Perspectives On Medical Research
Volume 4, 1993
Book Reviews
Edward H. Ahrens, Jr. The Crisis in Clinical Research: Overcoming
Institutional Obstacles.
Oxford University Pres& New York, 1992.
This provocative analysis of U.S. research funding documents a dramatic decline in patient-centered basic research on human physiology and pathology. Physician and clinical researcher Edward H. Ahrens, Jr. argues that "basic research" (the study of disease mechanisms) has shifted from the clinic to the laboratory, and this shift threatens to undermine research productivity. Ahrens provides thorough statistical evidence and political analyses of the factors that have contributed to this trend.
Ahrens reviews trends in the U.S. While the National Institutes of Health (NIH) budget constituted 41% of U.S. health R&D in 1979, the percentage dropped to 34% by 1988. Similarly, support for health R&D from other federal agencies fell from 19% in 1979 to 12% in 1988. However, industry support increased from 29% in 1979 to 41 % in 1988. Also, in constant 1979 dollars, total health R&D substantially increased--from $7.133 billion in 1979 to $18.729 billion in 1988. Although the 1991 NIH budget constituted only 3.8% of non-defense discretionary spending, this percentage has been growing annually by 6.7% since 1981.
Despite increased federal dollars for health R&D, the percentage of proposed projects awarded NIH grants has somewhat declined. From 1976 to 1988, 31 % of all NIH grant applications resulted in funding; in 1989 the figure was 27.5%. Factors that contributed to slightly heightened competition for grants include increases in the number of investigators and in research costs. Direct costs (the expenses of individual research projects) rose more than sevenfold from 1970 to 1988, while indirect costs (expenses incurred by the principal investigator's institution for such research overhead as building maintenance) rose almost fourfold. Indirect costs averaged 46% of direct costs, ranging from about 8% for training grants to 65% or more for research preformed at major medical centers.
From 1976 to 1988, MDs acting as principal investigators had a success rate of 31 % for initial grant application. Seven percent were successful upon second submission (most unsuccessful grant applications are resubmitted), and 8% of grants succeeded on the third to fifth submission. PhDs had virtually the same success rates: 31%, 8%, and 8%, respectively. Medical schools, however, significantly varied in their success rates. The top 40 medical schools had approximately 40% grant-application success, while the bottom 40 had only about 20% success.
Of extramural NIH awards, 52% went to U.S. medical schools and their affiliated hosptials. Non-federal research institutes (both non-profit and for-profit) and hospitals not affiliated with medical schools received 25% of the grant money, while schools of arts and sciences received 12%, public health and dental schools received 7%, and other institutions of higher education received 4%.
Ahrens examines the funding disparities between different types of research, particularly between "basic patient-oriented research" (basic POR) and other types of research that Ahrens also designates as "clinical." In Ahrens' terminology, basic POR studies the mechanisms of human disease in human patients; other "clinical" research includes applied POR--which studies the management of human disease (e.g., clinical drug trials, studies of preventive strategies)--in vitro research on materials of human origin, and "animal models" of human health and disease. Ahrens acknowledges, however, that the clinical relevance of animal models is controversial: "There is not now, nor theoretically will there ever be, a perfect animal model for any of the major human diseases." (p. 177) Despite their dubious utility, animal models of human diseases received, during the decade 1977-1987, more NIH grant money than any other research method--27.2% of all NIH extramural funding.
Ahrens' principal concern is the rapid decline in financial support for basic POR. Whereas this research "dominated the pages of clinical research publications and the annual meetings of clinical investigators" in the 1950s and 60s, "the pendulum has swung decidedly toward bench research [reductionist, "controlled" laboratory research that focuses on narrowly focussed aspects of a problem]. . . and away from Basic to Applied POR” (pp. 111-112). In a random review of recently funded grant proposals, Ahrens found that fewer than 8% of the projects were in the area of basic POR.
Why does basic POR have difficulty competing with other types of research for NIH funds? According to Ahrens, for one thing, basic POR researchers often have difficulty recruiting patients who faithfully adhere to the research protocol. Also, unlike those who experiment on animals, POR investigators are constrained by the requirement that protocols be acceptable to human-subject review boards. In general, too, basic POR is more costly than other types of health research. Reasons for this include costs of patient recruitment, hospitalization expenses, and the lenghty duration of many clinical research projects due to the long natural histories of many human diseases.
