potential problems with industry-supported clinical research

Device manufacturers and pharmaceutical com-panies are a significant source of research funding forclinicians in all specialties. Industry-clinician rela-tionships may provide important professional andfinancial opportunities, but they may also jeopardizenot only the investigators’ scientific integrity, butalso their primary responsibility to patient rights andsafety.

In this editorial, we review some important issuesraised by industry-supported clinical research,including the control by industry of the clinical trialand the data; discuss problems that may arise in therelationship between clinicians and industry; illus-trate some of the dilemmas with some recent exam-ples; and make suggestions that may avert potentialproblems. Our suggestions appear in italic type.

Most young clinicians consider themselves fortu-nate when they obtain funding from industry tocarry out research to support their academic devel-opment. They recognize that such corporate-fundedclinical research is generally less demanding thanpeer-reviewed funding because the company usuallysupplies the research protocols, prototype institu-

tional review board (IRB) applications, and patientconsent forms. Funding allows the investigator tohire research associates to collect and report thepatient data. In many multicenter trials, the compa-ny analyzes the data centrally. Despite these andother advantages from industry-supported research,there are also some risks, and not all are obvious tothe potential investigator—particularly, the controlof scientific data by the industry sponsor.

In a research study, both the investigator and thecompany share the objective that the new technolo-gy (typically a device or drug) will significantlyimprove our ability to diagnose disease or treatpatients. Both hope and expect that the joint ven-ture will reflect well on themselves and their institu-tions. However, the company and the investigatorhave additional, but differing, objectives in the sameresearch project, and these may come into conflict.

In funding the research, the company also has theunderlying objective to maintain or increase profit forshareholders and employees. In return for theirinvestment in a research project, the company can rea-sonably expect protection of its commercially valuableintellectual property, and, not unsurprisingly, contrac-tual agreements will reflect this. Because profit will, inpart, depend on a short time-to-market, the companywill be eager to obtain regulatory approval and pub-lish positive results as quickly as possible. The investi-gator may be concerned that steps in the usual scien-tific process are being circumvented.

Physicians have a primary duty to ensure ethicalpatient care and patient safety.1 While performingresearch, their primary goal should be the acquisi-tion of knowledge for the general good of patients.In pursuing these particular goals, the researcher musthave ready access to the data, verify the results andtheir analysis, and report those results in a timely andaccurate fashion. The company also has responsibili-ties in regard to patient safety, but in the analysis andreporting of results, a conflict with the company’sfinancial, marketing, and proprietary interests mayarise.

Potential problems with industry-supportedclinical researchRobert B. Rutherford and K. Wayne Johnston, Silverthorne, Colo, and Toronto,Ontario

From the University of Colorado School of Medicine andToronto General Hospital and the University of Toronto.

Competition of interest: currently none. Recent past: co-chair ofa transatlantic intersocietal consensus on peripheral arterialocclusive disease (TASC) supported by an unrestricted educa-tional grant from Schering AG, Berlin, Co-principal investiga-tor of a completed trial of oral Iloprost in chronic critical limbischemia, supported by Berlex, consultant on the design of clin-ical trials of the evaluation of thrombolytic agents (Abbott,Amigen); PI and member of the Scientific Advisory Board ofEVT during the phase I trials (R.B.R.).

Competition of interest: nil (K.W.J.).Reprint requests: Dr K. Wayne Johnston, Editorial Office,

Toronto General Hospital, 5 Eaton Room 312, 200 ElizabethSt, Toronto, Ontario, M5G 2C4, Canada.

J Vasc Surg 2000;31:1066-76.Copyright © 2000 by The Society for Vascular Surgery and

International Society for Cardiovascular Surgery, NorthAmerican Chapter.

0741-5214/2000/$12.00 + 0 24/39/106031doi:10.1067/mva.2000.106031

EDITORIAL

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JOURNAL OF VASCULAR SURGERYVolume 31, Number 5 Rutherford and Johnston 1067

Although a research agreement between a com-pany and an individual investigator may appearstraightforward, it is nevertheless part of a complexinteraction that also involves patients, IRBs, coinves-tigators, the university, the clinical division/depart-ment chiefs, the hospital administration, the scientif-ic community, and the regulatory body to which thecompany is responsible (Figure). With submission ofthe results of a trial for publication, this interactionalso involves scientific journals, their editors andreviewers, and finally, the readers.

Consideration of patient rights and safety isdominant. Approval of the contract between a com-pany and an individual investigator requires adher-ence to the policies of the hospital and universityand their approval of the content of the contract.The institution will want assurance that the investi-gator does not enter into a contract that raises a sig-nificant conflict of interest or conflict of commit-ment with the investigator’s hospital or universityactivities. The IRB must approve the ethics of thestudy and monitor it. During the study, the investi-gator should reassure the IRB, the clinicaldivision/department chief, and the hospital adminis-tration and university of the continued safety of thestudy. This requires reassurance by an independent

data-monitoring committee that the results supportthe continuation of the study. However, problemsmay arise if the data-monitoring committee is inap-propriately constituted and ineffective or if thecompany analyzes the data and determines what isreleased to the investigators.

