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Challenges in Interpreting the OBGYN Literature

The Invisible Hand of Industry

Guo, X. Mona MD*; Barber, Emma L. MD, MS†,‡,§

Author Information
Clinical Obstetrics and Gynecology: June 2022 - Volume 65 - Issue 2 - p 260-267
doi: 10.1097/GRF.0000000000000697
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Abstract

The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness

—Richard Smith, Editor, The Lancet1

Historically, scientific research was funded by the church, crown or through individual and family assets. In modern times, the vast majority of researchers obtain support through a mix of governmental, nonprofit institutions, and for-profit agencies. Over the past several years, however, the balance has shifted toward the private sector due to the general stagnation in federal funding for academia. In the United States, businesses spend $3 on research for every $1 spent by the government.2 This influx of industry investment in scientific research has opened important discourse on biases and conflicts of interest and poses unique difficulties in interpreting the results and conclusions of studies. As such, interpreting any scientific literature requires critical evaluation of the authors, institutions, and any associated funders to truly understand apparent or potential conflicts of interest.

Current State of Industry Involvement in United States Academia

Industry can be involved with academia in a variety of ways, through funding researchers, trials or studies themselves, or the means of knowledge dissemination (Table 1). Due to shifts in budget allocations and priorities, governmental agencies such as the National Institutes of Health or National Science Foundation are no longer the primary funders of basic science research in the United States.2,3 Similarly, over the past decade, the percentage of industry-funded clinical trials has increased by more than 40% while those that are NIH-funded has decreased by almost 25%.4 In fact, 70% of clinical trials in the United States are funded by industry4 and at least one-quarter of investigators and two-thirds of academic institutions have financial relationships with private companies.5

TABLE 1 - Ways That Industry Influences Studies
Funding trials and researchers
 Industry-sponsored trials (ISTs)
 Investigator-initiated trials (IITs)
 Collaborations with contract-reserach organizations (CRO) and site-management organizations (SMO)
 Providing resources, equipment or medications for studies
Funding means of knowledge dissemination
 Sponsored events (meals, travel, etc.)
 Medical conferences
 Journals and guidelines
 Advertisements

Given concerns about conflicts of interest and industry affiliation throughout all levels of academia, the United States Congress enacted the Physician Payments Sunshine Act in 2010 as the most recent step to increase transparency. The Act requires pharmaceutical companies, device manufacturers, and group purchasing organizations to report all transfers of value in both general categories like food and consulting fees, as well as grants and research payment made directly or indirectly to licensed physicians and teaching hospitals.6 These transactions are all reported online in a publicly accessible and searchable Open Payments Database (OPD), with almost 50% of physicians being listed as receiving any type of payment.7 This database may actually represent an underestimate, as a previous survey reported that over 90% of United States physicians had industry relationships.8

FUNDING TRIALS AND RESEARCHERS

In order to perform clinical trials, companies have traditionally required the personnel expertise and patient access afforded by academic medical centers. However, there is an inherent disconnect within these industry-sponsored trials (IST) between the goals of academic institutions, namely teaching and ensuring patient safety, and those of for-profit companies, which value speed and efficiency. Each day’s delay in coming to market equates to millions of dollars lost for the company. This has led to a diversion in direct funding away from academic centers requiring industry-investigator agreements and towards for-profit institutions like contract-research organizations (CRO) and site-management organizations. These commercial organizations employ the necessary investigators, pharmacists, statisticians, and support staff to conduct large multicenter trials, while allowing the company to retain control of the study design, data analysis and subsequent publication. Many new therapeutics in gynecologic cancers are studied through these mechanisms, including the SOLO1 study, published in the New England Journal of Medicine, which is the landmark study of PARP inhibitors in frontline maintenance for women with ovarian cancer and a BRCA mutation.9 In obstetrics, the recent approval of the postpartum depression drug, brexanolone, arose from CRO-assisted clinical trials.10

