TrialSite has been covering the serious shortcomings in US FDA’s current policies. The phenomenon of regulatory capture can be seen in many regulatory bodies; its corruptive characteristics can have far-reaching implications, threatening the independence and priorities of public health regulatory policies. How far-reaching is this issue within the leading regulators around the world? TrialSite probes further into leading health regulatory bodies in the US, UK, and European Union.
Regulatory Capture
Regulatory capture is a form of corruption where authoritative regulatory bodies act for political or monetary gain rather than in the interests of the public. This phenomenon is characterized by the coordinated efforts of regulated entities to lift constraints, decrease oversight efforts, weaken checks and balances, and gain advantages.
To assert influence, the industry hijacks regulators’ mandates and operations, making them cognitively and culturally captive to their influence. The agency’s independence is compromised by an increased inclination to serve the interests of the industry.
Unfortunately, the US Food and Drug Administration (FDA) has been accused of regulatory capture on a number of occasions:
Alosetron (Lotronex) was a drug for irritable bowel syndrome. In 2000, it was withdrawn from the market for causing more harm than good, including death. FDA agreed to release it again the following year, but under strict conditions: the prescribing doctor had to be trained and certified on the drug. The drug company disagreed, as it preferred the prescribing doctor to simply self-attest on their qualification. Despite several detractors in the advisory committee warning of more deaths, the FDA adopted the drug company’s recommendation, instead of its own advisory committee’s guidelines. This case is a prime example of captive decision-making by the FDA.
Vioxx, a nonsteroidal anti-inflammatory drug for arthritis among other conditions, triggered congressional interrogations after pulling out of the market in 2004. It caused an estimated 30,000 – 55,000 deaths and more than 100,000 heart attacks in patients before it was withdrawn. FDA investigator at the time, Dr. David Graham, told the senate in a congressional testimony that the regulator made it difficult to adequately analyze drugs. He reported threats and intimidation from supervisors who advocated for drug companies.
Proton pump inhibitors have demonstrated increased risks of kidney failure and other harmful adverse events. They have remained in the market nonetheless. This has brought lawsuits against manufacturers of Prevacid, Prilosec, Nexium, and Dexilant, with 15,164 filed by 2020. One claim against Prilosec asserted that “AstraZeneca knew of kidney risks for at least 10 years before warning the public.”
A study on the FDA conceded that the COVID-19 pandemic shows the mode of operation of the regulator as reactive, departing from “evidence-based decision-making frameworks”. This is the case not only in emergencies but also in its regulating operations.
The FDA authorized convalescent plasma on an emergency use basis during the pandemic over the behind-the-scenes protestations of the NIH. TrialSite suspected undue influence of the last POTUS (Trump).
Most recently the FDA approved the use of Biogen’s Alzheimer’s disease drug despite a lack of compelling clinical data. This decision was so controversial that Acting Commissioner Janet Woodcock called for an independent internal review process.
The list goes on as TrialSite could offer many more examples while also showcasing the revolving door from the agency to industry. One key takeaway from these cases is that there seem to be no accountability structures in place to protect consumers from culpable drug companies often enabled by the system.
User Fees and Licensing
The fees pharmaceutical companies pay to health regulatory bodies have been an object of debate and deliberation. This relates not only to the US FDA, but also to the UK’s Medicine and Healthcare Products Regulatory Agency (MHRA), and the European Medicines Agency (EMA), the regulating agency within the European Union.
In the US, Daniel Carpenter, Harvard professor of government, illuminates the covert symbiotic relationship between the FDA and big pharma. A significant amount of FDA funding comes from pharmaceuticals, thus raising ethical questions of industry influence on the direction of regulating policies.
Critics have drawn attention to how fee negotiations serve the pharmaceutical’s interests, such as fast-tracking of the approval process. For instance, the user fees paid to FDA have been implicated in influencing the emergency use authorization (EUA) speed in the COVID-19 pandemic, with some approvals happening within weeks.
In 2020, FDA received 2.7 billion dollars in user fees from the pharmaceutical industry, meeting 45% of its overall budget. This is in line with the Prescription Drug User Fee Act of 1992. During the negotiation rounds for the fee (every five years), the pharmaceutical industry calls the shots by setting up performance measures. This dictates certain compliances the regulator has to meet in order to qualify for the fees, including response time, approval speed, and efficiency.
