25 May 2022  How do YOU respond to Conflicts of Interest?
A prominent endocrinologist is a keynote speaker at a primary care conference that has attracted “Platinum, Gold, and Silver” sponsors. To begin her presentation on evidence about a new diabetes drug, she shows for one second a mandatory conflict of interest (COI) disclosure, indicating paid consultancies to Janssen and Novo Nordisk, and clinical research grants from Eli Lilly and Merck.
In the audience, many don’t seem to notice how rapidly the issue of possible bias was dismissed. Clinical pharmacist Kirsten has a different response. Potential COI piques her interest; she feels challenged to identify possible biases in the presentation. In this setting, how do YOU respond?
Infectious disease specialist Xavier notes that “conflicts of interest are normalized in our profession to the point that not having a COI is unusual.” With an important role in antibiotic stewardship, he worries that conflicts worsen the quality of prescribing. Like Kirsten, Xavier tries to avoid professional education events that depend on commercial sponsorship.
Soon after discovery and patent of a new potentially therapeutic molecule, a pharmaceutical company’s marketing department may help design “pivotal” randomized clinical trials (RCTs), including selection of comparator treatments and outcomes to be measured.1,2 It is also common practice to cultivate “expert” Key Opinion Leaders (KOLs) such as the vignette’s endocrinologist.3,4 Financial rewards for KOL’s can be substantial.5 In the USA they have been disclosed since 2013 at Open Payments6, though little known to the public. Similar disclosure does not exist in Canada.
While intended to maximize a product’s commercial success, such influences also help determine what health professionals learn about “evidence”.4 Marketing influences on clinical trial design may not be obvious to readers of medical scientific reports, but they inevitably favour sponsors’ products.7 Commercial influence on trial design can include the nature of the hypothesis tested, selection of comparator treatments and doses, outcome definitions, what results are ultimately reported (or not), and the packaging of “takeaway” messages to prescribers. Biased trial designs exaggerate apparent beneficial effects, underestimate harms, and even disguise results that are unfavourable to the drug.8 (Table)
|Example||Experimental hypothesis||Takeaway messages to clinicians||Contrasts with evidence|
|Type 2 diabetes||Lower glucose → better outcomes||Prescribe to ↓ HbA1c||HbA1c is not a reliable proxy for clinically important outcomes or long-term safety|
|Low impact fractures||↑ bone density prevents fractures||Prescribe drug to ↑ bone density (as measured)||Bone density and vertebral collapse fractures detected only by x-rays not reliable proxies for clinically important fractures or long-term safety|
|Pain||New drug “better” or safer than old; ↓ in mean pain scale = improvement||Prescribe new drug and ↑ dose if tolerated||Inappropriate comparator or dose; dose-response not proven; reported pain outcome may not correlate with improved function or long-term safety|
|Depression||New drug “better” than old; ↓ mean depression rating scale or ↑ % “response” or ↑ % “remission” defined as improvement||Prescribe new drug and ↑ dose if tolerated||Control only placebo or inappropriate comparator; dose-response not proven; “improvement” on depression scales may not correlate with function or long-term safety|
What is the effect of Sponsorship Bias?
A 2017 Cochrane review concluded that “sponsorship of drug and device studies by the manufacturing company leads to more favorable efficacy results and conclusions than sponsorship by other sources.” This influence cannot be explained by analyzing the “risk of bias” (experimental rigour).7 A study of 195 RCTs published in major clinical journals in 2013 identified 132 (68%) with personal financial ties between principal investigators and the drug industry. Authors with financial ties were more likely than independent researchers to publish results that are positive for a company’s products.9 Reporting of financial ties also remains unsatisfactory for meta-analyses, although Cochrane reviews have improved more than non-Cochrane reviews.10,11
Professional bodies define COI
Canadian Medical Association (CMA) Guidelines for physicians in interactions with industry state: “Conflicts of interest occur where judgments or decisions about a primary interest – in this case, patient well-being, trustworthy medical research and knowledge, and excellent medical education – are unduly influenced by a secondary interest … Physicians have a responsibility to ensure that their participation in collaboration with industry primarily serves the interests of their patients and the public”12 The BC College of Physicians and Surgeons13, College of Pharmacists14, and College of Nurses & Midwives15 all emphasize professional independence from the influence of industry. They counsel registrants to identify and avoid actual, potential or perceived COI.
Therapeutics Initiative’s approach to COI
The Therapeutics Initiative requires its members to avoid financial conflicts of interest. Thanks to public funding, we do not accept commercial support for our activities, including for our educational events.
Are YOU too smart to be influenced?
Many clinicians believe they are immune to pharmaceutical company influence, even if their colleagues are not.18 Like other humans, we underestimate our susceptibility to conflicted influencers who are expert at exploiting our subconscious biases.19 The CMA agrees: “physicians may not always be aware of, or be able to accurately self-assess, how their industry affiliations can subconsciously influence their judgment, their assessment or presentation of medical evidence, their clinical decisions and their prescribing.”12 Disclosure of potential COI does little or nothing to protect us.20,21
What can YOU do to avoid conflicted education?
