Journal of Cancer Education
ISSN: 0885-8195 (Print) 1543-0154 (Online) Journal homepage: http://www.tandfonline.com/loi/hjce20
Special communication—Clinical research‐a commentary Nathaniel I. Berlin MD To cite this article: Nathaniel I. Berlin MD (1992) Special communication—Clinical research‐a commentary, Journal of Cancer Education, 7:3, 209-213 To link to this article: http://dx.doi.org/10.1080/08858199209528169
Published online: 01 Oct 2009.
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Date: 05 August 2017, At: 07:52
J. Cancer Education. Vol. 7, No. 3, pp. 209-213,1992 Printed in the U.S.A. Pergamon Press Ltd.
0885-8195/92 $5.00 + .00 © 1992 American Association for Cancer Education
SPECIAL COMMUNICATION CLINICAL RESEARCH-A COMMENTARY
Downloaded by [Australian Catholic University] at 07:52 05 August 2017
NATHANIEL I. BERLIN, MD*
Clinical research including clinical cancer research is becoming an ever increasing subject of concern.1 There are three major considerations: (1) why it is necessary for us to do clinical research, (2) who will be responsible, and (3) the recognition that there has been a marked decrease in interest and participation in clinical research by physicians. This decline began about 20 years ago, which I first noticed when I was at the National Institutes of Health (NIH). In 1972, J.E. Rail, D.S. Frederickson, and I organized a meeting with senior medical students, interns, and residents on this subject. We created a structured questionnaire but never published the conclusions. It was of more value to us, as scientific directors (of NIAMD, NHLBI, and NCI, respectively) than to the biomedical research community at large, since the decline coincided with and was directly attributable to the end of the doctor draft. The doctor draft was a very potent stimulus to research. It gave a small number of physicians the opportunity to meet military service requirements by volunteering for the Public Health Service with assignment to the NIH. To some extent we anticipated or expected a decline but not of the magnitude that occurred. Wyngaarden's 1979 Presidential Address to the Association of American Physicians, "The Clinical Investigator as an Endangered Species," which was subsequently published in the New England Journal of Medicine1; the 1988 report of the Institute of Medicine (IOM), "Resource for Clinical Investigation" 2 ; Freireich's "A study of the status of clinical cancer research in the United States *Deputy Director, Sylvester Comprehensive Cancer Center, Miami, FL. Reprint requests to: Nathaniel I. Berlin, Sylvester Comprehensive Cancer Center, University of Miami, P.O. Box 016960 (D72), Miami, FL 33101.
(1990)"3; and Vaitukaitis's "The future of clinical research,"4 all highlight concerns about clinical research. Further Friedman et al., in "Poor funding rates of cancer clinical research: Intractable problem or solvable challenge,"5 and Kimes et al in "Training in clinical research in oncology"6 point the way to possible solutions. The question, "Why is it necessary to do clinical research today?" I think, can best be answered under three broad headings. The first is that there are still major clim'cal problems affecting the health of man, which I do believe should and can be studied today and must involve physicians, patients, and normal volunteers. Further advances in cell and molecular biology are coming at an ever increasing rate that will form the base of much of the clinical research of the future. Second, and possibly less evident but no less important, is that it is necessary to maintain a credible clinical research program nationally, and particularly to do this in the teaching hospitals, because I am convinced that it is a major factor in determining the quality of teaching and patient care. The words of the late Jack Masur, carved in the marble at the entrance of the Masur Auditorium of the Clinical Center of the National Institutes of Health, apply here: Hospitals with long traditions of excellence have demonstrated abundantly that research enhances the vitality of teaching; teaching lifts the standard of service; and service opens new avenues of investigations.
The third, and perhaps to some the most important, is that we will continue to need physicians who are capable of translating today's and tomorrow's basic science advances to tomorrow's clim'cal medicine. This will require clinical investigators, that is, individuals who know how to do clinical research.
