Clinical Research: Title and subTitle BreakPerceptions, Reality, and Proposed Solutions

ACADEMIC MEDICINE is in an embattled state and no group appears to feel as severely strained as those engaged in clinical research.^{1 - 12} In response to the concerns expressed by clinical researchers across the country, Harold Varmus, MD, director of the National Institutes of Health (NIH), impaneled a group of experienced clinical investigators and academic health center (AHC) administrators (the NIH Director's Panel on Clinical Research) to make recommendations¹³ that might guide the NIH toward policy changes that could alleviate the distress in the clinical research community. The panel worked diligently on the challenge and made several recommendations, some of which have already been implemented. In this article we provide the background for those recommendations, describe the recommendations themselves, and discuss the unfinished business that must be addressed if clinical research is to flourish in academic medicine.

During the past 30 years, the capacity to study mechanisms of cell function at the molecular level has understandably shifted the attention of the majority of biomedical scientists away from an analysis of "the whole animal" and toward more manageable and often more productive studies of the function of isolated cells and genes. This shift of emphasis has radically changed the demography of the NIH grantee population. Physicians are becoming a distinct minority. Indeed, much of the recent concern regarding the fate of clinical research grants at the NIH is based on the impression that the NIH-sponsored investigator with an MD degree is being progressively forced out of the extramural grant competition. Because it is assumed that most clinical investigators hold MD degrees, it is further held that a decline in MD grant holders must presage a reduction in the national commitment to clinical research.

Our panel analyzed the number of NIH grant applications and their success rates from 1972 through 1997 (Figure 1). In 1972, when the NIH extramural budget was approaching $1 billion, the total applications to NIH numbered about 10000, 4000 (40%) of which were submitted by MDs. The remainder (60%) were submitted by PhDs. The success rates of the 2 groups of applicants were equal at a relatively comfortable 40%. Therefore, an MD "presence" and presumably a clinical research "presence" was palpable in the extramural program. Twenty-five years later, in 1995, the NIH extramural budget had increased to $6 billion; grant applications from MDs had risen very slowly by 50% to 6000 but applications from PhDs had increased 300% to more than 18000. The massive increase in applications, particularly from PhDs, drove down the success rates of both MDs and PhDs in parallel. Today, MDs constitute only 25% of the applicants to NIH. They have maintained equal success rates but their relatively low application rate forces them into the status of an ever-dwindling minority. Because the NIH draws its peer reviewers from its grantees, it is feared that the influence of MDs (and particularly the influence of those MDs who actually study patients) on the future apportionment of NIH funds will rapidly decline. Furthermore, it is strongly suspected (without any data) that the MDs who are successfully applying share the scientific interests and much of the background of PhDs. This must be the case, it is concluded, because they are competing with PhDs in the tinderboxes of PhD-dominated NIH study sections.

Fearing that a perception of likely failure might discourage MDs from applying for NIH grants, our panel closely examined the number of first-time MD and PhD applications to NIH during the 3-year period from 1994 through 1996. Presumably, these applications are drawn from a group of relatively young investigators who are beginning their biomedical research careers. Our analysis, set out in Table 1, confirmed our apprehensions. First-time applications from MDs have dropped 30% in 3 years. Even MD/PhD first-time applicants seem to have been discouraged. They exhibit a 16% drop (although their absolute numbers are too small to be significant). First-time applications from PhDs have fallen by only 6%. If this trend continues, MDs will soon vanish from the NIH scene.

The data described in Table 1 definitely support the gloomy prognostications found in references 1 through 11 and also support the findings of Shulman,¹² who, in 1995, visited many AHCs as the Special Emissary of the Director of the NIH. Shulman estimated the morale of the centers and of clinical investigators in particular. His report confirmed the dispirited attitudes of clinical investigators and MDs in general regarding the likelihood of funding of clinically relevant research grant applications in the study sections of the NIH. Shulman also observed that clinical investigators feel abandoned not only by NIH but also by AHCs themselves. The sense of abandonment is not due to willful neglect by AHC administrators but is instead related to the financial pressures on the centers and their faculty practice plans created by the emergence of managed care insurance plans.

