researchers' views of the acceptability of restrictive provisions in

Accountability in Research, 12:163–191,Copyright © Taylor & Francis Inc.ISSN: 0898-9621 print DOI: 10.1080/08989620500216380

163

28GACR0898-96211545-5815Accountability in Research: Policies and Quality Assurance, Vol. 12, No. 03, January 2005: pp. 0–0Accountability in Research RESEARCHERS’ VIEWS OF THE ACCEPTABILITY OF RESTRICTIVE PROVISIONS IN CLINICAL TRIAL

AGREEMENTS WITH INDUSTRY SPONSORS

Clinical Trial Agreements with Industry SponsorsM. M. Mello et al. MICHELLE M. MELLO, J.D., PH.D., M.PHIL.

Department of Health Policy and Management, Harvard School of Public Health, Boston, MA

BRIAN R. CLARRIDGE, PH.D.

Center for Survey Research, University of Massachusetts Boston, Boston, MA

DAVID M. STUDDERT, LL.B., SC.D., M.P.H.

Department of Health Policy and Management, Harvard School of Public Health, Boston, MA

We conducted a mail survey of 884 U.S. medical school faculty active in clinicalresearch to elicit their views about the acceptability of provisions in contracts forindustry-sponsored clinical trials that would restrict investigators’ academicfreedom and control over trials. We compared their responses to results from a

This material is based on work supported by the National Institute of NeurologicalDisorders and Stroke and the Department of Health and Human Services’ Office ofResearch Integrity under Award Numbers 1-R01-NS46777-01 and 1-R01-NS42438-01A1.Any opinions, findings, and conclusions or recommendations expressed in this publicationare those of the authors and do not necessarily reflect the views of the National Institute ofNeurological Disorders and Stroke or the Office of Research Integrity. Preliminary find-ings from this study were presented at the Research Conference on Research Integrity inSan Diego, California in November 2004.

Dr. Mello conceived the study design, analyzed the data, and drafted the manuscript.Dr. Studdert participated in the study design, survey instrument development, andinterpretation of findings, and critically revised the manuscript for important intellec-tual content. Dr. Clarridge led the development of the survey instrument and collectedthe data.

The authors thank Hershel Alexander, Hisashi Yamagata, and the Association ofAmerican Medical Colleges for making the Faculty Roster data available for this study. Weare grateful to Matthew Jans for his efforts in administering the survey, Marin Levy andJohn Barkett for assistance with the sample selection, Troy Brennan for assistance conveningfocus groups, and John Abramson and Marcia Angell for helpful comments on the draftmanuscript.

Address correspondence to Michelle M. Mello, J. D., Ph.D., M. Phil., Department ofHealth Policy and Management, Harvard School of Public Health, 677 Huntington Ave.,Boston, MA, 02115, U.S.A. E-mail: [email protected]

164 M. M. Mello et al.

similar survey of research administrators at 107 medical schools. There wassubstantial variation among clinical researchers in their acceptability judgments,with a relatively large proportion of clinical trial investigators willing to acceptprovisions that give industry sponsors considerable control over the disseminationof research results. There were significant differences in the perceptions of clini-cal trial investigators versus other recently published clinical researchers; investi-gators with a high versus low percentage of research support from industry;junior versus senior faculty; and investigators at institutions with high versuslow National Institute of Health (NIH) funding ranks. There was also a signif-icant divergence of views in a number of areas between clinical trialists andresearch administrators who negotiate clinical trial contracts on their behalf.Medical school faculty could benefit from additional guidance about what theirinstitution views as acceptable parameters for industry-sponsored clinical trialagreements.

Keywords: clinical trials, drug industry, publications/standards, research support,conflict of interest

A great deal of attention in recent years has been focused on theethical issues surrounding financial conflicts of interest in clinicalresearch (Angell, 2000; Bodenheimer, 2000; Boyd and Bero,2000; Cho et al., 2000; Lo et al., 2000; Martin and Kasper, 2000;Blumenthal, 2003; Kassirer, 2004). Much less is known aboutother aspects of the relationships between faculty investigatorsand industry sponsors that may have just as great a potential toaffect research integrity. Of particular interest are the terms ofcontracts that medical schools and their faculty execute withindustry sponsors to set up clinical trials.

These agreements may restrict investigators’ academicfreedom through provisions giving the industry sponsor con-trol over research data, study design, the conduct and termina-tion of the study, publication, and informal dissemination ofresearch findings. Hence, they pose a significant potentialthreat to research integrity (Schulman, Seils et al., 2002;Weatherall, 2003; DuVal, 2004). Our study aim was to obtainclinical researchers’ views of the ethical acceptability of variousrestrictive contractual provisions, their perceptions of the effi-cacy of their institution’s office of research administration inprotecting clinical investigators from attempts by industrysponsors to assert controls over clinical studies, and the types ofinstitutional structures that they find helpful for assuringresearch integrity.

Clinical Trial Agreements with Industry Sponsors 165

Methods

Study Design

Researchers at the Harvard School of Public Health partneredwith a professional survey organization, the Center for SurveyResearch (CSR), to design and conduct a mail survey. The studydesign was informed by previous survey research on academicinvestigators’ research relationships with industry (Blumenthal,Campbell et al., 1996; Blumenthal, Campbell et al., 1997).

