A Proposal by FIM, the Foundation for Innovation in Medicine, To Accelerate Medical Discovery
October 1, 2003
Modern technology offers enormous promise in the battle against disease, disability and other things that ail us. The barriers (costs and risks) to evaluate this promise in clinical studies, the critical step in medical discovery, have been and are increasingly prohibitive. Attempts to remedy this situation have had minimal success.
It is urgent that a way be found to effectively diminish these barriers to clinical research. The result would lead to accelerated medical discovery, reduction of morbidity (suffering due to disease) as well as the rate of mortality and help reduce health care costs both in the short and long terms.
For these reasons, FIM, the Foundation for Innovation in Medicine, proposes that the Congress enact the Doctornaut Act, which would permit physicians to more freely volunteer for clinical studies than non-physician volunteers. A Doctornaut is a physician who volunteers for Phase II clinical research with fewer restraints than those of non-physician volunteers, and who is permitted to take greater risks than the former. Phase II is the early medical discovery phase in clinical research, where a substance(s) is preliminarily evaluated for efficacy and safety. It usually involves small numbers of volunteers. Among the benefits that will result from Congressional passage of the Act are:
- Rapid acceleration of medical discovery followed by:
- Reduced morbidity (increased quality of life)
- Reduced rate of mortality from disease
- Timely application of innovative medical therapies to clinical practice
- Reduced health care costs
Among the issues that need to be addressed to insure the success of this proposal are:
- Costs and risks to clinical investigators
- Risks to Doctornauts
- Clinical investigator immunity from suit
- Special consideration for the independent clinical investigator with the help of the hospitals of the Veterans Administration.
Congress has an opportunity to respond expeditiously to the needs of patients and the nation to enact a new law that will establish a new category of volunteers for clinical research, Doctornauts. As with astronauts, soldiers, police, firemen and many others, it is time to grant the right to physicians to take risks-even life-threatening risks-to help rid us of unnecessary suffering and premature death.
If physicians are willing to become Doctornauts, what, then, could be the objections? The Doctornaut Act would be an effective response to a national health issue that demands immediate attention. The “reduction of morbidity and cure approach- offers many more benefits to the American people from increased quality of life to access to more effective treatment than the predominately traditional national “care- approach.
In addition, it is an effective way to reduce health care costs, both in the short and long terms.
THE PATH TO CLINICAL MEDICAL DISCOVERY AND OUR NATIONAL COMPLACENCY ABOUT IT
Both as a nation and as patients (we are all patients!), it is critical to understand how medical discoveries are made. Potential medical breakthroughs become real ones only when they are proven to work in Phase II studies, the early phase of clinical research. Penicillin, dialysis, and coronary artery bypass were only shown to have real medical value after they were tested in people. And that’s where the major problem is-clinical research. Costs and risks to conduct Phase II clinical research have placed most of our creative clinical investigators on the sidelines. Drs. Joel Goldstein and Michael Brown, Nobel Prize winners in medicine, share the same concern, warning that patient-oriented research is in serious jeopardy. To add to this national medical tragedy, there is an ongoing alarming decline of U.S. clinical investigators.
Generally speaking, creative minds in all walks of life function either poorly or not at all in environments that are barrier-laden. When DaVinci or Einstein had an inspirational moment, the former would walk to his easel and begin to paint, while the latter would go to his blackboard and write equations, with only space as a barrier to each for fulfilling his moment of creativity. Not so in clinical research: The barriers to the clinical researcher are costly, risky and time-consuming, all powerful factors that profoundly discourage clinical research in general. For example, the average cost to obtain one successful FDA approval of a pharmaceutical exceeds $800,000,000 which in itself reflects the enormous barriers to clinical research.
Much of our promising medical technology is now waiting in laboratory lines in a preclinical bottleneck waiting to be evaluated by clinical testing. And there are no signs that things will improve.
