5
Birthing of clinical pharmacologists Neal L. Benowitz, MD San Francisco, Cal$ Before I discuss the birthing of clinical pharma- cologists, let me begin with another story of a birth- ing, The Birth of Enus, as depicted by Sandro Bot- ticelli in Florence in 1482. Venus was depicted as emerging naked from a clamshell and, according to some scholars, immediately subjected to the com- peting forces of the winds of passion and robes of reason. Not many clinical pharmacologists have been born in exactly this way. However, many are strongly influenced by the forces of passion and reason, although more typically in a complementary rather than in a competitive way. Clinical pharmacology training at University of California, San Francisco (UCSF) My clinical pharmacology birthing story starts with that of clinical pharmacology at the University of California, San Francisco, where I trained and now direct the training program. The clinical phar- macology program at UCSF was one of the first such programs in the United States. It was brought into being about 30 years ago by Ken Melmon. At this time, there was a great deal of excitement about clinical pharmacology as the new quantitative sci- ence of therapeutics, with an emphasis on combin- ing fundamental bench research and therapeutic de- cision making at the bedside. Subsequently, Henry Boume directed the program until about 15 years ago, when I became Director. The San Francisco training program has been highly fertile. Since 1965, 147 fellows have graduated from the training pro- gram. Most have pursued academic careers. Many From the Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospi- tal Medical Center, and the Departments of Medicine, Psychi- atry, and Biopharmaceutical Sciences, University of California, San Francisco. Presidential address to the American Society for Clinical Phar- macology and Therapeutics, March 5, 1997, San Diego, Calif. Received for publication July 15, 1997; accepted July 28, 1997. Reprint requests: Neal L. Benowitz, MD, Division of Clinical Phar- macology and Experimental Therapeutics, San Francisco General Hospital Medical Center, Bldg. 30, Room 3220, 1001 Potrero Ave., San Francisco, CA 94110. E-mail: [email protected] Chn Pharmacol Ther 1997;62:587-91. Copyright 0 1997 by Mosby-Year Book, Inc. 0009-9236/97/$5.00 + 0 13/l/85791 went on to become department or clinical pharma- cology division chiefs. Others hold prominent posi- tions in industry and at the U.S. Food and Drug Administration. Our clinical pharmacology program seemed to be doing what it was supposed to do, and doing it very well. Given the history of the clinical pharmacology program at UCSF, we fully expected our sixth 5-year renewal training grant application to the National Institutes of Health (NIH) to be favorably reviewed when it was submitted last year. It was no surprise to us that the study section in its review noted, “The program at UCSF remains under outstanding leader- ship . . . the quality of the senior faculty members is outstanding . . . the training program blends a con- structive mix of clinical, didactic, and seminar experi- ences . . . excellent opportunities for training in phar- macokinetics, biostatistics, and a variety of aspects of clinical research . . . a strong track record . . . having trained a signiticant number of leaders in the field.” However, the reviewers noted a new wind blow- ing. “In recent years, the number and quality of applicants has diminished significantly, especially the number of MDs interested in the research ex- perience in the discipline. Unfortunately, the pro- gram seems to have adopted a relatively passive approach to this trend.” I would personally disagree with the assessment of the reviewers about the quality of our fellows, but it is true that we have seen fewer applicants, and our group of fellows did include one PhD, and one PharmD, although their research was very directly clinical pharmacologic. This trend does suggest that some of the winds of passion have died down, to be replaced by puffs of indifference concem- ing clinical pharmacology training. The outcome of the training grant review process came as a surprise to me and to most of our faculty. We thought that a strong training faculty, a well- developed training program, and a good record of postdoctoral training in the past would convince the reviewers that UCSF was a good investment in train- ing dollars. We had thought that the issue of declin- ing number of potential trainees was of less impor- tance than the excellent career records of our recent trainees. We were clearly too complacent. 587

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Page 1: Birthing of clinical pharmacologists*

Birthing of clinical pharmacologists Neal L. Benowitz, MD San Francisco, Cal$

Before I discuss the birthing of clinical pharma- cologists, let me begin with another story of a birth- ing, The Birth of Enus, as depicted by Sandro Bot- ticelli in Florence in 1482. Venus was depicted as emerging naked from a clamshell and, according to some scholars, immediately subjected to the com- peting forces of the winds of passion and robes of reason. Not many clinical pharmacologists have been born in exactly this way. However, many are strongly influenced by the forces of passion and reason, although more typically in a complementary rather than in a competitive way.