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Masur's words clearly link patient care to teaching and to research. In teaching hospitals, medical students and house-staff should learn, if nothing else, something about the process of asking research questions because similar processes should be used in patient care. Much of this can be summarized as "Why am I doing what I am doing in the care of this patient?" or perhaps better, "What is the scientific base for what I am doing and how good is it?" If it is accepted that clinical research is important today, and will continue to be important, how can it be categorized? Before clinical research is subdivided or a taxonomy developed, a definition of clinical research is needed. The Institute of Medicine report2 separates clinical research and clinical trials with a description of each that constitutes a definition: Clinical investigation is defined as that segment of clinical research for which an investigator directly interacts with patients in either an outpatient or inpatient setting. This definition excludes studies for which material of human origin is obtained through a third party and for which an investigator has had no direct interaction with the patient. Clinical trial is defined as a scientific research study undertaken with human subjects to evaluate prospectively the diagnostic/prophylactic/therapeutic effects of a drug, device, regimen, or procedure used or intended for use in the practice of medicine or the prevention of disease. This definition of clinical trial is the official NIH definition. The National Institutes of Health report emphasized that these are narrow definitions of clinical investigation and clinical trial and were employed as a practical consideration for the purpose of focusing attention in their deliberations. The Committee felt that an appropriate definition of clinical investigation includes studies of individual subjects; groups of subjects; Phase I, II, III, and IV clinical trials; the use of human material for laboratory based research; epidemiological studies of investigation to protect or improve the health of individual patients through translation into clinical practice of scientifically tested and evaluated innovations and improvements in. preventive, diagnostic, therapeutic and rehabilitative technologies.
A recent NCI workshop on training of cancer clinical investigators developed this definition: Clinical oncology research is the investigative care of patients with cancer, not restricted to individual medical disciplines or practices, which is directed toward the study of biology, diagnosis, treatment, behavioral components, and/or prevention. It often involves laboratory and preclinical research with dynamic back and forth interactions between the laboratory and the clinic, but it always is motivated by observations in patients as a result of continuously ongoing activities in direct patient care.
It is not surprising that in these definitions there is the recurrent theme of patient-physician interaction with the goal of developing new information. The IOM report expresses reservations about the definitions they used, and the NCI workshop states that their definition was a consensus. Perhaps it is best to utilize Justice Brennan's opinion about obscenity—"I recognize it when I see it." Given this brief background, I believe clinical research can be put into six broad categories (the order is not significant). 1. Designed clinical trials. Well known are the therapeutic trials in cancer chemotherapy carried out by the cooperative chemotherapy groups. Another example is the screening trial that has been completed, which sought to determine in high-risk individuals, that is, males over 45 who are cigarette smokers, whether sputum cytology at 4-month intervals and a chest x-ray annually or even quarterly would reduce the mortality from lung cancer —it did not.7 2. Unplanned observations, namely, that a physician makes an unusual observation, seeks to develop an understanding, follows it up, and publishes it as a case report. I am not aware of any rigorous study of the contributions of case reports to our knowledge but it must be substantial. 3. Review of a given institution's experience with a given disease. These can be designated as case record reviews. It can probably be argued that much of our clinical practice is derived from this source. 4. The use of applied variables. These observations are often both physiological and biochemical. They may be carried out in the normal volunteer or patients. An example that comes to mind are the studies of the drugs that affect blood pressure. 5. Specimens attained from patients often in a planned way, but sometimes not highly planned, and stored in blood and tissue banks for future use or sent to laboratories for a variety of studies—
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these are specimens of blood, urine, clinical research. The answer is simple. This and tissue, both normal and abnormal. must be done by those whose training is in 6. The last is epidemiological. Particularly medicine—this includes all specialties—and well known are those that have described by physicians who have had specific training the epidemiology of cancer, particularly in research and have had research experience. incidence and mortality rates and com- This training may be through MD-PhD proparison of incidence and mortality rates grams, research fellowships, and traineeships. from one part of the world with those An editorial in The British Medical Jourof another. It should be remembered nal of 1980 asks the question, "MD or PhDs that much if not all of what we know in medical research?"9 This editorial was about the specific causes of cancer in stimulated by Wyngaarden's paper,1 which man have been derived from epidemio- reported that in 1966 44% of the NIH grants logical studies. It should also be recalled went to MDs, in 1977 it was 23%, which is the that much of our current preventive current