We as a nation are highly suspicious and fearful of clinical research. The latter is often referred to as human experimentation, which bespeaks of this suspicion and fear. This fear is utterly out of touch with the results of empirical research, which have demonstrated that it is much safer to be a research subject than it is to be a patient. Yet, astronauts who volunteer to risk and sometimes lose their lives for space exploration are admired. There was no national outcry against space exploration following the deaths of seven astronauts. They were revered. A recent USA Today CNN/Gallup Poll reports that three out of four Americans find fatal astronaut missions acceptable.
Witness, however, the national media coverage and uproar as a result of a single death of a volunteer at the University of Pennsylvania undergoing clinical testing of a promising type of gene therapy. Gene studies were suddenly halted and the physicians conducting the study were criticized nationally. Though certain mistakes were made, the public and political response was highly irrational and ultimately damaging to patients. New rules were then initiated which increased the already formidable costs and risks to clinical research. After the University of Pennsylvania came Johns Hopkins. Because of a single death, the FDA halted all clinical studies at this great institution. The result? More costs and risks. This trend continues unabated, with profound negative consequences on medical discovery.
Contrast this to the fact that there are many thousands of deaths in the United States due to marketed drugs, a fact which escape national awareness.
Over and above our national fear and suspicion of clinical research, we have an inexplicable national complacency about medical discovery itself. For example, it is almost the rule to read or hear such messages in the media as, “An effective new gene therapy has been found but it will take years of testing,- or “New drugs fight aging in animals but such developments for humans are years away,- or “New drugs for Parkinson’s disease are expected to take years of testing,- or “A new protein to treat skin cancer has been tested successfully and may be ready for humans someday.-
Why does it take so long for promising scientific research to be translated into effective medical treatments? Moreover, why doesn’t anyone in the media ask the question, “Why?-
Congress, in a similar vein and puzzling as it may seem, has never held a thorough Hearing on the “Why?- issue. Yes, the Congress occasionally senses that something is wrong, as exemplified by the Orphan Drug Act and Food and Drug Administration Modernization Act, FDAMA. Such Acts, however, do not get to the heart of the problem.
If the Congress were to have a Hearing and ask patients what they really want from our health system, they would say something similar to the following, “If I have my disease or disability, get rid of it. If I don’t have it, I don’t want to get it.- They want what we call the prevention and treatment of disease. Patients’ first priority is not free hospitalization or reimbursement for their drugs-they prefer to be healthy!
Paradoxically, the Congress and other partners in the health community have primarily concentrated on the issue of care instead of cure.
THE DOCTORNAUT ACT
The Act will primarily address three categories:
- The rationale and ground rules under which a physician-patient, a Doctornaut, can volunteer to be a physician-research subject.
- Clinical investigator immunity from suit.
- Special consideration for the individual clinical investigator and a unique role for Veterans Administration’s hospitals.
DOCTORNAUT RATIONALE AND GUIDELINES FOR VOLUNTEERING
Rationale: Without the certainty of mathematics and Divine Revelation, moral/ethical issues are oftentimes controversial, particularly when dealing with volunteering for clinical research. The general good not uncommonly appears to conflict with the particular or individual good. In addition, the issue of free will combined with the Golden Rule underscores the debate of what is considered moral/ethical behavior in a particular situation.
Cutting through all these ambiguities and turning to history and tradition, which often times mirror what works in human behavior, physicians have frequently experimented on themselves or volunteered for clinical studies in order to advance medical discovery and, in so doing, benefited patients.
The list of high-risk self-experimentation by physicians to advance medical discovery is a long one. Forssmann threaded-in what many of his colleagues thought would be a fatal event-a rubber tube in his vein and guided it to his heart; Stapp tested the limits of human tolerance to the forces of crushing collision; GarrÃ¨, by making a skin incision, infected himself with potentially fatal staphylococci cultured from osteomyelitic bones and almost died, and, more recently, Marshall swallowed the H. pylori bacterium to determine its role in the pathogenesis of gastritis and gastrointestinal ulcers.
