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Featured Report:
Influence of Funding Source on Outcome, Validity,
and Reliability of Pharmaceutical Research
(A-04) Full Text

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Background of Report
Introduction
Sources of Publication Bias
Investigators and Authors
Journal Editors and Reviewers
Clinical Trial Agreements
Outcome Bias
Funding Source and Outcome
Funding Source and Publication Outcome or Status
Potential Remedies
Investigators and Authors
Uniform Institutional Practices
Journals and Journal Editors
Voluntary Industry Guidances
Other Recommendations to Reduce Publication Bias
Summary and Comment
RECOMMENDATIONS (Adopted AMA Policy)
References

NOTE:  This report of the Council on Scientific Affairs, presented as CSA Report 10 at the 2004 AMA Annual Meeting, represents the medical/scienfitic lliterature on this subject as of June 2004.

Background of Report

Resolution 514 (A-03), introduced by the American Psychiatric Association and the American Academy of Child and Adolescent Psychiatry and referred to the American Medical Association (AMA) Board of Trustees, asked that the Council on Scientific Affairs (1) study the impact of funding sources on the outcome, validity, and reliability of pharmaceutical research; and (2) develop guidelines to assist physician-researchers in evaluating and preserving the scientific integrity, validity, and reliability of pharmaceutical research, regardless of funding source.

Considerable research has been conducted on the issues raised in Resolution 514, and systematic reviews on the subject have been recently published. This report summarizes the findings of these reviews, updates new information, provides some perspectives on the topic, and offers some recommendations on how the AMA can continue to assist in improving the scientific integrity, validity, and reliability of pharmaceutical research. JAMA and other major-impact medical journals also have recently taken steps to address the problem of publication bias and to properly identify the conflicts of interest that inevitably emerge with the sponsorship of a market-driven enterprise such as prescription drug approval.

Methods: Literature searches were conducted in the MEDLINE and Lexis-Nexis databases for English-language review articles published between 1985 and 2003 using the search terms clinical trials; drug industry; financing, organized; publishing; and research or research support, in combination with economics or standards. This search identified 12 systematic reviews on the relationship between pharmaceutical industry sponsorship and research outcome, quality, or publication bias. Three of these reviews evaluated previously published information on the relationship between industry funding and outcome or quality; more than 2000 original studies were included in the original studies covered by these reviews.1-3 The findings of these 12 systematic reviews form the basis for discussion in this report. Recently published articles not covered in these systematic reviews and other original studies and editorials relevant to related issues also were analyzed. In addition, the draft report was offered to the AMA’s Council on Ethical and Judicial Affairs for its review and contribution to the discussion in the "Potential Remedies" section (see below). 

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Introduction

The results (and analysis) of clinical research that are published in peer-reviewed journals inform most treatment decisions, and influence public and private health care policy. A longstanding concern exists about the potential for publication bias in pharmaceutical research. Publication bias is the selective publication of studies based on the direction (positive), magnitude, and statistical significance of the treatment effect. Publication bias is often attributed to decisions made by author/investigators and journal editors, but in fact can intrude during the entire process of planning and conducting the clinical trial and publishing the results, leading to outcome bias.4

Studies with positive findings are more likely to be published than studies with negative or null results and an association exists between pharmaceutical industry sponsorship of clinical research and publication of results favoring the sponsor's products.1-3,5-16 Additionally, the publication of negative results may be delayed compared with the time to publication of studies with positive results. This relative time lag is not limited to industry-sponsored trials.17

This pattern of publication distorts the medical literature, thereby affecting the validity and findings of systematic reviews and meta-analyses, the decisions of funding agencies, and ultimately the optimal practice of medicine. However, without pharmaceutical industry sponsorship, important therapeutic advances would not have occurred. Modern drug therapy has changed the clinical landscape and represents a cost-effective intervention for disease prevention and treatment. Productive collaborations between the pharmaceutical industry and academic medicine or other research organizations have flourished over the last 30 years enabling a steady stream of new and innovative treatments to improve patient care. In 2002, total grant spending for clinical trials involving human subjects was approximately $5.6 billion, with more than 70% provided by the biopharmaceutical industry. If device manufacturers are included, the total fraction of grant support rises to 80%, with the remainder ($1.1 billion) supplied primarily by the National Institutes of Health (NIH).18 In 2002, approximately 50,000 clinical investigators received funding for at least one clinical trial conducted in the United States.18

