Stephen L. DeFelice, M.D.
Senator Tom Harkin (D-IA) has been instrumental in helping to shape the direction of the Translational Science efforts in Congress. Pictured with Stephen L. Defelice, M.D.
Awhile back I met with Gordon Bernard, a physician clinical innovator in septic shock research and currently the Associate Vice Chancellor for Clinical and Translational Research at Vanderbilt University School of Medicine. He patiently listened as I pointed out the urgent need for the Doctornaut Act in order to reduce counter-productive barriers to clinical research. After I delivered my piece, he educated me regarding the general Translational Scientific movement and the establishment of Clinical and Translational Science Awards (CTSA) and its patient-oriented goal to also reduce these barriers.
(For the record, Dr. Bernard conducted a clinical study in septic shock patients on a discovery I made in the past. Unfortunately, the results were not encouraging but, despite it all, we remain friends)!
The National Center for Research Resources (3/15/2011) describes the CTSA program as: “A national consortium of medical research institutions, funded through Clinical and Translational Science Awards (CTSA), is working together to improve the way biomedical research is conducted nationwide. Consortium members share a common vision to reduce the time it takes for laboratory discoveries to become treatments for patients, to engage communities in clinical research efforts and to train clinical and translational researchers. The momentum behind the CTSA program continues to build as new connections are emerging within, across and beyond the consortium. Launched in 2006, it now includes 55 medical researchers in 28 states and the District of Columbia. When the program is fully implemented, it will support approximately 60 CTSAs across the nation.”
The broader Translational Science movement continues to gather steam. The prestigious American Society for the Advancement of Science started the new journal, Science Translational Medicine.The highly respected Francis Collins, the Director of the NIH, is energetically pushing for ways to conduct more clinical trials on potential promising new therapies and has recently proposed a separate NIH unit for this purpose. It’s good news, indeed, for patients that a highly visible, distinguished physician and scientist has stepped forward and taken the lead in this very sensitive arena.
NOW HERE’S THE BAD NEWS: THE TRANSLATIONAL RESEARCH MOVEMENT NEEDS HELP: Unfortunately, our current regulatory ground rules, coupled with our pervasive, obdurate cultural suspicion of the risks in clinical research further coupled with our excessive general, cultural preoccupation with risk, remain unbudgeable and will continue to both retard and block clinical studies .If anything is impossible, it would be to convince Congress, let alone the FDA, to significantly lower the barriers for patient volunteers. There is little doubt that the CTSA will spur on innovative clinical research and medical discovery, not the least by reducing logistical logjams, but the principle barriers of the “system” will remain. In addition, the CTSA effort is limited in scope.
Though Thomas Aquinas believed that the argument from authority is the weakest of all, I remember what my father used to periodically emphasize. “Son, there’s an exception to every rule.” I’m speaking from extensive, personal experiences, which are tough to quantify, in the world of clinical research and drug development of new drugs starting from my initial clinical study with carnitine in 1965 up to the present dealing with FDA, Clinical Research Organizations (CROs), IRBs, the Orphan Drug Act, the CME, ethicists- moralists, corporations, academicians, lawyers and international regulators. Whom have I left out? Yes, the powerless patient!
There are huge barriers to clinical research studies. A recent study conducted by Ken Getz at the Tufts Center for the Study of Drug Development found that the median number of procedures per clinical study increased by 49% between 2000-03 and 2004-07, while the total effort required to complete those procedures grew by 54%. He states that, “More complex and burdensome protocols are extending study cycle times, increasing costs and challenging patient recruitment and retention.” He adds that enrollment criteria are discouraging patient enrollments dissuading volunteers from staying in the study until completion.
(As a reminder, may I interject here that the barriers to clinical studies were huge and growing and increasingly stifling a long time before 2003! This pattern should make us all very much disturbed about the inexorable continuum increasing of obstacles to clinical studies).
An eye-opening example of the pervasive multiple obstacles to entering Phase III clinical studies is given by, J. Evan Sadler, the President of the American Society of Hematology, who writes:
“Recent studies in basic and translational research have set the stage for tremendous progress in clinical hematology, but trials to pursue these opportunities can run afoul of many obstacles. For example, David Dilts, Director of Clinical Research of the Knight Cancer Center Institute, reported last year that opening a phase III cooperative group trial requires an average of 2.5 years to accommodate 118 decision points, complete more than 769 process steps, and receive approval up to 36 separate groups and individuals. Whether many of these steps improve trial quality or patient safety is doubtful. Many approved trials never enroll a single patient and barely half are ever completed, which is a total waste of human and financial capital. Small wonder that Garret Fitzgerald, M.D., Director of the Institute of Translational Medicine and Therapeutics at the University of Pennsylvania, has described our current system as “Spreading dysfunction that undermines progress for the sake of managing risks.”
NOW HERE’S THE GOOD NEWS: IT’S THE DOCTORNAUT ACT. The Doctornaut Act, which would permit physicians to volunteer for clinical studies with substantially fewer restraints than non- physicians, would quickly accelerate the number of potential therapies tested in clinical trials and, pari passu, accelerate medical discovery. It would, in my opinion, act synergistically with the general Translational Science movement particularly in Phase I and Phase II studies.
