How The Science Gets ‘Settled’

If you’ve heard it once, you’ve heard it a thousand times: The science is settled! If you disagree, you are branded ‘anti-science’ or ‘conspiracy theorist’.

You, too, might have the impression that the science on vaccines (or other drugs) is ‘settled’, and that’s not by accident. Here’s how the drug industry achieves that impression…

Clinical Trials

Almost 75% of U.S. clinical trials in medicine are now funded by the pharmaceutical industry [1].

Naturally, the industry has a huge financial stake in the outcome of these clinical trials – a phase III clinical trial may enrol 1000 – 5000 people over many years, and cost hundreds of millions of dollars to complete. Average cost per trial participant is around $36,000 [2]. That’s a lot of incentive to make it worth your while!

Analysis shows that trials funded by the industry are 5x more likely to recommend the experimental drug as treatment of choice, regardless of whether the results justify it, or not [3].

Clinical trials proceed in phases:

Phase I: Usually small numbers of healthy volunteers 20-100, to ascertain safety and dosage.

Phase II: Usually involves up to several hundred people with the disease/condition, or fits the user profile, to ascertain efficacy and side-effects.

Phase III: Involves several hundred to several thousand volunteers with the disease/condition, to monitor efficacy and adverse reactions.

There a number of ways clinical trials can be manipulated to give the results you want – or the appearance of the results you want…

First, you choose the people who are most likely to give the results you want. If you are looking at the safety of a vaccine, you enrol those who are least likely to have adverse reactions, and exclude those with a history of seizures, recent fevers or illness, or any blood clotting disorder [4]. (In the real world, these very people people are often urged to get the vaccine.)

Other methods used to increase the legitimacy of your product include [5]:

i) Seeding trials: Where a drug company induces a doctor to prescribe a certain drug to their patients, in order to gain feedback on the product. These are usually scientifically meaningless, have no clear end-points, but they are large-scale so represent considerable sales for the company. The doctor usually gets paid to enter patients in the trial.

ii) Switching trials: This is a variant of the seeding trial. Doctors are recruited to switch their patients from their usual treatment, to a new treatment. Again, the drug companies know that this will often lead to long-term customers.

iii) post-marketing surveillance: This is yet another variant of the seeding and switching trials, although with more scientific justification, as they are often published, and can provide important data on adverse effects. Again, doctors are paid substantial sums, and the patients may believe they are getting new and ‘better’ treatments.

iv) Dosage: The dose can be manipulated in order to give the desired results. For example, a competitor drug may be given at less-than-optimal dosage, to make the studied drug look more effective. Or the competitor drug may be given at higher-than-optimal dosages, to make the studied drug look safer.

v) Economic evaluations: These can be easy to manipulate, because they are too complex for the average journal editor or reader to fully understand.

Medical Journals

Now, when you get the favourable ‘results’, you have to let the world know all about it! A major randomised trial with favourable results, published in a prestigious journal, is a major win for a drug company, and an essential step in creating a ‘blockbuster’ drug [6-7].

A 2010 review of six major medical journals found that studies funded by industry are cited more often than those funded by other sources – more than twice as often in some journals [8].

So, if the industry-funded studies are more likely to recommend the drug in question (regardless of actual results), and then those same studies are used as a foundation for other research, being cited far more often than independent studies…can you see how the drug industry is able to build up an impression of their products being ‘rigorously tested’ and ‘highly effective’?

 The industry has figured out another way to keep their products in the editorial pages – it’s called ‘ghost-writing’. The drug company pays a writer to create an article containing ‘key marketing messages’, which is then sent to a doctor, who agrees to have his/her name attributed to the work in exchange for payment, before it is submitted to medical publications. Studies suggest that anywhere from 8% to 75% of journal articles may be ghost-written [9].

Clearly, this might appeal to some doctors who want the prestige of being a published author, quite apart from the financial incentive. The pharmaceutical company has final control over the paper, and if a doctor is not compliant enough, they simply get no further projects [10-11].

In many cases, if not all, the ghost-writer and the honorary author have not even viewed the raw data, they have merely been supplied with a summary from the sponsor company [12]. The honorary author is usually chosen because of their credentials, and their ability to influence other prescribers [13].

Of course, the desired effect of all this published data is threefold: a) it gives the appearance that the drug is thoroughly researched and widely accepted, b) which boosts doctor and patient confidence, c) while simultaneously providing an edge over rival products.

But…peer review!