Sample

The sample source was the Association of American MedicalColleges’ (AAMC) Faculty Roster. The Faculty Roster containsemployment and demographic information on approximately103,000 active faculty and 120,000 inactive medical school faculty;data are voluntarily supplied by all accredited U.S. medicalschools at the time of faculty members’ initial appointment andupdated as needed. The Faculty Roster has served as a datasource for more than 155 academic publications (Association ofAmerican Medical Colleges, 2004). We obtained AAMC’s permission,pursuant to its data release policy, to access information on facultynames, departments, clinical specialties, institutions, addresses,academic degrees, and academic ranks.

Our sample frame consisted of full-time faculty in the conti-nental U.S. in clinical departments that we judged as likely to conductclinical trials (dermatology, family medicine, internal medicine, neu-rology, obstetrics/gynecology, ophthalmology, orthopedic surgery,otolaryngology, pediatrics, psychiatry, and surgery). We drew a strati-fied random sample from the Faculty Roster in June 2003 consist-ing of 2,400 faculty who had recently published a clinical researchpaper. Strata were based on seniority of faculty and research inten-sity at the faculty member’s institution. We aimed to gather 1,200completed responses. The sample size was determined by thenumber of strata (6), the estimated effect size based on previous,related research (10%), and the estimated response rate afterexclusion of ineligible sample members (50%).

First, we randomly sampled 4,000 junior faculty (assistantprofessors) and 4,000 senior faculty (associate or full professors).


There were 121 schools represented in the sample. The 2 stratabased on seniority were further divided into 3 substrata of high,moderate, and low institutional research intensity, based on insti-tutional rank in the National Institute of Health’s (NIH) list ofresearch grants to U.S. medical schools in 2002. Cut-offs wereselected to create 3 subgroups of approximately equal size withineach faculty stratum. The top 23 NIH-funded medical schoolswere in the first substratum, the next 32 schools composed thesecond substratum, and the bottom 66 institutions were in thethird substratum.

Finally, to confine the survey to those who were active as clinicalinvestigators, we followed a previously developed methodology ofusing MEDLINE to identify faculty who had published at leastone clinical research paper in the last 3 years (Blumenthal,Campbell et al., 1997). Research assistants were trained to followa detailed search protocol in which they applied the NIH definitionof clinical research (Nathan, 1997). Uncertainties about eligibilitywere resolved by the principal investigator. Research assistantsworked down a random-ordered list of faculty in each of the sixstrata, applying the inclusion criteria until our target number of400 eligible faculty members in each stratum was reached.

Survey Questionnaire

The survey questionnaire was developed using a detailed process ofdrafting, expert consultation, and pilot testing, necessitated by thecomplexity of the subject matter and the range of research studiesand environments covered by the survey. An initial list of questiondomains was developed by the investigators and survey design con-sultants from CSR. This list was reviewed by an expert consultantwho was the head of sponsored research for a leading academicmedical center. The initial topic outlines were refined into prelimi-nary questions based on information provided by the expert.

A focus group was then convened, consisting of five facultymembers at Boston-area medical schools who were active as clinicalinvestigators. The discussion covered questionnaire topic areas,hypotheses, and reactions to specific questions. Information waselicited about differences in research environments and types ofclinical studies that could affect respondents’ understanding ofthe questions. The questionnaire was then revised.


The revised instrument was cognitively tested on 7 facultymembers, who were randomly selected from among those whomet the study inclusion criteria, but were not on the list for thesurvey mailing. Participants received copies of the survey andaccompanying mailings and were asked to answer the questionsaloud on the telephone. Interviewers interspersed scripted cognitivequestions at various points during this process and audiotapedthe interviews. Again, the instrument was revised.

The final eight-page questionnaire contained 32 questionswith a total of 70 parts. Questions covered information aboutthe investigators’ own research portfolio and involvement inclinical trials, personal dealings with their institutional officesof research administration, awareness and perceptions of insti-tutional policies concerning industry-sponsored research, andviews of the acceptability of ceding control over various aspectsof clinical trials to industry sponsors. The questionnaire elicitedwhether the respondent had recent experience as an investiga-tor in clinical trials and then triaged “trialists” and “non-trialists”into questions parallel in content, but with wording appropriateto each group.

Survey Administration

Following institutional review board approval, the survey wasmailed to the 2,400 eligible respondents in March 2004, alongwith a cover letter and fact sheet. A second mailing was sent twoweeks later, and 6 to 10 followup contacts were made with nonre-spondents by telephone and email over the next 5 months. Tele-phone numbers and email addresses were obtained by internetsearches following a search protocol.

A total of 884 completed questionnaires were received. Theadjusted response rate was 48%, after excluding from the samplesize of 2,400 (a) 371 cases in which the respondent returned asurvey indicating that he or she does not do any clinical research,(b) 158 cases in which we were never able to trace the individual,and (c) 32 cases in which the respondent was out of the countryat the time of the study. While lower than desired, we believe thisresponse rate to be more an artifact of our sample design andacquisition process than a realistic measure of the representativenessof the data collected.


