Conflicts of interest in translational research

Journal of Translational MedicineBioMed CentralCommentaryConflicts of interest in translational researchMalcolm R Parks* 1 and Mary L Disis 2Open AccessAddress: 1 Office of Research, University of Washington, Seattle, WA, USA and 2 Tumor Vaccine Group, University of Washington, Seattle, WA, USAEmail: Malcolm R Parks* - macp@u.washington.edu; Mary L Disis - ndisis@u.washington.edu* Corresponding authorPublished: 09 August 2004Journal of Translational Medicine 2004, 2:28 doi:10.1186/1479-5876-2-28Received: 27 July 2004Accepted: 09 August 2004This article is available from: http://www.translational-medicine.com/content/2/1/28© 2004 Parks and Disis; licensee BioMed Central Ltd.This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.AbstractTranslational research requires a team approach to scientific inquiry and product development.Translational research teams consist of basic and clinical scientists who can be members of bothacademic and industrial communities. The conception, pre-clinical testing, and clinical evaluation ofa diagnostic or therapeutic approach demands an intense interaction between investigators withdiverse backgrounds. As the barriers between industry and academia are removed, issues ofpotential conflict of interest become more complex. Translational researchers must become awareof the situations which constitute conflict of interest and understand how such conflicts can impacttheir research programs. Finally, the translational research community must participate in thedialogue ongoing in the public and private sectors and help shape the rules that will govern conflictsthat arise during the evolution of their research programs.IntroductionBy its nature, translational research crosses boundariesbetween basic science and clinical application. It placesresearchers in new contexts and ushers in a range of newcontacts and relationships. Crossing these boundariescontributes directly to the creativity and social impact oftranslational medicine. But crossing these boundaries alsogives rise to new and often conflicting obligationsbetween researchers, their employers, and their industrysponsors. The public is rightfully concerned that thefinancial interests of researchers, their institutions, andtheir corporate sponsors may bias research. Yet historyalso teaches us that industry collaboration is often essentialin realizing the promise of translational research.Industry collaboration has figured prominently in manytranslational research successes including recombinantgrowth hormone, angioplasty, stenting for coronary arterydisease, and many new medications and diagnosticdevices [1].Translational researchers must, therefore, understandwhat financial conflicts of interest are and how they aremanaged. Their industry partners must understand theconstraints placed on researchers by federal and universitypolicies as well as state laws. Relevant policies in theUnited States include the regulations issued by the PublicHealth Service and published as part of the Code of FederalRegulations (42 CFR 50.601–50.607) and in theNational Science Foundation Grant Policy Guide (Section510) [2,3]. Laws governing the use of state-ownedresources may also be relevant for those working at orwith public universities.What triggers financial conflicts of interest?Conflicts may arise whenever researchers' outside, personalfinancial interests have the potential to compromisean investigator's professional judgment and independencein the design, conduct, or publication of research.The most commonly regulated financial interests includeconsulting fees or compensation for personal services,Page 1 of 4(page number not for citation purposes)

Journal of Translational Medicine 2004, 2:28http://www.translational-medicine.com/content/2/1/28equity or other ownership interests, royalties, and intellectualproperty rights. A researcher may, for example, receiveconsulting income or equity in exchange for service on ascientific advisory board of a company that then sponsorsclinical research in her lab. Another researcher may bepaid for talks to physician groups about an approvedmedication while simultaneously conducting research onpotential off-label uses of the drug. The investigator or animmediate family member may hold stock in the researchsponsor. These examples are all common cases and mostinstitutions have relatively standardized ways of managingsuch common conflicts.Greater challenges are created when the financial relationshipsbetween commercial interests and investigators areeither ambiguous or complex. Ambiguity can result in anumber of ways, but one of the most frequent occurswhen investigators approach consulting as an extension ofdiscussions among academic colleagues. Thinking thattalking to a corporate representative is the same as talkingto an academic colleague, for example, may lead theinvestigator to make inappropriate disclosures that compromiseintellectual property rights or contractual obligations.Often it is not any one financial interest, but ratherthe combination of multiple financial interests that makesa situation unmanageable. It is extraordinarily difficult,for example, to manage situations in which an investigatoris the founder of a startup company, an inventor