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THE NEW CHIMAERA: THE INDUSTRIALIZATION OF ORGAN TRANSPLANTATION

Tilney, Nicholas L.1,9; Guttmann, Ronald D.2; Daar, Abdullah S.3; Hoffenberg, Raymond4; Kennedy, Ian5; Lock, Margaret6; Radcliffe-Richards, Janet7; Sells, Robert A.8For The International Forum for Transplant Ethics

Overview

Clinical organ transplantation has evolved through advances in patient care in parallel with investigations in associated biologies. It has developed from a cottage industry to an important medical specialty driven increasingly by the availability of newer and more effective immunosuppressive drugs, and dependent on consistently close collaborations between university-based clinical scientists and the pharmaceutical industry. Particularly during the past decade, however, this industry has undergone striking changes, consolidating into huge multi-national corporations, each competing for patients, their doctors, and for support of the allied hospitals. Because of the growth of “Big Pharma,” the relationship between academia and industry has changed. There have been many advantages to such mutually dependent interactions. A combination of university-based expertise and the specialized knowledge and resources of industry have produced important scientific gains in drug development. Commercial sponsorship of applied research has been crucial. The orchestration of multi-center controlled clinical drug trials has provided invaluable information about the effectiveness of newer agents. But there are also disadvantages of increasing concern. Indeed, the power of “Big Pharma” in many medical fields including transplantation is such that presentation of data can be delayed, adverse results withheld, and individual investigations hampered. Clinical trials may be protracted to stifle competition. Monetary considerations may transcend common sense. Several measures to enhance the clinical relationship between the pharmaceutical industry and those involved with organ transplantation are suggested, particularly the use of third party advisors in the production of clinical trials, support for more basic research and in the dissemination of results. In this way, the increasingly problematic phenomenon of commercialization of the field of transplantation can be tempered and controlled.

1 Brigham and Women’s Hospital.

2 McGill University.

3 Department of Surgery, College of Medicine, Sultan Qaboos University.

4 Honorary Fellow, Wolfson College, Oxford University.

5 School of Public Policy, University College, London.

6 Department of Social Studies in Medicine, McIntyre Med Science Building, McGill University.

7 RFUCMS, University College, London.

8 Royal Liverpool University Hospital, Liverpool.

9 Address for correspondence: Nicholas L. Tilney MD, Brigham & Women’s Hospital, 75 Francis Street, Boston, MA 02115.

Received 3 July 2000.

Accepted 4 August 2000.

The relationship in biomedicine between academia and industry has changed dramatically during the present era of financial expansion and corporate consolidation. Advantages of such a change include important scientific collaborations and significant company funding for relevant research. Disadvantages have ranged from conflicts of interest between physicians and scientists and their commercial partners to undue influence of marketing stratagems in influencing patient care (1,2). Indeed, concern is becoming so acute that the Dean of the Harvard Medical School has recently opened serious discourse with the faculty regarding stringent guidelines for company interactions with university based investigators. These guidelines may provoke major changes throughout the entire academic community.

The field of organ transplantation has been influenced considerably by this collaboration particularly as its development has relied substantially on the search for ever more effective immunosuppressive drugs. In the beginning of the experience, the transplant clinician-scientists had little background knowledge about immunosuppression, a word not even coined until the 1960s. Data about the new drugs were collected from in vitro observations, animal experiments, and from prior use of their parent compounds in individuals with cancer. Dosages, schedules, potency, and short- and long-term side effects and complications all had to be identified through testing of patients in the few contributing units. In almost all cases, the participating pharmaceutical companies encouraged clinicians to gather results, first on a few then on increasing numbers of allograft recipients. The compounds were donated in exchange for information. Financial support for the specific clinical studies was minimal. No agreements were signed, the subject of intellectual property was not discussed. Controlled animal experiments to define mechanisms of action, immunological effects, and the efficacy of particular agents were designed by individual investigators who received adequate amounts of material and/or small support grants that often supplemented research funds from government agencies or foundations. The subject broadened rapidly in the early 1980s with the introduction of cyclosporin A and the resultant improvement in graft survival. Within a few years, clinical testing of the new compound spread from a handful of units in Europe and North America to more than 100 patient-based studies in 19 countries on 5 continents (3). Enthusiasm ran high that transplantation of a variety of organs was becoming routine treatment for those with end-stage disease.

