For Publication, NY Times, August
1, 2001
Dear Editor,
Drs. Shaywitz and Ausiello thoughtful essay(NYT Week in Review 7/29/01)
reminds us that while all clinical research involves some risk, it is also
possible to inform subjects of risks and to protect subjects from unnecessary
risks. In order for subjects to be protected and to knowingly accept risks, not
just clinical investigators and institutions but also the sponsoring
pharmaceutical company must be considered as potentially jointly responsible.
The requirement to meaningfully inform patients who are clinical research
subjects is central not only by way of respecting their autonomy but also by way
of protecting subjects from unnecessary risks and early intervention and damage
control to reduce the level of necessary risk. A well informed research subject
can not only make a meaningful choice as to clinical research trail
participation but can also alert the clinical investigator earlier and more
effectively as to emergent side effects. This is why an informed consent process
including the assessment and enhancement of patient competency to communicate
even unexpected side effects is important. However such an informed consent
process involves sponsors allocating sufficient funds and to allow for the
training of clinical investigators and disclosing sufficient information in a
meaningful manner to allow for meaningful informed consent.
According to the Nuremberg Code and its progeny codes for clinical
research, in addition to clinical investigators, sponsors are accountable for
protecting human subjects from unnecessary risks. Support of such codes via a
reasonable and fair policy delineating sponsoring pharmaceutical company
responsibility is essential to avoid putting especially vulnerable patients at
risk for sponsors shopping for the most compliant and cheapest clinical
investigators and Institutional Review Boards. Without any sponsor
accountability it is foreseeable that an atmosphere will be created where
diligent clinical investigators and institutions who emphasize that informed
consent is not a mere pro forma exercise but a process will be pressured by the
clinical research market to lower their standards for informing and thus
protecting vulnerable human subjects.
Yours very truly,
Harold J. Bursztajn, M.D. Associate Professor of Psychiatry Harvard
Medical School co-Director, Program in Psychiatry and the Law Harvard
Medical School @ Massachusetts Mental Health Center
(NYT Week in Review 7/29/01)
The Necessary Risks of Medical Research
By DAVID A. SHAYWITZ and
DENNIS A. AUSIELLO
"FATAL Disease Cured by New Therapy" — it's the
headline of researchers' dreams.
As modern biological science generates an ever-rising flood of promising
discoveries, from the potential of embryonic stem cells to the nature of the
human genome, the idea of one day being able to cure cancer, Parkinson's disease
and other terrible illnesses no longer seems so fanciful. In fact, there is
often an exhilarating sense these days that a cure for something — or for
everything — is near.
It is not surprising, therefore, that following the recent deaths of
Jesse Gelsinger and Ellen Roche in government-sponsored clinical trials at two
major American universities, some have questioned why, in the era of transgenic
mice and computer modeling of molecules, we still experiment on people. As one
patient recently asked, "Why don't they just give us the good stuff?"
The answer is that it is terribly difficult to figure out what the good
stuff is. And while the lab can identify promising new therapies, proof that
they work can only come from clinical research, in which real people are
carefully administered medicine and the results are meticulously documented.
More often than not, even the most obvious and intuitive of treatments provide
wholly unexpected results.
A classic example is the group of drugs called beta- blockers, medicines
known to decrease the strength of heart muscle contraction. For years, they were
not given to patients with weak hearts, until clinical trials demonstrated they
actually helped patients live longer.
Or consider the use of bone marrow transplants to treat patients with
advanced breast cancer. In part because other treatments were often only
minimally effective, transplant seemed like a promising alternative. So
promising, in fact, that it was difficult to set up clinical trials, as no one
wanted to be randomly assigned to the non-transplant group. It took a decade
until several studies concluded transplant was no better than conventional
therapy.
Equally revealing are the raw statistics of new drug discovery: for every
5,000 compounds evaluated for treatment, only five will make it to clinical
trials, of which just one will make it to market. How can the best scientists
with the best labs money can buy be wrong 4,999 out of 5,000 times?
Ever since the discovery of DNA's structure in 1953, it has seemed only a
matter of a few years before biology became a predictable process for
understanding diseases at the most fundamental level, and then designing cures
for them.
It was in this hope that special programs were established at the
National Institutes for Health and other research institutions to encourage
doctors to pursue this new science. As a result, many of the country's most
prominent doctors — including J. Michael Bishop, chancellor of the University of
California at San Francisco, and Harold Varmus, president of Memorial
Sloan-Kettering Cancer Center — made their reputations through elegant
laboratory investigation. Dr. Bishop and Dr. Varmus received the Nobel Prize for
their discoveries.
Recently, however, doctors have begun to ask why the cures that molecular
biology promised have not appeared, and to wonder if the laboratory is the best
place to pursue them. Patients continue to suffer from cancer and heart disease,
despite national crusades against both. And treatments for molecular diseases
like sickle cell anemia and cystic fibrosis have evolved little, even though the
genetic defects have been exquisitely defined.
The problem is that most biological systems remain too complex for
science to predict how they will react to theoretically valuable treatments. And
for that reason, the work that has actually changed how doctors treat the sick
has come mostly from those researchers who focus on patients, not genes. For
example, landmark population-based studies like the British Doctors; Study, the
Framingham Heart Study and the Nurses' Health Study revealed the risks of
smoking, hypertension and high cholesterol, and encouraged treating these
problems aggressively.
Overall, it is becoming increasingly apparent that what really makes a
difference for patients is not a doctor's detailed knowledge of the biology, but
rather, his or her familiarity with the existing clinical literature, and
particularly with current clinical trials. The best evidence of this is that the
doctors other doctors turn to for care are usually not medical scientists, but
scholarly clinicians fluent with the best data. Some have even had a role in
generating it.
This is not to say that laboratory science has been neglected. Laboratory
scientists are playing increasingly important roles in clinical research — for
example, by suggesting disease genes for which patients might be screened. This
year alone, such approaches have led to discovery of genes responsible for some
forms of liver disease, lung disease, and diabetes in infants.
In addition, while drug discovery in the past relied heavily on trial and
error, the medicines of the future will result from a careful study of the
underlying biology. Already, the anti-cancer drug STI-571 and the protease
inhibitor class of anti-H.I.V. medicines were developed with a specific drug
target in mind.
Still, predicting how a new drug will work in the human body remains well
beyond the reach of science. The clinical trial, not scientific theory, remains
an absolute necessity.
The stakes are high. Clinical research is directly responsible for many
advances in modern medicine, as well as for ensuring that patients do not waste
time, money and hope on ineffective therapies. At the same time, as science
generates ever more promising research leads, clinical investigators will feel
pressed to work faster, with fewer safeguards.
When medical research causes the death of a human being, the wish to stop
using people as test subjects is perfectly understandable. Such deaths should
remind researchers of their absolute responsibility to explain experimental
treatments to patients clearly and fully, and to do everything possible to
minimize risks. But risk, in the end, defines why the research is being done.
And even the most careful scientists and the most obsessive oversight cannot
eliminate it entirely. David A. Shaywitz is a medical resident at Massachusetts
General Hospital and a clinical fellow at Harvard. Dennis A. Ausiello is
physician-in-chief of Massachusetts General Hospital and Jackson professor of
clinical medicine at Harvard.