Clinical pharmacology training at University of California, San Francisco (UCSF)

My clinical pharmacology birthing story starts with that of clinical pharmacology at the University of California, San Francisco, where I trained and now direct the training program. The clinical phar- macology program at UCSF was one of the first such programs in the United States. It was brought into being about 30 years ago by Ken Melmon. At this time, there was a great deal of excitement about clinical pharmacology as the new quantitative sci- ence of therapeutics, with an emphasis on combin- ing fundamental bench research and therapeutic de- cision making at the bedside. Subsequently, Henry Boume directed the program until about 15 years ago, when I became Director. The San Francisco training program has been highly fertile. Since 1965, 147 fellows have graduated from the training pro- gram. Most have pursued academic careers. Many

From the Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospi- tal Medical Center, and the Departments of Medicine, Psychi- atry, and Biopharmaceutical Sciences, University of California, San Francisco.

Presidential address to the American Society for Clinical Phar- macology and Therapeutics, March 5, 1997, San Diego, Calif.

Received for publication July 15, 1997; accepted July 28, 1997. Reprint requests: Neal L. Benowitz, MD, Division of Clinical Phar-

macology and Experimental Therapeutics, San Francisco General Hospital Medical Center, Bldg. 30, Room 3220, 1001 Potrero Ave., San Francisco, CA 94110. E-mail: [email protected]

Chn Pharmacol Ther 1997;62:587-91. Copyright 0 1997 by Mosby-Year Book, Inc. 0009-9236/97/$5.00 + 0 13/l/85791

went on to become department or clinical pharma- cology division chiefs. Others hold prominent posi- tions in industry and at the U.S. Food and Drug Administration. Our clinical pharmacology program seemed to be doing what it was supposed to do, and doing it very well.

Given the history of the clinical pharmacology program at UCSF, we fully expected our sixth 5-year renewal training grant application to the National Institutes of Health (NIH) to be favorably reviewed when it was submitted last year. It was no surprise to us that the study section in its review noted, “The program at UCSF remains under outstanding leader- ship . . . the quality of the senior faculty members is outstanding . . . the training program blends a con- structive mix of clinical, didactic, and seminar experi- ences . . . excellent opportunities for training in phar- macokinetics, biostatistics, and a variety of aspects of clinical research . . . a strong track record . . . having trained a signiticant number of leaders in the field.”

However, the reviewers noted a new wind blow- ing. “In recent years, the number and quality of applicants has diminished significantly, especially the number of MDs interested in the research ex- perience in the discipline. Unfortunately, the pro- gram seems to have adopted a relatively passive approach to this trend.” I would personally disagree with the assessment of the reviewers about the quality of our fellows, but it is true that we have seen fewer applicants, and our group of fellows did include one PhD, and one PharmD, although their research was very directly clinical pharmacologic. This trend does suggest that some of the winds of passion have died down, to be replaced by puffs of indifference concem- ing clinical pharmacology training.

The outcome of the training grant review process came as a surprise to me and to most of our faculty. We thought that a strong training faculty, a well- developed training program, and a good record of postdoctoral training in the past would convince the reviewers that UCSF was a good investment in train- ing dollars. We had thought that the issue of declin- ing number of potential trainees was of less impor- tance than the excellent career records of our recent trainees. We were clearly too complacent.

587

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588 Benowitz CLINICAL P HARMACOLOGY &THERAPEUTICS

DECEMBER 1997

Thus the status of clinical pharmacology training programs is not as idyllic as that of the Botticelli Venus. Our priority score for funding was marginal. We finally did receive funding, but for only 3 years to give us time to demonstrate our ability to attract an increased number of quality applicants.

Declining interest in clinical pharmacology training

The declining number of recent medical gradu- ates interested in careers in clinical pharmacology is not just a phenomenon at UCSF. There has been a decline in the number of clinical pharma- cology training programs and the number of train- ees in the United States since 1978. Data com- piled by Dr. Alison Cole of the National Institute of General Medical Sciences (NIGMS) indicate that in 1978 there were 16 funded clinical phar- macology training programs, with 55 training slots. In 1992, there were eight training programs with 35 slots, and in 1996, there were eight train- ing programs with 28 slots. Several of the cur- rently funded training programs are at risk of not being refunded. This continued decline of interest in an institutional capacity for training clinical pharmacologists represents a serious threat to our discipline that must be examined.