on apatent licensed to the company, a consultant to the company,and the recipient of other government and industrygrants for closely related research.How institutions manage potential conflicts offinancial interestSpurred by a combination of bad experiences and newregulations, most research institutions now have policiesin place for the management of some aspects of personalfinancial interests in research. One strategy is simply toprohibit personal financial interests in research. The Associationof American Universities, for example, advocatesoutright prohibition in cases involving research onhuman subjects unless there are "compelling circumstances"that justify an exception [4]. Prohibition forcesfinancially interested researchers to either divest theirinterests or to remove themselves from the research.Although effective, prohibitions are blunt tools and in ouropinion should be used only as a last resort. We say thisnot only because prohibiting financial interests may leaveany number of other equally biasing interests in place [5],but also because, when properly managed, financial interestsmay play a positive role in the development of a translationalresearch program. Access to company resourcesand sharing investigator knowledge are often critical totimely translations of basic science to clinical practice. Thecomplex research enterprise needed to develop clinicalproducts is simply beyond the scope of what many investigatorscan achieve on their own in academic institutions.Fortunately, there are usually less draconian alternativesto outright prohibition. These strategies seek to ensure theintegrity of the research, guarantee public scrutiny andaccess, and, of course, to protect human participants [6].One of most common is to assign key research activitiessuch as recruiting, consenting, and data analysis to teammembers who have no financial stake in the results.Multi-center designs ensure that the biases of any oneinvestigator are less likely to influence the final results.Independent data safety monitoring boards or other oversightcommittees may also check the influence of personalfinancial interests. So, too, will requirements to disclosefinancial interests to publishers, conference organizers,and institutional review boards.Research integrity is further protected by a vigilant stanceregarding publication restrictions. Industry partners havea legitimate interest in protecting proprietary information,but this can usually be honored by providing a shortperiod for review prior to submitting a manuscript forpublication. No contract or agreement, however, shouldgive the sponsor the right to control publication. Workthat requires such control is more appropriately done inindustry rather than in academic laboratories. The closeattention to publication restrictions is particularly importantwhen a researcher may have a student working on anindustry sponsored project. Junior and student scientistsworking in a research program, who may not have anyrelationship with a company, must be able to have freedomin pursuing aspects of projects outside the bounds ofthe research agreement and publishing data in a timelyfashion.Translational research that results in the development of anew company presents particular opportunities and challenges.Because of the importance of small companies toeconomic growth, public research universities often viewthe number of university-related startups as an index oftheir contribution to the state economy. More specificinstitutional interests are created when universities takeequity in startups through licensing agreements. Unlikemore established firms, start-up companies are oftenhighly dependent on obtaining favorable research outcomesfrom a particular project. In many cases, prohibitionmay be the only way to manage the tangle ofinstitutional and individual interests than can result inthis situation. Universities may create "firewalls" betweenthe management of equity and researchers [7]. They mayrequire divestiture or bar researchers from receiving grantsback from companies to which their inventions have beenlicensed. Consulting and other company contacts may bePage 2 of 4(page number not for citation purposes)

Journal of Translational Medicine 2004, 2:28http://www.translational-medicine.com/content/2/1/28restricted when the investigator or the university has a significantfinancial interest in the startup. Although universitiesare still coming to grips with their own institutionalfinancial interests, there is an emerging consensus thatthey should not conduct clinical research on their owninventions unless a strong case for locating the research atthe university can be made on clinical grounds [8,9]. Fornovel biologic therapies, the investigator who inventedthe approach may be ideally suited to complete the clinicaltranslation. The failure of many novel agents to demonstrateactivity in Phase I may be linked to a disconnectbetween the scientist developing the agent and the physicianrunning the clinical trial. Translational research isdefined as that person being one and the same.Recently, the American Association of Medical Collegespublished suggested guidelines for the management ofconflict of interest based on input from a number of medicalschools [10]. Such documents not only