level, and that decline was paralleled medicine practices have been derived by an increase to 70% of the grants going to from epidemiological studies and much PhDs, the difference is largely due to those of what we know of diseases that are with both the PhD and MD degrees. now preventable are derived from epiGiven this background of a decline in the demiological studies. One of the more number of physicians interested in a research interesting current efforts, in the epi- career and an equal decline in the number of demiology of hepatitis, has led to the medical students interested in research, one development of a vaccine for the pre- must ask why this is so in terms of what is vention of Hepatitis B infection and missing and what are the deterrents. I think possibly liver cancer (primary hepato- there are two things that are missing. One stems from the education goals of the medicellular cancer). cal school. The degree, Doctor of Medicine, Closely linked to this discussion of the cat- is not a research degree, nor can the individegories of clinical research must be a recogni- uals trained in medicine be expected to do tion of the work reported by Feinstein, Koss, meaningful clinical research without further and Austin in 1967 in the Annals of Internal research training and experience. The conseMedicine that demonstrated a phenomenon quence is that a number of people who are that has become very familiar.8 They demon- finishing medical school, or who are now in strated from the abstracts submitted to the clinical training, are asking themselves what a American Society of Clinical Investigation career in research entails. This must be viewed that there has been a marked shift in studies in terms of what are the research career incenby those who considered themselves to be tives, what are the research career rewards clinical investigators from human/patient/ and, increasingly, what is the opportunity for clinical-oriented to laboratory animal-oriented a long-term research career? These questions studies. Some of the reasons for this stem can be translated in simple terms to what are from the fact that as the number of clinical in- the opportunities for stability in a research cavestigators increased and as the technology of reer? There are probably at least seven major the biological sciences advanced, it rapidly be- deterrents. The first deterrent is that most came apparent that one could carry out much people who graduate from medical school do more research that was related to clinical so with a substantial debt. This they must pay medicine in the experimental animal, in tissue back at some time, and for some, repayment culture, or in-vitro cell free systems than in is in the public service sector, which precludes man, and that one could do it more easily, ask starting on a research career, and for some, simpler questions, and develop less ambigu- the debt may be as high as $100,000. Early reous answers. In a sense this represents the ap- payment is often required, and there are often substantial interest payments, which begin plication of the reductionist theory. fairly soon after medical school is completed. The third major question is who should do
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The second deterrent becomes apparent from an examination of the age at which significant decisions have to be made. At around age 1718 the decision is made to enter college. For most, but not all, in the freshman year of college, the decision is made to undertake a premedical curriculum. At age 21 or 22 there is a self-review of one's career, and the decision must be made to seek admission to medical school. Most complete medical school around age 25-26 and at that time begin a 3 to 5-year period (and in some instances even longer) of clinical training as interns, residents, and clinical fellows. This means that physicians may be as old as 30 before completing their formal training in clinical medicine and are able to enter a full-time research training post, which is less rewarding financially than the practice of medicine. At this time many also face the additional financial burden of a family. One should contrast the age 30 to begin a career in clinical research to age 21, 22, or 23, or even earlier for starting a research career in the biological sciences. I recognize that some begin training earlier as MD-PhD degree candidates and some do so while in medical school without seeking the PhD. Perhaps the most difficult to evaluate and understand, but nevertheless this must be done in some fashion, is the young physician's view of clinical research in terms of the opportunities and the rewards. This can best be epitomized by recapturing a conversation with a senior medical student held in 1980. When I asked one of the medical students where she went to school and what was her major, she replied that she went to the University of Michigan and her major was cell biology. What was her intent at the time of entering college? "To do biological research." Why did you go to medical school rather than continue on to graduate school? Her answer was that she wanted security and "did not want to go chasing grants for the rest of her life." At that time it was a surprise to me that this view had spread to the undergraduate college level. It may very well reflect the thinking of medical students and house officers who have been in institutions where research is strong and who have seen examples of the consequences of the