In brief, our original sample consisted of AAMC-listed facultymembers who had been listed as authors on articles listed inMEDLINE. We have ample evidence that there were many indi-viduals in our sample who were listed as authors on publishedarticles, but who did not belong in the study. For example, statisti-cians are conventionally listed as authors, but their activities aretoo distant from the actual trials for their participation in ourstudy to be of value. As described above, 371 individuals identifiedthemselves as ineligible, and it is realistic to assume that a consid-erable percentage of the remaining nonrespondents are of similarcircumstance. Their nonresponse is likely based on an appropriateassessment that the study was not meant for them. Nonrespon-dents are also disproportionately made up of interns and fellowswho participated in only one research publication during theirtraining and then left the academic environment. For these rea-sons, we believe the 48% response rate reported here is moreakin to a 60% response rate from a study in which all the sampledindividuals are known to be appropriate respondents prior to thestart of the study.

Statistical Analysis

Professional survey coders double-entered and 100% verified thedata. We analyzed the data using the SPSS 12.0 and Stata 8.2statistical software packages, incorporating appropriate correc-tions for clustered data. In our analyses, all cases were weightedaccording to the probability of being in a given stratum and theobserved non-response within that stratum.

Subgroup comparisons were performed using Stata’s com-mands for complex survey data. For ordered categorical vari-ables, an adjusted Wald test using an approximate F statisticwas used. For other variables, the usual Pearson chi-square sta-tistic was transformed to an F statistic. All statistics, except thesample characteristics (Table 1), are presented as weightedproportions.

In order to compare the responses of researchers who didand did not have experience as an investigator in clinical trials,we created an aggregate “approval score” by summing acceptabilityratings on 7 restrictive provisions about which both trialists and


non-trialists were surveyed (sponsor will own the data, sponsormay alter the study design, sponsor will write up results, sponsormay make revisions to investigators’ manuscript, sponsor may insertits own statistical analyses into manuscript, sponsor may decidethat results should not be published, sponsor may bar investigatorsfrom discussing an ongoing trial, and sponsor may prohibit datasharing with third parties after trial is over). We also comparedthe acceptability ratings of trialists to those of of 107 researchadministrators with responsibility for negotiating clinical trialagreements at U.S. medical schools, who had answered some ofthe same questions in a separate survey (Mello et al., 2005). Forthis comparison, we created a second “approval score” representingtrialists’ and administrators’ judgments on 15 restrictive provisions.(Non-trialists were not included in this comparison, because thequestionnaire posed only 7 of the 15 questions to them; they weredirected to skip the rest, because we determined on the basis offocus groups and cognitive interviews that few would have thedetailed knowledge of clinical trials necessary to render aninformed judgment).

We used ordered logistic regression analysis incorporat-ing complex survey design adjustments to examine predictors ofacceptability ratings (completely acceptable, moderately accept-able, not very acceptable, or not at all acceptable) for each of 7individual contractual provisions. To investigate predictors ofscores on the 7-point approval score, we used linear regressionincorporating complex survey design adjustments and a log trans-formation of the dependent variable to reduce non-normality.

Explanatory variables in all models consisted of investigatorcharacteristics (gender, trialist, senior faculty, low percentage ofsupport from industry, high percentage of salary coveragerequired from external grants, high and low research productivity),institutional characteristics (high and low NIH funding rank, useof educational seminars and written tools to help faculty workwith industry sponsors), and interaction terms (trialist*seniorfaculty and trialist*low industry support). Research productivitywas measured by comparing each respondent’s total number ofrefereed publications to the distribution of publications amongothers of their rank (junior/senior). Specification tests and col-linearity checks were performed to verify the appropriateness ofthe model specification.


Results

Respondent Characteristics

The responding clinical researchers had a mean of 16 yearsresearch experience after completing their training (Table 1).Approximately 41% of respondents were tenured full professorsand 72% were male. The leading medical specialties representedwere internal medicine (30%), pediatrics (15%), surgery (11%),and psychiatry (10%). About two thirds of our respondents hadserved as a principal investigator or co-investigator in a clinicaltrial in the past 5 years (“the trialists”); the remainder conductedother clinical research and some also conducted nonclinical studies.On average, respondents spent 38% (s.d. 31%) of their profes-sional time on research activities.

Government grants were the largest source of support forrespondents (45%, on average; s.d. 40%), although there wassubstantial variation among respondents. Industry grants rankedsecond (mean 36%, s.d. 38%), foundations third (11%, s.d. 22%),and internal grants last (7.5%, s.d. 20%). Trialists averaged 46%(s.d. 38%) support from industry, as compared to 10% (s.d. 23%)for non-trialists. On average, respondents had had 3.2 (s.d. 5.6)grants from industry sponsors in the past 5 years, with 38% ofrespondents reporting no industry grants during that period.

Acceptability of Restrictive Contractual Provisions

Among investigators who conduct clinical trials, there was a highdegree of consensus about the acceptability of a few restrictive provi-sions (Table 2). Trialists generally felt that it was unacceptable toallow an industry sponsor to decide that trial results should not bepublished (92% said not very or not at all acceptable) or bar investi-gators from obtaining other funding to conduct work in the samearea (93%) They generally found acceptable provisions allowing thesponsor a limited pre-review period for manuscripts (87% saidmoderately or completely acceptable) and provisions prohibitinginvestigators from discussing ongoing trials with third parties (79%).