Publication bias involving industry-sponsored trials may be exacerbated because many drug trials are conducted to gain regulatory approval, not to test a novel scientific hypothesis or to examine relative therapeutic efficacy versus another treatment. Much of the clinical trial information is unpublished at the time of marketing. Physicians would like to know how one drug compares with other available therapeutic options, and the health care system wants to take cost utility into account, but such information is usually not available initially and may never become available. These deficiencies raise broader issues related to drug approval and marketing. 

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Sources of Publication Bias

Investigators and Authors. One direct source of publication bias is the failure of investigators to submit completed research for publication.19-21 Quantitative studies with significant results are more likely to be submitted, and studies with positive results are submitted more rapidly. Given available time and resources, some investigators are unwilling to submit studies with null or unimportant results because they believe the manuscript will be rejected anyway.

Also, investigators (including academic faculty who receive industry funding) may be subject to prepublication review or restricted access to data. Cross-sectional surveys indicate that industry-sponsored faculty are more likely to report restrictions on the dissemination of their research findings and to be denied access to the entire data.22-25 Delayed publication may occur because of clinical trial agreements that require information to remain confidential for an extended period to enable patent protection, protect a corporate "lead" in the field, or resolve disputes over intellectual property.22-25 Another behavior of academic faculty that is associated with pharmaceutical sponsorship or the presence of commercial agreements is refusal to share information with colleagues.24,25

Because pharmaceutical companies now exert more direct control and ownership of the clinical trial process, published reports also may contain declared authors who have not participated in the design or interpretation of the study, with only limited access to the original data.

Journal Editors and Reviewers. As mentioned above, authors may fail to submit negative studies because of fear of rejection by journal editors. The ideal articles for journals are those with findings that will affect clinical practice. Indeed, instructions to authors may contain phrases such as the journal "gives priority to reports of original research that are likely to change clinical practice or thinking about a disease."26 Under this rubric, even confirmatory trials (positive or negative) would achieve lower priority. In terms of external advice received by journal editors, selected referees may demonstrate bias against papers with results that are contrary to their own perspectives. This type of confirmatory bias, in which the referees' judgment is colored by their own preconceptions and experience, contributes to poor interrater reliability.27 In a study of articles submitted to JAMA from 1996-1999 that reported results of controlled trials involving an intervention and comparison group, the odds ratio for publishing studies with positive results was 1.30. This difference in publication rates between those with positive and negative results was not statistically significant, suggesting publication bias was not evident in editorial decision-making.28

Clinical Trial Agreements. A large percentage of companies providing support for clinical research obtain patents and market products as a result of this relationship. One survey revealed that 53% of signed clinical trial agreements in a sample of university-industry research centers allowed publication to be delayed, 35% allowed the sponsor to delete information from the publication, and 30% allowed both.22 Commercial interests and intellectual property are often the main reasons for lack of publication of clinical studies funded by the pharmaceutical industry.29,30 In the last decade, some high-profile cases of direct interference have been noted.31-34

Nevertheless, industry's dependence on academia has lessened in the last decade with a shift to contract research organizations (CROs), site management organizations, and commercial drug trial networks.34 There are several reasons for this development, including changes in the pharmaceutical industry itself (ie, employment of competent researchers to design, run, and interpret trials) and the fact that CROs have been able to use community physicians as a reliable source of patient enrollees, can run trials less expensively and more efficiently than academic medical centers, and generally impose a less cumbersome trial agreement process.

