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Law and Medicine Lawrence O. Gostin, JD, Section Editor Conflict of Interest Dilemmas in Biomedical Research Michael 0. Wit:, PharmD, JD, Lawrence O. Gostin, JD BIOMEDICAL :-esearchers in medical centers, universities, and other nonprofit research insttutauns routinely collabo- rate with for-profit companies on research. These academic- industry collaborations have generated lifesaving new prod- ucts, as well as profits for the companies and the researchers. Because of the baneficial effect of biomedical technology trans- fers on the United States' competitiveness and public health, Congress has made a national priority of bringing academia and industry together.1z However, the industry-academia collaborations ha %re their costs. They create conflicts between the researcher's (and possibly the institution's) academic in- terests and financial interests. These conflicts of interest threaten the objectivity of science, the integrity of scientists and institutior.s, and the safety of medical products. At the present time, federal employees working in federal laboratories are constrained by numerous conflict of interest re- strictions .~' Researchers outside the federal government, how- ever, are subj ect to minimal restri ctions, even if they receive fed- eral funds. This article examines the existing and pending regulations and guidelines governing conflicts of interest in biomedical research and development conducted outside of federal labo- ratories. Our premise is that commercializing biomedical re- search is a worthy public goal and publiclprivate research collaborations help to achieve that goal. Our view is that uniform federal standards are required, however, to avoid conflicting interests that undermine scientists' integrity. Fed- eral rules are needed to require disclosure of conflicts, limit the most troublesome forms of conflict, and create uniformity in ethical standards across the country. FEDERAL LEGISLATION SUPPORTING INDUSTRY-UNNERS(iY COLLABORATION Federal legislation, since 1980, has facilitated industry- university collaborations and speeded promising new prod- ucts from the laboratory to the market. This legislation, how- ever, has brought academia and business together without adequately regulating the consequences of the interactions. The Stevenson-Wydler Technology Innovation Act of 1980, eestablished a policy of "stimulating improved utilization of fed- erally funded technology developments by state and local gov- ernments and the private iector."6 The act created an Office of From the Technology Resource Group, Sacramento, Calif (Dr Witt), and American Society of Law, Medicine and Eth;cs, Boston. Mass (Mr GosGn). Mr Gostin is currently VisR,ng Professor at the Georgeto+m University Law Center, Washington, DC. and The Jofv s Hopkins School of Hyg:ene and Public Health, Baltimore, Md. Reprint requests to Office of the Managing Director, Technology Resource Group, 3108 Ctairidge Way, Sacramento, CA 95821 (Dr Y, tt). 0 Research and Technology Applications, whose primary pur- pose was to investigate projects that could be used by govern- ment or private industry.7 Each agency implemented this re- quirement by having its own version of such an office (ie, the Office of Technology Transfer at the National Institutes of Health [NIH] handles this function for the Department of Health and Human ,~ervices). The act also created the Center for the Utilization of Federal Technology, established within the National Technical Information Services, to provide indus- try with a central source of information on federally owned or developed technologies with potential commercial application.~ Later in 1980, Congress accelerated technology transfers by amending the patent and trademark laws for the purpose of supporting small business. The Bayh-Dole Act9gave inven- tors in small business firms and nonprofit organizations the power to retain ownership rights to patents in inventions de- veloped with federal funding.10 Prior to the Bayh-Dole Act, the federal government owned the rights to most federally supported inventions, and for-profit firms wishing to develop federally supported inventions had to wade through abureau- cratic maze to obtain a license." Congress recognized that the federal government had been unsuccessful in nurturing the development of new products for the market and that it was in the public interest to bring innovative ideas into clinical practice without unnecessary delays.u A policy statement by the Reagan administration extended the Bayh-Dole coverage beyond small business firms and nonprofit organizations.",ts The Bayh-Dole Act enabled institutions and their investiga- tors to license patents from federally supported work to com- panies interested in developing marketable products. This has allowed the institutes and researchers easier access to money, both for research and for personal profits, and opened up to industry a large market for potential commercial advantage." CONFLICTS OF 1lVTEREST: DEFINING THE PROBLEM The concept behind technology transfer is usually straight- forward. Researchers develop scientific ideas with federal sup- port in university or other nonprofit research institute labo- ratories. Resulting inventions are licensed to for-profit com- panies, sometimes early in the developmental precess. The companies supply incentives to the investigator and to the investigator's institution in exchange for the idea and its de- velopment. Many scientists conducting federally supported research have personal contracts with the companies that pur- chased licenses in the developing research. Such an investi- gator may be paid as a company "consultant" and may receive an equity interest in the company, a seat on the company's board of directors, or a percentage of future sales. Such co- JAMA, February 16, 19°4-Vo1271, No. 7 Coc•flict of Int~rest in Research-Vdtt & Gostin 547 G11 UMI Article Clearinghouse has reproduced this material with permission of the copyright owner. Further reproduction is prohibited.