In addition to these factors, the composition of NIH grant review committees often has the effect of discouraging basic POR, since these committees are generally comprised of scientists and physicians who favor laboratory research. Increasingly, Ahrens says, funding decisions are based on a project's likelihood of producing publishable results, rather than its actual scientific merit. He notes that many laboratory researchers, "lacking familiarity with POR, believe that POR facilities exist simply to act as the final step in translating flashes of genius of laboratory scientists into clinical reality. . . . In fact, this has happened only rarely. During my 40 years at the Rockefeller Hospital, I recall only one instance in which a laboratory investigation by biochemists was turned into a testable hypothesis in patients--namely, the treatment of sickle-cell crisis with cyanate." (p.146)
Basic POR investigators also face deterrents within their own academic institutions. Under increasing fmancial pressure, many medical centers have made income generation the priority. Since services to patients readily generate income, physicians who would otherwise conduct POR research are often required to spend most of their time providing these services.
Advocating the restoration of balance to U.S. health research, Ahrens recommends more unrestricted training grants to encourage young POR scientists, even if this means less funds available for specific research projects. Also, he proposes designating special grant-review committees to consider basic POR projects only, so that these projects will not compete directly with those representing other research approaches.
Ahrens argues forcefully that basic patient-centered research is vital and that the declining support for this research could seriously undermine medical progress.
Stephen R. Kaufman, M.D.
Michael Balls, James Bridges, Jacqueline Southee (eds.) Animals
and Alternatives in Toxicology: Present Status and Future Prospects.
VCH Publishers, New York, 1991
This book presents the proceedings of a conference held in November of 1990 at the Royal College of Physicians in London. Conferees discussed the Second Report of the Fund for Replacement of Animals in Medical Experiments (FRAME) Toxicity Committee. The nineteen prominent toxicologists who comprise the Committee had formed twelve working parties to investigate specific topics. Thirty additional leaders of the toxicology community had input to the working parties, helping them to assess the prospects for decreasing or eliminating animal testing and develop recommendations for minimizing animal use and suffering.
Most working parties of toxicologists acknowledged that current animal tests are inadequate. However, most were not optimistic that non-animal methods would completely replace animal tests in the near future. Most working parties concluded, on scientific as well as animal welfare grounds, that toxicity tests need improvement. According to Andre McLean, considerable progress has been made, but there is work to be done:
Great advances in various databases mean that computer searches are accessible to everyone. . . . unquestionably. our power of intellectual analysis has improved enormously. Against that, our use of animals in toxicology appears very crude and old-fashioned -- sometimes because we haven't yet got an alternative, but sometimes because we have not thought of how to do things a different way. . . The idea that the regulators should still demand out-of-date, useless, scientifically invalid, hopeless studies, which involve animals, is a scandal at the political level, which to a considerable extent is out of our [ttoxicologists'] direct control. (p. 342)
Although some conference participants seemed unduly reluctant to recommend significant change, the proceedings do provide a thorough analysis of the scientific strengths and weaknesses of animal and non-animal tests.
Kathryn Hahner, Ph.D.
Irwin D. Bross. Scientific Fraud vs. Scientific Truth.
Biomedical Metatechnology Press, Eggertsville, New York, 1991.
In this collection of case studies, Irwin Bross details how "Official Science" bureaucrats use fraudulent "scientific" data to defend political policy. Bross--who has co-authored over 350 scientific papers, has been involved in the major clinical trials of many cancer treatments, and has worked within the scientific establishment for years—develops the thesis, "The establishment is the enemy of the enterprise."
Most research scientists, Bross argues, genuinely pursue truth, but science administrators reach positions of prominence because of their political loyalties. The politicians who appoint these administrators are beholden to the wealthy industry concerns that underwrite their campaigns. Science administrators are puppets of big business, and "science" itself is a public relations tool that provides "evidence" (often fraudulent) to support industry's positions.
For example, science administrators continue to advocate high-dose radiation tests on animals as a (supposed) means of establishing limits of "safe" low-dose radiation exposure (such as that occurring during X-ray tests) even though the high-dose animal data cannot be extrapolated to low-dose human exposure. The nuclear industry uses the inaccurate and invalid animal data to defend itself against evidence of increased cancer incidence near nuclear power plants; the Department of Defense uses the data to defend itself against disability claims by cancer-stricken veterans exposed to nuclear bomb tests during the 1950s.
In Scientific Fraud vs. Scientific Truth Bross expands on themes he has discussed in such earlier works as Crimes of Official Science; A Casebook (1987) and Scientific Strategies to Save Your Life (1981). He updates readers on the Love Canal controversy, involving a continuing misinformation campaign by Official Science. He also argues, as he has for years, that routine mammography increases a woman's risk of breast cancer. Bross' claim has been strengthened by a recent Canadian study in which women who received routine mammographies had a 52% greater rate of death from breast cancer than women who did not.