Clinical investigators or study groups can also directly propose trials to a manufacturer through investigator-initiated trials (IIT). Researchers may have new ideas to expand a product’s use outside of current indications, make different treatment comparisons, or desire to test certain therapeutic parameters. IITs often lead to greater applicability of a product and generate more safety data while providing data in pragmatic, real-world situations that could lead to policy or guideline changes. In these cases, the company provides a drug or device and/or financial support for conducting the study but does not sponsor the trial itself. As such, the study design, recruitment, analysis, and decision to publish can fully rest with the investigator.11,12

FUNDING THE MEANS OF KNOWLEDGE DISSEMINATION

By far the largest percentage of payments in the OPD are attributed to “Food and Beverage” payments, which can likely be explained by interactions during industry-sponsored meals. These luncheons and dinners represent one relatively direct way that companies can share new research, products and services. Similarly, academic conferences allow for industry to reach a large number of providers through not only product showrooms but by hosting symposia, workshops, research presentations, and sponsoring conferences themselves. Multiple studies have shown that a large number of meeting abstract authors and presenters have industry funding.13–17

From abstracts to journal publications to and society guidelines, industry remains intimately involved in every aspect of medical information dissemination. Up to a third of trials published in major medical journals are funded by industry, and these trials are more often cited than trials with nonindustry support. Due to this, increased publication of ISTs is associated with an increased impact factor for the journal itself and thus an increased profit-margin18; for example, omitting ISTs could decrease the impact factor of the New England Journal of Medicine by 15%. The majority of clinical practice guideline authors in various specialties also have financial relationships, mostly in research-related funding.19,20

More conspicuously, advertisements are abundant in research journals and newsletters as they contribute a significant amount to a publication’s annual revenue.21,22 The experience of flipping past pages of ads is part of the consumption of medical literature and companies have consistently spent more on promoting products to the prescriber than other forms of marketing.23 These advertisements are very lucrative (a return of 3 to 5 dollars per dollar invested) and play a large role in influencing provider prescribing habits by highlighting the very latest in research and data.22

WHAT ABOUT OBSTETRICS AND GYNECOLOGY (OB/GYN)?

Few studies have examined the field of OB/Gyn and its interactions with industry. The American Congress of Obstetrics and Gynecology was one of the first professional societies to issue standards on the relationship between providers and industry.24 However, while 65% of surveyed OB/Gyn providers in one study were familiar with these guidelines,25 >75% were comfortable with accepting incentive items and meals from pharmaceutical companies while feeling that they would not be influenced by these interactions. In fact, almost 40% of OB/Gyns surveyed disagreed that industry-physician interactions should be more tightly regulated.

The Sunshine Act has provided some circumferential evidence through the OPD in how OB/Gyn physicians are involved with industry. Half of practicing OB/Gyn providers receive financial payments, although the monetary value is typically less than other surgical specialties.26 Of the subspecialties, female pelvic medicine and reconstructive surgery and gynecologic oncology receive the highest median payment values, with >90% and 75% (respectively) of practicing providers with some industry relationship.26–28 In recent years, while the number of providers receiving general payments have decreased, research-related payments have notably increased.27 This may suggest a shift toward more generally accepted industry-physician relationships such as research funding.

At gynecology-specific research conferences (the annual meetings of the American Urogynecologic Society, Society of Gynecologic Surgeons and Society of Gynecologic Oncology), there was poor accuracy of self-reported disclosures during research presentations when compared against industry-reported disclosures the OPD. Specifically, most presenters were not or incompletely disclosing potentially relevant relationships to their audiences, and those with disclosures tended to have inconsistencies, even between their own presentations.15–17 Although average payment amounts were relatively small, numerous studies have shown that physicians’ practices are influenced by industry affiliations despite believing these relationships to be insignificant or irrelevant.29,30

The Debate

THE CON SIDE

Maintaining objectivity is paramount in ensuring the validity and reliability of any study results, especially ones that will be applied to clinical practice. With increasing industry sponsorship and involvement in research, a main criticism lies in the biases and perverse incentives that arise if monetary gains are contingent on results. Numerous studies have shown that ISTs are more likely to have favorable results than non–industry-related trials, and have positive conclusions that may not align with the results.31–34