POTENTIAL PROBLEMSThe following discussion presents some of the

problems that may arise in corporate-sponsored clin-ical investigations. It is organized in order of thechronology of events that occur during the course ofa study, not in order of perceived importance.

Financial conflict of interestAfter publication of the first study of the efficacy

of tissue-type plasminogen activator, it was reportedthat several of the investigators owned stock in thesponsoring company.2 Concerning this, the follow-ing is recommended by the American MedicalAssociation: “in order to avoid criticism that thedecisions an investigator makes during the studymight have been biased by financial conflict of inter-est and the concern that the validity of the scientificdata may have been jeopardized, the investigatorshould not hold stock or stock options in the spon-

Complex interactions in relationship between industry and an investigator.

soring company or be an officer of the company.”3

Investments in mutual funds that are managed byothers may be overlooked, but all known holdings inthe company, including those by close family mem-bers or practice partners, should be declared to alertthe readers of potential competition of interest.

Although the above recommendation warnsagainst stockholding by the investigator, a companymay offer stock after completion of the research, inrecognition of contributions to the development ortesting of a device or drug. This is not wrong, aslong as it is not by prior tacit agreement, but failureto disclose this when research is presented or pub-lished is inappropriate and has led to increasing pub-lic criticism, as exemplified by the recent media cov-erage of the Heart Port device and coronarystents.4,5

Nondisclosure agreementsNondisclosure agreements protect the company

against the investigators divulging proprietary infor-mation and thereby devaluing the product.Investigators appreciate the need of the company toprotect proprietary information, but they may notfully comprehend the legal verbiage or the legalimplications in the nondisclosure agreements thatthey are asked to sign. Such agreements are usuallydrawn up by the company’s lawyers to protect theirclient’s proprietary interests, and only occasionallyare the investigators’ rights addressed as well. Inaddition, the agreement may not give the consultantor the investigator appropriate credit or reward forinnovative ideas or constructive advice, which mayhave significantly improved the ultimate design of adevice or determined the success of a trial.

The research contractThe contract to perform a research study in col-

laboration with industry may be complex. Fewinvestigators ask a lawyer to review the contract thecompany asks them to sign. They do not want toappear to be looking a gift horse in the mouth; how-ever, knowing that it may be a one-sided agreement,one should read over all contracts and pay particularattention to certain details (eg, be sure that the inves-tigator has access to the data and that the right to pub-lish important aspects [with co-investigators] is notinappropriately restricted by the agreement). Clausesin the contract dealing with publication rights, confi-dentiality, intellectual property, access to data, andconflict resolution, in particular, should be carefullyreviewed by the institution as well as by the investiga-tor, to ensure patient safety through prompt access to

data and to guard the scientific freedom of the inves-tigator.

The Olivieri case at the Hospital for SickChildren in Toronto illustrates the complexity of thisproblem. The following paragraph was included inthe contract of a drug study6:

Contract provides that all information whether writtenor not, obtained or generated by you during the term ofthe LA-02 Contract and for a period of three years here-after, shall be and remain secret and confidential and shallnot be disclosed in any manner to any third party exceptwith the prior written consent of Apotex. Please be awarethat Apotex will take all possible steps to ensure that theseobligations of confidentiality are met and will vigorouslypursue all legal remedies in the event that there is anybreach of these obligations.

—Excerpt from a letter dated May 24, 1996, from DrMichael Spino, vice president of Scientific Affairs, ApotexResearch Inc, to Dr Nancy Olivieri.

During the study of the drug deferiprone for thetreatment of iron overload in patients with thal-assemia major, Dr Olivieri became concerned thatthe drug lost effectiveness with long-term use andsuspected that it might worsen hepatic fibrosis.When these safety concerns were reported to thehospital’s research ethics board, she was instructedto change the wording of the informed consent.When informed of the change, Apotex terminatedthe drug trial in Toronto. When it was determinedthat the data of others reflected similar observations,Dr Olivieri and her colleagues, in the face of threat-ened legal action from Apotex, published the con-troversial findings in the New England Journal ofMedicine.7 Although not a vascular example, thisstudy is cited because it raised important issues with-in the scientific community related to contracts withcompanies that are signed by an individualresearcher, and the researcher’s hospital researchinstitute, hospital administration, hospital institutionreview boards, and university. It also illustrates theimportance of institutional policies and proceduresthat define the responsibilities for scrutinizing a contract.