The potential for a negative effect of managed care on the revenues of AHCs is illustrated in Figure 2. In 1960, the total revenues of all of the AHCs in the United States was less than a half billion dollars. Research grants accounted for more than half of that revenue, most of which was contributed by the NIH. In 1995, the total revenues had risen to nearly $30 billion (about 3% of the national health care budget). Ominously, less than a third of the revenue was contributed by research grants and NIH was responsible for only two thirds of that research grant contribution. Industry and, to a lesser extent, private foundations now provide one third of the research budget of the AHCs. The $20 billion revenue gap between research grants and the total AHC budget is filled by payments from insurance carriers. But the determination of managed care–oriented insurance carriers to reduce their payments to AHCs and practice plans in response to the demands of US employers to lower the cost of health care has begun to erode the financial security of most of the AHCs. Even the research grant base of the revenue is unstable because industrial grants rarely, if ever, foster the unfettered research careers sought by young faculty members. The negative result of overdependence on clinical revenue to support research is already being appreciated. There is evidence of an inverse relationship between NIH research awards and managed care plan penetration in the United States.¹⁴

In the face of revenue instability within the AHCs that forces full-time faculty members to derive their salaries from clinical care and a mere 25% success rate on NIH grant applications, many young MD faculty members who hope to study patients believe that there is no interest at the NIH in clinical research, particularly with respect to R01 allocations, and that study sections are stacked against them.¹⁵ In truth, a substantial number of clinically oriented faculty members have not been properly trained to do modern research, whether basic or clinical. They may have learned 1 or 2 techniques in their fellowship experience and they try to apply those methods in patients, but this approach rapidly leads to paralyzed academic investigator's disease syndrome (PAIDS), so well described by Goldstein.¹⁶ Crushed by towering debts that result from the explosion in tuition revenues of US medical schools, they leave the field for clinical practice (where many are equally unhappy and insecure).

These were the well-known circumstances that faced our panel when we first gathered in 1995. As we began, we wondered whether the accusations of indifference at the NIH were justified. Anxious to remove ourselves from sterile debates about the relative values of basic vs clinical research and believing that the nation needs more of both, we decided first to try to define clinical research and then to assess the actual contribution of the NIH extramural budget to the field.

We chose to look at clinical investigation more broadly than did the Institute of Medicine in 1994.⁵ The Institute of Medicine particularly focused on 1 subset of clinical investigators, those who carry out translational research from the bench to the bedside and apply for grants that are reviewed in the Center for Scientific Review (the former Division of Research Grants). They concluded that only 10% of the NIH budget is devoted to that group of investigators. Our panel recognized that grants are reviewed by the institutes and the Center for Scientific Review and saw clinical research as a much broader entity. We agreed that translational research on human subjects, including the development of new technologies, studies of the mechanisms of human disease, and evaluation of therapeutic interventions, is a vital as well as traditional aspect of clinical research. But we also felt strongly that clinical trials are greatly important to medicine, as are epidemiological and behavioral studies. We additionally concluded that excellent outcomes and health care services studies represent valuable clinical research that can influence clinical practice.

Given this broader definition of clinical research and the multiple sites of review, we decided to analyze the contribution of the NIH extramural budget to the fields. We began with very limited knowledge. In fact, we knew only the clinical trials budget. Assuming that the total budget for clinical research must be something in excess of the clinical trials budget, we read the abstracts of every competing grant awarded in 1996, whether it was reviewed in the Center for Scientific Review or in the special review groups impaneled by the individual institutes of the NIH. We scored the grants as clinical or nonclinical research grants. The results, shown in Table 2, surprised the panel and its initial critics.

The NIH awarded 5616 competing grants in 1996 and spent about $1.5 billion in the process. Clinical research grants, as we defined them, numbered 1567 (nearly 30%) and accounted for 36% of the awarded dollars. The vast majority of the clinical research grants were R01s because the latter dominate the NIH portfolio. About half of the grants were reviewed in the study sections and the rest in the special panels of the individual institutes. Of some concern was the finding that MDs constituted only 36% of the principal investigators of the grants that we scored as clinical research grants (Table 3). Even in clinical research, PhDs outperform MDs, probably because many more apply, particularly in fields such as biostatistics, epidemiology, behavioral medicine, and outcomes research.

We concluded that although the NIH is supporting clinical research to a much greater extent than has been appreciated, at least from the view of the aforementioned Institute of Medicine analysis, the morale of young potential investigators is still poor and must be improved. After careful study of the Shulman article,¹² our own independent findings, and the literature to which we refer herein, we came to the following recommendations.

With respect to the fraction of the NIH budget devoted to clinical research, the panel concluded that the budget should be regularly monitored to be certain that the present distribution is at least maintained. The panel recognizes that basic research must logically demand a very high fraction of the budget because in the absence of a flow of basic findings, clinical research will stall. But there must be continued production of useful clinical research that can be rapidly applied for the benefit of our patients, the taxpayers who fund the research in the first place.

The panel carefully considered the national infrastructure of clinical research—the General Clinical Research Center (GCRC) program and the Warren Magnuson Clinical Center on the NIH campus.