After the review of the UCSF training program, I started thinking about and sought the counsel of many colleagues about ways to enhance interest in clinical pharmacology in the future. I would like to present some of these thoughts regarding the future of clinical pharmacology. These thoughts have been strongly influenced by members of the Division of Clinical Pharmacology at UCSF, par- ticipants in a recent NIGMS workshop on post- doctoral training and recruitment in clinical phar- macology, and responses to an informal survey I conducted among a group of clinical pharmacol- ogists in our society.

Why and when have clinical pharmacologists entered the field?

I surveyed a number of our colleagues about why they decided on clinical pharmacology as a career and about their level of satisfaction with their choice. My focus was primarily MDs, although a few PhDs and PharmDs were also interviewed, For the most part, the clinical pharmacologists I interviewed have found and still find clinical pharmacology to be highly satisfying. The attributes of clinical pharmacology that were most appealing included the following:

1. A sense of excitement in being involved in the development of new drugs

2. Excitement in participating in activities that af- fect the health of large populations of patients

3. Great satisfaction at being able to work at the interface between fundamental research and clin- ical therapeutics

4. Many reported enjoyment and excitement in teaching therapeutics to medical students, resi- dents, and postdoctoral trainees

5. A number cited the breadth and flexibility of clini- cal pharmacology in pursuing research interests, allowing them to address individual patient needs and to participate in the development of new drugs

Thus the joys and excitement of clinical pharma- cology continue to be experienced by practicing clin- ical pharmacologists and continue to hold promise for future clinical pharmacologists. However, as I will discuss later, some of the breadth and, in a sense, the very bridging functions of clinical phar- macology that create much of the excitement also create some serious problems in recruiting new clin- ical pharmacologists to academic careers.

When do clinical pharmacologists learn about clin- ical pharmacology? The majority of physician-clinical pharmacologists learned about clinical pharmacology in medical school. This occurred usually by interaction with prominent clinical pharmacologists, either in pharmacology courses, clinical pharmacology rota- tions, or through ward-attending rounds. Some of these mentors (and the group I surveyed is older than the average in our society) included Harry Gold, Walter Model& Ken Mehnon, Dan Azarnoff, and Lou Lasagna. Exposure to clinical pharmacologists both at the bedside and as collaborative researchers during residency and NIH fellowships were also sources of exposure. Some learned about clinical pharmacology during PhD programs in which clinical pharmacology was an elective area. The main reason for selecting clinical pharmacology as a career was interest in the subject matter. The most commonly cited subject mat- ter interests, at the initiation of their careers, were being able to link fundamental and clinical research, a desire to pursue a specialty that was not limited to a specific organ system, and specific interests in drug therapy and toxicology.

Why are fewer individuals interested in pursuing clinical pharmacology training today?

I can present several likely explanations but few data on this question. First, there is a declining

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CLINICAL PHARMACOLOGY &THERAPEUTICS VOLUME 62, NUMBER 6 Benowitz 589

interest in subspecialty fellowship training within academic medical specialties in general. In 1992, 1303 American graduates entered U.S. subspecial- ties match.’ In 1996 the number was 699, a decline of 46% over 4 years. Currently fewer than 50% of fellowships in gastroenterology, cardiology, and pul- monary disease are filled by American graduates. This decline in interest in fellowship training is pri- marily attributable to a perception that job opportuni- ties are fewer, which is most obviously true for clinical practice. Job opportunities for specialists in academic medicine are also fewer than they were 20 years ago and today are often soft-money positions, which raises concerns about job security, particularly in a field where it is difficult to fall back to clinical practice-if research grant applications are not funded.

Second, the current emphasis on more cost- effective health care means that the types of stu- dents desired by the medical school admission com- mittees, as well as the types of students who are now interested in medicine, have changed. Today more medical students have an interest in primary care and fewer are interested in basic research careers. Many of those who are interested in research are interested in epidemiologic and health care services research that seem to address the most highly pub- licized current health care problems.

Third, as I mentioned before, one of the entice- ments into clinical pharmacology has been being able to combine laboratory research, clinical re- search, patient care, and teaching. However, the traditional concept of an academic physician with multifaceted interests and skills, which in many ways has been the ideal for the academic clinical pharma- cologist, is being challenged. In many medical schools, including my own, there is a push toward faculty specialization, with faculty salaries linked to specific duties. Department chairs are likely to rec- ommend that physician-scientists focus nearly all of their efforts in research, whereas clinician-teachers are urged to focus most of their efforts on patient care and teaching. Crossing the bridge from bench to bedside is not particularly encouraged.