operation between investigators and industry is common.16," There is nothing inherently wrong with permitting acade- micians to reap financial reward for scientific innovation. Scientists, no less than other contributors to societal welfare, deserve fair compensation for their work and achievements. Nor is profiting from government funding unique to science. It may offend certain segments of society that individuals and institutions profit from work financed by the taxpayer. With- out such incentives, however, medical products essential to the public health may not reach the public. The problem arises when objectivity, truth telling, and disclosing results of research, all essential to scientific rigor and integrity, are compromised by the desire for greater reward. When the enrichment of scientists is directly related to the "success" of the scientific endeavor, society runs the risk that researchers will knowingly influence the outcome of "neutral" scientific inquiries. Conflicts of interest can also undermine the robustness and openness of science itself. Scientists may be diverted from conducting research of public health or societal value to con- ducting research of commercial value; researchers may have a divided loyalty between their academic employers and com- mercial sponsors; and researchers with a direct profit motive in the product may fail to report or share the results of investigations in a timely manner.'&19 The problem of conflicts of interest may grow as federal research dollars decrease and are replaced by funding from the private sector. A researcher investigating a product with major implications for the health of the community is entrusted by the public with a respon- sibility to conduct the research with objectivity and rigor. Researchers, particularly those conducting clinical trials, carry a fiduciary duty to the public. Like fiduciaries, there is a presumption against conflicts of interest real and perceived 20 CURRENT CONFLICT OF INTEREST RULES AND GUIDELINES Current conflict of interest rules and guidelines are highly variable. Provisions governing conflicts of interest exist at the federal level through regulations and Public Health Ser- vice (PHS) policy, at the state level through nonprofit cor- poration legislation, and at the institutional level through individual university policies. Federal Policy, Guidelines, and Rules Despite the national attention to conflicts of interest in medi- cal research, few federal rules or guidelines a• a force for aca- demic research institutions. Federal regulations govern only serious scientific misconduct, not simple conflicts of interest; these regulations prohibit fraud, fabrication of results, plagia- rism, and the clear violation of scientific research norms 21r'2 Thus, a researcher who has intertwining academic and financial interests may not be violating federal law in the absence of de- monstrable fraud or publishingdeliberately misleading results. In 1987, the PHS adopted a general policy requiring in- stitutions to develop conflict of interest guidelines as a con- dition of federal research fundingP Such policy, strength- ened in 1991, now requires [r]ecipient organizations ... [to] establish safeguards to prevent employees, consultants, or members of governing bodies from using their positions for purposes that are, or give the appearance of be- ing, motivated by a desire for private financial gain.... These rules must also ind3cate the conditions under which outside activities, re- lationships, or financial interests are proper or improper, and provide for notification of these kinds of activities, relationships, or financial interests to a responsible and objective institute official. The institutional guidelines must specify the administra- tive action taken for violations. The PHS policy does not dif- ferentiate, however, between various types of conflict of in- terest, nor does it indicate those that should be disclosed or prohibited. The policy simply delegates the responsibility to identify and manage conflicts to federally funded institutions. NIH-Proposed Guidelines The NIH proposed conflict of interest guidelines in Septem- ber 1989?' The guidelines required institutions to maintain records of disclosure for3 years, to promptly notify the federal funding agency of any conflict, and to resolve violations prior to accepting funding. Individuals were required to disclose fully "all financial interests and outside professional activities by all who are in a position to make decisions" concerning re- search proj ects. Disclosure requirements included funding for laboratory activities, services, consultancies, honoraria, and other benefits. All disclosures had to be reviewed by institu- tional panels. The guidelines specifically prohibited research- ers from holding equity or options in any company that would be affected by the outcome of the research. The NIH guidelines were widely criticized in the research communitybecause of theirrestrictiveness, their prevention of fair remuneration to scientists, and their chilling effect on co- operative ventures between companies and university re- searchers. Opponents focused on the lack of distinction be- tween basic research and later-stage clinical trials, the inordi- nate cost of disclosure and record-keeping requirements, and the constriction of the flow of funding from the private sector.