There was considerable heterogeneity in acceptability rat-ings, however, for a larger number of provisions: allowing thesponsor to own the data, barring the investigators from altering


TABLE 1 Respondent characteristics (n = 884)†

n %

Primary department:‡

Internal medicine 251 30Pediatrics 130 15Surgery 90 11Psychiatry 84 10Neurology 59 7Ob-gyn 42 5Family medicine 27 3Ophthalmology 27 3Orthopedic surgery 20 2Urology 20 2Neurosurgery 15 2Otolaryngology 11 1Dermatology 10 1Other 60 7

Academic rank:Professor 363 42Associate Professor 239 28Assistant Professor / 245 28

Instructor / LecturerOther 18 2

Tenure status:Already tenured 343 41Tenure-track, not tenured 139 17Non-tenure-track 359 43

Age:<35 45 536–40 121 1441–50 323 3851–60 252 29>60 120 14

Graduate degrees:MD 706 82PhD 222 26

Physical/biological science 85 10Social science 65 8Statistics/epidemiology 12 1Other field 21 2

Other 78 9Gender:

Male 633 72Female 250 28

(Continued)


TABLE 1 (Continued)

n %

Research types:Clinical trials (“Trialists”) 593 67

Drugs 447 51Devices 176 20Other 98 11

Other clinical research 676 77Epidemiologic/population studies 322 36Pre-clinical studies 255 29Other 72 8

External salary coveragerequirement:<=25% 479 5526–50% 88 1051–75% 81 9>75% 158 18Don’t know 69 8

Medical school NIH funding rank:Top 25th percentile 428 4850–74th percentile 259 2926th–50th percentile 127 14Bottom 25th percentile 70 8

Mean: s.d.:Years clinical research experience 16 10Number of peer-reviewed articles

Last 3 years 11 12Lifetime 62 77

Percent time on research activities 38 31Number of grants from industry 3 6

sponsors, last 5 yearsPercentage of research dollars in last

5 years, by sponsor type§

Industry 36 38Government 45 40Foundation / other external 11 22Internal 8 20

† Percentage of completed responses. Percentages may not sum to 100 due to roundingor because multiple responses were permitted. Statistics presented are unweighted sam-ple characteristics.

‡ As reported by respondent; some responses differed from the department listed inthe Faculty Roster.

§ Responses involving a large arithmetical error in calculating distribution of researchdollars across sponsor types (the sum was < 98% or > 102%) were excluded.

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the study design, allowing the sponsor to write the manuscript ina multicenter trial, allowing the sponsor to insert its own statisti-cal analysis, prohibiting site-level investigators from publishingindependently of the group in a multicenter trial, and sharingdata with third parties after the trial is over. Some of these provi-sions potentially represent substantial encroachments on academicfreedom, yet relatively large proportions of trialists expressed awillingness to accept them. Nearly half of trialists felt it would beacceptable to give the sponsor the right to insert its own statisticalanalyses and nearly 40% thought it acceptable to allow the spon-sor to prohibit investigators from discussing research results afterthe trial was over. In addition, 37% of trialists would permit thesponsor to alter the study design after the research contract wasexecuted; a similar proportion would give sponsors the right tomake revisions to manuscripts written by the investigators, otherthan edits relating to protection of proprietary information.

Predictors of Acceptability Ratings Among Investigators

Compared to trialists, non-trialists were consistently more disap-proving of the various restrictive provisions and showed less internalvariation in their ratings (Table 3). For example, less than onethird of non-trialists believed it was acceptable to allow an indus-try sponsor to insert its own statistical analyses in manuscripts(27% moderately and 3% completely), compared to nearly halfof trialists (39% moderately and 9% completely). The differencesin acceptability ratings were statistically significant for all 7 provi-sions tested. Low percentage (< 20%) of research support fromindustry was also a strong predictor of the likelihood that investi-gators would find each provision unacceptable (P < 0.05 orhigher for all). For example, 20% of investigators with low indus-try support found it acceptable to allow sponsors to alter the studydesign, compared to 41% of investigators with more industrysupport (P < 0.0001).

On the 7-point approval score, the mean proportion of pro-visions rated completely or moderately acceptable by trialists was37%, significantly higher than the 19% approved by non-trialists(P < 0.001). The mean proportion also differed significantly forinvestigators with low and high levels of industry funding (24% vs.38%, P < 0.0001) and for investigators at schools in the top tercile


of NIH funding rank compared to others (29% vs. 34%, P < 0.05).Examining clinical trialists only, the difference between investiga-tors with low and high industry support remained significant(40% vs. 47%, P < 0.001), there was a significant positive correlationbetween percentage of industry support and the proportion ofprovisions rated acceptable (Pearson correlation coefficient = 0.21,P < 0.001), and the proportion rated acceptable increased mono-tonically over successive quartiles of the industry support variable(38%, 43%, 46%, 53%).