Bross' evidence that top science administrators have, for decades, intentionally deceived the public is compelling. He encourages grass-roots campaigns aimed at increasing the public's scientific literacy; public ignorance, he maintains, allows "scientific" misinformation to flourish. Bross suggests zero-budgeting the NIH, which he considers thoroughly corrupt, and instituting a decentralized scientific enterprise comprised of independent clinical researchers dedicated to truth and public health.
Stephen R. Kaufman, M.D.
Reitman, Judith. Stolen for Profit: How the Medical Establishment
is Funding a National Pet-Theft Conspiracy.
New York, Pharos Books, 1992.
A dog or cat owner's worst nightmare is that their beloved companion might end up a research subject. Investigative reporter Judith Reitman thoroughly documents that this has been the fate of millions of "lost" and stolen pets. The animal-research industry has created a lucrative market for "random-source" dogs, paying up to $300-550 for large dogs. Unlike purpose-bred dogs, former pets are "ideal" research subjects because they are accustomed to human interaction and unlikely to resist or bite during frightening or painful procedures.
Reitman focuses on a recent Los Angeles criminal case in which a ring of dealers was found guilty of pet theft. Responding to "Free To A Good Home" ads in local papers, the dealers claimed to be interested in adopting pets but actually sold them to labs, including Cedars Sinai, Loma Linda, and the Veteran's Hospital in Sepulveda.
The problem of pet theft extends well beyond one local network, however. Reitman details numerous episodes nationwide in which entire neighborhoods have had dogs disappear over a short period. One lab sought to obtain 126 German Shorthaired Pointers within six weeks. Mary Warner of Action 81, a grassroots organization that monitors and documents pet theft, has commented, "Where did the researchers from the lab expect to get [them]? Well, residents near the lab soon found out."
Large-scale, organized pet theft would be impossible if the U.S. Department of Agriculture enforced existing legislation. Reitman documents how key USDA administrators have impeded efforts to regulate lab animal acquisition. A network of "bunchers" (those who collect animals, often through theft or false representation, for sale to licensed dealers), dealers, and local law-enforcement officials prevents pet owners from locating their lost animals, while USDA officials look the other way. Research institutions claim that, to the best of their knowledge, they do not purchase stolen animals. However, they generally bar pet owners from entering lab-animal facilities to search for lost companions, and many purchase from dealers who routinely falsify records, listing non-existent or long deceased persons as those who supply them with dogs and cats.
Not surprisingly, the pet-theft network treats the animals abusively. Bunchers and dealers, for example, regularly handle animals in the most brutal manner, as well as transport and hold them under grossly inhumane conditions. Still research institutions continue to do business with the pet-theft network and are unlikely to be swayed by animal welfare concerns. (The animal research industry has affiliated with organizations such as Putting People First, that openly derides concern for animals.)
Reitman documents her arguments conclusively. However, not totally convincing is her evidence regarding a 1992 report that concluded that the animal-research industry is not primarily responsible for the stolen pet problem, although it does contribute heavily, Reitman suggests that a foundation with weak ties to the animal-research industry influenced the contents of a report prepared by the Animals' Agenda, prompting the animal rights magazine to minimize the animal research industry's complicity in the stolen pet trade. In general, Reitman's book does offer abundant evidence that the animal-research industry and the medical establishment are integrally involved with the stolen pet trade.
Stephen R. Kaufman, M.D.
Committee on the Use of Animals in Research. Science, Medicine,
and Animals.
National Academy Press, Washington, D.C., 1991
With the professed purpose of informing the debate on animal research, the Committee on the Use of Animals at the National Academy of Sciences (NAS) has produced the booklet Science, Medicine, and Animals, aimed at the general public. In reality, the Committee has produced a one-sided document that uncritically endorses animal experimentation. By dismissing animal rights as a dangerous minority viewpoint and failing to provide a fair, accurate explanation of the concept, the booklet avoids addressing legitimate moral concerns about animal research. Similarly, this document avoids addressing valid scientific objections to animal experimentation by never so much as acknowledging the growing criticism from within scientific circles.
In a manner of presentation that favors vague generalization over specific evidence, the booklet ranges from cancer and heart disease to psychology research and control of infectious diseases to pound seizure and animal rights. Even those sections that include detailed discussions omit crucial facts. For example, one section mentions a lymphoma patient who was cured by chemotherapeutic agents allegedly discovered in mice; while describing the disease and treatment in some detail, the section fails to identify the drugs used. Thus, the claim that these agents were developed through animal studies can be neither verified nor disproved.