Ideally, individual researchers should seek expertadvice before making a commitment that may beinappropriate. It would be of great help if societies col-laborated to obtain legal advice in drawing up a gener-ic confidentiality document and contract. In doing so,it would be valuable to identify the items that should beincluded in research contracts—items that would beviewed as fair and standard practice and would protect

JOURNAL OF VASCULAR SURGERY1068 Rutherford and Johnston May 2000

the rights of scientific investigators, patients, and insti-tutions, as well as the sponsoring company. In particu-lar, it is important to define the right to have access todata and present and publish the data in a timely fash-ion, regardless of the results of the study.

An exemplary relationship between industry andinvestigators is illustrated in a recent publication onthe economic analysis of low-dose heparin versus thelow-molecular-weight heparin enoxaparin.8 Underthe heading of “funding” the following statementwas made:

Unrestricted funding for this analysis was provided inpart by Rhone-Poulenc-Rorer (Quebec, Quebec), themanufacturer of enoxaparin. The terms of the contractwith the company were determined at the outset after weproposed the study design and methods, including mea-surement, modeling, and analytical strategies. We retainedthe rights to control entirely the methods and conclusionsthroughout the study and to publish or otherwise dissem-inate the results of the study and their conclusions regard-less of outcome. The company received a copy of thereport and manuscript before publication but was specifi-cally precluded from influencing us at any stage after thecontract was signed.

As will be seen below, the ability of investigatorsto make statements such as this, according to theirresearch contract, is far too uncommon.

Addressing these issues at the outset and havingthem addressed in the contract in a manner that isfair to both the company and the investigator canavert significant problems later.

Development of research protocols In carrying out a clinical trial, the investigator

has the ethical responsibility to ensure that thedesign and execution of the study protect thepatient’s rights. The investigator has a responsibilityas a scientist to see that it is properly designed so asto produce meaningful data to answer the questionposed by the trial. Having a research protocolalready drawn up by the sponsoring company is con-venient and can serve as a useful starting place fordiscussions between the sponsor and the potentialcollaborating investigators; however, investigatorsshould not simply accept the drafted protocol. Theyshould take an active role in improving the design ofthe trial.

Conflicts may arise if the investigator recom-mends changes in the company’s original protocol(eg, because it lacks objective enough end points,has too favorable exclusion and inclusion criteria,lacks appropriate controls or uses comparison with

historical controls, does not account for treatmentcrossovers or does not analyze their impact on out-come judged solely on an intent to treat basis, hastoo short a follow up, or fails to include a cost analy-sis and quality-of-life assessment). The investigatorshould oppose any aspects of the trial that mighthinder determination of conclusive and meaningfulresults, or might produce results that can be gener-alized or will be accepted by one’s peers.

Conflict may also arise because the company’sunderlying goal may only be to prove “safety andefficacy” in the broadest terms and take the quickestroute to gaining regulatory approval, rather than tocompare the treatment with current competitiveapproaches. Depending on whether their back-ground is primarily in marketing or in research anddevelopment, those responsible for the company’ssponsorship of a clinical trial may be more comfort-able with simply achieving recognition of safety andefficacy than with attempting a comparison with analternative treatment. Once approved by the regula-tory agencies, marketing strategies rather than riskingscientific comparisons may be used to pursue advan-tages over competitive treatments. The investigatorshould take the responsibility to help ensure proper strat-ification, comparable study groups, accurate power esti-mates, definitions of what constitutes a reportable com-plication, and gathering and analyzing the data in aformat that is compatible with standardized reportingpractices. Even though some companies hire experi-enced trialists as consultants, investigators involved inthe study are more likely to have detailed knowledgeof the key clinical issues involved.

Comparative groups: inclusion and exclusioncriteria. The outcome of a trial and its generalizabil-ity are greatly influenced by the inclusion and exclu-sion criteria. In the early studies of endograftsdesigned for abdominal aortic aneurysm (AAA)repair, inclusion of only cases with favorable anatomyis a cautious approach and furthers one of the com-pany’s goals of demonstrating safety and successfuldeployment, but the results cannot be generalized tomost patient with an AAA. Liberal inclusion criteriacan have the same effect; examples include trials oflaser and atherectomy devices, and stent studies thatincluded patients with lesions that would have yield-ed good results with PTA alone, and trials of endo-grafts for occlusive lesions for which good resultshave been established for PTA and stenting. Afterinitial studies that demonstrate safety, each newadvance in technology (and cost) should be tried on themarginal lesions that the simpler technology cannot sat-isfactorily address.