At the heart of the scientific process is the concept known as peer review – where an author’s work is subjected to the scrutiny of other experts in the same field, before being published. The public perception is that the peer review process acts like a stop-gap that upholds the integrity of the scientific process, and filters out errors or fraud, but does it really?

The British Medical Journal decided to test for themselves how reliable the peer-review process is, by inserting major errors into papers before sending to reviewers. Some reviewers didn’t pick up any of the errors, while most picked up only about a quarter. Nobody picked up all the errors [14 -15].

So far, the evidence suggests that the peer review process is ‘slow, expensive, ineffective, something of a lottery, prone to bias and abuse, and hopeless at spotting errors and fraud [16] – but of course, the average internet troll doesn’t know that, yet!

The New England Journal of Medicine has long been ‘the journal to beat’ [17], yet two former editors-in-chief left their role in the top job, and went on to publish books exposing the excessive influence of the drug industry [18-19].

Meta-Analysis

A meta-analysis looks at data from multiple studies, and is used as part of systematic review. Naturally, these are useful and important in the interpretation of data.

A systematic review of vaccine meta-analyses, found that the methodological quality of all 121 meta-analyses included in the review (100%), were unsatisfactory. “The most frequent limitations include non-comprehensive bibliographic research; bias in the selection of the studies; lack of quality assessment of individual studies; absence of evaluation of heterogeneity among studies and publication bias” [20].

So, 100% of the vaccine meta-analysis cherry-picked the studies they wanted to include, in order for the ‘systematic review’ to show the results they wanted…These are the same meta-analyses that are used to guide government policies and legislation, WHO guidelines, doctors opinion…

The Role of Media

In order to further spread the good news of your product, you also need to make some news headlines, via press releases. The media are usually fairly compliant – they want a catchy headline, and…after all, drug companies do help to fund their jobs, via billions of dollars in advertising revenue [21].

A review of health news and current affair items on free-to-air TV in Sydney, Australia, estimated that up to 42% may have ‘been triggered by press releases and other forms of publicity [22].

Advertising and press releases are not the only way the pharmaceutical industry can influence the media. Another avenue is through a situation known as an interlocking directorate. This occurs when the director of one company sits on the board of directors of another company.

Many of the major news corporations have directors who also sit on director boards for pharmaceutical companies – and these cosy relationships have been shown to effect how health news is portrayed [23].

According to research, ‘the media can play an important role in influencing both the demand and supply of medical treatments, regardless of evidence of effectiveness [24].

Media coverage can increase uptake of the seasonal influenza vaccine, especially if reported in a headline, that includes words such as ‘vaccine shortage’ [25]. (Creates a sense of urgency.)

The so-called ‘swine flu pandemic’, which turned out to be more panic than pandemic, featured experts and academics making media appearances, promoting the use of retroviral drugs. It was later found that those who promoted retroviral drugs, were 8 times more likely to have links to industry – via research grants, honorarium payments, advisory roles, employment, board membership, speaker’s fees, etc – than those who did not comment on their use [26].

Getting Your Product Approved

Of course, all your journal articles and press releases are kind of pointless if you can’t get your drug through the regulatory process. In the US, UK, Australia and Canada, the regulatory agencies are all funded by industry (user-pays system), rather than by government [27-30].

Congressional investigations and reports have made damning conclusions on both the CDC and FDA: The Committee’s investigation has determined that conflict of interest rules employed by the FDA and CDC have been weak, enforcement has been lax, and committee members with substantial ties to the pharmaceutical companies have been given waivers to participate in committee meetings” [31].

If that’s not enough, you also have the ‘revolving door’ between government and industry – former employees now hired by drug companies to liaise with their former work-mates in the regulatory system. Studies suggest that more than half of former assessors at the FDA move on to positions within the pharmaceutical industry [32] – obviously their ‘inside knowledge’ is extremely valuable to the drug companies.

Occasionally, the door swings in the opposite direction – pharma employees moving into government jobs. The current secretary of the Department of Health and Human Services (HHS), Alex Azar was formerly a pharmaceutical lobbyist, and president of the US division of pharmaceutical giant Eli Lilly and Co [33]. In case you are not American, like myself, the HHS department guides the nation’s healthcare programs and policies, so…fairly influential.

Regulatory agents are not only funded by industry, as we have already noted, but they also rely on industry to conduct the trials, provide the safety data, and notify them of any issues that may arise post-licensure. The agencies themselves do not conduct clinical trials [34-37].

