(A Compelling Reason for the Need for Female Doctornauts)

Stephen L. DeFelice, M.D.

This commentary deals with my recent personal experience regarding how an FDA senior physician blocked a clinical study of a promising new therapy for women with late stage ovarian cancer who face a certain rendezvous with death.

Before I begin I’d like to explain to those of you who are not familiar with the Orphan Drug Act its history and intent.About a quarter of a century ago a very dedicated group persuaded Senator Orin Hatch and Representative Henry Waxman to support the enactment of the successful Orphan Drug Act (1983) to spur clinical research and development of pharmaceuticals for the

treatment of orphan or rare diseases.It is estimated there are approximately 7,000 known rare diseases with therapies available for only a handful.

The Act simply grants what could be considered a “use” or methods patent in which the institution that sponsors the research and obtains FDA approval will have the exclusive right to make the medical claim to doctors.

For example, if a naturally existing non-patented muscle growth factor would help muscular dystrophy patients increase their mobility, then the company that does the research could only make that exclusive claim even though other companies can market it.It is not the strongest of what is called a proprietary position, but it has worked.

The first step is for FDA to grant an “Orphan Drug Designation” in order for a company to financially support the research and development of an orphan drug. Financial support comes in the way of early write offs for investment and research into orphan drugs and extended periods of exclusivity necessary for the company to recoup its investment.

To further encourage corporate investment in rare diseases, the Congress made a very wise and compassionate decision to broaden the definition of rare diseases to include a prevalence of 200,000 or fewer patients per year.Late stage ovarian cancer patients fall into this category.

In the past I, collaborated with Dr. Claudio Cavazza the proprietor of the Italian pharmaceutical company, Sigma tau, and we were successful in obtaining two orphan drug designations for the natural substance , carnitine, for the treatment of the rare and oftentimes fatal disease in children, Primary Carnitine Deficiency, and later on for certain patients undergoing renal dialysis.

I was 28 years old when I brought carnitine into the United States in 1965 and conducted the first clinical study on it. Shortly after, while in the military service during the Vietnam War, I became Chief of Clinical Pharmacology at the Walter Reed Army Institute of Research (WRAIR) where I was responsible for designing the clinical protocols and supervising the first clinical studies for anti-malarial and anti-radiation fallout drugs among others that showed promise in animal studies.

There I met and became close friends with Major James Vick, an expert cardiovascular pharmacologist. It’s a long story but together we found in laboratory studies that carnitine blocked the common cardiac toxicity of the chemotherapeutic drug, doxorubicin or Adriamycin. We wondered whether carnitine would also block its cell kill capacity so we tested this possibility in Chinese hamster ovarian culture cells. Carnitine not only did not block doxorubicin’s cell killing capacity but synergistically increased it tenfold! It’s important to note that carnitine itself had no cell killing effect.

Later on, I decided to test both drugs in human ovarian cancer cell cultures. The study was done at Vanderbilt University Medical Center and was I excited about the results! Carnitine did increase the cell killing capacity (apoptosis) of doxorubicin.Then came a truly exciting surprise- carnitine itself had a powerful apoptotic effect. (The full story can be found at <

Since both carnitine and doxorubicin are generic substances lacking patents I decided to obtain an orphan drug designation for patients with late stage ovarian cancer in order to obtain at least some type of proprietary or patent-like position which would open up the door, though not widely, to obtain pharmaceutical company support for the clinical study. Lady luck then came my way for I found a corporate leader who promised to fund the clinical study only, however, if I obtained the orphan drug designation. We both signed an agreement which was good news indeed. Based on my past very positive experiences with the officials of the FDA Orphan Drug Division, I fully expected to obtain approval without problems.