Outcome Bias. When control lies with the commercial rather than academic or public sector, bias can also envelope the process through the trial design.4,36 Outcome bias can result from the use of unreliable methods or instruments, as well as inadequate sample size or comparison groups. Favorable results are more likely if: (1) the drug is tested in a healthier population (ie, younger, fewer comorbidities, milder disease) that is not representative of the actual patient population that will take the drug; (2) the drug is compared with an insufficient dose of an alternate product; or (3) multiple surrogate endpoints (which may not correlate with more important clinical endpoints) are studied but only results favoring the product are published. Industry-funded studies are also much more likely to use placebos or inactive controls, a practice that increases the likelihood of achieving positive study results.7,15

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Funding Source and Outcome

For reasons cited above, growing concern exists about the influence that industry sponsorship exerts on clinical trial design and outcome, academic freedom, transparency in the research process, and ultimately, the public good. With regard to the extent of financial relationships, at least $1.5 billion flows from industry to academia annually, so a significant percentage (at least 25%) of academic investigators receive industry funding for their biomedical research, and at least one-third have personal financial ties with industry sponsors.26 Correspondingly, many universities may hold equity in the sponsor's business (as well as accept funding).

Because of these financial relationship, questions have been raised about whether such financial relationships could create institutional conflicts of interest involving research integrity and/or the safety and welfare of human subjects. Because of the increasing trend for faculty researchers to be involved in financial relationships with their research sponsors, Boyd and Bero37 concluded that "guidelines for what constitutes a conflict and how the conflict should be managed are needed if researchers are to have consistent standards of behavior among institutions." In keeping with this recommendation, the Association of American Medical Colleges (AAMC) formed a task force on conflicts of interest in clinical research. In 2002, the task force released a report that provided guidance on addressing the financial interests of faculty, as well as other individuals involved in the clinical research enterprise.38

Funding Source and Publication Outcome or Status. Results of 3 recent systematic reviews confirm that industry-sponsored research tends to yield pro-industry conclusions.1-3 Even among comparison trials, the sponsor's drug is almost always deemed equivalent or superior to the comparator.12

The favorable relationship between funding source and outcome extends to pharmacoeconomic studies and sponsored meta-analyses.2 Authors who have financial relationships with pharmaceutical companies may be more likely to produce proindustry conclusions.39 This fact and other evidence support the notion that conclusions are generally more positive in trials funded by the pharmaceutical industry, in part due to biased interpretation of trial results.40

Although lower quality studies lend themselves inherently to biased results, this does not appear to account for the relationship between industry funding and the bias towards positive published outcomes. With one major exception,41most authors have concluded that industry-funded studies published in peer-reviewed journals are of equivalent or higher quality than non-industry funded clinical trials.7,8,41-43 This view does not necessarily apply to industry-sponsored symposia journal supplements. Research funded by drug companies is more likely to be published in the proceedings of symposia than non-industry sponsored research.44 Some, but not all studies have concluded that randomized controlled trials published in these supplements were generally of lower quality, although the relationship between funding and positive outcome persists.8,45,46

Despite these consistent findings over the last 15 years, results of a recent pilot study of randomized controlled trials published in 5 leading medical journals (including JAMA) failed to document any association between funding source, trial outcome, and study quality.47 This could reflect the beneficial effects of more stringent editorial policies that have been adopted by the editors of these journals.

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Potential Remedies

Investigators and Authors. In addition to ethical and legal guidelines that are intended to help protect human subjects, individual investigators should be mindful of guidelines developed to prevent or mitigate potential conflicts of interest that could lead to publication bias. In particular, 2 ethical opinions included in the AMA’s Code of Medical Ethics, E-8.031, "Conflicts of Interest: Biomedical Research," and E-8.0315, "Managing Conflicts of Interest in the Conduct of Clinical Trials," (AMA Policy Database), recommend the disclosure of financial compensation from or other material ties to companies whose products they are investigating to various stakeholders, including journals editors. It is also recommended that physicians should not enter into research contracts that permit the sponsoring company to unduly delay or otherwise obstruct the presentation or publication of results.

Uniform Institutional Practices. A 2001 report issued by the U.S. General Accounting Office noted that equity ownership or investment in a research sponsor may "color [an institution’s] review, approval, or monitoring of research…or its allocation of equipment, facilities, and staff for research."48 In response to these concerns, the AAMC task force authored a second report that laid out a conceptual framework for assessing institutional conflicts of interest in human subjects research.49 As a fundamental principle "institutions should ensure that, in practice, the functions and administrative responsibilities related to human subjects research are separate from those related to investment management and technology licensing." The report also contained a series of recommendations regarding: (1) authority/responsibility of institutional officials; (2) circumstances or other financial relationships that should trigger close scrutiny; (3) an appropriate internal committee structure and review process; (4) institutional behavior within the confines of multi-center or single, primary site trials; (5) use of external institutional review boards (IRBs); (6) conditions where recusal may be warranted; (7) policies applying to IRB members; and (8) disclosure requirements.