encouragedialogue concerning these issues, but also provide someguidance for individual institutions establishing theirinternal policies.How financial conflicts of interest can affect yourresearch programUnrecognized and unmanaged conflicts of financial interestrepresent major risk factors for programs of translationalresearch. Even when properly disclosed andmanaged, however, outside financial interests may limityour research activities in a variety of ways, ranging frommild to severe. If nothing else, time and staff resourcesmust be allocated to institutional and extra-institutionalreview processes. Because approval is required beforefunding is released or human subjects are enrolled, thepace of research is slowed by outside financial interests.Scientists with personal financial interests in the researchwill usually find themselves barred from participating insensitive research activities, especially those involvingdirect contact with human subjects. This increases thecosts of research as additional staff or consultants arehired to do the work that the financially interested partywould have otherwise performed. But even this strategymay prove difficult if key staff or alternative expert consultantsalso have financial interests. There is a tippingpoint beyond which so many potential team members arefinancially involved that the interests simply can not bemanaged and outright prohibition becomes the onlyoption.In the most extreme circumstances it is possible forresearchers to research themselves out of a job. Their personalfinancial interests in a research sponsor may be sogreat or so complex that their employers are unable toaccept further funding from that sponsor. A line of translationalresearch may simply end for a researcher when heor she is barred from carrying the work into the clinicalarena as a result of individual or institutional financialinterests. This can occur even when the researcher is notactively seeking financial gain. Early basic science work,for example, may lead to an invention that the universitydecides to patent and license. In most universities theresearcher is entitled to a share of whatever revenue is produced.The researcher now has a personal financial interestthat requires management and may disqualify her orhim from participation in later clinical work designed totranslate the basic science into practice. This is an extremecase, of course, but it does happen and it illustrates theoften unseen and unintended implications of how financialinterests are usually managed.Dealing intelligently with financial interests inresearchPublic concern about personal and institutional interestsin research is not going to go away. Nor is the need forindustry collaboration in translational research. Indeedthe need for collaborations between industry andacademia is only going to grow as we move beyond asequential "bench to bedside" model to acknowledge thebenefits of combining clinical and basic biological studies[11]. If financial interests can not be avoided, we can atleast be more thoughtful about how we manage them-asindividual researchers, as industry collaborators, and asacademic research institutions.Individual investigators should recognize that disclosureof personal financial interests, while perhaps uncomfortable,is vital to continued public confidence in science.They must also balance their wish for personal gainagainst the additional oversight and management of theiractivities that will inevitably result. They should recognizethat some financial interests are more easily managedthan others. Consulting income paid as cash, for example,is much more easily managed than consulting incomepaid with equity in the company. The latter creates a longtermfinancial interest and may imply management influence.The understandable desire to "share the wealth"with team members by assisting them in obtaining outsidefinancial interests of their own backfires when it thenbecomes necessary to remove them from the tasks thatthey were hired to do in the first place.The decision to create a company in order to further atranslational research agenda is appealing, often appropriate,but always more complex than researchers typicallyappreciate. It is a risky conceit to believe that one's successin obtaining research grants and managing a researchteam is adequate preparation to launch a business. This isborne out by the fact that technologies licensed to companiesfounded by faculty inventors are generally less suc-Page 3 of 4(page number not for citation purposes)