Similarly, the booklet claims that "surgical procedures, pain relievers, psychoactive drugs, medications for blood pressure . . . all have been developed and tested in animals," Again, the authors fail to identify the specific measures--thereby preventing focused analysis or dispute of their implication that animal testing contributed to the development of these measures.
Like many other documents that promote animal research, this publication falsely equates animal testing with discovery through animal research. Though virtually every therapeutic procedure in the last decades has been tested on animals, this is certainly not the same as assuming that these procedures were discovered, in animal studies. In fact, careful examination of medical history suggests that medical discovery generally does not involve animal experimentation.(1,2)
Using this false equation of testing with discovery, the NAS report credits animal experimentation with the discovery of chlorpromazine's antipsychotic properties. In truth, chiorpromazine's antipsychotic effect was discovered in human, not animal, studies. A European pharmacology panel has concluded:
Many valuable drugs (e.g., chiorpromazine as a tranquilizer, imipramine as an antidepressant, beta-adrenoreceptor blocking agents as antihypertensives) have been discovered by observation of their effects in patients suffering from the condition in question. None of these established drugs would have been put forward initially for evaluation for these indications if prediction of therapeutic effect from animals had been mandatory before clinical use. Even with hindsight, some of their valuable effects still have not been shown in animal experiments.(3)
So, while chlorpromazine was indeed tested on animals, it was by no means discovered in animal studies.
Another case in point is the discovery of AZT's anti-HIV properties, which the booklet attributes to work with primate models of AIDS. In fact, AZT's ability to inhibit HIV replication was first demonstrated in 1985 using a T4-lymphocyte culture infected with the virus.(4) Several weeks later, AZT underwent clinical trials, although no animal tests to show its efficacy had been conducted. The National Cancer Institute researchers who discovered AZT's anti-HW action have written: "Thus, AZT, a drug chosen on the basis of its selective in vitro antiviral effect against HTLV-llI [HIV] has been shown to confer a clinical benefit in patients with advanced disease."(5) As mandated by law, AZT was tested on animals; the discovery of its anti-HIV properties, however, did not come as a result of animal experimentation.
Even the authors' assertion that animal toxicity testing helps promote safety is disputable.(6-8) Animal toxicity studies commonly yield misleading and contradictory results. In fact, approximately 90% of drugs fail human clinical trials after passing animal tests--primarily because they produce adverse reactions in humans.(9) Emerging non-animal methodologies provide a prospect for better, more accurate results. For instance, bone-marrow suppression is a common human adverse reaction to non-steroidal anti-inflammatory agents, but this effect is not predicted by animal studies.(8) In contrast, human granulopoiesis culture can predict this serious adverse drug reaction and even provide a semi-quantitative assessment of the risk.(10)
Since the NAS booklet fails to acknowledge any case of animal experimentation's inefficacy, there is good reason to conclude that it was intentionally written as propaganda. The authors' statement, "It makes no sense to sacrifice future human health and well being by not using animals in research today," demonstrates the use of unrestrained hyperbole that pervades the publication. Such emotional hyperbole is particularly unworthy when it emanates from an organization charged with advancing science, which rests on scrupulous avoidance of claims not securely founded on evidence. The public, whose tax dollars help fund the NAS, has much cause to complain.
1. Reines BP. On the locus of medical discovery. J Med Phil 1991;16:183-209.
2, Reines BP. Psychopharmacologic discovery: The relative contributions of clinical and laboratory studies. Perspec Med Res 1990;2:13-26.
3. Anon. Towards a more rational regulation of the development of new medicines; Report of a European Workshop held in Sestri Levante, Italy, Sep. 28-30, 1976. Europ J Pharmacol 1977; 11:233-238.
4. Mitsuya H, Weinhold KJ, Furman PA, et al. 3'-Azido-3'-Deoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Nail Acad Sci USA 1985;82: 7096-7100.
5. Mitsuya H, Broder S. Strategies for antiviral therapy in AIDS. Nature 1987;325:773-778.
6. Weatherall M. An end to the search for new drugs? Nature l982;296:3S7~390.
7. Rang HP, Dale MM. Pharmacology. London, Churchill Livingstone, 1987.
8. Heywood R. Clinical toxicity - could it have been predicted? Post-marketing experience, in Lumley CE, Walker SR (eds). Animal Toxicity Studies: Their Relevence for Man. Britain, Quay Publishing, 1990, pp 57-67.
9. Levine RR. Pharmacology: Drug Actions and Reactions. Boston, LitLie, Brown & Co, 1978, pp 406-407.
10. Gillian ML, Williams JRB. The effects of some non-steroidal anti-inflammatory drugs on human granulopoiesis in vitro. ATLA 1985;13:38-47.
Nir Shalev