The Fate of Failed Clinical Trials

Now, what happens if, despite your best efforts, the clinical trials still didn’t give the results you wanted? You can still salvage your reputation by:

a) Just cut the trial short – to save money [38-40], or

b) Simply decide not to publish unfavourable trial results, even though doing so is considered to be scientific malpractice [41-42].

Research shows that less than half of government-funded clinical trial results are published in peer-reviewed medical journals within 30 months of trial completion [43].

One pharmaceutical company managed to suppress trial results for seven years, when they revealed that the drug in question was no more effective than cheaper generic formulations [44].

That, my friends, is a tiny glimpse into how science gets ‘settled’.

Any questions?

References

[1] Bodenheimer, T. 2000. Uneasy alliance: Clinical investigators and the pharmaceutical industry. New England Journal of Medicine 342:1539-1544.

[2] pHRma: Biopharmaceutical industry-sponsored clinical trials: impact on state economies, http://phrma-docs.phrma.org/sites/default/files/pdf/biopharmaceutical-industry-sponsored-clinical-trials-impact-on-state-economies.pdf. Accessed September, 2017.

[3] Als-Nielsen B, Chen W, Gluud C, Kjaergard LL. Association of Funding and Conclusions in Randomized Drug Trials A Reflection of Treatment Effect or Adverse Events?. JAMA. 2003;290(7):921–928.

[4] US National Library of Medicine: ClinicalTrials.gov. Hepatitis A vaccine, Inactivated and Measles, Mumps, Rubella and Varicella Virus Vaccine Live Safety Study, https://www.clinicaltrials.gov/ct2/show/NCT00326183?term=vaccine&recrs=e&cond=varicella&age=0&phase=3&fund=2&rank=4. Accessed October, 2017.

[5] Smith R. Medical journals and pharmaceutical companies: uneasy bedfellows. BMJ : British Medical Journal. 2003;326(7400):1202-1205.

[6] Guyatt GH, Naylor D, Richardson WS, et al. What is the best evidence for making clinical decisions? JAMA. 2000 Dec 27; 284(24):3127-8.

[7] Smith R. Medical journals are an extension of the marketing arm of pharmaceutical companies. PLoS Med. 2005 May; 2(5):e138.

[8] Lundh A, Barbateskovic M, Hrobjartsson A, Gotzche pC. Conflicts of interest at medical journals: The influence of industry-supported randomised trials on journal impact factors and revenue-cohort study, pLOS One, 2010, 7(10): e1000354.

[9] Hill M. Ghosts in the Medical Machine, Philadelphia Inquirer, 20th September 2009.

[10] Petersen M. Madison Ave. Plays Growing Role in Drug Research. New York Times. 2002 November 22. Available at: www.nytimes.com/2002/11/22/business/22DRUG.html?pagewanted=5, Accessed January, 2019.] [Ngai S, Gold J. L, Gill

[11] Rochon P.A. Haunted Manuscripts: Ghost Authorship in the Medical Literature. Accountability in Research. 2005;12:p103–114.

[12] McHenry L. Of Sophists and Spin-Doctors: Industry-Sponsored Ghostwriting and the Crisis of Academic Medicine. Mens Sana Monographs. 2010;8(1):129-145.]

[13] Ibid.

[14] Godlee F, Gale CR, Martyn CN. Effect on the quality of peer review of blinding reviewers and asking them to sign their reports: a randomized controlled trial. JAMA. 1998 Jul 15; 280(3):237-40.

[15] Schroter S, Black N, Evans S, et al.Effects of training on quality of peer review: randomised controlled trial.BMJ. 2004 Mar 20; 328(7441):673.

[16] Smith R. The trouble with medical journals. Journal of the Royal Society of Medicine. 2006;99(3):115-119.

[17] Smith R. Lapses at the New England Journal of Medicine. Journal of the Royal Society of Medicine. 2006;99(8):380-382.

[18] Angell M. The Truth About Drug Companies: How They Deceive Us and What To Do About It. New York: Random House, 2005.

[19] Kassirer JP. On The Take: How Medicine’s Complicity With Big Business Can Endanger Your Health. New York: Oxford University Press, 2004.

[20] De Vito C, Manzoli L, Marzuillo C, et al. A systematic review evaluating the potential for bias and the methodological quality of meta-analyses in vaccinology, Vaccine, 2007, 25(52):8794-806.