Blinding and randomization. Blinding andrandomization in prospective trials are obviouslydesirable but not always possible. Blinding is not fea-sible when the compared treatments are perceptiblydifferent; unfortunately, this opens the door notonly to investigator bias, but also to patient bias. Insome of the AAA endograft trials, patients random-ized to surgery backed out and went to another par-ticipating institution for another roll of the dice.Randomization may also present a problem if theindividual investigator concludes that one treatmentis clearly preferable. This raises the question, shouldthat individual participate in the trial or continueentering patients? Freedman9 addressed this ethicalchallenge in clinical research by suggesting that clin-ical equipoise (ie, uncertainty) exists if the informedprofessional group (not an individual) has notreached a consensus and that it is ethical for the indi-vidual to enter patients into a trial that will give adefinite answer to the question at hand. Recentdebates over clinical trials on carotid angioplastyhave repeatedly raised the issue of clinicalequipoise.10,11

It is important that the mechanism for random-ization be predefined and independent of investiga-tor and sponsor input. Further, validation of the suit-ability of the patient for inclusion in the trial must beefficient, and not too complex or time-consuming, sothat the process does not interfere with recruiting abroad spectrum of cases. In trials of thrombolyticagents for acute arterial occlusion, those with acutelimb-threatening ischemia were grossly underrepre-sented, in part because of the complexity of the studydesign and the time consumed by the randomizationprocess.12 Another contributor to this was a naturalselection bias in the group with acute ischemiabecause the treating physician could exclude a patientfrom randomization if the physician thought thatpatient safety was at risk.

End points. The choice of end points of a trialis critical. What end point constitutes evidence ofefficacy of treatment? Under what conditions willthe trial be stopped? Some end points are desirablebut unrealistic. In pharmacotherapy trials for criticallimb ischemia, the Food and Drug Administration(FDA) has insisted that the primary end pointsinclude salvaging limbs and saving lives rather thanusing the useful and potentially achievable clinicalgoals of relieving rest pain and healing ischemiculcers. This may have resulted in falsely negativestudies. Similarly, in the case of the thrombolytic tri-als, restoring graft or artery patency for a reasonableperiod would be a more realistic end point, consid-

ering that the treatment of the underlying lesions,not the method of clot removal, determines long-term outcome. This too has contributed to negativeresults of trials.

Combining end points may add strength to thestatistical analysis, decrease the number of casesrequired, and save costs, but this approach mayreduce the generalizability. In the STILE trial,12

four clinical end points were combined into oneclinical outcome, resulting in the premature stop-ping of the trial when two less important end points,major morbidity and ongoing ischemia, created astatistically significant difference in combined clini-cal outcome in favor of surgery, at a time when themore important end points of mortality and ampu-tation were not significantly different. Again, theresult was a negative trial for the tested therapy.

The appropriate selection of objective end pointsis essential but does not solve the problem of a trialthat does not have a proper comparative controlgroup. This is particularly true of treatments forsevere limb ischemia, because patients may improvespontaneously with time rather than as the result oftreatment (eg, sympathectomy, use of hyperbaricoxygen, spinal cord stimulation, and, up until now,VEGF).

Cost considerationsIt is reasonable for a sponsoring company to aim

to obtain scientifically valid data to support regula-tory approval and the introduction of their productinto the medical market place and to expect thestudy to be carried out in a time-efficient mannerand at reasonable cost. The investigator and the hostinstitution can reasonably expect fair compensationfor their participation. Attempts to limit the expen-diture on a clinical study may compromise the qual-ity of the data. In discussions with company represen-tatives over the design of a research trial protocol, oneshould be wary if the company is unwilling to modifythe protocol (eg, the number of patients recruited or theduration of follow-up) because of cost considerations.This is a warning sign that you may be dealing witha company whose resources are too limited to sup-port a proper study or one that places its financialinterests above scientific investigation.

In being reimbursed for running a clinical trial,the investigator faces a potential conflict of inter-est—specifically, the conflict between (1) ensuringthat the individual patient’s rights to receive themost appropriate medical care are guaranteed and(2) the investigator’s self-interest in obtaining reim-bursement for entering patients into the study and


other benefits that might accrue to the investigatorfrom participating in the study.13 Clinicians shouldexpect to be reimbursed fairly for their time spentmanaging the patients and the project, the salaries ofstudy coordinators and fellows, and the overheadand miscellaneous expenses. The American MedicalAssociation recommends that remuneration of theinvestigator should be commensurate with theefforts and that funds should be administered by theinstitution that pays the direct and indirect costs.However, it seems reasonable that unforeseen “prof-it” could be used to assist funding other research oreducational programs or trainees. Most institutionshave mechanisms to prevent faculty from personallyreceiving the excess money generated from aresearch study; however, policies on the use of theprofit for academic purposes are often vague. TheIRB should be informed of funding agreements, and itshould be disclosed whether the investigator has anyother relationship with the sponsoring company, such asstockholder, corporate officer, or paid consultant.However, disclosure alone is not a remedy; IRBsneed to develop recommendations for understand-ing and managing the conflict so that patients’ rightsare protected.