Indeed, before receiving his medical degree, a young Peruvian medical student named Daniel CarriÃ²n injected himself with an aspirate from a Verruga peruana lesion, in order to prove that this lesion was the precursor to Oroya fever. He proved the point, but died in the process.
The vast majority of such acts, be they self-experimentation or otherwise, however, are hidden, escaping the pages of medical history. For the record, it is interesting to note that some physicians who support the Doctornaut concept (Appendix) have either experimented on themselves or volunteered in clinical studies.
In conclusion, the general good has overwhelmingly benefited from the particular acts of Doctornauts who have taken risks. Some have legitimately questioned whether modern-day U.S. physicians are willing to take the high risks to which earlier generations of doctors exposed themselves. Despite the overwhelming indications that physicians are willing to take risks in clinical research, be they small or great, to advance medical discovery and help patients, this is a question that should be addressed.
About twenty years ago, the Foundation for Innovation in Medicine (FIM), which has a particular interest in stimulating clinical research on natural substances, conducted a random mail survey of physicians to determine if they were willing to assume the role of a Doctornaut in clinical studies involving natural substances. A total of 3,100 inquiries were mailed to a cross-section of 2,100 male M.D.’s, 500 female M.D.’s and 500 Doctors of Osteopathy. Age was also considered. Half of the male physicians surveyed were 50 years old or younger.
A total of 10.3%, a good response with this type of survey, of the physicians responded. A simple “yes- or “no- was required for the following question:
“Would you as a physician-patient want the privilege to volunteer for clinical research of natural substances under the supervision of a physician-clinical researcher without FDA, institutional or other restraints?-
Yes % No %
Male M.D.’s Total 52.5 47.5
Male M.D.’s Under Age 50 56.6 44.4
Male M.D.’s Over Age 50 50.0 50.0
Male D.O.’s 60.0 40.0
Female M.D.’s 56.3 43.7
The results of the survey clearly support that some American physicians are willing to be Doctornauts. Some will argue that modern U.S. medicine has changed radically since then and currently physicians may not be as willing to take risks. Let’s assume that this is correct, and that only twenty-five percent-about one-half the number two decades ago-would volunteer to be Doctornauts.
Today, there are approximately 700,000 physicians in the U.S., which would make available 175,000 Doctornauts!
At a later date, consideration could be made for international Doctornauts to participate in clinical studies conducted in the United States.
Ground Rules for Volunteering: The Doctornaut system must be under the control of physicians or medical peers only. Also, in order to avoid creating another complicated structure to monitor the clinical trials, a subgroup of existing IRBs should be formed, M.D.-IRBs, composed of physicians only with separate ground rules.
The ground rules are as follows:
- An IND is optional. FDA should, however, be informed of the existence and progress of the studies.
- Protocol rejection: The protocol can be rejected on the basis of risk and/or design.
Regarding risk, there generally should be a proportionality between risk and benefit. For example, a Doctornaut with a fatal disease can take a greater risk, including a life-threatening one, than a healthy physician. On the other hand, the principle of proportionality is not strictly binding. For example, many healthy volunteers are organ donors, placing themselves at risk if the remaining organ, such as a kidney, becomes diseased.
Also, the Doctornaut must have the “capacity- to make a decision to volunteer in the study which judgement is made by the physician clinical researcher. Capacity includes the following: The Doctornaut can make a reasoned judgement, can communicate, and understands the risk-benefit of participating in the study, and what would happened if he or she did not participate.
Regarding the clinical design, the standard of acceptance should be that it can be “reasonably assumed- that the results of the Phase II study are due to the substance(s), device(s) or process(es) evaluated. This means that the clinical study designs can be much more flexible than those set by the federal government.
For example, current FDA Guidelines require a separate evaluation of each component of a combination therapy. This requirement may be scientifically sound, but it is medically unnecessary, and often prohibitively expensive. Individual components of a combination need not be individually evaluated against the combination itself. The evaluation of the risk-benefit of the total combination is sufficient.
It is believed that no “magic bullet- for the treatment of many cancers is on the near horizon. In the meantime, for example, a combination pharmaceutical approach, along with other possible therapeutic modalities such as gene therapy, would be more productive.
