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Stephen L. DeFelice, MD

DeFelice Commentaries

NREA, Nutraceutical Research and Education Act

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Senator Harkin on FIM



The Patient Always
Gets Screwed

Promising Ovarian Cancer Therapy Blocked

Carnitine-Ovarian Cancer Promise and a Failed Attempt at a Clinical Study

When Was The Last Cure?

Translational Science - How Doctornauts Can Help

Senator Tom Harkin (D-IA) has been one of the leaders in Congress on Translational Science.

Doctornauts Barry Marshall and Lukas Wartman: Living Proof of the Urgent Need for the Doctornaut Act

View the Discussion Draft of the Doctornaut Act Prepared by Former Senator Bill Frist.

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 condition.

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 treatment.

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.