In common with other industries, the major pharmaceutical companies have experienced startling changes during the 1990s. Mergers, acquisitions, restructuring, and relentless competition have characterized this era of “Big Pharma.” The number of new drugs has increased in parallel with powerful methodologies, often based on ideas developed in academic laboratories that include molecular engineering, exploitation of cell physiology, and the influence of particular molecules within the cell. At the same time, there has been a growing tendency for entrepreneurial university-based scientists to exploit their ideas and expectations by forming small companies or joining large ones. Transplantation has been at the center of this revolution. Indeed, the field has evolved within a relatively few years from a cottage industry to a large specialty enterprise, driven by the introduction of several effective immunosuppressive drugs, each positioned by their supporters to take a share of a highly visible market. As a result of this shift, the competitive field of multi-center clinical drug trials has burgeoned into an influential force. Initially created to acquire knowledge about the efficacy of a given medication, these market-penetration trials have provided a respectable means not only for individual investigators and their academic institutions to gain prestige but for the companies to license and market their new compound.

Important and desirable gains accrue from a close and mutually dependent relationship between physicians who administer drugs to patients and the pharmaceutical industry that produces them (4). The relationship is to the advantage of all, particularly through the funding of patient-based and applied investigations not supported by federal sources. In addition, a combination of university scientists who have joined companies, venture capital, and the resources of “Big Pharma” may produce excellent science that leaner university-based resources cannot support. The enduring need for the development of specific new drugs for specific medical conditions are met by industry; industry, in turn, is dependent on, and will sponsor efforts of, academic doctors who study their actions in preclinical models and who recruit patients into clinical trials. Once an agent has been found to be effective and has been licensed, the medical profession is crucial in prescribing it.

There may also be significant disadvantages to such interactions. The emergence of a large and well-funded biotechnology industry is shifting increasingly from academic, federally funded research toward the private sector, with growing numbers of faculty moving to industry (3). The course of investigations, and even entire academic careers, are being diverted from basic biology to clinical trials, sometimes of limited scientific value, and often involving practitioners uncritical and untrained in such methods (1). Financial considerations may become more acceptable without the scrutiny of peer review (4,5). With an influx of industrial support toward the development of a particular agent, for instance, academic departments may be pushed into investigative channels for which they were not designed. The normal ambitions of academics—visibility, promotion, recognition, and leadership—may become diluted by business concerns primarily dedicated to monetary gain. Commercial interests regarding patent rights have also disturbed the traditional academic approach that scientific or medical knowledge belongs to the broader community; the ongoing controversy about patenting portions of the human genome is an example. Publication may be delayed or even prevented if a patent is pending or, more ominously, if the results of industry-supported university-based research are unfavorable. Secrecy may be forced on the investigators or a company may withhold confidential information about a product from the general medical community (6–8). The desire for prolonged confidentiality by “Big Pharma” may disturb the traditional flow of scientific and medical information, in which facts generated by one investigator are reported openly and reviewed by peers who then go on to repeat and build on the initial findings. Indeed, progress in medical research may be in increasing jeopardy because of secrecy and the complex legal arrangements required by industrial sponsors of those who test particular agents (9).

There may also be problems with the clinical trials. Licensing trials tend to require huge patient numbers to ensure a high probability of reaching statistical significance. A large number of centers are recruited to take part. This ensures “seeding” of the drug for subsequent postlicensing studies. In addition, emphasis of the notion that the introduction of a new drug will often cost $300–500 million has the effect of forcing small companies to seek out “Big Pharma” for partnering in research and development, clinical studies, licensing and marketing, rather than being able to contribute on their own. The current consolidations will likely see fewer pharmaceutical companies involved in transplantation. The commitment to a particular drug in a trial may also preclude the clinical investigators and their teams from testing concurrently other promising agents from other companies. This issue is particularly serious in a field with a limited number of transplant professionals, centers, and patients.

The once informal relationship between the pharmaceutical industry and medical academia is also changing through increasing networking of company staff with via company sponsored conferences, prolonged clinical trials, and rewards for those involved. Properly designed clinical trials have given way to market penetration studies; these are of dubious scientific benefit and aim to familiarize doctors with new drugs (freely provided for “trial” purposes) and are motivated by the desire of companies to sell their products.