A fourth issue affecting interest in clinical phar- macology training was discussed by the participants at the NIGMS workshop. It is the debt burden of medical graduates, reported to average $85,000 at some medical schools. Fellowship training stipends in clinical pharmacology are usually less than the salaries of medical residents, making it even more difficult for trainees to manage during fellowship than it was during residency. Several surveys have

shown that the optimal time period for research training to be competitive for NIH funding is 2% to 3 years. Understandably, very few fellows are willing to live for 3 years on the salary of a fellow with such a burden of debt.

Approaches to increasing the interest of physician-scientists in clinical pharmacology

I would like now to discuss my thoughts on ways in which we may increase the interest of physicians and young scientists in clinical pharmacology (Table I). First, we need to make information about clinical pharmacology training easily accessible to anyone who has interest. The obvious way to do this is through the Internet. The American Society for Clinical Pharmacology and Therapeutics (ASCPT) now has a site on the Worldwide Web, and a listing of clinical pharmacology training programs has been placed on the Web. Currently this web site contains names and addresses of program directors. Eventu- ally, like its predecessor the Peterson’s Guide (last published in 1988),’ it will contain descriptions of the faculty research and particular opportunities in each program. Links would be made available to the home pages of various training programs.

The next step in my view is to more aggressively promote clinical pharmacology career opportunities to students. Because most clinical pharmacologists learn about clinical pharmacology in medical school, we need ways to enhance the visibility of clinical pharmacology to medical students. Today, most fac- ulty in pharmacology departments are cellular or molecular biologists. Relatively few are clinical pharmacologists. Thus there is less opportunity for medical students to be exposed to and to learn about clinical pharmacology in most second-year medical school courses. A few clinical pharmacologists still do teach in the second year, but probably more are involved in fourth-year medical school courses. Thus it is essential that clinical pharmacology faculty take the opportunity to discuss career options in clinical pharmacology with medical students they teach. Last week, at the final lecture of the fourth-year therapeutics course at UCSF, I spent the last 5 minutes discussing career possibilities in clinical pharmacology, handing out a flyer summarizing those opportunities, and a telephone number for students to call if they developed an interest in clinical pharma- cology in the future. This was the first time most of these students had ever thought about the types of careers that constitute clinical pharmacology.

Clinical pharmacology role models need to be

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590 Benowitz CLINICAL PHARMf, COLOGY & THERAPEUTICS

DECEMBER 1997

Table I. Approaches to increasing the interest of physician-scientists in clinical pharmacology Readily available information on training opportunities

Guide to Clinical Pharmacology Programs on ASCPT web site (http://www.ascpt.org) Link to individual training program

Promote clinical pharmacology career opportunities Medical students Residents MD/PhD programs Combined specialty fellowships Postgraduate courses Publications

Broaden ski113 available in clinical pharmacology training programs Fundamental laboratory research Clinical investigation Pharmacoepidemiology Health care services (therapeutics) research Formulary development and management Pharmacoeconomics

Enhance support for clinical pharmacology training National Institute of General Medical Sciences (NIGMS),*Division of Research Resources Centers for Education and Research in Therapeutics (CERT) Pharmaceutical industry

Expand job opportunities Hospital pharmacy and therapeutics committees health plan and pharmaceutical benefits management companies-

P and T activities Lower financial barriers

Salaries comparable to those of residents Debt management and debt forgiveness plans

visible to physicians in clinical training. In the past, the presence of a clinical pharmacologist attending physician on a clinical service or participating in a clinical pharmacology rotation exposed residents to career clinical pharmacologists. These types of ex- posures are likely to become fewer because of the increased demands for academic faculty to focus their time in research, as opposed to clinical care. Those clinical pharmacologists who are still practicing at the bedside need to generate excitement about therapeutic-analytic thinking and evidenced-based medicine. Some of our colleagues, such as those at Vanderbilt and the University of Pennsylvania, have been successful and often recruit residents to their fellowship programs. Far more of this needs to occur.

Another approach to attracting residents is to develop combined training programs in clinical pharmacology and other specialties. Specialties such as cardiology, infectious disease, and rheumatology may support l- or 2-year clinical training experi- ences, whereas support from clinical pharmacology would support 2 or more years of research training. In some cases, joint initial recruitment programs could be developed.

