COVID-19 and Beyond: Presents An Historic Opportunity for the FDA Commissioner to Create a Two-Tier System to Accelerate the Discovery of Cures and Breakthrough Therapies for Diseases and Disabilities
Stephen L. DeFelice, M.D., Chairman
SUMMARY
Covid-19 is a national overdue wake-up call to the disturbing reality that, despite the richness of our technology and abundance of creative scientists and physicians, the major weapon we currently have is quarantine. And few have asked the question why. And few have also asked, despite such richness and creativity, why there are so few cures for diseases and disabilities in general.
There is one uncontestable yet puzzlingly unrecognized reason for this absence. It’s due to the prohibitive barriers to evaluate potential new therapies in clinical studies, the critical step in medical discovery. Penicillin and insulin were only discovered when administered to patients with bacterial infections or diabetes. It therefore, logically follows that if such barriers are “effectively” reduced, a flood of potential therapies will be clinically tested, including anti-viral ones, and more cures and break-through discoveries made– beginning, yes, in the near term.
Beginning way back in 1972, I had proposed ways to reduce such barriers, but our culture has always viewed the risks of clinical research as morally unacceptable, even labeling it as human experimentation where, though untrue, volunteers were generally viewed as laboratory guinea pigs subject to the unregulated whims of the clinical researcher.
As a solution to assuage such safety concerns in a culturally acceptable way, FIM has, despite many efforts, unsuccessfully proposed that physicians or doctornauts, because of their training, knowledge and duty, should have the right to volunteer for clinical trials much more easily and rapidly than non-physicians. In this way many more potential therapies would be clinically tested dramatically increasing medical discovery.
FIM believes that the national alarm of COVID-19, if presented “effectively”, will open the doors of public receptivity for the establishment of physician volunteers. And the good news, though difficult to accept, is that this can be done by a single stroke of the pen by FDA Commissioner and physician, Stephen M. Hahn.
And finally, though it will initially be viewed as too good to be true, the establishment of physician volunteers or doctornauts will also lead to breakthrough therapies for children as well as to a substantial reduction in health care costs beginning in the near term.
FIM proposes a Two-Tier System where Institutional Review Boards or IRBs will share with the already swamped FDA by just a single viral disease, to share in invigorating the initial medical discovery system.
The Two-Tier Proposal: History & Rationale
New physician FDA Commissioner, Stephen M. Hahn, can, with a single stroke of his pen, not only accelerate the discovery of a cure for the COVID-19 and other viruses but for much of what ails us. “What am I drinking,” you ask? It’s a cocktail of vast personal experiences dealing with medical discovery in general, carnitine in particular and an unbudgeable cultural blind spot to the critical, fundamental role of clinical studies in discovering break-through therapies and cures.
As a nation, it’s time to recognize that medical discoveries are ultimately the result of testing them in patients. Insulin and penicillin, though promising in laboratory studies, were only proven to be effective when administered to patients with diabetes or bacterial infections. But for historic reasons, the costs and risks of conducting clinical studies are pervasively prohibitive to the majority of creative doctors and scientists and are only affordable by the pharmaceutical industry, certain foundations and the federal government. We have, unnoticed, systematically eliminated the ability of thousands of creative physicians and scientists from clinically testing their own ideas; and that’s one critical cause for our lack of cures, unnecessary suffering and premature death. Ask yourself, “When was the last cure?” The most frequent answer to this question is polio, way back in the 50’s and few are disturbed by this alarming fact. Though the aforementioned barriers to medical discovery are self-evident, the puzzle is why we haven’t recognized this as a fundamental step in solving the problem.
And now another disturbing puzzle: During the Vietnam war, I was stationed at WRAIR, the Walter Reed Army Institute of Research, where we were, even way back then, fully aware of the coming threat of biological warfare, including bacteria and viruses. Subsequently, the genetic engineering revolution and CRISPR arrived which now make it increasingly easy to genetically modify these organisms to dramatically increase their lethality. And make no mistake about it; this process is now being broadly implemented from governments to rogue, independent researchers some of whom are not the kindest of humans. Health and military experts were aware of this threat but puzzlingly took insufficient action on ways to discover effective therapies.
