientists are
competitive; that competitive spirit benefits the search for truth and benefits all of us as we are all patients at
some point. The challenge lies in what, in fact, they are competing for? Is it a Nobel Prize, is it money, is it
the next best cure, is it a safer way to develop drugs? I suspect that the first three are perfectly
understandable; the last one is, alas, for many scientists a fast track to the agony of defeat. I suspect that
some of Dr. Nissen’s methods were aimed to avoid that agony. This work may not put him on the fast track
to a Nobel Prize (at least for this part of his varied accomplishments) but it is important, innovative and
valuable to society in its own right.
For a great video of that famous “agony of defeat” clip and to see how Vinko Bogataj was transformed into a
moment of victory, see: http://www.youtube.com/watch?v=PGr7jYkCidA.

Ogan Gurel, MD
gurel@aesisgroup.com
http://blog.aesisgroup.com

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Druge Safety Device Safety Avandia Steven Nissen Francis Moore Medical Science Nobel Prize Aesis Research Group Ogan Gurel MD

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