Frankly speaking, a number of my colleagues most of whom, might I add, are highly competent clinical research veterans, have their doubts whether doctornauts would make a significant contribution to translational discovery research. Generally, their initial reactions were those of apprehension rather than optimistic enthusiasm which, in large part, understandably reflect our imbedded cultural fear of risk. Senator Bill Frist, who had a Discussion Draft of the Doctornaut Act circulated for comments, and I discussed this legitimate concern. We agreed that guidelines for doctornauts participation in clinical studies should balance this concern without unreasonably compromising the necessary risk involved of doctornaut participation in clinical studies.
Let’s now talk about the role CTSAs and doctornauts could play: There are two types of clinical research: pioneering and applied. A pioneering clinical study leads to an important medical discovery such as the H. pylori study by the doctornaut, Dr. Barry Marshall. This type of discovery occurs outside the “system” and comes out of the blue. After the discovery phase then applied clinical research follows in a larger population to better characterize the efficacy and safety of the discovery. With respect to the clinical investigator, I do not consider the first clinical study of a pharmaceutical company discovered molecule, even if it is a medical breakthrough, as pioneering. It is applied. I also do not consider a large clinical trial to determine whether statins or beta- blockers reduce the incidence of myocardial infarction or stroke as pioneering. It is applied. In fact, the vast majority of clinical studies are not pioneering from the point of view of the clinical researcher. The idea isn’t his or hers but put on the clinical research plate by a third party. Our system does not encourage clinical initiative; on the contrary, it powerfully discourages clinical researchers from even daring to think about their own innovative ideas. It’s just too hard to get the job done. The mere existence of the Translational Science movement confirms this reality. This state of affairs must be remedied by our leaders who are concerned about “Cure” as well as “Care”.
What I’m not clear on is the breadth of the mission statement of the CTSA endeavor. Is it primarily to reduce the barriers to clinical studies for promising drugs or devices discovered by third parties, which is a very welcomed step forward in applied research in itself, or, does it also encourage clinical researchers to come up with their own pioneering ideas or by brainstorming with their colleagues?
FIM’s principal objective is to reduce the barriers to Phase I-II studies, the medical discovery step, for both pioneering and applied research and also to encourage and expand the former’s innovative potential which, given today’s expanding technology, is breathtaking. But there is little recognition of this marvelous reservoir from any quarter including the medical research community.
Let’s take some theoretical case scenarios of pioneering clinical studies which hopefully will get the Translational Science leaders thinking more toward how CTSAs can bring into the research fold our potential medical innovators. What can they do to pursue their creative ideas?
1. The blood brain barrier exists for a reason but, because of unknown risks, one must be very careful in any attempt to “open” it. Selective types of small molecules, fortunately, can pass across the barrier, opening the door to expand the pool of potential therapies for CNS diseases and disabilities. In certain instances, however, the oral administration of small molecules may need help to achieve sufficient CNS efficacious tissue levels. For quite a while it has been known that both mannitol and cerebral ischemia do temporarily open the barrier, but clinical studies to better define this phenomenon are lacking. Let’s say that a young curious clinical investigator believes that properly opening the barrier can lead to major medical breakthroughs. He then collaborates with his scientific colleague to design laboratory experiments with a medical device and come up with a way of combining both experimental procedures to effectively open the barriers for a brief, controlled period where small molecules can be administered intravenously to increase tissue levels. Oral administration can then follow maintaining such levels.
2. A cardiovascular physician, while reducing a patient’s body temperature to 91 degrees after cardiac arrest in order to preserve his brain function during a clinical study, is reminded by his nurse that the patient also has early stage pancreatic cancer. An idea spontaneously jumps to mind. Can the patient’s hypothermic state make his tumor or even other tumors more sensitive to chemotherapeutic agents than at normal body temperatures? He then wants to know what the next step should be to test his hypothesis. He discusses the next step with his scientific oncologist colleague experts, and they conduct several animal studies at the physician’s own expense. Creative minds despise barriers, and he didn’t want to wait for the long period of time it takes to obtain a grant, particularly when it is highly probable, because of its out-of-the box approach, that the grant request would be denied. DaVinci simply walked to his canvas with brush in hand with only air as the barrier to create the Mona Lisa and, similarly, Einstein to the black board with chalk in hand to divine his Theory of Relativity. And all Marshall had to do was swig down his H. pylori soup.
3. A busy practicing rheumatologist makes the diagnosis that his mother has crossed the Rubicon and is on her way to crippling rheumatoid arthritis. He simply refuses to accept her rendezvous with pain and loss of mobility which is not a recipe for happiness. He decides to find an answer and surrenders his practice to another physician. He then contacts two expert research scientists in the field, and they work together to come up with a novel treatment approach with FDA approved drugs. They decide to achieve greater efficacy reaching certain blood levels by periodic intravenous infusion of two drugs followed by oral administration of three drugs between the intervals hoping to temporarily halt the process. This regimen is to be repeated when there are signs of the process acting up. (At this point I’d like to raise the point of FDA’s policy on combination drugs which IRBs tend to honor for study approval. This issue is addressed on my Commentary entitled, Medical Versus Scientific Clinical Research: Time for an Immediate Change!