In the multivariate analysis, greater permissiveness (higherapproval score) was significantly associated with being a trialist (β =0.41, P < 0.001) and being at a medical school ranked in the bottom25th percentile of NIH funding (β = 0.12, P < 0.05). Senior faculty(β = −0.19, P < 0.001) and faculty at medical schools in the top 25th

percentile in NIH funding (β = −0.074, P < 0.05) were less permissivethan others. Low percentage of industry support was not a significantpredictor, but the trialist*low industry support interaction termwas significant and negatively signed (β = −0.23, P < 0.05). Thetrialist*senior faculty interaction was positively signed and borderline-significant (β = 0.13, P = 0.053). No other variables achieved statisticalsignificance at conventional levels.

In the models predicting acceptability ratings for the 7 indi-vidual components of the approval score, being a trialist andbeing a senior faculty member remained significant in all but onemodel. Low NIH rank was significant in the models predictingacceptability ratings for allowing the sponsor to alter the studydesign (β = −0.85, P < 0.01) and allowing the sponsor to own thedata (β = −0.79, P < 0.01). Low research productivity was positivelyassociated with willingness to allow the sponsor to make revisionsto the investigator’s manuscripts (β = 0.39, P < 0.05). Investigatorsat institutions that offered educational seminars were significantlyless accepting of provisions allowing the sponsor to make manu-script revisions (β = −0.34, P < 0.05). No other variables achievedstatistical significance in any of the 7 models.

Comparison of Acceptability Ratings: Clinical Trial Investigators versus Research Administrators

On the 15-point approval score, the mean proportion of provisionsconsidered acceptable by trialists (45%) and administrators

177

TA

BL

E 3

Dif

fere

nce

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per

cept

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s of

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178

TA

BL

E 3

(Con

tinue

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(44%) was similar. However, these close overall scores mask sub-stantial differences in attitudes toward particular provisions. Trialistswere significantly more likely than administrators to approve ofseveral highly restrictive provisions, such as allowing the sponsorto make revisions to manuscripts, insert its own statistical analysesin manuscripts, decide that the results should not be published,and prohibit investigators from discussing trial results after thetrial is over (Table 3). On the other hand, administrators weresignificantly more likely than trialists to allow sponsors to own thedata, alter the study design, pre-review manuscripts, and delaypublication in order to file a patent application.

Perceptions of Office of Research Administration

Investigators rated their office of research administration’s abilityto maintain ethical standards when negotiating clinical researchcontracts quite positively (48% very high, 32% high, 8% medium,2% low, 10% don’t know). One third (35%) felt that the officewas overprotective, while 63% felt it was about right, and only 2%felt it was underprotective. Thirty-six percent said they often oralways felt that some of the provisions the research administra-tion office wanted in research agreements were unnecessary, and49% felt that it often or always took too long to negotiate and exe-cute agreements. Trialists, senior faculty, and investigators with alow percentage of industry funding were significantly more likelythan other investigators to find these faults with research adminis-trators (for all subgroup comparisons, P < 0.01 for taking too longand P < 0.05 for unnecessary provisions). Trialists were also morelikely to give their research administration office a high ratingoverall (84% vs. 71%, P < 0.0001).

Only 30% of investigators felt their office of research admin-istration had stricter standards for what could be in a clinical trialagreement than they did (13% believed they had stricter stan-dards and 57% thought the standards were the same). Inresponse to the same question, 91% of administrators felt thattheir office had stricter standards, and none felt investigators hadhigher standards. Junior faculty were significantly more likelythan senior faculty to believe their personal standards werestricter than those of their research administration office (34%vs. 26%, P < 0.05).


Disagreements With Office of Research Administration and Industry Sponsors

Trialists reported that disagreements with research administratorsabout the terms of a clinical trial agreement were rare (Table 4).When disagreements did occur, they were most likely to be overconfidentiality issues or data ownership. Disagreements withindustry sponsors were more common. A sizeable minority ofinvestigators reported that they sometimes or often had differentviews from an industry sponsor about what provisions should bein a clinical trial agreement. The most common areas of disagree-ment with sponsors were ownership of the research data andrights to disseminate study results.

Tensions in the Research Environment

Only a small proportion (17%) of investigators involved in clinicaltrials felt that competition for research funds created pressure attheir institution to compromise on contract language with industrysponsors. Half felt no such pressure and a third said they did notknow. Among those who perceived the pressure, 12% characterizedit as great, 39% moderate, and 49% little. In contrast, 69% percentof research administrators perceived that pressure to compromiseexisted, with 24% of those who perceived pressure describing it asgreat and 53% describing it as moderate. The difference betweenthe proportions of administrators and investigators who perceivedpressure to exist was statistically significant (P < 0.001).