instability of research support (epitomized by "He lost his grant") and the instability of career support for young and for established investigators. There also appears to be a commonly held view that clinical research grant applications to NIH do not fare as well as basic science grant applications and that this has led to a decrease in grant applications from MDs. The decrease is a fact, but those submitted by MDs fare as well as those submitted by PhDs.4 The fourth deterrent is that the training requirements imposed by the specialty and subspecialty boards for certification in clinical medicine have become long and, to some degree, with less provision for a research experience. For example, in internal medicine, three years of house officership is often followed by two years of a clinical fellowship, which leads to a certificate in internal medicine and a certificate in one of the subspecialties, a path many rightly follow. The fifth deterrent is that it is becoming increasingly difficult to translate knowledge and particularly laboratory techniques gained in the undergraduate college and medical school to current research questions. I can well remember when I began research at the University of California, I was able to use a good bit of the knowledge and a good bit of the laboratory techniques I had acquired in the undergraduate college and medical school to begin my research. I then added to these the techniques and technology that I was utilizing at Berkeley. I think that the complexity of the technology that is used in laboratory research today and the decrease in the exposure of medical students and undergraduate students to the laboratory, provides much less of a base for the beginning of a research career in terms of ability to carry out specific laboratory tasks. The sixth deterrent, which may be less apparent to many of the young physicians in training but more apparent to those in midcareer or more senior, is what I choose to term "the quality of clinical research" as perceived by the basic scientists. The basic scientists tend to hold, and it is difficult to prove or disprove, that the research being carried
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Clinical research—a commentary
out by clinical researchers is not as good as that being carried out by basic scientists. I am not convinced that they fully understand the constraints imposed upon clinical investigators. Nevertheless, there is a widespread feeling that this is true. The last deterrent, which is probably less well known than any of the others, relates to the grant review process. I think the current pattern for three-year grant awards, as contrasted to five and seven-year awards by the National Institutes of Health in the past, is a serious deterrent. Further, the time required for review of a grant has now become as long as a year between application and award, and perhaps the most important is a feeling that many of the review committees are not necessarily qualified to review some of the projects that they have been assigned to review. This, of course, is difficult to prove, but nevertheless reflects a widely held opinion. Further the low funding rate—of the order of 20%30%—can be disheartening, considering the time required to prepare a grant and the long delay in review before a decision is made. I think one can draw the conclusion that for physicians there are major deterrents to begin a clinical research career and there are no simple solutions, but solutions are being proposed. These difficulties have led to the Institute of Medicine report2 and to the studies by Freireich and by Vaitukaitis,3'4 a workshop by the NCI, and to proposals for new study sections dedicated to reviewing Only clinical research applications and new training programs designed to acknowledge the long training required. While it is too early to realize the impact of these studies on policy and practice, their recommendations may not be sufficient, for in fact it may be necessary to restructure at a most fundamental level how biomedical research is supported. We may need to move from reviewing scientific proposals to reviewing scientific productivity, and we may need to stabilize institutional support and not thorough indirect cost rates. What we must do is turn our attention to what it is that would make clinical research attractive as a career,
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and then we must make the effort to develop the resources so that we can once again bring into clinical research a sufficient number of our younger physicians. While this review has been more negative than positive, the rewards of a research career can be very substantial: recognition by colleagues and, in some instances, fame in the community at large; and, difficult to quantify, the sheer delight and satisfaction that can be drawn from developing new knowledge, for it is new knowledge and the transmission of that new knowledge that is a powerful incentive and a source of delight that for some has overcome the deterrents, and can continue to do so. Note: The theme presented here was originally presented in 1981 at a Grand Rounds at the Walter & Eliza Hall Institute of Medical Research Melbourne, Australia, while the author was a Fogarty Senior International Fellow of the National Institutes of Health. REFERENCES 1. Wyngaarden JB: The clinical investigator as an endangered species. N Engl J Med 301:1254-1259, 1979. 2. Institute of Medicine: Resources for Clinical Investigation. IOM-88-07. Washington, DC: National Academy Press, 1988. 3. Freireich EJ: A study of the status of clinical cancer research in the United States (1990). J Natl Cancer Inst 83:829-837, 1991. 4. Vaitukaitis JL: The future of clinical research. Clin Res 39:145-156, 1991. 5. Friedman MA, Cain DF, Bronzert D, Wu RS: Poor funding rates of cancer clinical research: Intractable problem or solvable challenge? J Natl Cancer Inst 83:838-841, 1991. 6. Kimes BW, Cairoli V, Freireich EJ, Karp J, Yang SS: Training in clinical research in oncology. Cancer Res 51:753-756, 1991. 7. Berlin NI, Buncher CR, Fontana RS, Frost JK, Melamed MR: The National Cancer Institute Cooperative early lung cancer detection program: Results of the initial screen (prevalence). Early lung cancer detection: Introduction. Am Rev Respir Dis 130(4):545-570, 1984. 8. Feinstein AR, Koss N, and Austin JHM: The changing emphasis in clinical research. Ann Intern Med 66:396-419, 1967. 9. Anon. MDs or PhDs in Medical research? BMJ: 1:274, 1980.