This reporting and publication bias may in part be due to industry control of their research. Through CROs and site-management organizations, pharmaceutical companies control the analysis and dissemination of data, which can lead to withholding of unfavorable results not only to the public but even to their own researchers.35,36 Industry-sponsored trials may be prematurely terminated for financial as opposed to clinical reasons, which leads to inappropriate conclusions and an inability to provide valid answers to the hypotheses the study was originally designed to test.35 These exaggerated conclusions are often seen in medical advertisements, which do not often convey the full results and information necessary for safe prescribing. Indeed, almost half of advertisements in a sample of major medical journals failed to adhere to at least 1 of the 21 FDA prescription drug advertising guidelines.37 While not illegal, the existence of data selection and suppression adds a large unknown variable to any data interpretation, and contracts often obstruct researchers from independently publishing any data against the wishes of the manufacturer.4 Moreover, any financial tie with industry in-and-of-itself can lead to undue pressure on an investigator to adjust elements of their publication, regardless of who controls the data.38

Another phenomenon occurring in at least 20% of publications in high-impact journals involves using ghost and guest writers.4,39 Through employing professional medical writers, companies can selectively analyze and/or present their data in the most positive light without needing to disclose authorship. Meanwhile, inviting a prestigious investigator who is uninvolved in the research as a guest/honorary author provides clinical legitimacy and branding to the study without requiring the oftentimes busy investigator to conduct a thorough review of the study design, data, or analysis.40 These instances of inappropriate authorship are hard to uncover but lead to difficulties in interpreting the biases of the underlying work and pose significant implications for scientific accountability.

Many of the above concerns arise when study outcomes are disappointing or financially inadequate to a for-profit organization. Investigators may be placed in a difficult situation balancing their research integrity with a need for continued study funding or publications for academic advancement. With inflated or inappropriately interpreted results, equivalently efficacious or even inferior products may obtain approval and lead to cost inflation for the end-users of these studies: patients and the medical system.

THE PRO SIDE

On the other hand, it takes millions to billions of dollars to bring a new drug or device to market, and for-profit companies are much better situated to invest the capital required in personnel and infrastructure. As national funding for research and development has continued to decrease over the past decade, corporate sponsors have picked up much of the monetary slack. Basic economic principles of market competition lead to innovation and scientific developments; without industry support, many of the major medical advancements of the past few decades would not have come to clinical use. What is more, the efficiency of a corporate structure allows for a much more expedited timeline in bringing novel therapeutics to market.

Despite concerns with reporting biases, trials funded by for-profit organizations often have better methodologic quality,31 likely due to greater financial support, resource availability, and the need for accountable results which will pass muster of regulatory bodies. One cross-sectional study found that randomized controlled trials in high impact journals with industry collaboration, as opposed to only industry funding, were more likely to use high quality methods such as blinding and intention-to-treat, while not having a greater likelihood of positive results.41 This finding contradicts earlier research but may be due to a recent shift in trial and article guidelines that were created in response to publication concerns.

Proponents further emphasize the role of industry in education, whether through advertisements or sponsored events. Research is published at such speeds that it is increasingly challenging for the modern physician to stay up to date on the newest medication or devices, or to stay current on practice-changing guidelines. Interestingly, patients also express little to no worry about industry relationships and would nevertheless proceed with a clinical trial despite knowing that their provider was paid by the pharmaceutical company.42,43 In general, physicians broadly perceive collaboration with pharmacy and industry as appropriate as well. This attitude was particularly notable for surgical specialties which may reflect the complex relationships with device manufacturers and industry representatives that are necessary for their practices.44

Guidelines for Interpreting the Literature

It is clear that industry involvement in medical literature is here to stay and may have benefits to the advancement of medical science. OB/Gyn is a diverse field with industry relationships evident in cancer therapeutics, prenatal genetic testing, implantable medical devices, medical therapies, and surgical devices. As such, it is crucial that obstetricians and gynecologists are equipped to evaluate the medical literature in the context of the current environment (Table 2).