Role of Written Guidelines

Every faculty respondent reported that their institution had atleast 1 of 5 specific kinds of written tools for aiding faculty and/orresearch administrators in negotiating contracts for industry-sponsored trials. The most prevalent types of tools of which inves-tigators were aware were a general statement of ethical or legalprinciples to which the institution adheres (67%) and a checklistof topics that clinical trial agreements should cover (37%). Fewerrespondents reported that their institution had a list of specificprovisions that clinical trial agreements should contain (37%), alist of provisions that were unacceptable (28%), or a boilerplate

182

TA

BL

E 4

Sour

ces

of c

linic

al tr

ial i

nve

stig

ator

s’ d

isag

reem

ents

wit

h in

dust

ry s

pon

sors

an

d re

sear

ch a

dmin

istr

ator

s (n

= 59

3)†

How

oft

en d

o yo

u an

d a

(res

earc

h a

dmin

istr

ator

/ in

dust

ry

spon

sor)

hav

e di

ffer

ent v

iew

s on

cla

uses

in c

linic

al tr

ial

agre

emen

ts c

over

ing…

Dis

agre

emen

ts w

ith

In

dust

ry

Spon

sors

‡D

isag

reem

ents

wit

h R

esea

rch

A

dmin

istr

ator

s

Oft

enSo

met

imes

Rar

ely

/ N

ever

Oft

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met

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Rar

ely

/ N

ever

Con

fide

nti

alit

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tria

l par

tici

pan

t rec

ords

an

d in

form

atio

n1

1485

415

81C

onfi

den

tial

ity

of th

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by th

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sear

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1681

411

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wn

ersh

ip o

f th

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ta p

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ced

by th

e re

sear

ch7

2667

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86R

igh

ts to

pub

lish

524

712

890

Rig

hts

to d

isse

min

ate

stud

y re

sult

s5

2670

27

91In

dem

nif

icat

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issu

es (

liabi

lity)

822

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/AN

/AN

/AO

wn

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ip o

f in

ven

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s an

d in

telle

ctua

l pro

pert

y5

1877

N/A

N/A

N/A

† Prop

orti

on o

f com

plet

ed r

espo

nse

s. P

erce

nta

ges

may

not

sum

to 1

00 d

ue to

rou

ndi

ng.

‡ Exc

lude

s 78

clin

ical

tria

l in

vest

igat

ors

wh

o re

port

ed th

at th

ey h

ad n

ever

wor

ked

wit

h in

dust

ry.


agreement to use as a starting point in negotiations (30%).Research administrators reported higher prevalence of each ofthese five kinds of tools (from 65% to 84%), which suggests thatmany faculty may be unaware of institutional policies.

In general, researchers felt that written policies were usefulin helping them and their institutions maintain ethical standardsin industry-sponsored research (Table 5). To a somewhat lesserextent, they found it useful for research administrators to closelyinvolve investigators in the negotiation process and to offer edu-cational seminars for faculty. Fewer faculty found external guide-lines (such as those of the International Committee of MedicalJournal Editors) helpful.

Discussion

This study found substantial variation in clinical researchers’views of the ethical acceptability of restrictive provisions in contractsfor industry-sponsored trials, with a relatively large proportion ofclinical trial investigators willing to accept provisions that givesponsors considerable control over the dissemination of researchresults. Several characteristics of respondents were correlatedwith tendencies toward permissiveness; specifically, being a clini-cal trialist, junior faculty status, personally having a relatively highlevel of industry funding, and working at a medical school with arelatively low level of research intensity (as measured by NIHfunding rank) were all associated with greater willingness toaccept restrictive contractual provisions. We also found signifi-cant differences in the views of clinical trialists and the researchadministrators who negotiate clinical trial contracts on theirbehalf. Several findings merit further comment.

A larger than expected proportion of investigators consideredit acceptable to allow industry sponsors to retain control over keyaspects of the dissemination of clinical trial findings. It is reassur-ing that 92% of respondents considered it inappropriate to allowindustry sponsors to decide that study results should not be pub-lished, but troubling that about 4 in 10 investigators who conductclinical trials would find it acceptable for a clinical trial agree-ment to allow sponsors insert their own statistical analyses intomanuscripts, make substantive revisions to manuscripts, and pro-hibit investigators from discussing research findings after the trial

184

TA

BL

E 5

Res

earc

her

s’ p

erce

ptio

ns

of m

ech

anis

ms

for

ensu

rin

g in

tegr

ity

in in

dust

ry-s

pon

sore

d re

sear

ch (

n= 8

84)†

How

use

ful d

o yo

u th

ink

each

of t

he

follo

w is

in h

elpi

ng

acad

emic

inst

itut

ion

s an

d th

eir

facu

lty

mai

nta

in e

thic

al

stan

dard

s in

indu

stry

-spo

nso

red

rese

arch

?

%

Ver

y U

sefu

lM

oder

atel

yU

sefu

lN

ot V

ery

Use

ful

Not

At A

ll U

sefu

lD

on’t

K

now

Wri

tten

inst

itut

ion

al p

olic

ies

on fi

nan

cial

con

flic

ts o

f in

tere

st57

336

14

Wri

tten

inst

itut

ion

al p

olic

ies

abou

t wh

at is

an

d is

not

ac

cept

able

in c

linic

al r

esea

rch

agr

eem

ents

5734

51

5

Clo

sely

invo

lvin

g fa

cult

y in

vest

igat

ors

in c

linic

al r

esea

rch

ag

reem

ent n

egot

iati

ons

5035

72

7

Edu

cati

onal

sem

inar

s fo

r fa

cult

y in

vest

igat

ors

4041

132

5E

xter

nal

gui

delin

es s

uch

as

thos

e pr

omul

gate

d by

the

Inte

rnat

ion

al C

omm

itte

e of

Med

ical

Jou

rnal

Edi

tors

2542

153

15

† Prop

orti

on o

f com

plet

ed r

espo

nse

s. P

erce

nta

ges

may

not

sum

to 1

00 d

ue to

rou

ndi

ng.


is over. Contractual provisions that preserve such rights for industrysponsors may lead to conflicts and disputes between investigatorsand sponsors in the event that study findings are not what thesponsored hoped (Rennie, 1997; Hilts, 2000; Saltus, 2000), andmay affect the quantity and quality of clinical research findingsthat reach the public.