Now we are faced with the COVID-19 pandemic and, again puzzlingly, the only bullet we had in our anti-viral armamentarium was quarantine! And also puzzlingly, few have asked the question why. You would think that the public should be informed of the following questions that have not been answered:
Why isn’t there an effective treatment for COVID-19? Anti-viral therapies generally are either pharmaceuticals or vaccines administered for either prevention or treatment: What are the steps from the laboratory to clinical studies to FDA approval and the time required for each step? What are the costs for each step for a successful therapy to be available to doctors? What percentage of anti-viral therapies fails in clinical studies? Even if discovered, how much time does it take to manufacture enough for millions? What are the economic realities that negatively impact anti-viral research?
What then is the readily available solution? The good news is that our country is blessed with the most creative medical-scientific minds in the world. The solution is to “effectively” decrease the prohibitive barriers to evaluate potential therapies in clinical studies. Please note the word, “effectively.”
Since history is a great teacher, let’s take a step back in time describing two of FIM’s major unsuccessful attempts to encourage clinical research studies on potential therapeutic modalities. The first was the Nutraceutical Research and Education Act or NREA which was designed to substantially encourage clinical studies on dietary supplements and special diets. It was based on the successful Orphan Drug Act which led to FDA approval of carnitine for a fatal disease in children, Primary Carnitine Deficiency. It was introduced in Congress by Congressman Frank Pallone, the current Chairman of the House Energy and Commerce Committee which has broad jurisdiction pertaining to health care, including the FDA. It met with zero interest by all appropriate parties. The message? An ingrained, broad spectrum cultural blind spot to the critical importance of clinical research.
In my first book, Drug Discovery: The Pending Crisis published in 1972, before many Americans were not yet conceived, I correctly predicted that there would be few cures discovered in the near term because of the risks and costs to conduct innovative early clinical studies. The reason? There were a number of large impact events such as thalidomide and the rise of safety-oriented consumerism all of which created a grossly misleading public image that clinical research is not only extremely risky, but even evil! Thus the term, Human Experimentation, oftentimes replaced that of Clinical Research. The solution? I proposed that physician volunteers be permitted to participate as subjects for clinical studies much more easily than others. Thus, more promising therapies would be tested and, pari passu, more discovered. Despite a subsequent extensive personally funded public educational effort, there was not only zero interest, but, in addition, I was accused of being an Auschwitz doctor by more than one major media outlet. Not a pleasant experience, to say the least, when one is trying to help the afflicted by decreasing suffering and premature death.
But through the decades, because of its enormous promise to reduce the extensive suffering of disease, FIM continued to pursue the effort. I then coined the term “doctornaut” to describe such physician volunteers in an attempt to encourage Congress to enact “The Doctornaut Act” which would render doctornauts a reality for all diseases and disabilities. We even conducted a national physician survey asking whether doctors would freely volunteer for clinical research on natural substances which hold enormous promise but generally lack patents and, therefore, economic incentives to find sponsors to support clinical studies on them. We asked the question, “Would you as physician-patient want the privilege to volunteer for clinical research on natural substances under the supervision of a physician-clinical researcher without FDA, institutional and other restraints?” A total of 3,100 inquiries were mailed and over 10% responded, and over 50% agreed that they would. We used this survey in another broad educational effort but, once more, there was zero interest until I met a number of times with physician and then Senate Majority Leader, Bill Frist, who, as a former physician researcher, would readily grasp the promise of doctornauts. My pitch was that there were then currently 800,000 physicians in the United States and that, after I personally contacted a number of them who were surveyed, they all would volunteer for therapies in general, natural or not, which would make immediately available 80,000 volunteers. Dr. Frist took the bull by the horns and circulated a draft of the Act to appropriate parties for comments and suggestions. The result? Once more, zero interest and thus, as with the NREA, the Doctornaut Act fell by the wayside.
After having gone to the top without results, FIM surrendered the ship until the emergence and the public panic of the COVID-19 pandemic which is unequivocally an eye-opening wake-up call regarding both the crucial fundamental role of clinical research and that of doctornauts. Unfortunately, it will require a major effort to rapidly–for speed is now paramount– gather sufficient congressional support to enact the Doctornaut Act. Increasing members of Congress are being infected with COVID-19 the impact of which on national policy will be interesting to observe. Yes, in the past Congress has enacted the Orphan Drug and Translational Research Acts and the Administration, as a result of COVID-19, a number of short cuts to begin clinical studies, but they are clearly not enough.