TABLE 2 - Questions to Ask When Evaluating Industry-funded Studies
General information
 Who are the authors? What are their affiliations?
 Who are the authors? What are their affiliations?
 Are there any funding sources? If so, how do the interests of the funding source align with the research itself?
 Is there a contract-research organization or site-management organziation involved?
 Are there undisclosed payments (research, or otherwise) on the Open Payments Database, openpaymentsdata.cms.gov?
Methodological evaluation
 What is the hypothesis and the study design?
 Is the hypothesis able to be answered by this study design?
 What is the primary endpoint? Is it clinically meaningful?
 Are there surrogate endpoints? If so, would these change clinical practice?
 What is the comparator arm (if any)? Is this comparator arm the standard of care?
 Is the trial adequately powered to answer the outcomes of interest?
Additional considerations for clinical trials
 Is this trial listed on clinicaltrials.gov?
 Does the reported study design match with the plans uploaded to clinicaltrials.gov?
 Are the published analyses prespecified?
 Is there a data safety monitoring board or external oversight?

It perhaps goes without saying, but when evaluating a new clinical trial or addition to the medical literature, first, one must get back to the basics. The study design should be clearly stated in the methods and the reader should evaluate whether the hypothesis proposed to be tested is appropriate for such a study design. In addition, the primary endpoint, the endpoint for which the study is powered, should be clinically meaningful. Surrogate endpoints should be evaluated in their clinical context and the reader should determine if effects on this surrogate is something that would drive their clinical practice. If the study has multiple arms, the comparator arm should be evaluated. Does the comparator arm describe the standard of care and how might the comparator arm influence enrollment and results? Oversight by an institutional review board must be discussed and the approval number specifically listed.

Clinical trials have further specific protections and reporting mechanisms which are important to evaluate. All clinical trials are required to be described and their study plans uploaded to clinicaltrials.gov before the start of the trial. Hypotheses are prespecified and must be recorded here. Furthermore, the Federal Food and Drug Administration Amendments Act requires that study results must be uploaded to the website within 1 year of trial completion. Unfortunately, compliance with this is poor with 40.9% of studies uploading results within the 1-year deadline and 64% uploading them at any time point.45 This is true for both industry and non–industry-funded studies.46 When evaluating a new clinical trial, the reader should be wary of analyses which were not prespecified and even if prespecified, are not the primary outcome as the trial may not be appropriately powered to answer such a question. If this is unclear to the reader, upon review of the manuscript, clinicaltrials.gov can be a helpful repository of information. Data safety and monitoring boards are also required for multisite trials and for trials which test the effectiveness of an intervention where the potential for toxicity is more than low risk. Use of data safety and monitoring boards should be described in the methods.

In regard to funding, all manuscripts should list relevant funding sources as well as potential conflicts of interest of the authors. Author affiliations are also an important source of information as some authors may be employees of the company which may indicate a more active role in the study design, execution, and scientific writing. The details of the payment should also be specified. Payments to the authors’ institution in the form of research dollars are an IIT structure which allows the trial design and oversight to be done within the academic institution. Payments to the authors themselves may indicate advisory boards, speaker’s bureaus or consulting fees. These relationships should be put into context of what is being studied and what the company would gain given the results. It can sometimes be difficult to discern the nature of the relationship from disclosures published along with the article. This is where the OPD can be helpful as it can be used to distinguish research payments to institutions which are not recorded, research grant payments to an individual which are recorded, and payments to the prescribing physician themselves. In addition, the dollar amount noted in the database may be instructive as higher dollar amounts may indicate a deeper relationship between an author and the company. Furthermore, many journals will list the contributions of various authors, assuring that all authors had access to the data or that the data was not only analyzed by industry partners may help to ascertain biases.

Industry involvement in research in obstetrics and gynecology is prevalent and growing. These relationships have the potential for bias and conflicts of interest, but they also have the benefits of furthering the field and providing much needed funding and innovation. It is important for physicians to realize that information disseminated by industry is oft biased, and their aim is persuasion as opposed to education. Understanding the nature of these relationships is an important part of reading and interpreting the medical literature. Through a careful review of most manuscripts, the majority of these relationships can be discerned, and the literature interpreted with this context. In situations where relationships are unclear, resources such as clinicaltrials.gov and the OPD are helpful adjuncts.

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Keywords:

conflict of interest; financial disclosure; clinical trials; bias; industry funding

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