Our data suggest that investigators who are more familiarwith industry-sponsored trials tend to have more accepting viewsof restrictive contractual provisions. Researchers who identifiedthemselves as clinical trial investigators were more permissivethan researchers who did other kinds of clinical research, andamong trialists there was a “dose-response” relationship betweenpercentage of support received from industry and permissiveness.Additionally, researchers with relatively high levels of industrysupport were more permissive than both researchers with lowerindustry support and research administrators concerning con-tractual provisions relating to dissemination of research findings.

At least three dynamics may drive such associations. One pos-sibility is knowledge: those who are experienced in runningindustry-sponsored clinical trials have a better understanding ofhow arrangements between industry and academia work, andtheir greater willingness to accept various restrictive provisionsmay stem from insights into the benignity of these provisions inpractice. A second possibility is that trialists’ permissiveness mayreflect a predilection, conscious or subconscious, to endorse whatis customarily approved and included in such agreements. If trial-ists’ responses recorded actual practice, rather than a considerednormative judgment about ethical acceptability, then the surveymay have encountered a kind of measurement error.

A third possibility is that the experience of being a clinicaltrial investigator, especially one who relies heavily on industryfunding, tends either to attract researchers with different ethicalnorms or relax researchers’ ethical norms. In evolutionary terms,there may be a kind of Darwinian selection of scientists who haverelatively permissive views into industry-sponsored clinical trialresearch. Alternatively, there may be a Lamarckian acquisition ofthe trait of ethical permissiveness among scientists after theyundertake clinical trial work. In the latter scenario, familiaritybreeds tolerance, rather than contempt. This explanation ispotentially quite troubling because it amplifies ongoing concerns


about conflicts of interest, namely, the notion that those closestto clinical trials are, by virtue of their association and potentiallyalso their reliance on industry support, vulnerable to departuresfrom ethical norms that others in the scientific community findunacceptable. The potential for this dynamic to arise refocusesattention on the office of research administration, whose key roleis to protect the investigator, the institution, research subjects,and the public, by ensuring that agreements with industry areconsonant with prevailing ethical norms.

We identified several contrasts between the views of clinicalinvestigators and those of research administrators about theacceptability of restrictive contractual provisions. We hypothesizedthat research administrators would have more stringent standardsconcerning restrictive provisions than faculty investigators.Indeed, our survey of administrators suggested that they viewedthemselves as bulwarks against imprudence, haste, or naivete onthe part of faculty investigators regarding the language of clinicaltrial agreements (Mello et al., 2005). Fifty-six percent of researchadministrators felt that faculty investigators they worked with typi-cally did not have a good understanding of the guidelines andprinciples that the research administration office used to createclinical trial agreements, and more than 90% felt that investiga-tors had less stringent standards for clinical trial agreements thanthe office did. Interestingly, our faculty survey found that mostinvestigators believed that it was themselves, not administrators,who were stricter.

Our data largely bear out our hypothesis that administratorwould have more rigorous standards than faculty, but present amore complex picture than anticipated. On what many in theresearch community would regard as bedrock issues of academicfreedom (DuVal, 2004), administrators had the more stringentstandards. Investigators were significantly more willing thanadministrators to countenance restrictions on their rights to publish,control revisions to manuscripts, control statistical analyses, anddiscuss results with others after the trial ends. On issues thatmight be considered less critical, such as ownership of data anddelaying publication in order to file a patent application, admin-istrators were far more permissive than investigators.

Existing literature on financial conflicts of interest, publicationbias, and quality problems in industry-sponsored research (Bero


and Rennie, 1996; Bekelman et al., 2003; Lexchin et al., 2003)sheds light on the dynamics surrounding our study findings. Toour knowledge, no prior study has examined researchers’ ethicalnorms concerning provisions in clinical trial agreements withindustry sponsors. Previous explorations of researchers’ ethicalnorms have focused on attitudes towards conflict-of-interest poli-cies (Boyd et al., 2003; Lipton, Boyd et al., 2004) and behaviorsthat could be construed as scientific misconduct, such as plagia-rism and selective presentation of results (Korenman et al., 1998;Berk et al., 2000).

Work by David Blumenthal and colleagues has explored theactual experiences of biomedical researchers concerning industry-sponsor control over dissemination of research findings. In onesurvey of life science faculty (including both clinical and nonclin-ical faculty), a significantly higher proportion of faculty withindustry funding than without (27% vs. 17%) reported that publi-cation of their research results had been delayed by more than 6months on at least one occasion (Blumenthal, Campbell et al.,1996; Blumenthal, Campbell et al., 1997). Among researchersreporting publication delays, 28% attributed the delay to thesponsor’s desire to postpone the dissemination of undesiredresearch results. The same survey found that faculty with industryfunding were significantly more likely than faculty without indus-try support to have refused requests from other academic scien-tists to share research results or biomaterials (Blumenthal,Campbell et al., 1996; Blumenthal, Campbell et al., 1997). A sur-vey of pharmaceutical, chemical, and agricultural companiesfound that 58% of companies with academic research relation-ships typically required investigators to keep research results con-fidential for more than 6 months in order to file a patentapplication, and 47% acknowledged occasionally requiring inves-tigators to maintain confidentiality longer than was necessary tofile for a patent (Blumenthal, Causino et al., 1996).