ISSN: 0885-8195 (Print) 1543-0154 (Online) Journal homepage: http://www.tandfonline.com/loi/hjce20
Special communication—Clinical research‐a commentary Nathaniel I. Berlin MD To cite this article: Nathaniel I. Berlin MD (1992) Special communication—Clinical research‐a commentary, Journal of Cancer Education, 7:3, 209-213 To link to this article: http://dx.doi.org/10.1080/08858199209528169
Published online: 01 Oct 2009.
Submit your article to this journal
Article views: 1
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=hjce20 Download by: [Australian Catholic University]
Date: 05 August 2017, At: 07:52
J. Cancer Education. Vol. 7, No. 3, pp. 209-213,1992 Printed in the U.S.A. Pergamon Press Ltd.
0885-8195/92 $5.00 + .00 © 1992 American Association for Cancer Education
SPECIAL COMMUNICATION CLINICAL RESEARCH-A COMMENTARY
Downloaded by [Australian Catholic University] at 07:52 05 August 2017
NATHANIEL I. BERLIN, MD*
Clinical research including clinical cancer research is becoming an ever increasing subject of concern.1 There are three major considerations: (1) why it is necessary for us to do clinical research, (2) who will be responsible, and (3) the recognition that there has been a marked decrease in interest and participation in clinical research by physicians. This decline began about 20 years ago, which I first noticed when I was at the National Institutes of Health (NIH). In 1972, J.E. Rail, D.S. Frederickson, and I organized a meeting with senior medical students, interns, and residents on this subject. We created a structured questionnaire but never published the conclusions. It was of more value to us, as scientific directors (of NIAMD, NHLBI, and NCI, respectively) than to the biomedical research community at large, since the decline coincided with and was directly attributable to the end of the doctor draft. The doctor draft was a very potent stimulus to research. It gave a small number of physicians the opportunity to meet military service requirements by volunteering for the Public Health Service with assignment to the NIH. To some extent we anticipated or expected a decline but not of the magnitude that occurred. Wyngaarden's 1979 Presidential Address to the Association of American Physicians, "The Clinical Investigator as an Endangered Species," which was subsequently published in the New England Journal of Medicine1; the 1988 report of the Institute of Medicine (IOM), "Resource for Clinical Investigation" 2 ; Freireich's "A study of the status of clinical cancer research in the United States *Deputy Director, Sylvester Comprehensive Cancer Center, Miami, FL. Reprint requests to: Nathaniel I. Berlin, Sylvester Comprehensive Cancer Center, University of Miami, P.O. Box 016960 (D72), Miami, FL 33101.
(1990)"3; and Vaitukaitis's "The future of clinical research,"4 all highlight concerns about clinical research. Further Friedman et al., in "Poor funding rates of cancer clinical research: Intractable problem or solvable challenge,"5 and Kimes et al in "Training in clinical research in oncology"6 point the way to possible solutions. The question, "Why is it necessary to do clinical research today?" I think, can best be answered under three broad headings. The first is that there are still major clim'cal problems affecting the health of man, which I do believe should and can be studied today and must involve physicians, patients, and normal volunteers. Further advances in cell and molecular biology are coming at an ever increasing rate that will form the base of much of the clinical research of the future. Second, and possibly less evident but no less important, is that it is necessary to maintain a credible clinical research program nationally, and particularly to do this in the teaching hospitals, because I am convinced that it is a major factor in determining the quality of teaching and patient care. The words of the late Jack Masur, carved in the marble at the entrance of the Masur Auditorium of the Clinical Center of the National Institutes of Health, apply here: Hospitals with long traditions of excellence have demonstrated abundantly that research enhances the vitality of teaching; teaching lifts the standard of service; and service opens new avenues of investigations.
The third, and perhaps to some the most important, is that we will continue to need physicians who are capable of translating today's and tomorrow's basic science advances to tomorrow's clim'cal medicine. This will require clinical investigators, that is, individuals who know how to do clinical research.