But, to repeat, the extremely good news is that there is a doable rapid way to render doctornauts a reality by a single stroke of the pen of FDA Commissioner, Dr. Hahn. He hails from the great medical institution, MD Anderson, noted for its major role in combating the scourge of cancer. What is particularly characteristic of this institution is its bullish approach and extensive experience with the fundamental role of clinical research in medical discovery. He needs no convincing not only of its importance but also the urgent need to expand it.
The Two Tier FDA Proposal
In order to better protect the rights and safety of volunteers in clinical studies, the FDA established regulations for Institutional Review Boards or IRBs composed of diverse specialists such as physicians, lawyers and ethicists. The clinical protocols must be approved by each IRB followed by periodic reviews of the ongoing clinical studies. And they usually review multiple clinical protocols.
There are nearly 3000 IRBs in the United States. There are also approximately 1.1 million physicians with about 300,000 over the age of sixty, the latter who are living with the great major diseases such as diabetes, cancer, ischemic heart disease, heart failure, arthritis and various degrees of dementia up to late-stage Alzheimer’s who can volunteer after early diagnosis when they are still aware that they will reach this end stage.
It’s important to note that many physicians are research oriented with creative, independent innovative ideas outside of our standard system to tackle disease but can never be clinically tested because of the aforementioned safety-based prohibitive barriers. One such innovative physician, Barry Marshall, ignored the barriers and experimented on himself to demonstrate that the bacterium, H. pylori, is a cause of gastritis and gastrointestinal cancer and won a Nobel Prize for his courageous act. And, which is revealing to note, he was labeled the “guinea pig doctor.”
It is difficult to quantify the number of U.S. scientists, but there is a multitude of them ranging from biochemists to engineers. And as with physicians, they have a reservoir of innovative ideas that will never be clinically evaluated. But by creating a system for physicians and scientists to test them clinically, it will lead to an immediate collaboration unleashing a font of creativity between the two.
Generally, though overlapping, there are two phases in clinical research: a) the initial innovative-discovery phase where a substance such as a drug, biologic or medical device is shown to have a promising effect in a limited number of volunteers and b) if promising, to further pursue this therapeutic promise as well as evaluate its safety in a large number of patients. For example, the effectiveness of penicillin can be shown on a handful of patients with bacterial lobar pneumonia after which larger studies can be done to evaluate whether it’s effective in other infections and how safe it is. Of course, with certain substances such as antidepressant drugs, larger numbers are required in both phases.
Within the past decade we have seen an enormous breathtaking escalation in our technological capabilities from genetic engineering to medical devices many of which vary in complexity and will demand clinical testing.
Because of the number of and continued explosive advances, including emergency biological warfare ones, we cannot expect the FDA to have sufficient expertise to regulate them. It is already swamped by a single corona virus and unequivocally needs a helping arm. For this reason, and for the sake of present and future patients, it makes compelling sense to relegate much of the early innovative phase of clinical research to the IRBs. As we have seen, IRBs were primarily established to guard the safety of volunteers. FIM proposes that their mission should be expanded to include the ability to assess the efficacy of ongoing clinical trials and report to the FDA periodic updates of study results on efficacy and safety before the completion of such trials.
There is little doubt that, because of the complexities of new technologies, certain IRBs will specialize in selected sectors such as genetic engineering and medical devices which the FDA should welcome.
Physician volunteers or doctornauts are primarily indicated for the early discovery phase. If any major discovery is made, patent or no patent, nothing will stop its further development and availability to patients in our dynamic country.
Generally speaking, there are two medical discovery sectors: a) Major and financially resourceful- pharmaceutical, biologicals and medical device corporations along with the NIH. Great as they are, they understandably offer limited therapies to be clinically evaluated in our heavily regulated costly system. Though there are more promising therapies in their systems, primarily those with patents or some type of proprietary protection are usually developed and b) As previously mentioned, huge untapped individuals with innovative therapeutic ideas in the physician-scientist sector with little or no financial resources which are rarely pursued.
Bottom line, we have in our country a cornucopia of promising therapies on the near horizon which promise doctornauts can help make possible to clinically test unleashing the tremendous discovery capacity of both sectors to conquer diseases and disabilities. This can begin almost immediately.
The very good and yet unrecognized news is that the FDA has the authority to implement the IRB-Doctornaut Two-Tier System. The following is a description of the existing regulations which would permit the FDA Commissioner to exercise such authority:
The FDA requires Institutional Review Boards or IRBs composed of a variety of disciplines to review and approve the design of clinical study protocols before any study can commence at a given institution. It also has authority to formulate and modify IRB policies and has ample authority under the FDC Act to implement the Doctornaut program.
