Tanned and trim, Dr. Stephen L. DeFelice stepped lithely into the medical office on the Upper East Side he uses for Manhattan get-togethers. It was late on a July afternoon, uncomfortably warm outside. Dr. DeFelice wore a crisp navy blazer. A bow tie, his signature item of apparel, draped around the unbuttoned collar of his shirt.

I had arrived some minutes before, taken a small elevator to the air-conditioned conference room on the second floor, and seated myself at an oval wood table burnished to a high gloss – time enough to feel that an Italian flair for enjoying life's sensory pleasures directed Dr. DeFelice to choose this meeting place. The room, elegantly furnished, looked onto the street through three French windows. A bamboo sapling in a planter stood before each outer window. One starkly utilitarian furnishing struck my eye: a white chalkboard on a side wall. Dr. DeFelice tends to scratch words and phrases on the board for emphasis during extemporaneous presentations, an academic touch. After meeting him in 1993, I've come to appreciate that at heart he is a physician who has been searching since 1965 for innovative, quicker ways "to hit diseases," as he puts it, "that do ugly things to people."

I've published two interviews with Dr. DeFelice in the Townsend Letter (July and October 2007). The first interview dwelt on nutraceuticals and the Nutraceutical Research and Education Act (NREA), legislation proposed by Dr. DeFelice and introduced in Congress by Representative Frank Pallone (D-NJ) in 2000.

Dr. DeFelice has a knack for coining memorable terms. He dates the coining of "nurtraceutical" to a leisurely stroll in the Piazza Navona in Rome in 1989 after a superb dinner topped off with a smooth grappa. (The Oxford English Dictionary now includes the word "nutraceutical" and credits him for the coinage.) He had been seeking a single word or sound-byte phrase that encompassed foods, compounds in food, dietary supplements, herbal remedies, functional and designer foods, etc., all potentially useful in treating and preventing disease. He felt that if he could give this nebulous field an identity, Congress might enact legislation encouraging clinical research on all of them.

Concluding my first interview with Dr. DeFelice, I applauded him for devising a pragmatic mechanism – the NREA – for approval of nutraceuticals, one that fully recognizes that under our free-enterprise system, capital won't gravitate toward research without a market payoff. I underscored my fundamental interest in the NREA; if passed, it might bring about a change in the treatment paradigms for many diseases – from late-stage, invasive, costly interventions to prevention or early-stage-modulations, which are much less invasive and much more cost-effective.

My second interview with Dr. DeFelice began with his "Doctornauts" initiative, a proposal allowing physicians to volunteer as subjects for clinical studies with minimal restrictions on participation. My interview then concentrated on what Dr. DeFelice believes is our nation's "cultural blind spot" to the importance of medical research. As prime factors in perpetuating this blind spot, he pointed a finger at the FDA, medical ethicists, and consumer groups focused on the safety of new drugs rather than on the urgent need for more effective drugs for diseases resistant to current treatment. He especially decried the intrusion in medical decision-making by third parties, a trend gaining momentum since the 1960s. Dr. DeFelice largely attributes this policy development to the notion that the FDA and experts appointed by the FDA are more competent than patients and doctors in determining access to experimental treatment. He viewed such intrusions as a "rape of patients' rights" (his sound-byte phase) and shredded the rationales put forward by medical ethicists to condone them.

Dr. DeFelice's first book, Drug Discovery: The Pending Crisis, published in 1972, warned that new medical therapies can only be discovered by conducting clinical trials, the crucial step in the discovery process. Increase the cost, risk, and other factors (such as labor-intensive procedures) of conducting clinical studies, he contended, and fewer medical discoveries will be made. Ultimately, who pays the price? he asked. Patients!

Recognizing that consumerism and its obsession with safety was on a rapid unstoppable rise and that the 1962 amendments to the Food, Drug, and Cosmetic Act, which authorized the FDA to approve drugs on the basis of efficacy as well as safety, would further hinder clinical research, Dr. DeFelice broached his proposal for MDs to volunteer as subjects in clinical trials. Twenty years later, he hit on the memorable word "Doctornauts" for the proposal. That caught the attention of Senator Bill Frist (R-TN) when Frist was majority leader in the Senate. (A physician, Bill Frist has since left the Senate and returned to the field of medicine.) Frist urged Dr. DeFelice to develop the idea for a Congressional bill. Dr. DeFelice has been working on it, confident that "Doctornauts" would almost immediately, dramatically, increase new therapies for patients. The support technology, he has observed, already exists, but a quick means for clinically evaluating most of these discoveries is lacking.