209
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N. I. BERLIN
Masur's words clearly link patient care to teaching and to research. In teaching hospitals, medical students and house-staff should learn, if nothing else, something about the process of asking research questions because similar processes should be used in patient care. Much of this can be summarized as "Why am I doing what I am doing in the care of this patient?" or perhaps better, "What is the scientific base for what I am doing and how good is it?" If it is accepted that clinical research is important today, and will continue to be important, how can it be categorized? Before clinical research is subdivided or a taxonomy developed, a definition of clinical research is needed. The Institute of Medicine report2 separates clinical research and clinical trials with a description of each that constitutes a definition: Clinical investigation is defined as that segment of clinical research for which an investigator directly interacts with patients in either an outpatient or inpatient setting. This definition excludes studies for which material of human origin is obtained through a third party and for which an investigator has had no direct interaction with the patient. Clinical trial is defined as a scientific research study undertaken with human subjects to evaluate prospectively the diagnostic/prophylactic/therapeutic effects of a drug, device, regimen, or procedure used or intended for use in the practice of medicine or the prevention of disease. This definition of clinical trial is the official NIH definition. The National Institutes of Health report emphasized that these are narrow definitions of clinical investigation and clinical trial and were employed as a practical consideration for the purpose of focusing attention in their deliberations. The Committee felt that an appropriate definition of clinical investigation includes studies of individual subjects; groups of subjects; Phase I, II, III, and IV clinical trials; the use of human material for laboratory based research; epidemiological studies of investigation to protect or improve the health of individual patients through translation into clinical practice of scientifically tested and evaluated innovations and improvements in. preventive, diagnostic, therapeutic and rehabilitative technologies.
A recent NCI workshop on training of cancer clinical investigators developed this definition: Clinical oncology research is the investigative care of patients with cancer, not restricted to individual medical disciplines or practices, which is directed toward the study of biology, diagnosis, treatment, behavioral components, and/or prevention. It often involves laboratory and preclinical research with dynamic back and forth interactions between the laboratory and the clinic, but it always is motivated by observations in patients as a result of continuously ongoing activities in direct patient care.
It is not surprising that in these definitions there is the recurrent theme of patient-physician interaction with the goal of developing new information. The IOM report expresses reservations about the definitions they used, and the NCI workshop states that their definition was a consensus. Perhaps it is best to utilize Justice Brennan's opinion about obscenity—"I recognize it when I see it." Given this brief background, I believe clinical research can be put into six broad categories (the order is not significant). 1. Designed clinical trials. Well known are the therapeutic trials in cancer chemotherapy carried out by the cooperative chemotherapy groups. Another example is the screening trial that has been completed, which sought to determine in high-risk individuals, that is, males over 45 who are cigarette smokers, whether sputum cytology at 4-month intervals and a chest x-ray annually or even quarterly would reduce the mortality from lung cancer —it did not.7 2. Unplanned observations, namely, that a physician makes an unusual observation, seeks to develop an understanding, follows it up, and publishes it as a case report. I am not aware of any rigorous study of the contributions of case reports to our knowledge but it must be substantial. 3. Review of a given institution's experience with a given disease. These can be designated as case record reviews. It can probably be argued that much of our clinical practice is derived from this source. 4. The use of applied variables. These observations are often both physiological and biochemical. They may be carried out in the normal volunteer or patients. An example that comes to mind are the studies of the drugs that affect blood pressure. 5. Specimens attained from patients often in a planned way, but sometimes not highly planned, and stored in blood and tissue banks for future use or sent to laboratories for a variety of studies—
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211
these are specimens of blood, urine, clinical research. The answer is simple. This and tissue, both normal and abnormal. must be done by those whose training is in 6. The last is epidemiological. Particularly medicine—this includes all specialties—and well known are those that have described by physicians who have had specific training the epidemiology of cancer, particularly in research and have had research experience. incidence and mortality rates and com- This training may be through MD-PhD proparison of incidence and mortality rates grams, research fellowships, and traineeships. from one part of the world with those An editorial in The British Medical Jourof another. It should be remembered nal of 1980 asks the question, "MD or PhDs that much if not all of what we know in medical research?"9 This editorial was about the specific causes of cancer in stimulated by Wyngaarden's paper,1 which man have been derived from epidemio- reported that in 1966 44% of the NIH grants logical studies. It should also be recalled went to MDs, in 1977 it was 23%, which is the that much of our current preventive