Another example supporting the “total combination approach- would be to evaluate a nutraceutical (primarily dietary supplements with medical-health benefits) that contains twenty ingredients of vitamins, minerals and other dietary substances in a clinical study to determine if it could significantly improve the immune system. If all of the possible combinations of this nutraceutical were to be evaluated in 1,000 volunteers at a cost of $10,000 per volunteer, then the total cost would be $24,300,000,000,000,000,000,000,000, exceeding the total annual gross product of all the nations of the Earth for all time!
We seemed to have forgotten that a meal, the greatest combination in the world, no matter where its origins, keeps us alive fueling our body’s defenses that fight off disease. Do we need to study each individual component of all the diets in the world to prove this point?
Also, the pervasive current government-academic cultural emphasis on the need for double- blind studies should not play a dominant role in the MD-IRB decision making process. Historical controls are often sufficient. For example, a double blind study in not necessary to demonstrate that insulin can reverse diabetic coma, penicillin cure bacterial lobar pneumonia and that a stem cell implant creates new arterial pathways around a blocked coronary artery.
3. For the aforementioned reasons, guidelines should be carefully applied on a case by case basis.
4. The studies can be terminated by the M.D.-IRB, the FDA or the sponsoring party for reasons of negligence, willful misconduct, significant failure to adhere to the protocol, and the occurrence of unexpected, unacceptable adverse effects during the study.
CLINICAL INVESTIGATOR IMMUNITY TO SUIT
Generally speaking, to date, suing by patient volunteers has not been commonplace. One reason is that in the informed consent document that is signed, there is an explanation to the volunteer about the degree of coverage for research-induced injury. Regarding pharmaceuticals, for example, the coverage generally relates to any drug adverse effects whether the sponsor is a pharmaceutical company or an individual clinical investigator.
Another reason is that the clinical research process takes place in patients, and it can be difficult to distinguish what is the cause of the adverse effect, if something goes wrong.
Recent happenings, however, indicate that suing in clinical research may become commonplace, as it is in other sectors of American society. For this reason, it is imperative that the clinical investigator-as with astronauts, military personnel and others-be immune to suit from any quarter, except for intentional wrongdoing or gross negligence.
SPECIAL CONSIDERATION FOR THE INDIVIDUAL CLINICAL INVESTIGATOR AND A UNIQUE ROLE FOR THE VETERANS ADMINISTRATION HOSPITALS
There is a large, untapped reservoir of potential individual clinical investigators with medical-breakthrough ideas that cannot see the light of day because of cost-risk factors. Large companies, foundations and government bodies generally provide sufficient coverage not only to cover the costs of the clinical study but also insurance in case something goes awry. Individual researchers can be covered by their medical institutions, but high-risk clinical research is discouraged because of its accompanying risk.
The Veterans Administration hospital system is a unique institution which can not only help veterans, but also broaden its role in the health system by partnering with individual clinical researchers, both within and outside of the Veteran Administration System, whose innovative medical ideas not only permit them to conduct clinical research at their facilities, but also to cover all costs.
These hospitals are experienced in matters of clinical research and have, in large part, fixed operating costs or overhead, an important factor in substantially reducing the additional costs of clinical research. FIM believes that this is an extremely cost-effective way for the government to help achieve the goals of The Doctornaut Act.
TIMELY APPLICATION OF INNOVATIVE MEDICAL THERAPIES TO CLINICAL PRACTICE
New innovative medical discoveries will follow two paths, each of which will expedite the addition of successful therapies to the physicians’ armamentarium.
The paths are: a) One that does not require government approval, and b) one that does require government approval.
The paths not requiring government approval, for example, will involve off-label use of FDA-approved drugs or medical devices and also new surgical techniques that standard IRBs would not approve for non-Doctornaut volunteers because of unacceptable risk.
Innovative therapies requiring government approval, such as pharmaceuticals, can be placed in a “fast track- approval system such as stipulated under FDAMA.