Journals and Journal Editors. The publishing community has taken steps to increase the quality of published reports and to reduce publication bias associated with clinical trials and the conflicts of interest that may arise out of industry funding of investigators. The Consolidated Standards for Reporting of Trials Group (CONSORT) developed a statement intended as an evidence-based approach to improve the quality of reports emanating from randomized controlled trials (RCTs). Originally published in 1996 and revised in 2001, the CONSORT statement comprises a checklist and flow diagram for the reporting of RCTs, primarily those constructed as parallel-group studies.50 The checklist includes items, based on evidence, that need to be addressed in the report to avoid biased estimates of treatment effect and to properly evaluate the findings. The flow diagram assists readers in analyzing the progress of trial participants from the time they are randomized until the end of their involvement with the trial. Adoption of the CONSORT statement by journals (including JAMA) is associated with improvement in the quality of published reports.51 Companion efforts to increase the quality of meta-analyses of RCTs (QUOROM), observational studies (MOOSE), and assessments of diagnostic tests (STARD) have been drafted or are under way.

Journal editors also have taken steps to reduce publication bias by revising the "Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication." This document was developed by the International Committee of Medical Journal Editors (ICMJE) and is widely used as the basis for editorial policy. The revision established more rigorous criteria for the acceptance of research sponsored by the pharmaceutical industry, particularly regarding declaration of potential conflicts of interest related to individual authors’ commitments or project support. Among the salient points are:

  • researchers should not enter into agreements that interfere with their access to the data or their ability to analyze the data independently, to prepare manuscripts, and to publish them.
  • authors should describe the role of the study sponsor(s), if any, in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the report for publication.

These tenets hold that the sponsor must impose no impediment, direct or indirect, on the publication of the study's full results, including data perceived to be detrimental to marketing of the drug. Journals adhering to this approach will not review or publish articles based on studies that are conducted under conditions that allow the sponsor to have sole control of the data or withhold publication.52 Accordingly, journals should encourage a culture of transparency in research and reporting by publishing study protocols and publishing all data from drug studies, including negative results, in concert with a comprehensive trials registry (see below) and development of accessible electronic databases.

Voluntary Industry Guidances. In recognition of the need for proactive involvement of the pharmaceutical industry in addressing publication bias, the Pharmaceutical and Research Manufacturers of America adopted voluntary principles on its members’ relationships with those involved in the clinical research process.53 While these principles "commit to timely communication of meaningful results of controlled trials…that are approved for marketing regardless of outcome," they do not commit "to mak[ing] the designs of clinical trial protocols available publicly at inception, as in a clinical trials registry."

Staff from a small cadre of pharmaceutical companies have also developed guidelines for good publication practices, which they have offered for voluntary use by sponsors when they seek to publish results from their clinical trials.54 The Good Publication Practice for Pharmaceutical Companies is intended for use in conjunction with the ICMJE-derived "Uniform Requirements" and the CONSORT statement. The guidelines cover publication standards, including a commitment to publish results from all clinical trials; premature, duplicate, or redundant publication; contractual relationships between sponsors and investigators; study tags or identification; and authorship, including the role of professional medical writers. The guidelines and a list of pharmaceutical companies and CROs that have endorsed their use can be found at www.gpp-guidelines.org.

Other Recommendations to Reduce Publication Bias. A number of other steps have been recommended to address the problem of publication bias, to improve the quality and reliability of published drug studies, and to assist physicians in accessing, summarizing, and applying information on new drug treatments.

  1. Register all clinical trials at inception.55 Over the last 30 years there have been a number of events and initiatives related to the goal of trial registration. Industry, government, and certain collaborative registers have been formed (see Table), but no comprehensive system for tracking, organizing, and disseminating information about ongoing clinical trials currently exists. This could be implemented by having the Department of Health and Human Services, the parent agency that encompasses the NIH and the Food and Drug Administration, take responsibility for ensuring trial registration in the United States. A recent example of such collaborative action is the GemCRIS system for registration of gene-transfer studies and facilitated reporting of adverse events.