current level, and that decline was paralleled medicine practices have been derived by an increase to 70% of the grants going to from epidemiological studies and much PhDs, the difference is largely due to those of what we know of diseases that are with both the PhD and MD degrees. now preventable are derived from epiGiven this background of a decline in the demiological studies. One of the more number of physicians interested in a research interesting current efforts, in the epi- career and an equal decline in the number of demiology of hepatitis, has led to the medical students interested in research, one development of a vaccine for the pre- must ask why this is so in terms of what is vention of Hepatitis B infection and missing and what are the deterrents. I think possibly liver cancer (primary hepato- there are two things that are missing. One stems from the education goals of the medicellular cancer). cal school. The degree, Doctor of Medicine, Closely linked to this discussion of the cat- is not a research degree, nor can the individegories of clinical research must be a recogni- uals trained in medicine be expected to do tion of the work reported by Feinstein, Koss, meaningful clinical research without further and Austin in 1967 in the Annals of Internal research training and experience. The conseMedicine that demonstrated a phenomenon quence is that a number of people who are that has become very familiar.8 They demon- finishing medical school, or who are now in strated from the abstracts submitted to the clinical training, are asking themselves what a American Society of Clinical Investigation career in research entails. This must be viewed that there has been a marked shift in studies in terms of what are the research career incenby those who considered themselves to be tives, what are the research career rewards clinical investigators from human/patient/ and, increasingly, what is the opportunity for clinical-oriented to laboratory animal-oriented a long-term research career? These questions studies. Some of the reasons for this stem can be translated in simple terms to what are from the fact that as the number of clinical in- the opportunities for stability in a research cavestigators increased and as the technology of reer? There are probably at least seven major the biological sciences advanced, it rapidly be- deterrents. The first deterrent is that most came apparent that one could carry out much people who graduate from medical school do more research that was related to clinical so with a substantial debt. This they must pay medicine in the experimental animal, in tissue back at some time, and for some, repayment culture, or in-vitro cell free systems than in is in the public service sector, which precludes man, and that one could do it more easily, ask starting on a research career, and for some, simpler questions, and develop less ambigu- the debt may be as high as $100,000. Early reous answers. In a sense this represents the ap- payment is often required, and there are often substantial interest payments, which begin plication of the reductionist theory. fairly soon after medical school is completed. The third major question is who should do
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N. I. BERLIN
The second deterrent becomes apparent from an examination of the age at which significant decisions have to be made. At around age 1718 the decision is made to enter college. For most, but not all, in the freshman year of college, the decision is made to undertake a premedical curriculum. At age 21 or 22 there is a self-review of one's career, and the decision must be made to seek admission to medical school. Most complete medical school around age 25-26 and at that time begin a 3 to 5-year period (and in some instances even longer) of clinical training as interns, residents, and clinical fellows. This means that physicians may be as old as 30 before completing their formal training in clinical medicine and are able to enter a full-time research training post, which is less rewarding financially than the practice of medicine. At this time many also face the additional financial burden of a family. One should contrast the age 30 to begin a career in clinical research to age 21, 22, or 23, or even earlier for starting a research career in the biological sciences. I recognize that some begin training earlier as MD-PhD degree candidates and some do so while in medical school without seeking the PhD. Perhaps the most difficult to evaluate and understand, but nevertheless this must be done in some fashion, is the young physician's view of clinical research in terms of the opportunities and the rewards. This can best be epitomized by recapturing a conversation with a senior medical student held in 1980. When I asked one of the medical students where she went to school and what was her major, she replied that she went to the University of Michigan and her major was cell biology. What was her intent at the time of entering college? "To do biological research." Why did you go to medical school rather than continue on to graduate school? Her answer was that she wanted security and "did not want to go chasing grants for the rest of her life." At that time it was a surprise to me that this view had spread to the undergraduate college level. It may very well reflect the thinking of medical students and house officers who have been in institutions where research is strong and who have seen examples of the consequences of the