To publicize results, “Big Pharma” has begun to devote entire international meetings to discuss their new agents. Guests may be flown in from all over the world not only to present their own relevant data but also to hear those of others. Although seemingly open to papers presented by investigators reporting on the products of competitors, control of the program lies with company organizers. Although such sessions and their subject matter are portrayed as the sharing of medical science, little information is unveiled without a coincident marketing message. The conferences, beautifully organized and held in alluring venues, often seem more like “infomercials” than opportunities for the gathering of scientific facts, with the sponsors apparently more interested in selling their products than in promoting new investigations. The published proceedings of these meetings are not subject to peer review, yet they achieve visibility and add possible spurious importance to a product and may be considered guides to therapy by practitioners. The sponsor, the academic consultants, and the company representatives who sell the drug may quote favorable reports in advertisements. To be fair, however, the outcome is not always unfavorable as at least two important clinical trials have arisen from such conferences.

Drug companies also offer lead clinicians free transport to and accommodation at meetings where peer reviewed data are presented, providing welcome supplements to institutional travel grants. The corporate sponsorship of and presence in local professional meetings, or the provision of food for in-house seminars, research meetings, and didactic sessions for trainees in teaching hospitals or medical schools has been an additional subject of discussion amongst many academics. Company funded “satellite” meetings attached to a large general meeting of a professional society have become routine. Tickets to sporting events or other entertainment may be presented. Conference organizers anxious to restrain registration fees and maximize attendance solicit these fringe gratuities. Professional societies profit therefore.

Although generating good will and encouraging interactions with physicians, the corporate motives are more complex than altruism alone. Successful industry depends on the creation, production, and marketing of products for profit, thereby executing their particular “business model.” The changing balance between science in academic departments and “science” driven by commercial needs has provided financial and promotional advantage to those working within each system. Universities have, in addition, repealed their previous position of disdain toward commercial interests, and actively encourage their basic science and clinical faculty to develop industrial ties and sponsorship for their research. The disadvantages of such a liaison have increasingly become acceptable to them. Although some useful clinical drug trials have resulted from this new relationship between doctors and supplier, the field has subtly changed; industry now has increased control of a field initially driven by scientific advancement. And medical faculties have freely supported the subordination of academics to industrial interest.

We view these developments with some concern, believing that threats to intellectual independence (in whatever guise) may subvert the integrity of faculty research, reduce pressure on governments to fund basic and applied science and seduce researchers away from “curiosity-driven science”(2) We propose measures to accentuate the best aspects of the relationship while minimizing the unfavorable.

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RECOMMENDATIONS

1) Committees comprised of independent academics and professionals should be given the responsibility to organize and appraise clinical trials working through institutional clinical research offices. Pharmaceutical interests could be included and could contribute to planning and analysis of trials but should not control or direct them. This relatively dispassionate structure would obviate any self-interest on the part of clinicians or those in the participating company, reduce or eliminate potential abuse or bias, enhance credibility, and encourage acceptance of drugs that were shown to be innovative and useful.

2) Industrial support for international and national conferences should be donated to the central program organizing committees that would be responsible for appointing speakers and for funding travel grants where appropriate. These donations should be acknowledged in brochures and elsewhere and the names of donating companies could be attached to specific lectures or sessions, so long as they did not influence the choice of speakers or the content. Specific named traveling fellowships could be created. Particular care should be taken to separate satellite meetings organized by industry from the official proceedings of conferences. In the same way local educational meetings could be supported by industry with full acknowledgment of their donations, but they should not influence speakers or content of lectures.

3) Company funding for relevant associated basic research should be contributed to a central foundation organized by the professional societies and responsible for the investigations. The foundation would distribute the properly acknowledged funds on the basis of peer-reviewed grant applications. This arrangement would obviate questions of corporate influence on particular studies.

4) Contractual agreements regarding ownership of data or objective reporting of the results should be formalized between industry and academia before the initiation of a study or trial. Although such contracts are usually in place, they must more strongly emphasize freedom of publication and dissemination of adverse results, censure undue company pressures on the reporting scientists and on peer-reviewed journals, and control premature marketing claims.

The following justifications of these recommendations are offered. 1) They will restore professional autonomy and integrity. 2) The credibility of industry will be enhanced. 3) Patient care will be improved by ensuring the provision of properly evaluated products. 4) The cost of drugs may be reduced through a decrease in promotional expenditure and unnecessary or overlapping clinical trials.

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REFERENCES

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© 2001 Lippincott Williams & Wilkins, Inc.