The 75 GCRCs in the United States are funded by the Division of Research Resources of the NIH. They provide a small but important segment of the clinical research infrastructure of the AHCs fortunate enough to be awarded GCRCs in a national competition. In these centers new diagnostic techniques and treatments derived from laboratory analyses can be offered to patients with serious diseases under carefully controlled conditions. Such patient-oriented studies are expensive and time consuming and require staffs of trained nurses, laboratory technicians, and data managers. However, the GCRCs in the individual AHCs could play a broader role in clinical research affairs in the AHCs in which they are located. They could, for example, supervise the scientific review of all protocols, provide mentoring for young clinical investigators, mount didactic courses in clinical research, centralize contracting with pharmaceutical and biotechnical companies for industry- or investigator-initiated clinical trials, and mount a quality assurance program for clinical trials within the AHC. These functions would surely require increased and stable budgets.

The productivity of the Warren Magnuson Clinical Center on the NIH campus was also examined by the panel because it is the largest clinical research center in the United States and reflects the commitment of the NIH administration to clinical research. The panel concluded that the center is in the midst of both scientific and administrative evaluation. Further inquiry by this panel did not seem reasonable at this time but the center is not as strong as it can and should be and the panel believes that its productivity should be watched with great care.

If clinical research is to flourish, medical students must become interested in the field. Today, medical students have multiple opportunities to gain experience in basic research but few to engage in clinical research. The panel urged the NIH to emulate its highly successful Howard Hughes Medical Institute–supported medical student program in basic science and invite a national cohort of medical students to explore clinical research on the NIH campus. The program began in 1996 and is highly successful. It should be continued and pursued by the major AHCs, those with the capacity to deliver several different mentored opportunities in clinical research to students.

The quality of clinical research training is highly questionable in the United States. Our institutional training grants in the specialties leave much to be desired. Courses that offer training in biostatistics, epidemiology, pharmokinetics regulatory issues, and ethics are woefully deficient. Successful mentors are few and far between and the few are burdened with excessive clinical responsibilities. Grants to support the training of nascent investigators beyond the fellowship experience are almost nonexistent. The panel made 3 recommendations to deal with these deficiencies, all of which have been implemented.

First, we recommended K30 grants to offer didactic courses in clinical research. Second, we asked for K23 grants for young clinical investigators emerging from specialty training programs. These would be 5-year full salary awards to allow young investigators to work with mentors on clinical research projects. Finally, we asked for K24 awards to cover half of the salaries of the mentors themselves. This would relieve the mentors of excessive clinical responsibilities. All of these new awards have been announced this year.

Future NIH panels that review institutional training grants in the medical specialties should pay close attention to the success of graduates of these programs in K23 and K24 competitions. Programs that do not produce competitive clinical investigators should be eliminated.

Study sections that review patient-oriented research applications should be organized or restructured from the current study section organization. Specifically, patient-oriented grant applications should be evaluated by study sections in which at least half the grant applications involve patient-oriented research.¹⁵

Training programs for clinical research, including those sponsored by the NIH, should encompass formal instruction in the relevant scientific disciplines as well as appropriate mentoring, the basis of all graduate and postgraduate training in research. Formal training may include better training in biostatistics, epidemiology, and other methods for conducting clinical trials; clinical genetics; molecular biology; and pharmacology. A number of experimental programs are being developed to address these issues in several universities and the NIH should provide institutional grants to support such training in certain centers.

Adequate mentoring for clinical scientists is more difficult to solve. There is a paucity of adventurous and truly outstanding clinical investigators ready to apply either basic laboratory or large-trial methods to important questions and able to engage trainees in those exciting enterprises. Peer review of training grants in medical specialties should emphasize a track record of accomplishment in clinical research so skillful mentors who remain in academic medicine will become program directors and spawn new leaders for the future.

Collaborative projects such as program project grants should be emphasized by the NIH. Clinical research is not an isolated activity but, rather, the application (with exquisite care) of basic biomedical science to vulnerable humans, our patients. Clinical research cannot and should not be separated from basic science, and the NIH should continue to encourage clinical investigators and basic scientists to work closely together to frame important questions. The program project grant, one of the most important mechanisms to foster such vital integration, is a relatively small but important part of the NIH portfolio, and the NIH should consider broadening a policy to encourage that such grants, when practical, contain at least 1 highly meritorious clinical research project with adequate funding of clinical extenders and data managers.

Pharmaceutical and biotechnical companies have remarkable basic science laboratories and scientists eager to collaborate with academic clinical investigators. Although there are several stumbling blocks to be resolved, including issues of conflict of interest and ownership of intellectual property, pharmaceutical companies can be ideal sites for training in the art and science of clinical pharmacology. Training programs in AHCs should take advantage of the opportunity to weld collaborations with colleagues in these companies.