instability of research support (epitomized by "He lost his grant") and the instability of career support for young and for established investigators. There also appears to be a commonly held view that clinical research grant applications to NIH do not fare as well as basic science grant applications and that this has led to a decrease in grant applications from MDs. The decrease is a fact, but those submitted by MDs fare as well as those submitted by PhDs.4 The fourth deterrent is that the training requirements imposed by the specialty and subspecialty boards for certification in clinical medicine have become long and, to some degree, with less provision for a research experience. For example, in internal medicine, three years of house officership is often followed by two years of a clinical fellowship, which leads to a certificate in internal medicine and a certificate in one of the subspecialties, a path many rightly follow. The fifth deterrent is that it is becoming increasingly difficult to translate knowledge and particularly laboratory techniques gained in the undergraduate college and medical school to current research questions. I can well remember when I began research at the University of California, I was able to use a good bit of the knowledge and a good bit of the laboratory techniques I had acquired in the undergraduate college and medical school to begin my research. I then added to these the techniques and technology that I was utilizing at Berkeley. I think that the complexity of the technology that is used in laboratory research today and the decrease in the exposure of medical students and undergraduate students to the laboratory, provides much less of a base for the beginning of a research career in terms of ability to carry out specific laboratory tasks. The sixth deterrent, which may be less apparent to many of the young physicians in training but more apparent to those in midcareer or more senior, is what I choose to term "the quality of clinical research" as perceived by the basic scientists. The basic scientists tend to hold, and it is difficult to prove or disprove, that the research being carried
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Clinical research—a commentary
out by clinical researchers is not as good as that being carried out by basic scientists. I am not convinced that they fully understand the constraints imposed upon clinical investigators. Nevertheless, there is a widespread feeling that this is true. The last deterrent, which is probably less well known than any of the others, relates to the grant review process. I think the current pattern for three-year grant awards, as contrasted to five and seven-year awards by the National Institutes of Health in the past, is a serious deterrent. Further, the time required for review of a grant has now become as long as a year between application and award, and perhaps the most important is a feeling that many of the review committees are not necessarily qualified to review some of the projects that they have been assigned to review. This, of course, is difficult to prove, but nevertheless reflects a widely held opinion. Further the low funding rate—of the order of 20%30%—can be disheartening, considering the time required to prepare a grant and the long delay in review before a decision is made. I think one can draw the conclusion that for physicians there are major deterrents to begin a clinical research career and there are no simple solutions, but solutions are being proposed. These difficulties have led to the Institute of Medicine report2 and to the studies by Freireich and by Vaitukaitis,3'4 a workshop by the NCI, and to proposals for new study sections dedicated to reviewing Only clinical research applications and new training programs designed to acknowledge the long training required. While it is too early to realize the impact of these studies on policy and practice, their recommendations may not be sufficient, for in fact it may be necessary to restructure at a most fundamental level how biomedical research is supported. We may need to move from reviewing scientific proposals to reviewing scientific productivity, and we may need to stabilize institutional support and not thorough indirect cost rates. What we must do is turn our attention to what it is that would make clinical research attractive as a career,
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and then we must make the effort to develop the resources so that we can once again bring into clinical research a sufficient number of our younger physicians. While this review has been more negative than positive, the rewards of a research career can be very substantial: recognition by colleagues and, in some instances, fame in the community at large; and, difficult to quantify, the sheer delight and satisfaction that can be drawn from developing new knowledge, for it is new knowledge and the transmission of that new knowledge that is a powerful incentive and a source of delight that for some has overcome the deterrents, and can continue to do so. Note: The theme presented here was originally presented in 1981 at a Grand Rounds at the Walter & Eliza Hall Institute of Medical Research Melbourne, Australia, while the author was a Fogarty Senior International Fellow of the National Institutes of Health. REFERENCES 1. Wyngaarden JB: The clinical investigator as an endangered species. N Engl J Med 301:1254-1259, 1979. 2. Institute of Medicine: Resources for Clinical Investigation. IOM-88-07. Washington, DC: National Academy Press, 1988. 3. Freireich EJ: A study of the status of clinical cancer research in the United States (1990). J Natl Cancer Inst 83:829-837, 1991. 4. Vaitukaitis JL: The future of clinical research. Clin Res 39:145-156, 1991. 5. Friedman MA, Cain DF, Bronzert D, Wu RS: Poor funding rates of cancer clinical research: Intractable problem or solvable challenge? J Natl Cancer Inst 83:838-841, 1991. 6. Kimes BW, Cairoli V, Freireich EJ, Karp J, Yang SS: Training in clinical research in oncology. Cancer Res 51:753-756, 1991. 7. Berlin NI, Buncher CR, Fontana RS, Frost JK, Melamed MR: The National Cancer Institute Cooperative early lung cancer detection program: Results of the initial screen (prevalence). Early lung cancer detection: Introduction. Am Rev Respir Dis 130(4):545-570, 1984. 8. Feinstein AR, Koss N, and Austin JHM: The changing emphasis in clinical research. Ann Intern Med 66:396-419, 1967. 9. Anon. MDs or PhDs in Medical research? BMJ: 1:274, 1980.
