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Thinking about Life Sciences

http://blog.aesisgroup.com

Monday, May 01, 2006

Drug /Device Safety Debate to Yield Big Changes, Grow More

Controversial

It’s not just medical students who speak a smidgen of Latin as many also know the famous Hippocratic
dictum primum non nocere - or “first do no harm”.
Safety is Primary
To be precise, while this phrase is not found in the Hippocratic Oath, it is nonetheless attributed to
Hippocrates as well as to the Roman physician Galen. In a sense, it is of even larger significance than the
Hippocratic Oath as it defined the whole nature of ancient medicine in that therapeutic interventions were
generally so ineffective that safety was held to a higher (indeed the highest) standard than efficacy.
The ancients were smart, and in realizing that the risk-benefit balance was so much against them, they
insisted that physicians focus more on not harming their patients than on necessarily treating them. To put
this in perspective, the Code of Hammurabi specifies that a physician whose surgery has caused a patient
to lose an eye shall himself lose a hand.
The Fall of Safety
In the world of modern medicine (roughly defined as starting in the early 20th century until the last decade
of the 20th century), the risk-benefit profile of interventions was completely turned around. Medicine
(such as antibiotics) and surgery (such as coronary bypass) were so remarkably effective that – while safety
was not patently ignored – it became less of a significant factor in the context of the overall risk-benefit
profile. While patients have died from antibiotics (and they still do), the overall benefit is so
overwhelmingly positive that the decision to treat is quite clear.
The Rise of Safety (again)
For a number of reasons, this paradigm is changing. We are now in transition to a world of post-modern
medicine where the principle of primum non nocere will take on greater significance. Illustrious companies
such as Merck (with Vioxx) and Guidant (with its short-circuiting defibrillators) have literally been caught
in the middle of this transition. Thirty years ago (during the heyday of modern medicine), it is likely that
these tragic situations may not have existed or may not have raised the same firestorm of controversy that
they have today. By analogy, consider the situation with smoking bans in public spaces (specifically in bars
and restaurants). Some cities (most notably Chicago) have such bans while others (such as Cleveland) do
not. A statewide smoking ban in Ohio, by the way, is under consideration. As a society, we are in a
transition phase in estimating and regulating the risk-benefit profile attributable to second-hand smoke.
What are the factors behind the transition from modern to post-modern medicine?
1. Greater Efficacy of Medicine
Modern medicine is a victim of sorts of its own success. For the ancients, treatments were so
ineffective that safety was paramount. We now have treatments that are so effective that a few
deaths (even if absolutely miniscule) become unacceptable. The risk-benefit profile has shifted.
2. The Coming of Age of the Baby Boomers

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It’s not that previous generations were so oblivious to safety. However, it is well known that
baby boomers have higher expectations of service, higher expectations of outcomes and higher
expectations of safety. In many ways, the health-care system is being driven by the needs and
expectations of these aging baby boomers. The “miracles of medicine” are now taken for
granted. A higher standard (ironically harking back to the days of the ancients) is now
demanded. “First do no harm!”
3. The Rise of Chronic Diseases
A combination of effective treatment for acute conditions and a longer lifespan is making
chronic disease much more prevalent. The world of post-modern medicine is defined more by
chronic conditions rather than by immediately life-saving acute interventions. The diagnosis of
cancer, for example, implies less of a drama-filled surgery (where the patient either lives of
dies) than by long-term treatment and management. While more people live with cancer today,
that also carries with it the risk of long-term treatment and its associated aggregate safety risk.
4. Aggressive Prevention
Like the long-term treatments that come with chronic disease, we are also increasingly
embracing the concept of aggressive prevention in which not only lifestyle changes but also
medications (such as statins) are used to prevent diseases.
5. Rise of Quality-of-Life Treatments
Drug-eluting stents have been shown to provide no additional mortality benefit over
bare-metal stents. However, by reducing restenosis rates, they do decrease the need for
patients to have a repeat procedure and thus in this manner improve quality of life. On the
pharmaceutical side, the rise of medications that improve quality-of-life, such as Viagra, rather
than strictly speaking improving mortality or morbidity, have clearly been on the rise. In all of
these cases, there is a much higher standard for safety to bear.
Consider that Cox-2 inhibitors (i.e. Vioxx) have been controversially considered as a preventative
prophylactic for colon cancer. If this had come to pass, the adverse outcomes and deaths that we saw for
the simple treatment of arthritis, for example, would have paled in numbers to those who would have
taken Vioxx in the hopes of preventing colon cancer.
The Role of the FDA
Given all these changes and the recent Merck and Guidant developments, we are now amid a storm of
controversy that has come to a head just this past week with the release of a new GAO report.
Commissioned by Iowa Sen. Charles Grassley, the report is deeply critical of the FDA’s current approach
to drug safety. Organizational dysfunction, bureaucratic politics and ineffective enforcement with respect
to drug companies were all cited as factors in compromising drug safety evaluation.The FDA has also
commissioned its own drug safety report with the Institute of Medicine, which is due to be released in
July.
The FDA has not been standing still. A new Critical Path initiative to “stimulate and facilitate a national
effort to modernize” the drug and device approval process is under active development. The FDA is also a
victim of its own success. The agency came into being during the period of pre-modern medicine typified
by “snake oils” and all sorts of generally benign but nearly universally ineffective potions and tonics. The
focus back then (the FDA was founded in 1906 during the Theodore Roosevelt administration with the
Pure Food & Drugs Act) was to protect the public against such ineffective medicines.
We now have a system that is unparalleled worldwide in terms of the rigorous emphasis on demonstrating
efficacy prior to market approval. Exactly 100 years later, we have gone from pre-modern medicine to
modern medicine and now post-modern medicine and the landscape (and regulatory expectations) are very
different.
The bottom line is we are likely to see even more controversy and changes ahead. Even though most of
these efforts are aimed at drug development and approval, it is actually more likely that even more

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significant changes will happen on the medical technology and device side. To some extent, this is because
the process for approval is less developed (read: less ingrained) for this sector. Another reason is that the
mainstay of drug safety evaluation lies in extensive post-market surveillance whereby doctors and drug
companies report adverse outcomes after drug approval with the idea that the larger statistical numbers
will be more sensitive to “small” safety concerns. For many devices, however, a safety concern “after the
fact” can be a significant problem as many devices will potentially require another (often more invasive)
surgery for their removal.
Stay tuned! I’ll be sure to keep you posted as the debate evolves.
Ogan Gurel, MD MPhil
gurel@aesisgroup.com
http://blog.aesisgroup.com/

Practice of Medicine Drug safety device safety Merck Guidant Vioxx FDA Reform Aesis Research Group Ogan Gurel MD

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