Institutional Review Board approvalThe IRB must ensure that the study design is sci-

entifically valid; approve the ethics of the study toensure that patients are properly enlisted, receiveappropriate informed consent, have a low risk-bene-fit ratio if enrolled in the study, and are not subject-ed to unnecessary procedures; and be sure that thefinancial arrangements are appropriate. In addition,the IRB should be in a position to monitor the studyas it progresses. To safeguard patient care, the inves-tigator must have reports from the data-monitoringcommittee to be able to communicate the results of thesafety of continuing the study to the IRB on a regularbasis. To fulfill its obligations, the IRB must be inde-pendent of the sponsor, investigator, and institution.

Data collection, analysis, and control of data:data monitoring committee

If the company controls the data and does notprovide frequent reports, including complications,the investigators may not be able to fulfill their eth-ical and moral obligation to the patients and theirresponsibilities to the IRB and institutions. Interimevaluation of the data is important to detect unex-pected complication, low accrual rates, protocol vio-lations, incomplete follow-up, and other problemsto ensure safety (because analysis of a clinical trial is

a dynamic process). An appropriately constituteddata-monitoring committee is the optimum method toprotect the patients’ interests by disclosing unexpectedcomplications, ensuring that there are no seriousmethodologic deficiencies that would prevent the studyfrom meeting the scientific objectives, and determin-ing whether the end point of the study, be it positive ornegative, has been reached. Explicit “stopping rules”should be defined. The committee should includeexperienced investigators, statisticians, and companyrepresentatives. Expert statistical advice is necessarybecause false conclusions may be drawn from anapparent statistically significant difference early in thestudy, when the number of patients entered is low.

On occasion, “leaks” of results have changed theinvestigators’ pattern of recruiting or excluding sub-jects for a trial and consequently affected the finaloutcome. For this problem to be prevented until thestudy is complete or stopped, the end point resultsmust be available to the data-monitoring committeebut not to the individual investigators.

Data analysis. Unfortunately, it has becomeincreasingly apparent that some presenters and pri-mary authors of manuscripts at our national andregional meetings have reviewed only the summa-rized analysis of the data that was supplied by thecompany. They have not reviewed the raw data orperformed or checked the statistical analyses andcannot supply the additional information requestedby discussants or reviewers.

For proprietary reasons, device manufacturersand pharmaceutical companies rarely release theresults of their own “in-house” research; there is alsoa perception that they may be selective about thedata from clinical studies that they choose to releaseto their clinical investigators to make public.Although the company and its consultants are notlikely to try to hide unfavorable data, by not releas-ing all the data to the investigators for analysis, thereis the risk that significant relationships in the data setare not analyzed. Thus, the use of summary data pro-vided by company officials can lead to problems.

There are many examples of the control of trialdata by industry. The often-quoted European ran-domized prospective trial in which the benefit of pri-mary stenting, with Palmaz stent, was comparedwith iliac percutaneous transluminal balloon angio-plasty (PTA) alone, completed many years ago, isone example. The results, claiming statistically sig-nificant advantages for primary stenting in both“clinical success” and secondary patency at 5 years,were presented at several meetings and in abstractform in 1993,14 but the study has not yet been pub-


lished as a peer-reviewed article. It is regrettable thatthe principal authors and the company have not per-sisted in achieving publication by providing the nec-essary data to satisfy peer review. Approval by theFDA has been obtained for this indication, and it ispresumed that this study was among the data pre-sented. With regulatory approval and marketing suc-cess achieved, the scientific aim of the study seems tohave taken a backseat.

Recently, summary data were the sole basis fortwo abstracts submitted to major vascular societies.This is a risky but not uncommon practice. Onepaper had to be withdrawn from the 1998 AmericanVenous Forum meeting because the company thatsponsored the study did not reply to repeatedrequests to supply the necessary background infor-mation (the denominators) to put the study’s find-ings in proper perspective in sufficient time to allowpresentation.15 When the actual data were ultimate-ly obtained, they did not match the summary dataoriginally submitted to the investigators for prepara-tion of the abstract. In presenting and publishing arecent analysis of the cost-effectiveness of an aorticendograft device,16 the authors were accused of nothaving data to support their direct cost analysis.Although an inquiry subsequently demonstratedthat a company consultant had raw data from mostof the individual centers and had supplied theauthors with summary data on which to base theirprojections, nonetheless, they were vulnerable to thecriticism of using summarized data rather than ana-lyzing the raw data themselves.

Finally when the results of a trial depend signifi-cantly on the interpretation of diagnostic studies,arrangements should be made for these studies to beindependently interpreted by blinded individuals (eg,those in a core laboratory who have no vested interest inthe outcome and are independent of company or inves-tigator interference).