This column expands Dr. DeFelice's comments on consumer groups who unwittingly hinder clinical research; it also offers his thoughts on the media's apparent disinterest in the acceleration of medical research and, particularly, their penchant for playing up adverse incidents and outcomes unexpectedly occurring in clinical trials.

I met with Dr. DeFelice in his Manhattan office last July for a briefing on his theory of how a combination of nutraceuticals, hormones, and antioxidants might reverse the mental and physical deterioration characteristic of the aging process, so I'll summarize his theory as well.

Consumer Groups
MC: In my interviews with you for the Townsend Letter, you recalled meetings with medical consumers concerned about certain ailments. You were attempting to enlist them in backing initiatives you had made that could expedite discovery of treatments for these ailments. Yet they were deaf to your appeals. How do you explain their behavior? Why this impenetrable block to what might benefit them?

SD: These people don't do their homework regarding the medical discovery process and the crucial need for making clinical research less risky and costly. If they did this homework, they would perceive the importance of clinical research not only for nutraceuticals, but for pharmaceuticals, medical devices, etc.

MC: In 1974, William Wardell, MD published a paper in the Journal of the American Medical Association. Titled "Drug Development, Regulation, and the Practice of Medicine," it contained the following paragraph:

The medical profession should point out that existing drugs are inadequate to deal with most of the diseases we face. The object of legislation in this area should be to protect the public against all diseases, not just iatrogenic ones. In my opinion, the public interest would be well served by policies designed to stimulate the development and introduction of better medicines…Public interest organizations should be educated to recognize the aforementioned point. The sick patient who needs more effective or safer therapy than is currently available will derive cold comfort from the present activities of the consumer groups who claim to represent his interests. If consumer groups fail to represent the patient's paramount needs, a separate organization is obviously required.

That paper appeared a generation ago. The public interest organizations with the most clamorous voices sing the same tune today; safety first, discovery of better drugs by and by. How do you rate prospects for the emergence of "a separate organization" that represents "the patient's paramount needs?"

SD: The prospects are poor and will continue [to be] poor because the consumer groups you refer to have a blind spot when it comes to recognizing that medical discoveries hinge on clinical research. Again, the underlying reason for the persistence of this cultural blind spot among these groups is their failure to do the necessary homework; failing to do the homework, they don't perceive the link between clinical research and the medical discovery process.

MC: You and I, Dr. DeFelice, have been following a case working its way up through the Federal courts – Abigail Alliance v. von Eschenbach. Early in October 2007, the Washington Legal Foundation (WLF), in an amicus curiae brief, petitioned the US Supreme Court to hear arguments on whether terminally ill patients have a constitutionally protected right to seek treatment with a drug not fully approved by the FDA when no other FDA-approved drugs are available.

The Abigail Alliance for Better Access to Developmental Drugs began this lawsuit five years ago. (The WLF joined in on behalf of the Abigail Alliance in 2003.) In May 2006, a panel of the US Court of Appeals, District of Columbia, ruled in favor of Abigail; then, in August 2007, a divided Appellate Court sitting en banc reversed the panel ruling.

Here are two patients' rights groups petitioning the Supreme Court to agree that once the FDA has determined, after initial trials, that a potentially life-saving investigational drug is sufficiently safe for expanded human trials, the Fifth Amendment's Due Process Clause gives terminally ill patients (and their doctors) the "right" to try the drug.

Most of these patients have no alternative; they won't survive the entire FDA 3-phase process of clinical testing and review. [In conversations with Dr. DeFelice for my interviews with him in Townsend Letter, he's repeatedly noted that Phase II trials are the critical test in demonstrating whether a substance has potential clinical benefit.]

Do you think there's a ghost of chance that the Supreme Court will even hear this case, much less issue an opinion counter to the FDA's drug approval policy?

SD: It would be very encouraging if the Court ruled in favor of the patients. But even if it doesn't, I still think there's plenty of room for us to proceed with my Doctornauts initiative in the courts, if Congress won't pass a law authorizing the proposal.

At 71 years of age, and not being a lawyer, I will need the help of more vigorous, legal groups. My plan is to find the appropriate group or groups and raise money to support the effort. Make no mistake, however; I will be the captain of the ship. I just have too much know-how to walk away.

In the final analysis, who truly represents the patients? We have forgotten to ask them. If asked, they would say, "If I have a disease or disability, get rid of it: If I don't, prevent it."

