Results A total of 190 papers describing 195 studies met inclusion criteria. Financial ties between principal investigators and the pharmaceutical industry were present in 132 (67.7%) studies. Of 397 principal investigators, 231 (58%) had financial ties and 166 (42%) did not. Of all principal investigators, 156 (39%) reported advisor/consultancy payments, 81 (20%) reported speakers’ fees, 81 (20%) reported unspecified financial ties, 52 (13%) reported honorariums, 52 (13%) reported employee relationships, 52 (13%) reported travel fees, 41 (10%) reported stock ownership, and 20 (5%) reported having a patent related to the study drug. The prevalence of financial ties of principal investigators was 76% (103/136) among positive studies and 49% (29/59) among negative studies. In unadjusted analyses, the presence of a financial tie was associated with a positive study outcome (odds ratio 3.23, 95% confidence interval 1.7 to 6.1). In the primary multivariate analysis, a financial tie was significantly associated with positive RCT outcome after adjustment for the study funding source (odds ratio 3.57 (1.7 to 7.7). The secondary analysis controlled for additional RCT characteristics such as study phase, sample size, country of first authors, specialty, trial registration, study design, type of analysis, comparator, and outcome measure. These characteristics did not appreciably affect the relation between financial ties and study outcomes (odds ratio 3.37, 1.4 to 7.9).

Objective To examine the association between the presence of individual principal investigators’ financial ties to the manufacturer of the study drug and the trial’s outcomes after accounting for source of research funding.

The movement towards transparency provides an opportunity to examine the extent to which investigators’ financial ties are associated with positive study outcomes. Several studies have examined this relation. 17 18 19 20 21 22 23 24 25 However, in most of these studies individual investigators’ financial ties were not disentangled from the funding source for the study. These two variables, although related, are different. Funding is awarded to institutions and represents professional gain, not personal financial gain. In addition, most previous studies have been limited to one specialty, 17 18 19 20 21 drug type, 22 23 or journal. 24 25 Some studies have found a positive association between investigators’ ties and outcomes, 19 20 21 23 24 25 and others have found no association, 17 18 22 although some negative studies may have been insufficiently powered. We examined the relation between financial ties with industry of principal investigators and study outcome across a random sample of RCTs published in 2013, which represents a cross section of the evidence base. We specifically focused on RCTs that examined the efficacy of drugs, because these studies have a high impact on both clinical practice and healthcare costs. We hypothesized that principal investigators’ financial ties with industry would be independently associated with positive study outcomes.

Relationships with industry are common among investigators, raising concerns about the effect that financial ties between researchers and industry may have on the evidence base. 11 12 In recent years, these concerns have led to calls for transparent reporting of these relationships. 13 As a result, many journals now require authors to report their financial ties by using the International Committee of Medical Journal Editors’ (ICMJE) disclosure form of competing interests. 14 The ICMJE recommends that all trials should be pre-registered in databases such as clinicaltrials.gov to minimize publication bias and increase transparency around trial conduct. 15 However, not all journals enforce the recommendations. 16 Even when trials are registered, the lack of publication of negative trials can diminish the effect of these policies. 4

Randomized controlled trials (RCTs) are considered the most reliable form of evidence in evaluating the safety and efficacy of drugs. 1 Because results of RCTs shape the evidence base, objectivity in the conduct of clinical trials has important implications for clinical practice and the health and safety of patients. 2 However, critics worry that involvement of the pharmaceutical industry may bias the design and interpretation of RCTs. 2 3 4 5 In a 2002 survey of 3247 National Institutes of Health scientists, 15.5% admitted to changing the design, methods, or results of a study in response to pressure from a funding source. 6 A systematic review of the role of funding on study outcome showed that industry funded studies were more likely than non-industry funded studies to have positive efficacy results (risk ratio 1.24, 95% confidence interval 1.14 to 1.35). 7 In addition, industry can subtly influence the conduct of RCTs through financial means other than study funding, including paid consultancy fees and honorariums to physicians. 8 9 Such relationships may alter physicians’ perceptions of the company’s products in a favorable light. 5 10

Methods

Search strategy We searched Medline for RCTs published between 1 January 2013 and 31 December 2013 in “core clinical” journals, as identified by Medline, and limited to English language, human subjects, and titles with available abstracts. Our search yielded 2851 papers.

Inclusion and exclusion criteria Eligible studies were RCTs evaluating the efficacy of drug interventions. We included studies in which the drug of interest was specified (for example, to determine whether eritoran, a TLR4 antagonist, would significantly reduce sepsis induced mortality)26 and excluded head-to-head studies in which the drug of interest was not specified in the paper or in clinicaltrials.gov, because we would be unable to determine whether the study was positive or negative. We excluded non-drug studies, such as studies of devices, supplements, and biomarkers. We also excluded non-primary studies, which included meta-analyses, subgroup analyses, and follow-up studies. We excluded studies without an identifiable funding source. We also excluded studies that did not have searchable financial ties because the manufacturer of the drug of interest was unclear.

Patient involvement We did not include patients in this study. Our focus was published RCTs. Patients were not involved in any part of the research process.