~ The guidelines were withdrawn within a matter of months by the secretary of health and human services in favor of a formal development of a Notice of Proposed Rule Making. The NIH has completed proposed federal regulations to replace the guidelines, and pending review by the secretary of health and human services, among others, will publish them for comment in the Federal Register. Based on statements made before Congress by agency officials, the proposed rules are expected to target clinical trials of drugs and vaccines. The scope of the proposed rules may also include basic research activities. The proposed rules probably will delegate considerable discretion to universities to approve, manage, or prohibit conflicts. The proposed rules, then, can reasonably be expected to leave most research short of clinical trials underregulated and delegate wide dis- cretion to individual institutions. Institutional Guidelines: Attempts to Control Conflicts of Interest in a Regulatory Void In compliance with existing PHS guidelines and in antici- pation of more specific regulations from the NIH, many in- stitutions have adopted their own guideline02'' The follow- ing is a comparison of guidelines offered by the American Medical Association (AMA), the American Federation for Clinical Research (AFCR), the Association of American Medi- cal Colleges (AAMC), and Harvard Medical School. The com- parison illustrates that these organizations appeared to have reached the same general conclusion on the issues most in need of regulation, which include the following: full disclosure of actual and potential financial interests; strict regulation of 548 JAMA. February 16, 1994-Vol 271, No. 7 Conflict of Interest in Research-Witt & Gostin

equity ownership and stock options in interested companies, especially by investigators conducting clinical trials; limita- tions on membership on boards of directors; a more permis- sive response to the receipt of honoraria and fees for services; and establishment of committees to review the disclosures. American Medical Association.-The AMA guidelines~l provide that, once a clinical investigator becomes involved in a research project for a company, the investigator cannot buy or sEll the company's stock until the involvement ends and the re- sults of the research are published?&p18' Presumably, a "clinical investigator" is someone conducting clinical trials and not a re- searcher engaged in basic research activities. The AMA would "manage" other "material ties" to interested companies. The AMA approves of corporate payments to a re- searcher and subjects the payments to disdosure and review made to the research institution, the research sponsor, and medi- cal journals 0P'11 Review committees at the medical centers would be required to examine the disclosures by clinical staff. The AMA guidelines reflect several themes: material ties should be managed rather than banned, clinical investigators must be subject to greater scrutiny of conflicts than inves- tigators in other stages of research, and conflicts should be managed through internal disclosure and peer review. These themes are echoed in the other guidelines. American Federation for Clinical Research. The AFCR guidelines;' allow "investigators actively carrying out ongo- ing evaluation of drugs or devices" to receive funding from a company to cover the costs of conducting the research itself. The AFCR guidelines forbid an investigator conducting clini- cal trials to own stock or receive stock options from a com- pany that stands to profit from the investigator's research. The guidelines also prohibit a clinical investigator from serv- ing on the board of such a company. The guidelines require investigators presenting results of their research in writing or orally to fully disclose all funding sources. The intent is to allow the audience to decide for itself whether the sources of support could have influenced the validity of the results or conclusions; peer review should suffice to control the actions of investigators. The AFCR guidelines require timely pabiication of results, al- lowing for the "normal and customary delay in reporting re- quired to allow the sponsoring company to file for patent rights." This rule confronts the persistent fear that scientists with a fi- nancial stake in their research will abandon the academic rule of disclosure in favor of fi ee market, protectice secrecy. In addi- tion, investigators should adhere to theiroR-ninstitution's guide- lines and make appropriate disclosures. FinaIly, the guidelines stress that the "[e]ducational and commercial objectives should be clearly separated." To that end, students should not partici- pate in industry-sponsored university-based research. Association of American Medical Colleges. The AAMC proposes3l that institutions must have the following five com- ponents for their conflicts of interest rules (1) standards of conduct that delineate the boundaries of conflicts of interest and commitment; (2) requirements for timely disclosures of relevant information; (3) adequate review of disclosed infor- mation and potential conflicts of interest; (4) procedures for enforcing standards and providing sanctions for violations; and (5) policies and procedures consistent with governmental policies and