The Media
MC: You set off on a media tour in 1972 to promote Drug Discovery: The Pending Crisis. You expected the media to comprehend that medical discoveries depend on clinical research. Their reception of the book's message didn't match expectations. What is most memorable about that tour?

SD: I studied very hard in preparation, and at the end, the media hadn't grasped the message at all. They narrowed in on the risks involved in clinical research. I don't recollect anybody in the media who supported clinical research or pursued its benefits.

They received me with suspicion, almost hostility. Sometimes subtly, sometimes not, the media treated me as a throwback to the doctors who tortured people in experiments during the Nazi and Stalinist eras.

MC: Disappointed yet not daunted, in 1976, you established the Foundation for Innovation in Medicine (FIM), a non-profit organization, and you sought exposure in the media again. How did they respond on your second go-around?

SD: FIM seemed to me a brilliant idea. Its primary mission was to educate the mass media about the importance of clinical research. I assumed the mass media had an extremely high level of interest in health matters, so I figured they would see the light, so to speak, and create a mighty wave of public opinion that would move Congress to enact laws effectively diminishing barriers to clinical research, thus spurring the discovery of new medical therapies.

I ran into the same stone wall I ran into on my media tour four years earlier, affirming my initial impression. Our nation and the media have no conception of the centrality of clinical research in the discovery process; it's not on either one's radar screen.

My attempts to obtain contributions for FIM's mission reflect that clinical research is nowhere near appearing on the national radar screen, much less the media's – then and now. I estimate that a grand total of roughly $25,000 in contributions have been donated to FIM since it was formed to the present (2006) – 30 years, less than $1,000 annually.

Aware early on that this would be the case, I decided I had no choice but to fund FIM's efforts personally until Congress stepped in with supportive legislation. I paid for the services of a number of public relations firms, for holding conferences, and for putting out books, position papers, and other media vehicles. The mass media remained stubbornly and inexcusably resistant.

MC: Despite two encounters with the media that would have soured most people, you tried them again in the 1990s. Any difference this time?

SD: I was on the verge of aborting efforts to stir interest in accelerating clinical research. Then, another idea on how to draw attention to the importance of clinical research popped into mind, one I thought was truly brilliant, which could not fail to engage the mass media and prompt Congress to pass legislation. I conceived the Nutraceutical Research and Education Act (NREA).

Between 1993 and 2000, FIM held high-level nutraceutical conferences yearly, most of them at the Waldorf Astoria in New York City, a few in Washington, DC. Manhattan was the media center of the world, Washington, DC not far behind, so I expected heavy media coverage. FIM invested substantially in a publicity campaign to attract the media to these conferences. The result? With perhaps two exceptions, no mass media folks attended; thus, the media exposure necessary to support passage of the NREA never materialized.

What puzzled and disturbed me most was that virtually all the mass media people in both New York City and DC were only a short cab ride away, yet they didn't see enough in these conferences to pay the fare. This finally persuaded me that, barring something unusual, any attempt to convince the media of the enormous importance of clinical research was destined for failure.

MC: I attended all but one nutraceutical conference at the Waldorf, including the last in 2000, when Congressman Frank Pallone announced that he had introduced the NREA in Congress. I always checked the list of attendees, full of upper-echelon representatives from the food industry, pharmaceutical companies, and medical academia. They were certainly willing to ante up the hefty fee for attendance. That the media ignored all this puzzled me too.

Eventually, I concluded that the media couldn't find a story in the conferences. To them, the presentations must have all seemed educational. Even Pallone's announcement wasn't newsworthy to them; they know well that bills are forever being introduced in Congress, but few make it out of committee to floor debate, and relatively much fewer get passed and signed into law. Convene a conference to announce passage of the NREA – that might rate coverage.

How do you account for the media staying away?

SD: Marcus, I hate to say it publicly, but the media folk who cover health matters are an intellectually lazy bunch. By far, the most common question asked by my media colleagues is, "Where is the story?"

Here it is. Modern technology offers us definite opportunities, opportunities only now opening, to increase our medical weapons against disease and disability – if we can put them through clinical trials more easily and quickly. The NREA is one means to accomplish this. I lean these days toward Doctornauts as the most effective means of getting this done. Tens of millions patients are needlessly suffering and prematurely dying. Doctornauts is a solution with a strong probability of significantly helping such patients. If that's not a story worth covering, what is?