[21] CBS News, Drug Ads: $5.2 billion annually – and rising, https://www.cbsnews.com/news/drug-ads-5-2-billion-annually-and-rising/. Accessed September, 2017.

[22] Chapman S, Holding SJ, Ellerm J, et al. The content and structure of Australian television reportage on health and medicine, 2005–2009: Parameters to guide health workers. Med J Aust, 2009, 191(11) 620–624.].

[23] Fairness and Accuracy in Reporting: Single-payer and interlocking directorates, The corporate ties between insurers and media companies, http://fair.org/extra/single-payer-and-interlocking-directorates/. Accessed February, 2017.

[24] Benelli E (2003) The role of media in steering public opinion on healthcare issues. Health Policy 63: 179–186.

[25] Yoo B-K, Holland ML, Bhattacharya J, Phelps CE, Szilagyi PG. Effects of Mass Media Coverage on Timing and Annual Receipt of Influenza Vaccination among Medicare Elderly. Health Services Research. 2010;45(5 Pt 1):1287-1309.

[26] Wise Jacqui. Academics who spoke out on swine flu risks were more likely to have industry links, study finds BMJ, 2013; 347 :f6758.

[27] Frontline. How independent is the FDA? http://www.pbs.org/wgbh/pages/frontline/shows/prescription/hazard/independent.html. Accessed October, 2017.

[28] House of Commons Health Committee. The Influence of the pharmaceutical industry: Fourth Report of Session 2004-2005.Published on 5 April 2005 by authority of the House of Commons London: The Stationery Office Limited.

[29] Government of Canada. Funding and Fees, https://www.canada.ca/en/health-canada/services/drugs-health-products/funding-fees.html. Accessed October, 2017.

[30] Productivity Commission. Submission To The Productivity Commission, re: Federal Government Cost Recovery, https://www.pc.gov.au/inquiries/completed/cost-recovery/submissions/medical_industry_association_of_australia_/sub012.pdf. Accessed October, 2017.

[31] FACA: Conflicts of Interest and Vaccine Development: Preserving the Integrity of the Process, Before the Government Reform Committee of the House of Representatives, 106th Congress, June 15, 2000.

[32] Bien, J., & Prasad, V. (2016). Future jobs of FDA’s haematology-oncology reviewers. BMJ (Online), 354, i5055.

[33] Brennan Z. Revolving Door Between Industry and FDA Continues to Spin, Regulatory Affairs Professionals Society, 6th September, 2018.

[34] US Food and Drug Administration. Clinical Trials: What patients need to know, https://www.fda.gov/forpatients/clinicaltrials/. Accessed October, 2017.

[35] Medicines and Healthcare products Regulatory Agency. Medicines and Medical Devices Regulation: What you need to know, http://www.mhra.gov.uk/home/groups/comms-ic/documents/websiteresources/con2031677.pdf. Accessed October, 2017.

[36] Government of Canada. Clinical trials and drug safety, https://www.canada.ca/en/health-canada/services/healthy-living/your-health/medical-information/clinical-trials-drug-safety.html. Accessed October, 2017.

[37] Therapeutic Goods Administration. TGA regulatory framework, https://www.tga.gov.au/tga-regulatory-framework. Accessed October, 2017.

[38] Psaty BM, Rennie D. Stopping medical research to save money. A broken pact with researchers and patients.  JAMA2003;289:2128-2131.

[39] Canadian Association of University Teachers: The Olivieri Report, https://www.caut.ca/docs/af-reports-indepedent-committees-of-inquiry/the-olivieri-report.pdf?sfvrsn=0. Accessed September, 2017.

[40] Lievre M, Menard J, Bruckert E.  et al.  Premature discontinuation of clinical trial for reasons not related to efficacy, safety, or feasibility.  BMJ.2001;322:603-605.

[41] Bodenheimer, T. 2000. Uneasy alliance: Clinical investigators and the pharmaceutical industry. New England Journal of Medicine 342:1539-1544.

[42] Chalmers I. Underreporting research is scientific misconduct.  JAMA.1990;263:1405-1408.

[43] Ross Joseph S, Tse Tony, Zarin Deborah A, Xu Hui, Zhou Lei, Krumholz Harlan M et al. Publication of NIH funded trials registered in ClinicalTrials.gov: cross sectional analysis BMJ 2012; 344 :d7292.

[44] Vogel G. Long-suppressed study finally sees light of day.  Science.1997;276:525-526. p

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