Under section 501(i) of the Act, 21 U.S.C. 355(i), the Secretary of HHS, whose authority has been delegated to FDA, “shall promulgate regulations for exempting from the operation of the foregoing [the NDA approval requirements] drugs intended solely for investigational use by experts qualified by scientific training and experience to investigate the safety and effectiveness of drugs” and to require informed consent of human subjects participating in a study of investigational drugs, except where consent is not feasible. FDA has promulgated investigational new drug (IND) regulations at 21 C.F.R. Part 312, IRB regulations at 21 C.F.R. Part 56 and informed consent regulations at 21 C.F.R. Part 50. Under the latter regulations “No informed consent , whether oral or written, may include any exculpatory language through which the subject or representative is made to waive or appear to waive any of the subject’s legal rights , or releases or appears to release the investigator, the sponsor, the institution, or it agents from liability or negligence.
FDA’s IND, IRB and informed consent regulations could be immediately amended and expanded through notice-and–comment rulemaking to encourage doctornauts by expressly providing them the opportunity and freedom to volunteer to receive investigational drugs and test them on themselves and their fellow doctornauts with IRB approval only and without having to submit an IND to FDA.
Given this authority, FIM’s proposed IRB amendment is as follows: “Physicians best understand the nature of disease and disabilities and the therapies employed to treat them. For this reason, they are permitted to take substantial greater risks than non-physicians in clinical studies. Each IRB has the right to make that judgment.
Let’s recognize that the FDA is already swamped with COVID-19, only a single disease, and more emergency types of threats are on the way perhaps sooner than we expect. For this reason, it is mandatory that another partner system be established to accommodate future events.
How the Two-Tier System Will Play Out With Doctornauts
Let’s begin with COVID-19: Growing numbers of doctors have already or will soon succumb to this virus. There is little doubt that, in addition to the old therapies that are being clinically tested, there are potential others that our innovative medical minds have already conceived, including the use of multiple combinations given intravenously and even in the ventilator tubing, that will never see the light of day. Yes, though the Administration has encouraged new regulations to reduce the barriers to clinical studies in emergency situations, promising therapies still must go through our regulatory system oftentimes requiring lengthy controlled trials in a significant number of patients. Speed is now critical and doctornauts are one immediate unquestionable key.
For example, our doctors, who are significantly ill or on ventilators, through fast-acting IRB systems can volunteer for what can potentially, as with penicillin and insulin, be breakthrough therapies such as a combination of anti-viral and antibody drugs, where activity can be rapidly evaluated in a very small population.
On all diseases and disabilities: It will rapidly open the doors to clinical research and medical discovery for all diseases and disabilities ranging from rare or Orphan ones, such as muscular dystrophy, to the more common ones, such as diabetes, cancer and Alzheimer’s.
On Children: Results discovered on doctornaut clinical studies can also be applied to children. A tearful mother once confronted me regarding how adult doctornauts could help her child with cerebral palsy. I mentioned two examples: effective brain medical device techniques and effective gene delivery systems to the brain discovered in doctornauts could then be employed in her child. The same holds true with cancer and other techniques and remedies.
On health care cost reduction: And finally, it will, beginning in the near term, substantially reduce health care costs. What better way to accomplish this than to cure the great diseases? Doctornauts will lead to the discovery of both high and low cost therapies which will compete with each other in our health system bringing about significant cost reduction.
Safety and Risk-benefit: A Warning to Our Leaders
Doctornauts, or no doctornauts, attempts to expedite clinical studies will inevitably result in significant adverse effects raising the issue of safety. Our leaders must be prepared to accommodate a potential national backlash by explaining the concept of risk-benefit to the public. As we have seen, exaggerated concerns over safety, fueled by mass media arousing public concerns, has been the dominant factor in creating barriers to clinical studies. The media has already begun to question the safety of old, time-tested antimalarials.
The Risk-Benefit Concept: Doctors and nurses treating COVID-19 patients, policemen, military personnel and astronauts, among others, all willingly risk their lives for the betterment of the lives of men, women and children. And this concept is acceptable to the public. The same, therefore, should hold true for clinical study volunteers who take risks not only for the benefit others but also to protect our nation against biological warfare.