Journal of Translational Medicine 2004, 2:28http://www.translational-medicine.com/content/2/1/28cessful than those licensed to companies with nonacademicfounders [12]. Even when the researcher has therequisite business experience, however, company formationmay result in profound conflicts of commitment,inappropriate use of university resources in support of thecompany, and confusion over intellectual property. Thesedifficulties combine to increase costs and slow, if notblock, progress on translational research efforts.In spite of a growing entrepreneurial spirit withinacademia, the culture gap between industry and academiaremains large. Industries seeking to partner with academicresearchers must understand that universities are not simplylaboratories for hire. They should not assume that theywill own or control publication of the research they support.Universities are not set up to guarantee the samelevel of security and secrecy than can be obtained inindustry laboratories. The open character of universities isin fact an asset- it is the foundation on which the creativeengine rests. Finally it is useful to appreciate that "indirectcosts" are real costs for universities. Indeed, even at thefull rate, universities subsidize research contracts [13].Efforts to avoid indirect costs, like efforts to negotiate contractsthat contain publication restrictions and overreachingintellectual property clauses, ultimately have the effectof disrupting working relationships and slowing the paceof research. By the same token, industry collaboratorsshould recognize that efforts to "build relationships" withacademic researchers and their staff by providing extrafinancial incentives and benefits are often counterproductive,not only because they fail to buy loyalty, but alsobecause they create unacceptable financial conflicts ofinterest for academic personnel.Universities, too, have much to learn about managingfinancial interests and collaborating creatively with theirindustry partners. Although a consensus regarding institutionalconflicts of interest is emerging, universities stillhave much to do in terms of implementation, particularlywith regard to credible external review of clinical researchopportunities in which the institution holds a financialinterest. Managing or avoiding institutional conflicts ofinterest will also require a more realistic view of technologytransfer opportunities. Although "big hits" do occur,they occur only rarely and revenue from technology transferoperations is typically only a tiny fraction of revenuefrom sponsored research. Universities run the risk of disruptingtheir larger research mission by overly aggressiveefforts to capture and commercialize intellectual property.Open publication and teaching should always be the mostsignificant "knowledge transfer" functions of a researchuniversity.The increasing complexity of translational research alsochallenges universities to devise new kinds of collaborationwith industry. Mankoff and her colleagues, for example,recently proposed the creation of centers that obtainrevenue from existing therapies, while simultaneouslyproviding material for biological studies and supportingexperimental therapies [11]. Before these more complexcollaborations can occur, however, there is much work tobe done to simplify material transfer practices betweenlaboratories and to create more straightforward ways forfacilities and personnel to be shared.Individual researchers, industries, and universities havemuch to learn about the management of financial interests.Given the potential for financial interests to disruptor even end programs of translational research, we believethat all parties would benefit from greater attention andgreater creativity in the management of conflicts of interest.A dialogue must be established between the individualinvestigator, industry, academic institutions, and thepublic to define the issues and develop rational solutions.Such a dialogue could be initiated by the development ofa focus on such topics at national meetings, by individualorganizations whose membership is involved in translationalresearch developing interdisciplinary panels to discussthe issues and attempt to develop guidelines, and byan integration of conflict of interest topics in the trainingof junior scientists. Solutions should enhance, notimpede, translational research.References1. Martin JB, Kasper DL: In whose best interest? Breaching theacademic-industrial wall. New England Journal of Medicine 2000,343:1646-1649.2. Foundation National Science: Grant Policy Manual. 2002.3. Public health policies of general applicability. Code of FederalRegulations 2000, Title 42: Part 50.601-50.607:.4. Universities Association of American: Report on Individual andInstitutional Financial Conflict of Interest. Washington (DC);2001.5. Brown WA: Financial gain: Just one of many motives. The Scientist2001, 15:39.6. Koski Greg: To protect those who serve. New England Journal ofMedicine 2000, 343:1643-1645.7. Johns Michael M.E., Barnes M, Florencio PS: Restoring balance toindustry-academia relationships in an era of institutionalfinancial conflicts of interest. Journal of the American MedicationAssociation 2003, 298:741-746.8. Emanuel EJ, Steiner D: Institutional conflict of interest. New EnglandJournal of Medicine 1995, 332:262-267.9. Research Task Force on Financial Conflicts of Interest in Clinical:Protecting subjects, preserving trust, promoting progress II:Principles and recommendations for oversight of an institution'sfinancial interests in human subjects research. Washington,DC, Association of American Medical Colleges; 2002.10. Mankoff SP, Brander C, Ferrone S, Marincola FM: Lost in translation:Obstacles to translational medicine. Journal of TranslationalMedicine 2004, 2:2-14.11. Shane Scott: Selling university technology: Patterns fromMIT. Management Science 2002, 48:122-137.12. Goldman CA, Williams T, Adamson DM, Rosenblatt K: Paying foruniversity research facilities and administration. .Page 4 of 4(page number not for citation purposes)