Interim data release. With nonrandomized stud-ies of new devices, preliminary interval reports of theprogress of the trial are possible and may even bedesirable. Unfortunately, many of the early reportscontain soft data and are often presented with enthu-siastic bias. At the beginning of such a study, duringthe active patient-recruitment phase, results can oftenbe obtained from investigators’ meetings, and theparticipants may be allowed (if not encouraged) topresent the data at meetings and symposia. In the caseof the evaluation of the Endovascular Technologies(EVT) device, restrictions were subsequently placedon the presentation of data released at investigators’meetings. It was announced that, because of the need

for compliance with “inside trader rules” when thecompany “went public,” official data updates wouldonly be released by the company. Such data disclo-sures took the form of periodic press releases, seem-ingly intended more for investors than for clinicalinvestigators. A more appropriate reason for a compa-ny not releasing data during the course of a trial is thedesire to avoid having to retract impressions from pre-liminary analyses, and rather wait for full analysis oncompletion of one of the phases of the trial. This hasbeen the explanation given for the Gore ExcluderTrial. Other companies have been willing to releasetheir device data from the Eurostar registry, butincreasingly companies are wary of releasing interimdata from ongoing FDA trials and will generally des-ignate one of the principal investigators to presentupdates at well-intended vascular symposia. Suchupdates of data are rarely critical and often presentsummarized data supplied by the company. Thisdeprives the vascular surgical community, who mostlyattend a limited number of meetings, of objectiveupdates of trials that could help in patient manage-ment decisions (eg, open AAA repair vs referral to anendograft trial and, if so, which one). This dilemmacould be avoided because in a properly constructedprospective device evaluation, the data are collected in away that will be suitable for submission to the FDA andfor publication; consequently, there is no reason whyinterim data releases, such as presentations at symposia,should not contain objective data and be reported byusing standard reporting practices. The details of thedevice and its use are proprietary; objective data from aclinical trial into which patients are still being actuallyrecruited should not be. One of the main reasons forregular objective and complete disclosure of the out-comes of new devices is the need to assess the failurerate and complications, particularly significant adverseevents. Even periodic investigators’ meetings may notfulfill this need when the data are prepared and pre-sented by company officials or the investigators areinstructed not to disseminate the information.

Presentation and publication of dataAdverse events. Significant delays may occur

between the initial discovery of device-specific prob-lems and their eventual dissemination at meetings orin published reports. Reports of serious complicationsshould be circulated immediately by the company to allinvestigators, who then have a responsibility to notifytheir patients, institution, and the IRB. In a recenteditorial, one of the authors of this editorial17

emphasized the importance of promptly disseminat-ing information if a problem is noted that potential-


ly reflects on the design or deployment of the device.When hook fractures occurred with the EVT device,the problem was quickly disclosed.18 However,when fabrication flaws were detected in anothercommonly used device, the Min Tec Stentor graft, itwas some time before there was public acknowledg-ment at meetings or in publications,19 although oneheard of “disappearing (breaking) sutures” from dis-cussions at investigators’ meetings. In an analysis ofthe Eurostar data20 it was reported that “breakage ofpolypropylene sutures connecting the rings of themetal stent frame has recently been observed in oneof the commercially available types of endografts,”but the device was not identified by name. Severalimportant issues are raised by these adverse events:Is it the company’s or the principal investigator’sresponsibility to disseminate information aboutadverse events? Who should receive such informa-tion—only potential device implanters or the vascu-lar community? What is the appropriate middleground between premature allegations of device fail-ures and delayed disclosure? And is it appropriate toaccede to company requests not to identify compli-cations by device name in registry presentations andpublications? These issues have been the subject ofan exchange in letters to the editors of this journalregarding the disclosures of adverse events associat-ed with the Stentor and the Vanguard devices.21,22

Min Tec’s Stentor device has been taken over byBoston Scientific Corporation and superceded bythe redesigned and differently fabricated Vanguarddevice. A case report of a Vanguard graft developingfabric erosions was published in this journal in June1999.23 The authors quoted a November 1998 let-ter that Boston Scientific Corporation sent to “all itscustomers,” noting that “late endoleaks due to holesin the fabric covering now have been reported to themanufacturer in six cases.” This letter also notedthat “the reported events occurred between five andtwelve months post-implant” and “only one of theevents described in this letter occurred within thisEurostar data set.” Five of these six cases had beendiscussed at a breakfast session at the MontefioreSymposium in November 1998. A year later, at thissame symposium, the nine cases were reported tohave fabric holes, but overall data on this uniquecomplication have yet to be published a year and ahalf after its first appearance. This may yet be foundto be simply a new and relatively low frequency formof endoleak with this device, but this potentiallyimportant information has not been promptly andwidely transmitted. How else can practicing sur-geons be sure that it is safe to refer their patients

with AAAs for implantation of a particular endograftor, if they have appropriate endovascular skills, beginusing a device that is now being marketed? Thus, theearly disclosure of possible device failures remains anagging issue. The Vanguard device was recentlywithdrawn, but according to a company spokesmanthis was not because of concern over the increasingnumber of fabric holes, but because of microscopicparticles separating from the sheath, although thelatter have not had any known clinical consequence.