REDUCTION OF HEALTH CARE COSTS
Many argue, with good reason, that although medical discovery often times improves the quality of life of patients, it significantly increases health care costs. The latter is particularly alarming when the demand for health care in the United States is increasing rapidly. As examples, the use of dialysis devices in the treatment of End Stage Renal Disease, and high technology pharmaceuticals are frequently cited. Dialysis treatment costs the federal government billions of dollars, and the annual cost of some high technology products, particularly for rare diseases, is in the tens of thousands of dollars.
We have entered the era of “creeping technology,- high-cost products with either promising or proven medical benefits that can often cost billions of dollars for each individual medical condition. For example, a new surgical technique for the treatment of emphysema can cost Medicare up to 15 billion dollars annually. Also, with the aging population, congestive heart failure is becoming commonplace. When the heart, despite the use of pharmaceuticals, begins to fail, a new medical device, L.V.A.D., or Left Ventricular Assist Device, can help the heart to pump more efficiently. It is estimated that this device could cost Medicare up to 12 billion dollars annually, and many more such “creeping technology- therapies are clearly on the near horizon.
Many of the new therapies are directed toward chronic diseases. Currently it is estimated that the annual cost for chronic diseases is $750 billion. With “creeping technology,- plus the aging baby boomer population that will soon become Medicare recipients, coupled with medical prescription reimbursement and increasing patient demand, health care costs will climb to exceedingly high levels.
Must we then assume that increased medical innovation will inexorably lead to astronomically increased costs? Of course not!
There are two ways to reduce such costs. The first is to reduce demand, which would be difficult to implement, because it would deprive Americans of the availability of effective medical technology. The second, more practical and desirable way is to discover relatively inexpensive therapies that can prevent, treat or cure disease, including disabilities.
For example, a significant percentage of patients who are on dialysis have heart attacks and strokes and are also diabetic. A well thought-out pharmaceutical-nutraceutical combination that could even partially prevent the blockage of large and small arteries would significantly reduce the need for dialysis as well as the number of heart attacks and strokes.
It is important to note that one principal reason behind high health care costs is the high cost of conducting clinical research, particularly when combined with the high costs of government approval such as an NDA. High costs to arrive at the marketplace frequently leads to high-cost products.
Doctornauts will lead to the discovery of both high and low cost therapies the latter of which can be used to reduce or at least spread out overall health care costs.
WHY DOCTORNAUTS ONLY?
As a group, physicians best understand the nature of disease and the therapies used in the medical armamentarium. They undergo, more or less, the same medical training and share a consistent fundamental knowledge base. In addition, physicians have a historical, moral obligation to help their patients and, by participating in Phase II clinical trials, which will inevitably benefit their patients, they fulfill part of that obligation. Once a promising new therapy is discovered in such trials, however, non-physician volunteers can then have the opportunity to participate in subsequent clinical studies.
CAN DOCTORNAUTS HELP CHILDREN?
A mother of a child stricken by a severe disability commented that Doctornauts are adults and questioned whether they can help children. The answer is, “Yes-! For example, positive studies on ways to transplant central nervous system tissue in adults can rapidly be applied to children with cerebral palsy or other central nervous system diseases. Also, one major factor in delivering effective gene therapy is the difficulty in finding carriers to deliver genetic material into cells. Once they are tested and discovered in Doctornaut clinical studies, the gene carriers can then be used for treatment in children.
Most important pharmaceuticals such as steroids and antibiotics were first tested in adults before being given to children.
As with adults, Doctornauts will both accelerate the discovery and delivery of new medical therapies to children.
MONITORING THE DOCTORNAUT ACT
The federal government, in order to assess the medical-health impact of The Doctornaut Act, should fund an independent, non-governmental organization to identify Doctornaut clinical studies and periodically report its findings.
It is anticipated that other organizations will also monitor some aspect of Doctornaut clinical studies including the establishment of lists of physicians who are willing to become Doctornauts for specific types of clinical studies.