Kirsten’s awareness of the speaker’s COI stimulates her feedback to the conference organizers: “Please aim for unconflicted speakers next time.” She also plans to seek high quality, unconflicted drug information for a more nuanced perspective. In his teaching about antibiotics, Xavier draws attention to the importance of understanding how COI can influence our prescribing, and he continues his work toward unconflicted treatment guidelines. Anyone can look for evidence from systematic reviews whose authors are limited to scientists without conflicts. (Box)
- Industry sponsorship of clinical trials can lead to biased conclusions, including exaggerated claims of efficacy and underestimation of harms.
- Sponsorship influences research design, conduct, publication, and use of results in systematic reviews and guidelines.
- Many Key Opinion Leaders provide promotion, not unbiased education.
- In research reports, review articles, guidelines, or continuing professional development events, look for commercial sponsorships. Ask yourself “Who paid for this and why? Is bias likely? What am I not being told?”
- Look for evidence reviews (like those from the Therapeutics Initiative) that strictly avoid conflicts of interest.
- Barbour V, Burch D, Godlee F, et al. Characterisation of trials where marketing purposes have been influential in study design: a descriptive study. Trials 2016; 17:31. DOI: 10.1186/s13063-015-1107-1
- Krumholz SD, Egilman DS, Ross JS. Study of neurontin: titrate to effect, profile of safety (STEPS) trial: a narrative account of a gabapentin seeding trial. Archives of Internal Medicine 2011; 171(12):1100-7. DOI: 10.1001/archinternmed.2011.241
- Scher JU, Schett G. Key opinion leaders – a critical perspective. Nature Reviews Rheumatology 2021; 17(2):119-124. DOI: 10.1038/s41584-020-00539-1
- Sismondo S. Ghost Managed Medicine. Mattering Press, 2018. DOI: 10.28938/9780995527775
- Moynihan R. Key opinion leaders: independent experts or drug representatives in disguise? BMJ 2008; 336:1402-3. DOI: 10.1136/bmj.39575.675787.651
- US Center for Medicaid and Medicare Services. What is Open Payments? https://www.cms.gov/openpayments (Accessed 16 March 2022)
- Lundh A, Lexchin J, Mintzes B, et al. Industry sponsorship and research outcome. Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No.: MR000033. DOI: 10.1002/14651858.MR000033.pub3
- Cosgrove L, Vannoy S, Mintzes B, Shaughnessy AF. Under the influence: The interplay among industry, publishing, and drug regulation. Account Res 2016; 23(5):257-79. DOI: 10.1080/08989621.2016.1153971
- Ahn R, Woodbridge A, Abraham A, et al. Financial ties of principal investigators and randomized controlled trial outcomes: cross sectional study. BMJ 2017; 356:i6770. DOI: 10.1136/bmj.i6770
- Benea C, Turner KA, Roseman M. et al. Reporting of financial conflicts of interest in meta-analyses of drug trials published in high-impact medical journals: comparison of results from 2017 to 2018 and 2009. Systematic Reviews 2020; 9(1):77. DOI: 10.1186/s13643-020-01318-5
- Turner K, Carboni-Jiménez A, Benea C, et al. Reporting of drug trial funding sources and author financial conflicts of interest in Cochrane and non-Cochrane meta-analyses: a cross-sectional study. BMJ Open 2020; 10(5):e035633. DOI: 10.1136/bmjopen-2019-035633
- Canadian Medical Association. Guidelines for physicians in interactions with industry. https://policybase.cma.ca/link/policy14454
- College of Physicians and Surgeons of BC. Practice Standard: Conflict of Interest. https://www.cpsbc.ca/files/pdf/PSG-Conflict-of-Interest.pdf
- College of Pharmacists of BC. Conflict of Interest Standards. http://library.bcpharmacists.org/6_Resources/6-1_Provincial_Legislation/5111-Code_of_Ethics_Conflict_of_Interest_Standards.pdf
- BC College of Nurses and Midwives. Conflict of Interest Practice Standard. https://www.bccnm.ca/NP/PracticeStandards/Pages/conflictofinterest.aspx
- Institute of Medicine (US). Clinical Practice Guidelines We Can Trust. Washington (DC): National Academies Press (US); 2011. https://pubmed.ncbi.nlm.nih.gov/24983061/
- Elder K, Turner KA, Cosgrove L, et al. Reporting of financial conflicts of interest by Canadian clinical practice guideline producers: a descriptive study. CMAJ 2020; 192(23):E617-25. DOI: 10.1503/cmaj.191737
- Steinman MA, Shlipak MG, McPhee SJ. Of principles and pens: attitudes and practices of medicine housestaff toward pharmaceutical industry promotions. American Journal of Medicine 2001; 110(7):551-7. DOI: 10.1016/s0002-9343(01)00660-x
- Sah S, Fugh-Berman A. Physicians under the influence: social psychology and industry marketing strategies. Journal of Law, Medicine & Ethics 2013; 41(3):665-72. DOI: 10.1111/jlme.12076
- Cain DM, Detsky AS. Everyone’s a little bit biased (even physicians). JAMA 2008; 299(24):2893-5. DOI: 10.1001/jama.299.24.2893
- Komesaroff P. Disclosure forms: what is revealed about the Emperor clothes? Internal Medicine Journal 2011; 41(4):297-8. DOI: 10.1111/j.1445-5994.2011.02469.x