rules. Disclosure by the investigators and de- tailed policies and procedures developed by the institution are at the core of the AA.NSC guidelines. It is a self-policing approach relying on "aggressive monitoringand conflict man- agement" by the institution. All privately and federally sponsored research agreements in which a faculty mem} x participates are subject to ascending re- view, in which each person's decisions are reviewed by the su- perior. Researchers would make full disclosure of financial inter- ests to their supervisors, who would make decisions reviewable by the dean, the chief executive officer, or a designated senior institutional official. Any decision would be reviewed further by a committee of institutional officials. The ascending review pro- cess makes the reviewers accountable and ensures that the re- viewers are familiar with the terms of the agreements. Harvard Medical School: The rules adopted by Harvard are among the toughest." Faculty members must disclose an- nually all potential conflicts, and a standing committee of faculty must give its approval for most financial connections between faculty and for-profit companies. Faculty members must obtain approval to conduct sponsored research for a business in which they or their family members have an interest. Other activities requiring approval include sitting on a review committee that is judging a technology in which they have an interest, serving as a managing executive for a biomedical company, or having a financial interest in a competitor of the university. Express ap- proval is required before a faculty member conducting clinical trials may hold stock in, or receive consulting fees from, a com- pany whose technology he or she is investigating. The Bayh-Dole Royalties: Not a Conflicts Issue? Missing from the guidelines discussed above is any mention of the payment of royalties to the investigator(s) by the insti- tutions. The Bayh-Dole Act requires nonprofit organizations to share royalties with the inventors ~l The inventors receive such royalties when the research institution assigns or licenses the invention and when it receives fees, labeled variously as roy- alties, license fees, or milestone or minimum sales payments, from the licensee/company. This provision gives an inventor considerable incentive to license his or her invention.'1`his rule thus created a potential financial conflict of interest, yet this potential is not addressed in existing guidelines. The decision to refrain from regulating royalties was pre- sumably based on the now dated view that there is a consid- erable time between the licensing of the invention and the receipt of fee (or royalty) income. With the increasing sophis- tication of university technology licensing offices and larger up-front and other fees being paid to universities, the prospect of receiving such income creates substantial finanual incen- tives for researchers to license their inventions to companies. This policy decision may also relate to an interpretation given to analogous provisions of the Federal Technology Trans- fer Act of 1986. The Technology Transfer Act has a royalty provision for federal employees in federal haboratories?' The Office of Government Ethics' (OGE) view is that this royalty provision does not violate the federal employee conflict of interest laws," a position not altogether supportable by the language of the two statutes.31 Nonfederal employees do not have the benefit of an OGE advisory opinion absolving Bayh- Dole royalties from conflicts scrutiny. LIABILITY RISKS OF RESEARCH INST(TIJTIONS AND INVESTIGATORS Conflicts of interest do not merely give rise to ethical concerns, but also may lead to legal liability. This potential for JAMA. February 16, 1994-Vol 271. No. 7 Con(Iict of Interest in Research-Witt & Gostin 549

liability is derived from several sources. First, state tort law imposes liability on institutions for the misconduct of their employees. A research institution could be held liable for the negligence, misrepresentation, or fraud of its investigator/ employee. For example, if a researcher misrepresents the quality of an invention that is commercialized, and the com- pany reasonably relies on such misrepresentation, the uni- versity could be held financially responsible for damages that result from the delay in marketing the product and/or in wasted or misdirected investments. Second, research institutions have various obligations under state nonprofit corporation laws and federal tax laws, any breach of which could jeopardize the institution's nonprofit sta- tus orsubject the institution to enforcement actions by the state attorney general. Typically, these laws require the directors to operate the research institution in a manner consistent with its charitable purpose; forbid certain director conflicts, ie, inter- locking or interested director transactions; and require the di- rectors to preserve and prudently invest corporate assets. Research institutions are unlikely to run afoul of these laws by creating arm's-length licensing arrangement.s with disinter- ested companies, with little inducement to the researcher or in- stitution to promote a positive outcome for the research. The most suspect form of arrangement, however, occurs when a re- search institution forms a for-profit corporation, particularly when the institution retains equity, invests university endow- ment funds or technologies, maintains positions on the board of directors, and/or retains management responsibilities.