Unfortunately, there are too few clinical pharma- cologists in medical schools to serve as role models to attract adequate numbers of young people into clinical pharmacology. A consensus at the NIGMS workshop was that a nationwide effort to promote the field of clinical pharmacology and its career opportunities is needed if we are to reverse the downward trend in recruitment of trainees. Such effort might include sending brochures to medical schools and residency directors and increasing the visibility of clinical pharmacology in postgraduate courses and in research and public policy publica- tions. Such a program to increase the visibility of clinical pharmacology will be spearheaded by an ASCPT task force, which will meet in the upcoming year. It is hoped that the American College of Clin- ical Pharmacology, the American Society of Phar- macology and Experimental Therapeutics, and other societies of pharmacologists and pharmaceu- tical scientists will join the effort.

In my opinion a part of a comprehensive plan to increase interest in clinical pharmacology should include broadening the mission of clinical pharma- cology training programs. It is ironic that the same

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CLINICAL PHARMA COLOGY & THERAPEUTICS VOLUME 62, NUMBER 6 Benowitz 59 1

factors that are promoting cost-effective health care and are dissuading many young physicians from en- tering medical specialties such cardiology, gastroen- terology, and pulmonary disease might favor future entries into clinical pharmacology. Clinical pharma- cology, with its focus on optimal drug use, fits well into the concept of a primary care specialty. Our health care system desperately needs clinical phar- macologists to organize formularies, to educate other physicians about the rational and cost- effective use of drugs, and to study the effectiveness and toxicity of medications. Thus the breadth of clinical pharmacology, while posing difficulties within the traditional medical specialist model, of- fers a variety of opportunities for a young person with broad interest in therapeutics.

Many of the currently funded clinical pharmacol- ogy programs, consistent with the stated goals of NIGMS, focus on laboratory-based, fundamental pharmacologic research. Although clinical pharma- cology has made very important contributions in fundamental research, there are not enough job opportunities for all clinical pharmacologists to suc- ceed in this arena. Expansion of training programs and funding of new programs that can provide for- mal training in research experiences in clinical in- vestigation, pharmacoepidemiology, health care ser- vices research related to therapeutics, training in formulary development and management, and train- ing in pharmacoeconomics would enhance the ap- peal of clinical pharmacology training programs to more people. At the recent NIGMS workshop, there appeared to be some willingness on the part of the administrative staff to consider more types of ther- apeutic research as worthy of funding, as long as it was high-quality and hypothesis-driven research. In my opinion, NIGMS support of such research is an important step forward for clinical pharmacology.

Other measures to increase interest in clinical pharmacology include enhancing support for train- ing programs. This could occur in part through new programs such as the Centers for Education and Research in Therapeutics (CERT) program, which has been crafted by Ray Woosley and his colleagues at Georgetown.3 Strong pharmaceutical company support for training should be expected because a significant number of clinical pharmacologists spend their careers in industry.

We should also consider expanding job opportu- nities for clinical pharmacology graduates. The so- cietal push toward more cost-efficient health care

means that better formularies, guidelines for medi- cation use, and ways to monitor safe and effective medication use are needed. Clinical pharmacolo- gists would be the best individuals to oversee phar- macology and therapeutic committee activities, in hospital settings and for health plans and phar- maceutical benefits-managing companies. Some hospitals have already bought into the concept of hospital clinical pharmacologists. An effort should be made to exand this type of position throughout the country.

The financial barriers to clinical pharmacology training need to be lowered. Higher salaries, at least comparable to those of the salaries of medical res- idents, and ways to forgive student debt would en- hance the appeal of postdoctoral training in clinical pharmacology, as in other specialty areas.

Conclusion My survey of clinical pharmacologists suggests

that most clinical pharmacologists are happy with their careers and enjoy what they are doing. The winds of passion and robes of reason complement one another to make for an exciting and intel- lectually satisfying professional life. Our colleagues are generally enthusiastic about the prospects that new career entrants can find the same level of sat- isfaction in clinical pharmacology in the future.

However, the birthing of clinical pharmacologists has become difficult. A major effort is needed to expand the visibility of our discipline, to broaden the scope of clinical pharmacology training, and to expand career opportunities, particularly in the area of health care services management. If we do so, I believe clinical pharmacology will emerge, like a reborn Venus, with more vigor and vitality than it had even in the 1970s. I urge the members of ASCPT to actively support the efforts of the ASCPT training task force that will seek to imple- ment strategies to promote clinical pharmacology across the country and around the world.

References 1. Schafer J. Subspecialty match portends trying times for

fellowship programs. J Investig Med 1996;44:279-88. 2. Ready B, editor. Clinical pharmacology: a guide to

training programs. 7th ed. Princeton (NJ): Peterson’s Guides; 1988.

3. Woosley RL. Centers for education and research in therapeutics. Clin Pharmacol Ther 1994;55:249-55.