Regulators or Cartel?

From FDA to MHRA: are drug regulators for hire?

In case you missed this one it’s worth a summary -

From FDA to MHRA: are drug regulators for hire? by Maryanne Demasi, (investigative journalist, Sydney, Australia) BMJ2022; 377 doi: https://doi.org/10.1136/bmj.o1538 (Published 29 June 2022)

Regulatory agencies have seen large proportions of their budgets funded by the industry they are sworn to regulate. These “user fees” that come from the industry being regulated is significant - In Europe, industry fees funded 20% of the new EU-wide regulator, the European Medicines Agency (EMA), in 1995. By 2010 that had risen to 75%; today it is 89%. Industry money saturates the globe’s leading regulators with the majority of regulators’ budget—particularly the portion focused on drugs—is derived from industry fees.

In this study Australia had the highest proportion of budget from industry fees (96%) and in 2020-2021 approved more than nine of every 10 drug company applications. Australia’s Therapeutic Goods Administration (TGA) firmly denies that its almost exclusive reliance on pharmaceutical industry funding is a conflict of interest (COI). In response to a query, the agency said, “All fees and charges are prescribed in our legislation. To provide transparency, the TGA fees and charges are published on the TGA website.”

Sociologist Donald Light of Rowan University in New Jersey, US, who has spent decades studying drug regulation, says, “Like the FDA, the TGA was founded to be an independent institute. However, being largely funded by fees from the companies whose products it is charged to evaluate is a fundamental conflict of interest and a prime example of institutional corruption.”

Light says the problem with drug regulators is widespread. Even the FDA—the most well funded regulator—reports 65% of its funding for the evaluation of drugs comes from industry user fees and over the years user fees have expanded to generic drugs, biosimilars, and medical devices.

“It’s the opposite of having a trustworthy organisation independently and rigorously assessing medicines. They’re not rigorous, they’re not independent, they are selective, and they withhold data. Doctors and patients must appreciate how deeply and extensively drug regulators can’t be trusted so long as they are captured by industry funding.”

External advisers

A BMJ investigation last year found several expert advisers for covid-19 vaccine advisory committees in the UK and US had financial ties with vaccine manufacturers—ties the regulators judged as acceptable. A large study that investigated the impact of COIs among FDA advisory committee members over 15 years found that those with financial interests solely in the sponsoring firm were more likely to vote in favour of the sponsor’s product, and that people who served on advisory boards solely for the sponsor were significantly more likely to vote in favour of the sponsor’s product.

In Australia, the membership of the TGA’s Advisory Committee on Vaccines is published on the agency’s website. The forms for recording past and current financial and non-financial interests are not, however, made public.

Transparency, conflicts of interest, and data

Most regulatory agencies do not undertake their own assessment of individual patient data, but rather rely on summaries prepared by the drug sponsor. The TGA, for example, says it conducts its covid-19 vaccine assessments based on “the information provided by the vaccine’s sponsor.” According to a FOI request from last May, the TGA said it had not seen the source data from the covid-19 vaccine trials. Rather, the agency evaluated the manufacturer’s “aggregate or pooled data.” The TGA does not have the individual participant level datasets pertaining to the covid-19 vaccine trials, which are held by the vaccine manufacturer.

Among global regulators, only two—the FDA and PMDA—routinely obtain patient level datasets. And neither proactively publish these data. Recently, a group of more than 80 professors and researchers called the Public Health and Medical Professionals for Transparency sued the FDA for access to all the data which the agency used to grant licensure for Pfizer’s covid-19 vaccine. The FDA argued that the burden on the agency was too great and requested that it be allowed to release appropriately redacted documents at the rate of 500 pages a month, a speed that would take approximately 75 years to complete. In a win for transparency advocates, this was overturned by a US Federal Court Judge, ruling that the FDA would need to turn over all the appropriately redacted data within eight months. Pfizer sought to intervene to ensure “information that is exempt from disclosure under the FOI act is not disclosed inappropriately,” but its request was denied.

Speedy approvals

Following the AIDS crisis of the 1980s and 1990s, PDUFA “user fees” were introduced in the US to fund additional staff to help speed the approval of new treatments.

Today, all major regulators offer expedited pathways that are used in a significant proportion of new drug approvals. In 2020, 68% of drug approvals in the US were through expedited pathways, 50% in Europe, and 36% in the UK.

Accelerated approval processes have resulted in new drugs that were more likely to be withdrawn for safety reasons, more likely to carry a subsequent black box warning, and more likely to have one or more dosage forms voluntarily discontinued by the manufacturer.

Aaron Kesselheim, professor of medicine at Brigham and Women’s Hospital and Harvard Medical School, says that accelerated approvals generally have a lower burden of proof for efficacy.

“The accelerated approval pathway explicitly changes the underlying efficacy ‘standard’ in that it allows approval based on changes to a surrogate measure that is not well validated, and is only reasonably likely to predict clinical benefit,” says Kesselheim who resigned from an FDA advisory committee last year in protest over the agency’s approval of a controversial Alzheimer’s drug. Following the committee’s vote against approval, the FDA shifted the goal posts, approving aducanumab through an accelerated approval based on the disputed surrogate measure of lowered visible β-amyloid protein levels.

The regulator-industry revolving door

Critics argue that regulatory capture is not only being baked in by the way in which agencies are funded, but also staffed. A “revolving door” has seen many agency officials end up working or consulting for the same companies they regulated.

At the FDA, generally regarded as the world’s premier regulator, nine out of 10 of its past commissioners between 2006 and 2019 went on to secure roles linked with pharmaceutical companies, and its 11th and most recent, Stephen Hahn, is working for Flagship Pioneering, a company that acts as an incubator for new biopharmaceutical companies.

Reform

Critics argue that both small and large structural changes are necessary to help restore regulators’ ability to carry out independent decision making, free of industry influence.

Light says it is no longer possible for doctors and patients to receive unbiased, rigorous evaluations from drug regulators. He suggests setting up non-profit organisations like Germany’s Institute for Quality and Efficiency in Health Care, which was established to carry out evaluations of approved drugs that are independent of industry, rigorous, unbiased, and transparent. “The question is why weren’t drug regulators doing this trustworthy, transparent, rigorous, unbiased job in the first place?” says Light. Light argues regulators now need their own watchdog and is calling for a drug and vaccine safety board, independent of the drug regulator, with the authority, staffing, and funds to investigate incidents of patient harm. “Countries have independent safety boards for airlines and their passengers. Why not for drugs and patients too?” says Light.