-,x These arrangements require close scrutinybecause the success of the for-profit corporation depends directly on the decisions and actions of the investigator and the research institution. The requirement for the directors to preserve and pru- dently invest corporate assets prohibits speculative invest- ments. Biomedical start-up ventures using innovative uni- versity biotechnology can be highly risky. Placing a signifi- cant proportion of an endowment or other resources in such high-risk ventures can be unlawful. The need to preserve assets can also be construed to require research institutions to protect their inventions through patent- ing. Intellectual concepts and discoveries are valuable assets of the institution. Giving away these assets by licensing or other commercialization without adequate compensation can be a fail- ure of the directors' duty to safeguard institutional resources. Clearly, a careful and prudent balance that maintains the chari- table and research mission of the institution is required. THE NEED FOR UNIFORM, NATIONWIDE STANDARDS Eradicating all conflicts of interest is impossible. It prob- ably is inadvisable as well. Productive collaborative relation- ships among knowledgeable, well-funded investigators in com- mercial and nonprofit settings bring substantial benefits to both parties and enhance the public health. Certain rewards, entirely unrelated to industry relationships or private spon- sorship, are inherent in the system. "Positive research results per se may contribute to opportunities for publication, pro- motion, tenure, and grant renewals:'-"'N91' Still, it is the ex- panding connections between industry and academia that create the greatest concern. After a decade of increasing interaction and much discussion, there are still no compre- hensive federal regulations to assist universities in coping with conflicts. Yet, the PHS requires institutional guidelines to be in place, and Congress is pressing for stricter and more detailed regulations. Research institutions, therefore, must adopt guidelines that will address the concerns of Congress and the public and will be consistent with regulations pre- dictably due from the NIH. Institutions and individual researchers need uniform na- tional guidance on the extent to which they may reap the profits of their inventions, while still maintaining the public's confidence in the objectivity of science. National guidance can provide clear, advance warning of the conflicts to be identi- fied and avoided; scientists would be better able to stay within the bounds of fair guidelines; and companies and aca- demic institutions could increase the development of prod- ucts for market without fear of improper intertwining of interests. With NIH rules in place, universities could base their rules on federal law, and researchers would have a better sense of appropriate limits of financial interests in the nonprofit setting. Ideally, a greater sense of uniformity would emerge. Federal regulations should avoid overly restrictive rules that could stifle Congress' stated national policy of stimulating technology transfers, but they should sut clear limits on the most damaging forms of conflict. Disclosure of financial interests is the bedrock of any sen- sible scheme. University guidelines rely on early and full dis- closure to expose conflict situations and deter misconduct. To- tal disclosure of a researcher's personal financial records, however, serves little purpose and is overly burdensome. Dis- closure of any private financial interests that are clearly rel- evant to the researchers' work at the university is essential. Equity ownership and stock options in interested companies are the least acceptable forms of financial interest for research- ers. The 1989 guidelines banned these interests altogether, while some institutional guidelines prohibit such interests for clinical investigators. It may be that the NIH regulations will apply only to clinical researchers, allowing equity holdings by basic science researchers to the extent acceptable to the indi- vidual research center. Nonetheless, institutions and research- ers would do well to avoid equity interests in any companies that stand to profit from the researchers' results. Investigators who have material interests (including eq- uity, royalty incentives, and ongoing sponsored research ac- tivities) in a for-profit corporation licensing a product from their research institute warrant careful scrutiny. The trans- actions should be carefully and continually reviewed by the research institution as to the fairness of the licensing terms, the scientific objectivity of the research, and the commitment to academic science and to the research institution. To avoid serious conflicts of interest, researchers should refrain from serving on the board of directors of interested companies. The 1989 NIH guidelines prohibited researchers from re- ceiving fees for management services. Presumably, payments for services on a corporate board would have been prohibited as well. It remains to be seen how the proposed regulations will confront this issue, but institutions should police these conflicts regardless of the NIH's stance. Honoraria, consultant fees, and payments from companies for work performed require the least stringent regulation un- less the product involved is in the later stages of product de- velopment, such as in clinical trials. The 1989 NIH guidelines generally prohibited researchers from receiving honoraria or fees for services from companies with an interest in a re- searcher's invention. The NIH position, however, received little support from the scientific community. Most institu- 550 JAM.A, February 16, 1994-Vol 271, t.--. 7 Conflict of Interest in Research-Wtt & Gostir