4. A fellow in neurology, while on weekend call and with some free time in his small quarters, reads in a lay journal that in Mongolia there is a virtual absence of Alzheimer’s disease. The author of the article observed that Mongolians eat about a pound a day of the cruciferous vegetable, turnips, usually divided into two meals. He visits the internet searching for the ingredients of this type of turnip but, alas, the answer was not to be found in cyberspace. He contacts his nutritionist friend who, somehow, is able to come up with the list. He is excited about conducting a nutraceutical clinical study. But the Mongolian turnips are not available in the U.S. which presents a problem.
Some ways in which doctornauts could increase the productivity of Translational Research clinical investigators for early clinical discovery studies, which is the principle objective of the Doctornaut Act, are as follows:
1. Broad expansion of IND exemptions which can apply to multiple clinical situations: There already exist IND exemption regulations but they are narrowly restrictive.
2. Significant increase in off- labeling studies.
3. More testing of multiple combinations for diseases and disabilities which FDA NDA policy, with few exceptions, effectively discourages.
4. Third parties, such as pharmaceutical and medical device companies, instead of sponsoring studies with one of their potential discoveries, can sponsor two or more.
5. More studies on the combination of medical devices and pharmaceuticals.
6. Create more entrepreneurial and charitable organizations to clinically evaluate both low and high cost potential therapies.
7. Internationally approved therapies not yet approved in the U.S. will be tested either alone or in combination with FDA approved ones.
8. Increase clinical studies on potential orphan drugs and “orphaned” phases of general disease such as late stage, drug resistant ovarian cancer.
9. Expand nutraceutical-pharmaceutical combinations.
10. Bring into the medical discovery potential the huge creative potential thinking of scientists-physicians to test their ideas. This is a critical element to maximize discovery productivity and must be effectively encouraged.
11. Other unforeseen situations that will eventually unfold as the system evolves.
Who will sponsor these clinical studies? A healthy Translational Science movement together with an approved Doctornaut Act will bring about a rapid and substantial increase as well a transformation of research and development players ranging from start-ups, charitable institutions such as foundations, traditional pharmaceutical and device companies and the government. The discovery field will be highly competitive with substantial funding for clinical studies. As previously mentioned, a broad variety of unique types of emerging therapies will not fit into regulatory categories. It is important to note that in our country, once breakthrough therapies are discovered, it is difficult to suppress them, and the regulations will necessarily bend. As Santayana noted about a century ago, America is unique by its preponderance of good will. This coupled with the forces of the marketplace will form a formidable anti-Luddite duo.
A justifiable concern is whether present day physicians, influenced by modern values, would volunteer as doctornauts. FIM’s top priority is an interest in the medical potential of natural substances that are not clinically exploited largely because of patent problems.
Some years ago, FIM funded a physician survey regarding their willingness to be doctornauts for natural substances. The following is a summary:
“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 considered. In addition, a telephone survey of seven academic institutions was conducted. A total of 10.3 percent of physicians responded. A simple “Yes” or “No” was required to 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?’
PHYSICIAN RESPONSE
| Yes % | No % | |
| Male M.D.’s Total | 52.5 | 47.5 |
| Male M.D.’s Under Age 50 | 56.6 | 4.4 |
| 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 |
| Academic Institutions | 57.7 | 42.3 |
But what is surprising today is that, with few exceptions, almost all of my current physician colleagues doubt whether modern physicians would volunteer to be doctornauts, even for non-risky clinical studies, without FDA supervision. They may be right but if a survey were conducted asking questions such as, “If you are still rational on your way to inevitable mind -destroying Alzheimer’s, or in the late stages of cardiomyopathy with a few years to live, or your cancer is out of control resistant to chemotherapy and you have a certain rendezvous with death within in a year, or two or if your arthritis is becoming so crippling that you can’t even embrace your beloved wife, would you volunteer to be a doctornaut?” Speaking to a number of physicians who have or may in the future have serious diseases I have found that, with few exceptions, they agreed to have the “right” to be a doctornaut. But this is only an impression and not solid survey data so let’s look at it another way: There are about 700,000 physicians in our country. If only 10%, an extremely conservative figure, of our current physician population agrees to be doctornauts, then there will be 70,000 doctornauts, an impressive healthy number, to test many applied and pioneering early clinical discovery studies.
In conclusion, my hat is off to those who conceived of and got the ball rolling on the essential importance of clinical research but let there be no doubt that the obstinate barrier “system” is still intact and even growing which will effectively frustrate the potential of the Translational Research movement. And, as is frequently the case, the patient pays the price.
The Doctornaut Act is a natural partner to the movement. To those of you in doubt consider Pascal’s Wager regarding the need to believe in the existence of God. “There is little to lose and much to gain.”