Previous research has also determined that medical schoolresearch administrators do not often ensure that clinical trialagreements contain provisions protecting investigators’ controlover key aspects of clinical trials and dissemination of findings(Schulman, Seils et al., 2002). A study conducted in the early1990s found that 35% of industry-academic research centersacross a range of fields (including medicine) permitted sponsors


to delete information from manuscripts and 53% permitted sponsorsto delay publication (Cohen et al., 1994). Our recent report onresearch administrators suggests that while many institutions arenow more highly attuned to the need for vigilance concerningsuch matters, there is substantial variation across institutions inthe level of stringency exercised in contract negotiations (Melloet al., 2005).

The primary limitation of our faculty survey is a responserate that could suggest the existence of response bias. We couldnot directly determine, on the basis of the available information,whether nonresponders differed systematically from respondersin their views toward clinical trials. We did compare nonresponseacross our six sample strata and found that senior facultyresponded at a significantly higher rate than junior faculty, andindividuals at academic medical centers with low NIH fundingranks responded at a lower rate than those at institutions withmore NIH funding. Both findings support our prior assertionthat the response rate differentials among subgroups in our sam-ple are likely a function of the greater applicability of our study toplaces where more research happens and faculty who have beenmore involved in the research. However, if this assertion is incor-rect, any bias associated with the observed disparities would runin the direction of understating investigators’ permissivenesstoward restrictive provisions, because a statistical association wasobserved between senior faculty rank and relatively stringent views.

We also examined nonresponse by medical specialty andfound significant differences. Physicians in neurology, urology,and dermatology were somewhat more likely to respond to oursurvey, while those in emergency medicine, family practice, oto-laryngology, and psychiatry were somewhat less likely to respond.Internists, our largest physician category, were in the midrange ofresponse rates. We have no explanation for the relationshipbetween response and specialty, nor do we have reason to believeit affects our results.

Another potential source of bias is that many of the surveyquestions dealt with ethically sensitive topics and may have gar-nered untruthful responses. To address this potential problem,we undertook extensive pilot work and formulated questions soas to minimize investigators’ anxiety (for example, by not askingfor reports of actual practices).


Our findings suggest that medical school faculty could benefitfrom additional guidance about what their institution views asacceptable parameters for industry-sponsored clinical trial agree-ments. Research administrators believed that faculty did not have agood understanding of these parameters, and faculty were notalways aware of extant institutional guidelines and policies. How-ever, faculty felt that such policies were or would be useful to them.Efforts by the International Committee of Medical Journal Editors(Editors, 2004) and other external groups to develop policies con-cerning control over industry-sponsored clinical trials have receivedmuch attention, but appear to be of limited usefulness from investi-gators’ perspective. We found that faculty consider it more helpfulto receive tailored guidance directly from their institution.

Clinical researchers have a strong interest in making certainthat the terms of the agreements that they and their institutionenter into with industry sponsors are appropriate. Aside fromensuring that clinical trials are conducted in a manner consistentwith the best principles of science and ethics, well-drafted con-tracts protect investigators from possible coercion (Schulman,Rubenstein et al., 1995) and prevent conflicts with sponsors,which can be personally and professionally devastating. Recentincidents, such as the case of Toronto hematologist Nancy Olivieri,powerfully illustrate the potential hazards of insufficient attentionto these matters (Drazen, 2002; Nathan and Weatherall, 2002;Olivieri, 2003; Schafer, 2004).

However, countervailing pressures may create a conflict ofinterest for investigators. Clinical researchers have a strong pro-fessional interest in obtaining the research funding and opportu-nities that industry sponsors have to offer. Competition for theseopportunities and the professional rewards they bring in terms ofpromotion and reputation may militate against adopting a strin-gent posture towards the language of proposed clinical trialagreements. One might argue that researchers ought to have thesame freedom of contract as other employment seekers in theopen market, but the consequences of their choices may redoundto the detriment of the public in unique ways. Research subjectsand consumers of research findings place their trust in investiga-tors to conduct and disseminate research in an unbiased fashion.However, researchers’ own conflicting interests may make it diffi-cult for them to fulfill their trustee role.


If so, then closer monitoring of researcher relationships maybe appropriate. In addition to educating researchers aboutappropriate ethical standards, both academic institutions (throughinstitutional review boards or conflict-of-interest committees) andmedical journal editors could engage in heightened oversight ofthe content of clinical trial agreements to ensure that their stan-dards are being met. The information in this study should assistacademic medical centers and journals in better fulfilling theirmission of supporting clinical research and instilling a culture ofresearch integrity.

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Documents

researchers' views of the acceptability of restrictive provisions in