We have a unique, highly promising and doable opportunity to rapidly advance medical discovery within a relatively short period of time. There are, unfortunately, strong forces impeding the fruition of this opportunity-and they are growing.
For example, most of the worldwide profits made by U.S. and international pharmaceutical companies with a United States presence are earned in the United States market which, in turn, support most of the costly research and development on drugs.
Many countries, including Europe, have price controls where profitability is minimum. The result? The citizens of these countries benefit from the profits made in the United States for drugs paid for by Americans: And there are no signs that this international policy will change.
But it appears that profitability in the United States may now be in jeopardy, as exemplified by Medicare prescription drug reimbursement and importation of drugs from foreign countries, which, if they occur, could lead to significant drops in profits critical to fuel all medical research, from the laboratory to clinical studies. The highly promising high-risk biotechnology industry would be particularly threatened.
This possibility augurs poorly for the patient.
In conclusion, FIM holds the firm conviction that the benefits of the Doctornaut
Act will be:
– Rapid acceleration of medical discovery followed by:
– Reduced morbidity (increased quality of life)
– Reduced rate of mortality from disease
– Timely application of innovative medical therapies to clinical practice
– Reduced health care costs
Stephen L. DeFelice, M.D.
The Foundation for Innovation in Medicine
Physicians In Support of Doctornauts
FIM, The Foundation for Innovation in Medicine, contacted physician leaders to discuss their thoughts on the importance of Doctornauts. All of the following agreed:
David P. Carbone, M.D., Ph.D.
Professor of Medicine and Cancer Biology
Vanderbilt School of Medicine
Director of Experimental Therapeutics Program
Vanderbilt-Ingram Cancer Center
Joseph R. DiPalma, M.D.
Dean Emeritus and Professor of Pharmacology
MCP/Hahnemann University School of Medicine
Elaine B. Feldman, M.D.
Professor Emeritus of Medicine, Physiology and Endocrinology
Medical School of Georgia
Former Director of The Georgia Institute of Human Nutrition
Louis Lasagna, M.D.*
Dean, Sackler School of Graduate Biomedical Sciences
Founder and Chairman
The Center for the Study of Drug Development
Robert J. Levine, M.D.
Co-chair of the Executive Committee
Yale University Interdisciplinary Project in Bioethics
Director, Law, Policy and Ethics Core
Center for Interdisclipinary Research on AIDS
Professor of Medicine and Lecturer in Pharmacology
D. Ted Lewers, M.D.
Chairman of the Board
Medical Mutual Liability Insurance Society of Maryland
Past Chair, Board of Trustees, American Medical Association
Donald B. Louria, M.D.
Professor and Chairman Emeritus
Department of Preventive Medicine
New Jersey Medical School
Chairman, The Advisory Board to the New Jersey Health, Wellness Promotion Act
Thomas F. O’Donnell, Jr., M.D.
President and CEO
New England Medical Center
Past President, The Society for Vascular Surgery
Michael J. Painter, M.D.
Professor of Neurology and Pediatrics
University of Pittsburgh School of Medicine
Past President, Child Neurology Society
Edmund D. Pellegrino, M.D.
Professor Emeritus of Medicine and Medical Ethics
Founder, Center for Clinical Bioethics
Richard S. Rivlin, M.D.
Senior Vice President, Medical Affairs
Naylor Dana Chair, Nutrition
Institute for Cancer Prevention
Past President, the American Society of Clinical Nutrition
George E. Schreiner, M.D.
Distinguished Professor of Medicine
Georgetown University School of Medicine
Shepherded the Medicare Amendment for Renal Dialysis Reimbursement
William E. Thornton, M.D.
Professor of Cardiology
University of Texas Medical Branch
Former NASA Physician-Astronaut Involved in Clinical Experimentation in Space
Raymond L. Woosley, M.D., Ph.D.
Vice President for Health Sciences
Arizona Health Sciences
Former Candidate for FDA Commissioner
*Dr. Lasagna, one of America’s greatest patient advocates, has recently passed on.