Institutional review boards could make registration a condition of approval. Industry compliance would also be enhanced if both the researcher and the individual patient insist that the trial be registered before enrollment, with explicit language to that effect in the informed consent document. Finally, legislation to fund, require, and enforce public registration of all trials involving human subjects (regardless of funding source) could be sought. While clinical trial registers address some problems, their effects on patient care will be limited unless they are backed by sound publication policies.

  1. Reduce bias in study design36 by conducting studies of comparative effectiveness and requiring data comparing new drugs with available alternatives for effectiveness and cost as part of the regulatory approval process. Alternatively, to provide physicians with the kind of information needed for optimal treatment decisions, establish a center for the assessment of pharmaceutical effectiveness funded by subscription fees on third-party payers, contributions by payers to address specific research questions, user fees, or taxes on pharmaceutical products.
  2. Reduce bias in study conduct36 by leaving the planning and monitoring of the research design completely to the funded investigators.

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Summary and Comment

When an investigator has a financial interest in or funding from a company with activities related to his or her research, the research is more likely to favor the sponsor's product, less likely to be published, and more likely to have delayed publication. Investigators and academic institutions can help ensure the integrity of clinical research by negotiating ethically acceptable contracts that allow full access to data and control of publication rights. Publication bias involving drug studies has been reduced by journal editors who have adopted the revised CONSORT statement, and via revision of the "Uniform Requirements" by the ICMJE. Adoption of these guidelines helps readers make informed judgments about clinical trials and potential biases involving authors, data analyses, and publication/interpretation of results. Thus, guidelines are already established that "assist physician-researchers in evaluating and preserving the scientific integrity, validity and reliability of pharmaceutical research, regardless of funding source" as requested by Resolution 514 (A-03).

Additionally, some progress has been made in registering clinical trials at inception. Development of a comprehensive trials registry will require a cooperative venture among all participants. Development of a registry will not guarantee publication of results, but would assist authors conducting systematic reviews and meta-analyses in identifying relevant studies for inclusion. Electronic databases that can serve as a repository of published results are needed to accommodate all trial results. Absent legislative action, IRBs and patient advocates form a potentially powerful coalition in requiring clinical trials involving human subjects to be registered as a condition for approval.

RECOMMENDATIONS (Adopted AMA Policy)

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of Delegates as AMA policy and directives at the 2004 AMA Annual Meeting:

  1. All medical journal editors and authors should adhere to the revised CONSORT Statement and Uniform Requirements for Manuscripts Submitted to Biomedical Journals. (Policy)
  2. The AMA recommends that (a) the Department of Health and Human Services establish a comprehensive registry for all clinical trials conducted in the United States; (b) every clinical trial should have a unique identifier; and (c) all results from registered clinical trials should be made publicly available through either publication or an electronic data-repository. (Policy)
  3. The AMA urges that Institutional Review Boards consider registration of clinical trials to an existing registry as condition of approval. (Policy)

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Table. Clinical Trials Registers

Register

Description/Comment

Information

Government

National Institute of Mental Health

Trials of pharmacologic agents
(1967-1972)

  

National Institutes of Health (NIH)

Years 1975-1979
Year 2000-present
HIV/AIDS trials


www.ClinicalTrials.gov
www.aidsinfo.nih.gov

NIH and the Food and Drug Administration

GemCRIS. Gene therapy trials from 1989-present

www.gemcris.od.nih.gov

United Kingdom

National Health Service Research Medical Research Council Trials

www.doh.gov.uk/research
www.controlledtrials.com

Collaborative Efforts

Oxford Database of Perinatal Trials

Comprehensive register of published trials (1986-1993)

Oxford University Press

Cochrane Central Register of Controlled Trial

Comprehensive register of controlled clinical trials identified by the Cochrane Collaboration

www.cochrane.org

TrialsCentral

Online register of >200 US-based trials registers

www.trialscentral.org

Current Controlled Trials

Meta register compilation of individual registers

www.controlled-trials.com

Industry Register

CenterWatch

Compilation of >41,000 active industry and government-sponsored trials

www.centerwatch.com

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References

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