Medical Versus Scientific Clinical Research: Time for an Immediate Change!
Alzheimer's disease and Septic or Toxic Shock as Examples
Stephen L. DeFelice, M.D.
The Panalba controversy took place in the 60's when I was a young
doctor. Panalba was a fixed antibiotic combination used to treat a
variety of infections. FDA, strongly supported by academic scientists
and doctors, established a policy requiring that each ingredient of a
fixed combination not only be individually tested but each potential
combination of them. It is interesting to note that the strongest
advocate supporting this policy was Maxwell Finland and its strongest
opponent, Louis Lasagna, both distinguished physicians and members of my
board at the time. I listened carefully and closely, first hand, to
their opposing arguments.
This policy led to our era of scientific clinical research (SCR)
not only for fixed combinations but other types of clinical studies and
relegated medical clinical research (MCR) to the sidelines.
The result? Medical discovery has been powerfully retarded and
those patients that are currently ailing as well as future ones, will
pay the heavy price of needlessly suffering from their diseases and
other maladies let alone die before their natural allotted time. How
come? SCR has enormously increased the personal effort and costs, both
formidable barriers, to conduct a clinical study, the critical step in
discovering new medical breakthroughs. Increased barriers to clinical
research, whatever they may be, decrease the discovery of new therapies.
This point should be self- evident but, for certain cultural reasons,
has eluded the health policy leaders and the media.
Both SCR and MCR share the common purpose of determining the
outcome of a clinical study. Does a drug work and is it acceptable safe?
But SCR, in addition, insists on knowing more about the scientific
details of the study. Let's return to combinations, as an example: If
there is a possibility that a combination of three drugs will be
effective in the treatment of Alzheimer's disease, a SCR protocol will
require that the individual drugs alone and all combinations thereof
must be tested as described above to determine what are their individual
contributions. A MCR approach would not, unless necessary, require such
scientific details and would directly evaluate the combination only to
determine its medical benefit. In other words, the benefit to the
patient, not science, is its primary medically justifiable concern.
Now let's look at the cost to conduct an SCR versus an MCR
clinically designed study in Alzheimer's patients and assume that the
study would take a year at a cost of $30, 000 per patient. The average
placebo response in medicine is 15-30%. To be convincing we should look
for at least a 50% treatment improvement over placebo, so let's say 25%
placebo response and 37% treatment response. Skipping over other
statistical considerations, the total cost of A SCR approach would be
$97,440,000 while that of a MCR $13,920,000!! But there are and will be
other potential combinations for the treatment of Alzheimer's and most
all other diseases. It is sadly self- evident that they will never be
tested unless our policy changes.
Furthermore, it is ironic that the SCR approach, like the MCR one,
includes the evaluation of the combination itself! Why, therefore, are
the other components required particularly when this requirement will
prevent the clinical studies from ever being done and patients deprived
of new therapies?
Let's take a look at potential new therapies for Alzheimer's
disease that are currently available such as Lipitor, sage extract,
leuprolide, huperzine A and raloxifene: Clinical studies are now being
conducted on each substance alone. It makes compelling medical sense to
select three of these substances with different modes of action and
evaluate all three together in an MCR type of study in order to increase
the probability of success within a short term period. There are
currently 4.5 million Alzheimers patients in the United States, and we
owe it to them to accelerate the discovery of new therapies for this
Here's another example that not only deals with patients in very
serious trouble but also with a potential national disaster: Septic or
toxic shock is a condition with about a 30% mortality rate that is
caused by bacterial and other toxins. It is becoming increasingly common
in our hospitals, particularly in the elderly, post-surgical
populations with compromised immune systems. There has been a number of
promising natural substances isolated by the biotechnology industry that
have shown much promise in laboratory animal studies in the septic
shock state but have, unfortunately, failed in clinical studies. Apart
from economic considerations, the next step, according to the MCR
approach, would be to select, let's say three of these substances with
different modes of action, which could complement each other. In
addition to shock, multiple deleterious effects take place such as
increased blood clotting, general decreased oxygen availability to body
tissues and significant brain damage in the survivors. As with
Alzheimers, a combination of three drugs directed to treat each
condition would then be administered to those septic shock patients who
have a highly probable rendezvous with death. There's little to lose and
much to gain.
Also, lethal toxins such as those produced by small pox or plague
that can be used by terrorists cause septic or toxic shock. This alone,
should awaken us to the critical necessity of the MCR approach!
The conclusion is that the SRC policy is clearly harmful to the
patient and must be modified. After all, in the actual practice of
medicine alls types of combinations are commonly and justifiably
administered by physicians to treat patients with diseases ranging from
rheumatoid arthritis to congestive heart failure unequivocally
supporting the reasoning behind the MCR approach. The good news is that
there are encouraging signs of change. The FDA has recently approved a
cocktail of three pharmaceuticals for AIDS patients without requiring
the prohibitively expensive SCR approach to assess its full therapeutic
evaluation. But we must have a clearly defined national policy to
encourage MCR for all appropriate conditions requiring medical
In the final analysis, when we're dealing with ways to conquer
disease to benefit the public, we should keep in mind the Chaos Theory
which believes that small events can lead to bigger ones be they
positive or negative. For example, the theory accepts the possibility
that if a tourist on Alcatraz casts a pebble in the Pacific Ocean the
ripple could somehow resonate to such a degree as to eventually cause a
highly catastrophic Tsunami somewhere in the Far East.
The SCR policy can be equated to that pebble.