Image: TBIT (Pixabay)
The Food and Drug Administration is doing a poor job of making sure the doctors who review drugs for possible approval are free of bias, alleges a new investigative report published this week in Science. Many of these reviewers, while having no clear financial conflicts of interest prior to their work for the FDA, went on to earn paychecks and research funding from the companies whose drugs they had earlier approved, the report found.
Many of the drugs the FDA evaluates for approval are reviewed and voted on by an independent panel of experts. Their recommendation, while not a binding guarantee, carries a lot of weight. Prior to being placed on the panel, experts are expected to disclose any industry payments or other conflicts. While conflicts are often a disqualifying factor in awarding a potential advisory role, doctors can be given a waiver.
Science writer Charles Piller looked at what happened to the financial coffers of over more than 100 doctors before and after their work on these panels. The doctors had been asked to review 28 drugs from 2008 to 2014 that subsequently won approval from the FDA. Piller and his colleague Jia You analyzed publicly available data from the Open Payments program, a repository of reported payments; research funding; ownership stakes doled out by the industry to physicians and teaching hospitals; and conflicts disclosed in the researchers’s work. The Open Payments program was founded in 2013, as part of the Affordable Care Act.
From 2013 to 2016, around 40 percent of these advisers received more than $10,000 (in the form of consulting fees and research funding, for example) from either the makers of drugs they had approved or from competing firms in the same field of research. Around a quarter had received more than $100,000, and seven doctors had received more than $1 million. Many top earners had also received money prior to or during their work on an advisory panel, and while these doctors disclosed their conflicts in their research around that time period, the conflicts often weren’t disclosed by the FDA through waivers issued to them.
“The people who are asked to weigh this evidence impartially often stand to gain tremendously in their further professional careers from a positive relationship with the company,” Vinay Prasad, a researcher at Oregon Health & Science University who has studied how financial conflicts can shape research, told Science. “It’s in their best interest to play nice with these companies.”
Even in cases where advisers are only getting money from other competing companies, the writers noted there’s still the danger of bias. Companies developing similar drugs can sometimes benefit from the approval of a competing product, which might establish the first of a new drug class or new approved use. And by bankrolling doctors who had approved earlier drugs in the same class, the companies might be able to better ensure favorable research on their behalf as their drug goes through the development pipeline. Other research into financial conflicts has found that doctors who receive industry funding are more likely to recommend the company’s drugs to their patients and to the public.
While there’s no clear-cut evidence that these drugs didn’t merit approval based on their trial results, there is the possibility that biased advisers might overlook a drug’s potential risks.
The Science report in particular highlights the antipsychotic Seroquel, developed by AstraZeneca. In 2009, Seroquel was approved to treat a wider variety of psychiatric conditions, including PTSD, following the positive recommendations of two advisory panels. Many of the advisors on these panels received money from AstraZeneca and its competitors in the years before and after their work, including one Duke doctor who earned $400,000 in direct payments for travel and consulting. But despite known concerns about Seroquel causing sudden cardiac deaths, no warning about the risk was affixed to the drug’s label until 2011, following several reported deaths in connection to the drug.
“The agency seems to have overlooked conflicting payments to advisers prior to approval, as well as after. And Seroquel was approved without a cardiac warning that had to be added later—after people died,” Piller told Gizmodo. In 2010, Piller also noted, AstraZeneca was forced to pay $520 million as part of a settlement with the US government for “alleged improprieties in the company’s clinical trials and improper marketing of Seroquel to treat unapproved conditions.”
The FDA declined to respond to Science regarding the findings in its report. The top-earning doctors who responded to Science offered boilerplate denials that the money they received was indicative of any personal bias, though many underscored the need for ensuring impartiality in the approval process.
“There is no question that we must appropriately address potential conflicts for our SGEs [special government employees, the official designation assigned to advisory experts],” a FDA spokeperson told Gizmodo via email. “At the same time we must also ensure that experts working in their fields are not unnecessarily excluded from participation in the advisory committee process. We continue to work to ensure the SGEs are thoroughly vetted and provide the appropriate mix of expertise on committees so that FDA scientists and staff get the advice they need to make the best decisions on behalf of the American public.”
It’s not simply advisory panels that might be prejudiced. A parallel investigation by Science found that many former FDA employees who oversaw the approval process of drugs while at the agency have since gone on to work for or advise these same companies. The findings mirror similar research about the agency’s revolving-door problem, published in The BMJ in 2016.
Piller does note that researchers he spoke to for his story have recommended plenty of potential short- and long-term situations toward making the approval process more bias-free.
“Experts suggest a few steps to solve the glaring conflict of interest problems in drug reviews: First, open up and improve the FDA’s secretive vetting process for advisors. From the outside, it looks as if advisers operate on an honor system, and that has eroded public confidence,” Piller said. The agency could also institute guidelines that ask doctors to avoid taking industry money from the companies they’ve evaluated, as several medical societies have recommended.
“Finally, it might be time for Congress to consider stronger revolving-door limits for FDA employees—given how commonly they move to lucrative jobs for companies they recently regulated,” Piller added.
This post has been updated.
[Science]