The NIH has a history of undertaking programs of debt relief for certain intramural clinical investigators to serve specific goals. We believe that NIH should also help abate the severe debt that many extramural clinical investigators face as they begin their careers. This would require an act of the US Congress recognizing clinical investigation as so endangered that it merits special debt relief. Although such a program might be difficult to implement fairly, there is ample precedent for the use of debt relief programs by the government to serve national needs. Increased sources of funds for debt abatement for those who choose a career in clinical research should also be developed within AHCs.

To reduce the burden of debt in the future, medical scientist training programs leading to the MD and PhD degrees should be encouraged, when feasible, to broaden the size and scope of their programs to include clinical research. Although the number of individuals trained in such programs would be small, it would enable a well-trained cadre of participants to commence careers in clinical research debt free. This type of program would require the determined cooperation of AHCs in devising appropriate training programs. The NIH could help by encouraging the development of such programs and particularly by supporting innovations in curriculum for graduate-level programs.

Certain AHCs have begun to appreciate the unique problems facing clinical investigators and are investing in the infrastructure to support clinical research. This effort should become more widespread. Despite their financial problems, it is essential for such centers to commit more support to clinical research; enable the best of their clinical investigators to use physician extenders in the form of data managers and auditors; hire additional clinicians so that clinical research projects can flourish while the investigators plan future projects; and provide efficient information systems that help faculty to care for patients, teach, and communicate with referring physicians. If more AHCs can be supportive and if the NIH programs that we suggest are put in place (and they are on the way), the conditions of clinical research will surely improve.

Even if AHCs and the NIH improve the climate for clinical research, it will not flourish unless private and public payers (including Medicare and Medicaid) support the clinical care of patients while they participate in peer-reviewed clinical trials, but all insurance companies need to operate on an even playing field. If it is determined that selected clinical trials should be supported by health insurance, all insurance providers should participate. If this does not occur on a voluntary basis, a tax on premiums that would be devoted to clinical research has been suggested by some as a way to establish fair contributions by all carriers.¹¹

The NIH cannot solve the problems of clinical investigation alone because it is only one of several contributors to the discipline. Health insurers and foundations are (or should be) enthusiastic supporters of clinical research in AHCs. Pharmaceutical and biotechnical companies are major participants in clinical research essential to drug development. Therefore, they are major users of clinical investigators and vital partners in the future of clinical research in AHCs, the spawning grounds of future investigators.

Health insurers, foundations, pharmaceutical and biotechnical companies, AHCs, and the NIH should collaborate in developing a joint policy for the support of clinical research and clinical research training. We call on the NIH to encourage the formulation of such a policy with a simple focus: to develop and implement a broad-based and long-term plan in which all of the participants make a sufficient but fair financial and intellectual contribution. The NIH has already begun this process. The effort must be encouraged by developing a series of leadership retreats that will lead to a commitment by the key participants to a renewed national program in clinical research. In the meanwhile, the NIH should make every attempt to restore its former Biomedical Research Support Grant program because it would at least support the clinical research infrastructure in awardee institutions.

Our panel was not able to complete an in-depth analysis of all the issues that threaten clinical research careers in the United States. Such unresolved issues include the needs of AHCs for further federal support at a time of serious financial constraint, the future of GCRCs and the NIH Clinical Center, and the recruitment of minorities into clinical research careers. All 3 of these areas require much more inquiry if a satisfactory policy is to be developed. The panel recommends that the NIH continue to ensure that its clinical research agenda remains central in its planning.

We are in the midst of a critical period in medicine.¹⁷ The promise of a future in which advances in basic biomedical research can lead to improved diagnosis and therapy is threatened by a loss of confidence on the part of clinical investigators and the future of medicine requires success in clinical research. The problems of clinical research are due in part to general problems of funding for medical education and research and in part to the impact of managed care systems on faculty practices and university hospitals. Nevertheless, many of the problems bedeviling the field are due to specific and correctable aspects of recruitment, training, nurturing, and promotion of clinical investigators. It is our belief that suitable improvements in recruitment, training, and the reward system will reinvigorate a threatened system and enable clinical investigators to compete more effectively for research funding. With respect to the more general problems, we call on the NIH to lead a collaborative effort of government, private foundations, insurance and pharmaceutical companies, and AHCs to enhance the national system of clinical research. We also call on young and mid-career clinical investigators to have confidence in their futures. Achievement of NIH or private research support is not easy and never will be, for either basic or clinical investigators. But the excitement of research and its triumphs are well worth the uncertainty. Both groups of investigators must be persistent and apply for NIH grants until they are successful. Finally, we call on AHCs to identify their most promising young clinical investigators and support them until they receive independent funding. Such a vote of confidence will go far to restore morale and bring the fruits of clinical research to the public that awaits and deserves them.