MC: The stories about health matters that the media seize on often deal with serious adverse effects of drugs in trials or with negative outcomes in tests of dietary supplements. That indicates to me more than laziness; I question whether the reporters possess basic knowledge about clinical trials.

Unforeseen adverse effects can occur in testing new treatments, especially when the number of subjects greatly expands. Negative results in studies on dietary supplements, particularly where previous studies have reported benefits, may be due to a number of factors: differences in study design, differences in the make-up or doses of the substances tested, differences in trial periods, etc. I suspect ignorance rather than laziness.

Your thoughts?

SD: The media are obsessed with describing, in great detail, stories of suffering and death from toxic reactions to investigative drugs. Not infrequently, these news stories imply evil doing by doctors and pharmaceutical companies. The extensive coverage of a single death after insertion of a gene in a human volunteer in a clinical study at the University of Pennsylvania, the dangerous adverse effects of Vioxx after marketing are representative of such stories.

Often, the media blame the FDA, which brings intense political heat upon the agency. The FDA responds by creating new, stringent requirements – ostensibly to insure safer studies. What is the inevitable result? The costs and risks of clinical research rise, further retarding medical discovery and diminishing patients' rights. The media hardly ever follow up on these critically important sequelae.

Dr. DeFelice's Theory of Nutraceutical Rejection-Need in the Reversal of Aging
At my meeting with Dr. DeFelice in his Manhattan office last July, he briefed me about his theory on how to reverse the mental and physical deterioration of aging. Studies he conducted in the mid-1960s on carnitine, a naturally occurring substance, had been the take-off point for the theory.

Carnitine transports fatty acids into cells to produce energy. Energy loss resulting mostly from a reduction in number and size of the mitochondria is a main sign that a person is aging. (The mitochondria in cells can be likened to furnaces where sugar and fats burn and ATP forms, generating energy to power all the body's activities; ATP is a molecule essential for producing this energy.)

Dr. DeFelice wondered if carnitine, taken with other energy-producing nutraceuticals, could help replenish the energy lost by aging cells? Over three decades, his own findings in studies on carnitine, and studies in the research literature on beta carotene and vitamins C and E (among other dietary supplements), had suggested to him that if the cells of the body need these nutraceuticals, they accept them; if not, they reject them.

Studies he found in the literature on growth hormones and testosterone showed that these increase production of ATP and that certain nutraceuticals (carnitine, CoQ10, and magnesium among them) also step up ATP production. Giving these nutraceuticals together with hormones to older people, he reasoned, could raise energy production in their mitochondria to levels necessary to retard the deterioration brought on by aging.

But there was a problem, he realized, involving ATP: free radical activity rises with ATP production. In addition to nutraceuticals and hormones, then, an anti-aging formula had to include selected antioxidants. It was also necessary, he determined, to vary the doses of nutraceuticals each day, so the body would absorb the right amount. In the end, he designed a seven-day formula varying the doses daily, which maximized ATP production and the antioxidant effect.

In 2005, Dr. DeFelice felt that medical and scientific data justified a clinical trial of his theory, using his formula. Consultations with experts confirmed the merit of such a study and his study design. He's now looking for funds to conduct a clinical study that would definitively test his theory. Dr. DeFelice is funding a study of L-acetylcarnitine at his own expense. Researchers at Vanderbilt University Medical Center (Tennessee) are assessing the potential of L-acetylcarnitine to counter septic shock caused by infection and bioterrorism pathogens.

Approximately 750,000 cases of severe sepsis occur annually in hospitalized patients, observed Dr. DeFelice. A third of these patients succumb, he said, noting for emphasis that septic shock takes more American lives per year than breast, colon, pancreatic, and prostate cancers combined. L-acetylcarnitine may protect the cardiovascular and nervous systems against this condition.

Bioterrorism pathogens can cause septic shock, and they can damage the brain. By itself or in combination with other substances, L-acetylcarnitine may protect against these toxic effects as well. It's noteworthy that Dr. DeFelice had first observed this protective effect in sepsis during his studies of carnitine and L-acetylcarnitine at the Walter Reed Army Research Institute back in 1965-66.