Some of you, at this point, have probably correctly guessed that I failed. The new Director of the Office of Orphan Products Development decided to change the rules after about a quarter of a century of effective ones and make it more difficult to obtain a designation by establishing an arbitrary and irrational policy. He wrote to me: “As stated in our July 10, 2009, sponsors seeking orphan-drug designations are required to provide evidence from either in vivo studies in a relevant animal model or from clinical studies in patients with the rare disease or condition treated with the drug to meet the requirements of an adequate scientific rationale. (21 CFR 316.20(b) (4)).Your September 9, 2009 amendment does not contain this type of information.We do not believe that in vitro studies using levo-carnitine in combination with doxorubicin in ovarian cancer cell lines provide a medically plausible basis for expecting levo-carnitine to be effective in treatment for ovarian cancer”.In vivo means a study in live animals or humans which, as I said previously, was not a policy of previous patient- oriented directors who understood that the Orphan Drug Act was there to offer hope to those where existing therapies were inadequate or do not even exist which is the case for most orphan diseases.

Now the following is how a physician (and I would guess previous FDA directors but I cannot speak for them) with the concerns of patients with ovarian cancer would have viewed the total picture:

1.Since these women have almost a certain rendezvous with death and since there are no major breakthroughs on the near horizon, the patient should have the benefit of the doubt of any potential new therapy that may be available. The combination of carnitine and doxorubicin represent such a therapy.

2.Both products are on the market and could be promptly administered and clinical results evaluated in a short period of time.

3.If the results are positive all women with late stage ovarian cancer will have the therapy immediately available.

4.Doxorubicin is FDA approved for the treatment of ovarian cancer because of its tumor kill capacity. This already demonstrates in vivo activity in patients so we know that even if carnitine doesn’t add to its activity the combination will be as doxorubicin itself.

5.Though doxorubicin is effective in these patients it is only minimally so. It needs lots of help.

6.Human cancer culture cells are predictive of doxorubicin’s clinical anti-tumor or apoptotic activity.Carnitine increases doxorubicin’s cancer cell kill capacity in the same predictive model which makes it reasonable to believe that it may do the same in patients!

7.Carnitine also demonstrates independent apoptotic activity in human ovarian cancer cells which brings up the possibility of a different mechanism of action and conceivably may be effective alone.

8.Carnitine is extremely safe and there is no risk to the patient. In fact studies show carnitine reduces doxorubicin’s toxicity including long term monkey studies.

9.Carnitine kills cancer tumor cells “in vivo” in hepatic and mammary fibro adenoma tumor in animals which both supports the anti-tumor activity in ovarian cancer cells as well as a unique apoptotic mechanism of action.

10.C125, a protein found in many tissues is a biomarker for the degree of ovarian cancer tumor mass. Though not related to ovarian cancer there is a clinical study evaluating the C125 levels to the concentration of carnitine. The higher the levels of carnitine, the lower the levels of C125 male semen which supports in vivo apoptotic activity.

11.And finally, and even with the strongest of patents, it is extremely difficult to find cancer volunteer patients in general.The National Cancer Institute estimates that 5% or less of cancer patients volunteer for clinical studies.


I had no choice but to try to find a single charitable hospital that would be interested in doing the study but without substantial financial support.It has been a failure despite the fact that we had booths at the Ovarian Cancer National Alliance annual meeting and the Revlon Walk/Run for Cancer in Central Park, created a website and made calls to a number of cancer institutes and oncologists. Patients simply are not available unless there are substantial funds to motivate the oncologists to enlist volunteers.

THE NEED FOR FEMALE DOCTORNAUTS: This case history is another example which spells out the urgent need for female doctornauts. If the Doctornaut Act was operational then we would have contacted female physicians with ovarian cancer who would volunteer to enter the study without the need for large grants. ALSO, IF I WOULD HAVE BEEN GRANTED ORPHAN DRUG DESIGNATION THERE WOULD HAVE BEEN ENOUGH CLINICAL DATA AT THIS TIME TO DETERMINE IF THE COMBINATION WAS EFFECTIVE IN REDUCING C125 AND TUMOR SIZE. IF SO, SINCE BOTH PRODUCTS ARE READILY AVAILABLE, WOMEN WOULD HAVE AVAILABLE TO THEM ADDITIONAL HOPE FOR SURVIVAL AND THE TRAGEDY OF THIS ALL IS THAT EVENTS SUCH AS THIS GO UNRECOGNIZED.