In the UK, the MHRA requires drug manufacturers to remit licensing and authorization fees. This in turn covers the cost of regulating the medicines from the payer. The House of Commons has made attempts in the past to point out the irony of the situation by highlighting the barriers it has created.
The EMA, the health agency regulating the industry in the European Union, has raised concerns among independent health consumer groups. They are alarmed by signs of regulatory capture in the agency. The consumer groups called for a review of EMA’s policies including fee-for-service from the pharmaceuticals, provision of “customized, confidential scientific advice” during the approval process to pharmaceuticals, lack of transparency, and access of clinical trial data.
Revolving Door Phenomenon: coincidental or calculated move?
The revolving door phenomenon among FDA high-ranking officials dates several years back as covered by TrialSite. Additionally, over 50% of former FDA medical reviewers work or consult for the pharmaceutical companies after departing the agency, as found in a study published in BMJ. Sometimes they go on to work for the drug company the FDA expert was assigned to review. The absence of statutory mandates for FDA employees in this regard creates conditions rife with conflict of interest.
In 2020, Stephen Lightfoot took on the role of chair of the UK’s MHRA. A 30-year pharmaceutical veteran, he worked at one point as an executive for Schering, a pharmaceutical associated with the infamous Primodos (more on this later). Prior to Lightfoot’s appointment was Ian Hudson, who had been a GlaxoSmithKline executive for years before getting into the health agency.
However, these are not isolated cases. Some of the division heads in the UK’s regulating body have previous ties in the pharmaceutical industry. These include:
Gerald Heddell, appointed as Director of the Inspection, Enforcement & Standards Division, was a former executive at GlaxoSmithKline.
Stephen Inglis, appointed as Director of the National Institute for Biological Standards and Control, was a former research director at Cantab Pharmaceuticals.
John Parkinson who was appointed as Director of Clinical Practice Research was a former consultant for pharmaceuticals.
Some repercussions of regulatory capture
The implications of regulatory capture can perhaps be understood best by examining some avoidable mishaps and pro-industry decisions.
Primodos in the UK
Primodos prompted a long-overdue hearing by the House of Commons and an expert panel work group (EWG) inquiry to investigate the drug. The final report showed MHRA’s culpability in approving Primodos – a drug that had caused birth defects for years. The UK government then agreed to amend that error promptly. One of the key decisions made was to place Stephen Lightfoot at the helm of MHRA in September 2020. Ironically, he had close ties with the manufacturer of Primodos as a former commercial director in the company.
Seroquel in the US
Dr. Thomas Laughren, a former director of FDA’s psychiatric products, became a consultant to psychiatric manufacturers after leaving FDA. While working in the FDA, he was pro-industry and fiercely defended controversial antipsychotic drugs. At one time he ran interferences on behalf of AstraZeneca at the FDA advisory committee meetings. Seroquel, the drug by AstraZeneca, was approved; it was later discovered to have a risk of sudden cardiac attack. This was not news to the FDA, as it had received the reports prior to approval.
Biogen
TrialSite has closely followed Biogen’s progress since 2019. Eyes are on the ongoing investigations of the FDA over the Biogen’s Alzheimer’s brand drug, Aduhelm. Not only did FDA’s own commissioner Janet Woodcock make the call to the watchdog, but the agency also lacked independence as a regulator. It departed from the norm during the approval by preparing a joint document with the manufacturer, as well as disallowing inquiry on data. It will be interesting to see what the FDA investigation turns up.
Ivermectin narrative
There seems to be an institutional bias against ivermectin, as TrialSite has widely covered. Regulatory health bodies around the world have changed their previous pro-ivermectin stances to align with FDA and WHO. Is this indicative of totalitarianism in regulatory capture? The recent scandalous email from an agency external affairs executive to Acting Commissioner Woodcock revealed an unacceptable initiative at the agency to initiate a disinformation campaign seeking to confuse markets and consumers—that ivermectin was simply a horse deworming drug but it is also an antiparasitic treatment that won a Nobel Prize, eradicated some major tropical-born disease and has been tested in 65 studies targeting COVID-19 to date. The U.S. government is funding a major ivermectin study in the ACTIV-6 study although critics fret the study protocol underdoses the regimen possibly purposely.
Is Monopoly the endgame?
Health agencies are mandated to serve the public’s best interest without fear or favor. However, what happens if loopholes are exploited to get special interest ahead? The due process of objective regulation and inspection is compromised, and consequently, the public interest is left at the mercy of the unbridled ambition of industry such as large pharmaceutical companies.