Preliminary screen and sample size calculation The 2851 titles and abstracts identified in the search were screened by one of four non-clinician abstractors (AA, RA, SS, AW) for possible relevance. Of the 1101 potentially relevant studies identified, we used a random number generator to select 250 for review. We did a κ test on a sample of 20 studies to determine the strength of the inter-rater agreement on study inclusion. κ was 0.87 (RA/AW) and 0.69 (AA/SS), indicating a high level of agreement for each pair. In the preliminary review, 87 of 250 papers met the inclusion criteria. We determined the prevalence of financial ties among principal investigators in this initial sample (financial ties were present in 78% of studies with a positive outcome and 59% of those with a negative outcome). On the basis of the prevalence of financial ties in positive and negative studies, we determined that we needed a total of at least 184 papers that met inclusion criteria to test our hypothesis. Using a random number generator, we randomly selected an additional 396 papers for full text review, of which an additional 148 studies were identified for inclusion. A total of 235 papers were identified for possible inclusion by non-clinician abstractors.

Final sample All 235 papers identified in the preliminary assessment were independently reviewed by two clinician reviewers (SK and DK) for inclusion. Disagreement on inclusion was resolved by discussion. A total of 45 papers were excluded in this stage.

Main outcome variable We focused on the results section of each paper to identify outcomes. The primary efficacy outcome was the outcome of interest and had to be specified in the trial publication or on clinicaltrials.gov. We defined the study outcome as positive if the hypothesis was supported for the primary efficacy outcome of the study and negative if it was not. For superiority studies, the study outcome was defined as positive if the drug of interest was statistically superior to the control (eg, P<0.05). For non-inferiority studies, the study outcome was defined as positive if the drug of interest was not significantly worse than the control (statistically non-significant difference). In studies with multiple primary efficacy outcomes, we considered the study to be positive if at least one efficacy outcome was positive for superiority studies and not significantly different from the control in non-inferiority studies. For the five papers that included multiple studies, we abstracted data on the outcome for each study separately. Study outcomes were assessed independently and in duplicate. Any disagreement was resolved by discussion.

Main independent variable We searched for financial ties among principal investigators, who we defined as the first author and senior author (last author) of each paper because these authors are generally most involved in major decisions about studies. If a study specified additional authors as first authors or senior authors, we included them all and considered them all to be principal investigators. We defined a financial tie as the direct compensation of a principal investigator by the manufacturer of the drug of interest in the form of advisor/consultancy payments, employee relationships, honorariums, speaker’s fees, stock ownerships, and travel/meal fees. We categorized papers in which the financial tie was not specified (eg, “financial interest with X company”) as “type not specified.” We also considered a financial tie to be present if the principal investigator was a named inventor of a patent related to the publication. Financial ties were limited to the drug company that manufactured the drug and did not include any parent company of the manufacturer. For the few papers in which the manufacturer was not disclosed in the publication, we searched clinical trial registries and Google to identify the manufacturer. The unit of analysis was the study; any financial tie present for any study principal investigator resulted in the study being assessed as having a financial tie. We searched five different sources for financial ties: the trial publication, Medline for other publications by the principal investigators, Google, ProPublica’s Dollars for Doctors, and the US Patent Office. We defined a financial tie as self reported if it was disclosed in the trial publication. We searched for additional financial ties in the other four sources outlined above. We report both self reported financial ties and the total financial ties (sum of the self reported financial ties and the financial ties identified via the additional search). Our method for searching for additional financial ties was based on a previously described method that used Medline and Google.27 In Medline, we reviewed the first 10 publications of each principal investigator in which the principal investigator was either first or senior author. We limited the search for financial ties to the two years before the online publication date of the RCT. When we identified a financial tie, we confirmed the identity of the investigator of interest by matching his or her reported institutional affiliation with the one documented in the article. In Google, we combined the principal investigator’s name with the name of the drug manufacturer and reviewed the first five pages of Google search results.27 We expanded our search and also included ProPublica’s Dollars for Doctors and the US Patent Office. In both these sources, we searched the principal investigator’s first and last name and reviewed all results in the two years before the online publication of the paper. For each study, one of four abstractors (AA, RA, SS, AW) identified the financial ties of the study authors and abstracted all the characteristics of the study, and a second abstractor independently verified the presence of a financial tie and abstracted all characteristics. Any disagreement was reviewed by two clinician reviewers (SK and DK) and resolved by consensus.

Covariates Our main covariate of interest was industry funding (dichotomized to any industry funding versus no industry funding) because several studies have found that industry funding is associated with positive study outcomes.72829303132 We abstracted funding information from the information listed in the published trial and trial registries. We also collected data on multiple characteristics of studies that we thought may be related to the presence of financial ties, including RCT phase (phase III versus other), sample size (separated into four quarters), first author’s country of origin (US versus other; if there were multiple first authors, we used the first listed author’s country), specialty (cardiology versus oncology versus other), trial registration (registered versus unregistered), type of analysis (superiority versus non-inferiority), study design (active comparator versus placebo or nothing), outcome measure (clinical versus surrogate endpoint), and blinding (double blind versus other).