-tional guidelines allow payments that simply pay a researcher for work performed on a company's beh-c If. The new NIH reg~-llations will probably relax the standards that appeared in their proposed guidelines. To the extent that the NIH does frdwn upon such payments, it may be an appropriate area for the institutions to use their power to waive insignificant con- flicts. To preserve the scientific integrity of the research in- stitution and to ensure the commitment of the researchers to their academic obligations and to their employers, full disclo- sure and ongoing monitoring of all fees should be required. Royalties paid through the institutions to researchers were addressed neither by the NIH nor through institutional guide- lines. The OGE concluded that Technology Transfer Act roy- alties were not a financial interest for purposes of federal conflict of interest laws. Consistent with this policy statement, the NIH rules cvill probably allow royalties provided under the Bayh- Dole Amendments. This position is disingenuous-royalty pay- ments create the same types of conflicts of interest as equity positions in, and other payments from, interested companies. It would be at least consistent to say that royalty pas rrlents from the institution should be subject to rules for ongoing in- stitutiona! management. However, once a drug enters clinical trials, an investigL.cor with an interest in the drug should ei- ther excuse himself or herself from the process, renounce that interest, or get an express waiver of the interest from the in- stitution. The investigator electing to continue involvement in the process should be allowed to receive payments from the institution andlor the company commensurate with the work actually performed. In this way, the payment structure would provide no incentive for a "successful" outcome of the trial. Once a conflict of interest has been identified, the institu- tion must manage it effectively in the best interests of the scientific community and the public. The AAMC offers a hierarchical list of possible courses of action: publicly dis- closing all relevant information; reformulating the research work plan; having an objective individual closely monitor the research project; requiring the researcher to divest himself or herself of all relevant personal interests; terminating or reducing the researcher's involvement in the relevant re- search project; or severing the outside relationships that pose conflicts.-`11P'1'1) The institution must treat conflicts seriously. This calls for the more severe restrictions on the hierarchical list for conflicts that jeopardize scientific objectivity, such as equity interests or any other financial arrangement where the researcher's enrichment is closely tied to "successful" outcomes in product development. Stricter measures also need to be taken the further along the• invention is in its stages of development. No relevant conflict can remain dur- ing the conduct of clinical trials because of the public trust placed in clinical investigators. Indeed, academic biomedical research institutions are en- trusted by the PHS and other granting institutions and foun- dations with a wide degree of latit,:de and flexibility in conduct- ing research and deriving financial benefit from the commer- cialization of such research. This trust carries with it a heavy moral burden to manage conflicts responsibly. While legislating such moral action is rarely effective, the NIH regulations could defensibly impose sanctions (including administrr.tive actions, legal penalties, and ultimately disbarment) on the offend:ng in- stitution(s) and scientist(s) for demonstrated failure to ensure objective conduct in and reporting of research. The public must have con idence that all conflicts ',vill be disclosed, the most serious conflicts Will be avoided, and sci- entific research -will remain rigorous and free from the ap- pearance of and actual improper influence. This public con- fidence will continue to make it possible for institutions and their investigators to receive reasonable incentives so that technology transfer can flourish. When the proposed NIH rules are published in the Federal Register, they should be measured against the need for uniform and meaningful na- tional standards essential to maintaining public co_nfidence in and the integrity of scientific research. This article was developed as part of the authors' course at the Harvard School of Public Health entitled "Commerciatiring Biomedical Technologies." We thank Anthony M. Allen, JD, for his research a_~~istance. We also thank Michael J. Astrue, JD, John H. Barton, JD, Alan H. Einhorn, JD, and George A. 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