Full disclosure of adverse events has subsequent-ly been seen with the problem of late rupture of aor-tic aneurysms “repaired” with the AneuRx device.Three cases were reported by Politz et al24 in theMarch issue of this journal, and an analysis byZarins, Fogarty, and White of all seven cases knownto date appears in this issue.25 Although thesereports differ somewhat in their interpretation of thepotential seriousness of this particular adverse event,at least the vascular community has been alerted andhas the opportunity to review the details. Journalsshould promptly report and fast-track articles address-ing potentially important adverse events.

Negative trials. There is a tendency not to sub-mit negative results for publication, and it is difficultto get negative trials published. Just like surgeonswith poor results, companies are not likely to wantto report negative trials. However, failure to publishnegative results may result in the continuation ofharmful patient treatment, unnecessary duplicationof studies, and failure to release important scientificdata; it also subverts the ethical principle of honesty inpublishing research data. In some instances, the con-tract between the investigator and the company mayappear to give the company the right to block pub-lication. Recently, an investigator was obliged to stepto the podium at a major national scientific meetingand announce that he was being prevented frompresenting the results of the study by the pharma-ceutical company sponsor.26 Permission was with-drawn the evening before presentation. Because ofcontractual agreements with the investigators, theindustry-sponsor maintained a right to block publicdisclosure. In an editorial discussing this incident,27

it was pointed out that the signed American HeartAssociation abstract submission document was alsobinding regarding presentation and that informedconsent documents generally include such state-ments as “the patients and their families have agreedto participate in an activity with risk and have theright to be assured that the results of the study willbe transmitted to the scientific community in a time-ly fashion.” The authors of the editorial maintained


“that these other documents (and the informed con-sent in particular) may also have legal standing ascontracts, and that inappropriate delays or limita-tions in the scope of presentations may representbreaches of these contracts.” Prevention of harm topatients has ethical standing that would likely out-weigh and supercede the obligations to follow theterms of a contract requiring nondisclosure.

A company may not have included a clause toprevent disclosure, but if it controls the pooled data,it can effectively prevent publication. This wasobserved a few years ago, when investigators fromone center, who had recruited by far the most casesin a negative trial, finally decided to exercise theirright to present and publish their own results28 afterit became apparent that the company was not goingto have the overall trial data published. After the pre-sentation, company officials tried unsuccessfully toundermine that publication through telephone con-tact with one of the former editors of this journal.When told that it was undergoing peer review and ifaccepted would be published, they then asked topublish a rebuttal article but declined when theyfound it too would have to be submitted for peerreview. After the article was published, they pub-lished a letter to the editor29; in addition, there weretwo seemingly spontaneous letters published by oth-ers,30,31 one of whom had a contract with the studysponsor, Curative Technologies, Inc. The primaryauthor’s reply32 effectively dismissed their objec-tions, but the company officials’ response demon-strates the extent to which a study sponsor may goto prevent or oppose publication of negative trialresults. To not allow publication of results interfereswith the investigator’s right to report scientific datafrom a trial in a timely fashion regardless of outcomeand with the patient’s right to know the outcomesince this information may modify their current orsubsequent management.

Hailey33 quotes two examples where companieshave used the court system to delay publication.Bristol-Myers-Squib Canada, Inc, tried unsuccess-fully to have the courts block the release of a sum-mary document on statins prepared by the CanadianCoordinating Office for Health TechnologyAssessment. Release of the report was delayed foralmost a year. Recently, the Ontario Ministry ofHealth requested that a group of experts formulateguidelines on the use of drugs aimed at treatingulcers and related diseases. When the panel conclud-ed that cheaper alternatives to Losec might be equal-ly effective, a lawyer for Astra Zeneca wrote the chairof the committee an intimidating letter requesting

that she not finalize and distribute the guidelinesand stating if she persisted, legal action would beinstigated. The company subsequently stated that ithas never had the intention of restricting aresearcher from publishing the study results.

Delays in publication. Although the companymay encourage early publication of favorable results,conflict between the company and the investigatormay result if the results are not favorable to the com-pany. Last summer, it was communicated to partici-pating investigators that enrollment had beenstopped in an almost 5-year randomized trial ofcarotid stenting using the Schneider Wallstent (nowowned by Boston Scientific Corp) versus carotidendarterectomy for carotid stenosis. More than 200patients had been entered, and the procedural mor-tality and neurologic morbidity were said to bemuch higher for the stent group than for thoseundergoing carotid endarterectomy. Inquiringabout possibly fast-tracking a report of this study,the senior editor of this journal was informed by aclinical research investigator coordinating the trialfor the company that “enrollment was stopped inJune [of 1999, but] we are continuing to follow thepatients and plan to do so for an indefinite period oftime. The data have not yet been presented or sub-mitted for publication. The investigators agreed thata publication committee should be identified andthat they would write the manuscript.” The replycontinued “the committee is just in the process ofbeing selected” and “there is no principal investiga-tor for the trial.” The trial sponsors appeared to bein no rush to present or publish the initial outcome(ie, mortality and neurologic morbidity) of the com-pared procedures, as is common practice for treat-ment of carotid stenosis, yet it would seem that if theoutcomes had been reversed and in favor of carotidstenting, their response regarding prompt presenta-tion and publication might have been quite differ-ent.