Dr. Stephen DeFelice, Novelist
Dr. DeFelice recently published two novels. In He Made Them Young Again (www.AuthorHouse.com), one of the protagonists, Sigismondo Malatesta, could well be Dr. DeFelice in fictional guise. Dr. Malatesta speaks like Dr. Stephen L. DeFelice; his voice has the same bite. A representative excerpt follows:

Sigismondo believed that many diseases could be better treated, or even cured, if one knew what was going on inside the body's cells. Then the doctor could give a specific formula of natural substances to correct the imbalance and, by so doing, eliminate or ameliorate the disease.
He used vitamin and mineral deficiencies as examples to support his theory… He postulated that multiple deficiency states in cells are the cause of many diseases including diabetes, heart disease, cancer, arthritis, and Alzheimer's, but modern science and medicine hardly make a great effort to discover them.
Sigismondo disdained what he considered the current rigid and sterile nature of modern medicine and its appalling lack of imaginative ways to defeat disease.

Afterthoughts
I have two afterthoughts about this column. The first pertains to consumer groups more concerned with the risk of adverse effects in clinical trials than on promotion of clinical trials to accelerate medical discoveries. These groups have been prominent since the 1960s. They have consistently supported the most extensive FDA regulation of virtually any substance that has a medical use. They have staked out a claim to represent the public on FDA matters, and Congress and the media have accepted their claim.

Congressional proponents of a tougher FDA have invited and continue to invite the leaders of these organizations to testify at hearings on bills to strengthen the FDA's hand in the approval process for new drugs and medical devices, and on bills that would authorize the FDA to regulate nutritional substances as restrictively as this agency does new drug treatments. When serious adverse effects occur unexpectedly in clinical trials or when a new test of a nutritional supplement previously thought safe surprisingly appears to show the opposite, the media quote the heads of these organizations, who invariably call for tighter FDA control of the clinical trial process or for strict FDA regulation of supplements.

But these consumer groups represent only certain segments of the public, and on occasion, they may even represent less than half of the public on FDA policy issues. Case in point: passage of the Dietary Supplement Health and Education Act, 1994 (DSHEA '94). Letters from citizen groups around the US supporting lobbying efforts by supplement industry coalitions cascaded into the offices of Senators and Representatives, sweeping away opposition to DSHEA '94.

Readers curious about the campaign to pass DSHEA '94 should get a copy of my interview with attorney Antonio Martinez, II, for the background and specifics of that campaign (Townsend Letter, July 2007). Here, I'll note that the sector of the public supporting DSHEA '94 included a host of Americans who take nutritional supplements, and the "citizen" groups they formed to back this legislation were mainly reacting to a belief that the FDA intended to remove many dietary supplements from health food stores and other over-the-counter sources.

Once DSHEA '94 became law, these citizen support organizations fell silent for the most part. No item on their political agenda had ever addressed the issue at the center of Dr. DeFelice's thinking – speeding up medical discovery through promotion of clinical research. The majority of these groups, I feel, polled on Dr. DeFelice's NREA initiative, would shy away, fearing that the process it provides for approval of nutraceutical claims could be twisted by the FDA into a means of limiting access to supplements. That the NREA, if enacted, would greatly multiply data on the effectiveness of nutraceuticals (data that's lacking, according to Dr. DeFelice) appears to be of secondary interest for these groups; what matters primarily is over-the-counter availability of supplements.

My second afterthought touches on groups cited by Dr. DeFelice (in my October 2007 interview with him) who represent patients and families confronted by diseases resistant to available treatment. Why are they "blind" to the importance of clinical research in speeding up discovery of better treatments for such conditions? Dr. DeFelice contends that these groups don't do their homework regarding the plus side of clinical research. I'll add to his contention that physicians who serve as expert consultants to these organizations often have a hard time comprehending – and accepting – clinical research that doesn't fit "inside the box." Patients and families belonging to these organizations tend to follow the experts.

In my second interview with Dr. DeFelice, on Doctornauts and the rape of patients' rights (Townsend Letter, October 2007), he tells a story about his attempts to persuade oncologists specializing in ovarian cancer to administer the nutraceutical carnitine together with the cancer drug Adriamycin. Adriamycin's ability to kill cancer cells is offset by its cardiotoxicity. Carnitine reduces the drug's cardiotoxicity, so combining it with Adriamycin would enable doctors to give stronger doses of the drug, increasing its destruction of cancer cells. He couldn't budge the oncologists, couldn't even get them to ask their patients to agree to try the combination. Dr. DeFelice ended this story by saying that if his Doctornaut initiative had been instituted 30 years ago, when the combination was first shown to be effective, some physicians with ovarian cancer would have volunteered to test it, and subsequently, many women who succumbed to this cancer could have survived.

Marcus A. Cohen
marcusacohen@aol.com