In addition to a responsibility to inform the vas-cular community, patients consenting to such a ran-domized trial are normally assured of obtainingprompt disclosure of the results of a trial if there is aclear difference between groups. Investigators shouldbe certain that a publication committee is establishedbefore the start of the study and that provision forprompt publication of the results is assured in theresearch contract they sign. The research contractshould specify that the company can only delay publi-cation for a reasonable time to allow them to review themanuscript and complete application for patent pro-tection or submission to a regulatory body. Ordinarily,


90 days is sufficient for these purposes, assuming thelatter contingency has been arranged for in advance.

Multiple publications. One of the problemswith multiple publications of the same longitudinaldata is that subsequent accounts may have differentstarting points, ostensibly because the device itselfhas undergone redesign. However, this practicehides “learning curve” data that may be importantinformation for others who are going to start to usethe technique. Although it is reasonable to show theimpact that improvements in the device or the skillsof those implanting it have on the results, it is moreappropriate to present the entire experience andthen carry out subgroup analysis to provide thereader with the full perspective. Detailed publica-tions covering results, complications, and specialaspects of a device are clearly justified, but others, inwhich essentially the same data are revisited with asomewhat different discussion, are clearly examplesof “salami slicing,” which prevents the reader fromgetting a broad perspective on the reported results.To avoid this problem, a publications committeeshould decide ahead of time how to fairly present thedata to avoid multiple publications and should resistcompany pressures to broadly publish similar data.

As pointed out by Rennie,34 multiple publica-tions from the same data set, along with the tenden-cy to publish only positive results, bias the opinionin the literature in favor of a device or a drug. A pro-posed solution is to register trials before they are car-ried out and to ensure publication of all results.35

Publication committees. The early establish-ment of a publications committee from among theprincipal investigators, a committee chaired by oneof them, is the optimum way to fairly divide up thedata emanating from a trial for publication. It shouldbe constituted at the outset of the study and bemade up of selected investigators, members of thedata-monitoring committee, and a representative ortwo of the company. In May 1998, a paper present-ed at the Eastern Vascular Society concerning “theorigin of perigraft flow after endograft aneurysmrepair,” based on an analysis of core laboratory datafrom phase II of the EVT trial, was withdrawn fromsubmission for publication at the time of the meet-ing at the insistence of a representative of EVT whodid not approve the release of the information atthat particular time, even though the submittedabstract and final manuscript had been reviewed andapproved earlier. The purported reason for thisaction was to allow prior publication of the “official”results of the second phase of this trial being pre-sented at the joint vascular meetings a month later.


This short delay in submission may seem innocuous(even though it was in violation of the society’s rulesfor submission of abstracts, namely, that if acceptedfor presentation, a manuscript will be submitted forpublication at the meeting); however, it demon-strates that company representatives are makingdecisions on submitted abstracts and manuscriptsubmissions that should be the purview of the entirepublication committee. Ironically, the major paperon the phase II results was presented and submittedfor publication, but after peer review it was neverresubmitted.

CONCLUSIONSEditorials of this nature run the risk of seeming

hypercritical or “holier than thou.” We realize thatmost research and development personnel in indus-try are scientists, too, and understand and respectthe investigator’s position in these research collabo-rations. This editorial is not primarily based on per-sonal negative experiences that may have given us abiased view of this scene. However, the corroborat-ed examples given have all been reported by col-leagues, witnessed at national or regional meetings,or have come to our attention while pursuing oureditorial duties.

We have identified some of the problems thatcan occur in the complex relationship in clinicalresearch studies between clinical investigators andindustry representatives. Industry seems to beexerting more control over the design, conduct,and data analysis in trials, and the busy clinicalinvestigator is less able to defend his or her rights asa research scientist. Because the aim of collaborativeclinical research with industrial sponsorship is todevelop safe and effective methods for diagnosingand managing diseases, clinical investigators shouldrecognize their primary responsibility. It may wellbe time to collectively look the gift horse in themouth and take a stand against inappropriate con-trol of clinical trials and their data by industry.

The opinions expressed are those of the authors, butthey acknowledge the helpful discussions with Drs V. M.Bernhard, J. L. Cronenwett, C. B. Ernst, R. T. Gregory,N. R. Hertzter, W. C. Krupski, J. Matsamura, M. F.McKneally, J. M. Porter, F. J. Veith, and Mr J. Hooverduring the preparation of drafts of the manuscript.

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potential problems with industry-supported clinical research

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