Anyone who has paid the least bit of attention to the doings of the U.S. Food and Drug Administration (FDA) in recent decades knows that accusations of “regulatory dereliction and corporate capture” are no exaggeration.

In fact, where regulation and approval of drugs and biologics are concerned, the mainstream media—including outlets such as ReutersSlateThe New Republic and PBS—are rife with stories of FDA misconduct.

The latest FDA critique comes not from the popular press, however, but from three high-powered experts affiliated with Harvard Medical School—who air their appraisal in the prestigious Journal of the American Medical Association (JAMA).

With combined degrees in medicine, law, business and public health, the trio examines trends at the FDA since 1983, reviewing evolving regulatory standards and drug approval processes over a nearly four-decade period.

The review reveals a troubling shift toward FDA use of “less data” to approve drugs and biologics—alongside an escalating reliance on pharmaceutical industry payments to cover the salaries of the very FDA reviewers issuing the approvals.

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“Special programs” = special shortcuts

Ordinarily, drug companies must complete three phases of clinical trials on new drugs or biologics (including vaccines) before the companies can submit an application to the FDA for approval. However, both companies and patients have often pushed for a faster FDA turnaround—“seen as a means of getting drugs to patients more quickly as well as allowing pharmaceutical companies to realize sales revenues sooner.”

As outlined by the Harvard authors, five “special programs” introduced from 1992 on allow pharmaceutical companies to dispense with some of the customary requirements (such as phase 3 clinical trials) under some circumstances. The five programs—ushered in through legislation such as the 1992 Prescription Drug User Fee Act (PDUFA) and the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA)—include the Orphan Drug Act (1983); the Fast Track program (1987); Accelerated Approval (1992); Priority Review (1992); and Breakthrough Therapy (2012). All five seek to speed up drug development and “reduce evidentiary requirements” for drug approval.

These legislative and regulatory initiatives have “substantially changed drug approval at the FDA,” according to the Harvard authors, who report that in 2018, four out of five drugs (81%) benefited from one or more forms of expedited approval. As one example, the proportion of drugs approved via the 1983 Orphan Drug Act (ODA) more than doubled, going from 18% in the decade after the Act’s passage (1984-1995) to 41% (2008-2018). The original premise underlying the ODA’s passage was that a pharmaceutical company developing an “orphan drug” (a drug for a rare disease) might—in the FDA’s words—“reasonably expect the drug to generate relatively small sales in comparison to the cost of developing the drug and consequently to incur a financial loss.”

However, a 2017 analysis reported that orphan drug status now confers significant market advantages: “Due to lower [research and development] costs . . . , expedited regulatory reviews, and minimal competition . . . , rare-disease-targeting orphan drugs are now amongst the most expensive and profitable drugs on the market in the world.” Up until 2010, children’s hospitals could obtain orphan drugs at a congressionally mandated discounted rate (30% to 50%), but after the Affordable Care Act eliminated the discounts, hospital officials began complaining about a jeopardized “ability to care for some of the sickest children with the most complex health care needs.”

Another outcome of the changing regulatory environment, conclude the JAMA authors, is that the FDA increasingly issues its approvals on the basis of “less data.” Eighty-one percent of new approvals in the mid-1990s (1995-1997)—versus only about half (53%) of new approvals in 2015-2017—benefited from at least two “pivotal” clinical trials. As “regulatory standards and approval come to rely on less substantial evidence,” say the authors, “the benefits of earlier access [to drugs] must be weighed against the possibility that patients will be exposed to drugs with benefit-risk profiles that may turn out to be less favorable than expected or for which clinical benefit is never confirmed.”

The FDA also increasingly allows drug companies to substitute surrogate measures for clinically meaningful endpoints in clinical trials, a replacement enabled by the 1992 Accelerated Approval program. (A “surrogate” measure or marker is a lab measurement or physical sign expected—but not proven—to predict the effect of the drug or biologic.) Nearly three out of five pivotal efficacy trials (59%) for new drug approvals relied on surrogate measures in the most recent time period (2015-2017), versus 44% in 2005-2012. In 2004—a dozen years after surrogate measures came into widespread use—an FDA official admitted that no surrogate markers had ever been validated (“that is, shown to predict the effect of the treatment on the clinical outcome of interest”), adding that “there are a number of difficulties in interpreting trials that use surrogate markers as primary measures of drug effect.” As the JAMA authors put it, “a surrogate measure that does not predict actual patient benefit may accelerate approval of a drug that presents risk but could be of little clinical use.”

User fees = conflicts of interest

The PDUFA legislation passed in 1992 gave pharmaceutical companies the green light to make payments to the FDA (called “user fees”) in exchange for expedited approval of drugs and biologics. For the FDA, user fees have turned out to be the gift that keeps on giving. In 2018 alone, according to the Harvard trio, user fees covered “80% of the salaries of review personnel responsible for the approval of new drugs.” From 2013-2017, user fees amounted to $4.1 billion, up from $330 million over the period from 1993-1997 (an 1142% increase). By way of comparison, the user fee amount that flowed in from industry from 2013-2017 (five years) is roughly the same as the total compensation ($4.2 billion) slowly and begrudgingly awarded by the taxpayer-funded National Vaccine Injury Compensation Program since 1988 (32 years).

In an editorial accompanying the JAMA review, a former FDA Principal Deputy Commissioner wrote that “The overall picture is not of a struggling FDA, but rather of a regulatory process that has evolved over time into a thicket of special programs, flexible review criteria, and generous incentives.” Others who commented on the JAMA findings alluded to the potential for user fees to introduce conflicts of interest into the FDA’s regulatory process—but stopped short of issuing any accusations. Dr. Steven Joffe of the University of Pennsylvania stated:

“There is certainly a potential for conflict in the [FDA’s] decision-making between the interests of the regulated industry and the interests of the public’s health, and so it would be better if the bulk of the agency’s budget came from the public—i.e., taxpayers—whose interests it is charged with protecting. However, I do not mean to imply that the agency’s decision-making has in fact been compromised by this arrangement.”

Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, was more blunt when interviewed by PBS’s Frontline about the pharmaceutical industry’s “inroads into the FDA.” Dr. Wolfe noted that when drug companies started “paying cash right up front, for FDA review,” the FDA “started looking upon the industry as their client, instead of the public and the public health, which should be the client.” Referring, in addition, to the FDA’s aversion to controversy—and an appalling lack of congressional oversight—Wolfe suggested that the FDA’s watchwords have become: “Please the industry. Avoid conflict. Look upon our role as getting out as many drugs as possible.”

In 2000, Wolfe commented on the withdrawal from the market of drugs that had received expedited FDA review—including widely used allergy and diabetes drugs—stating that “[the] fast track [process] is being abused.” In 2016, the author of an article in the Journal of Pharmacology & Pharmacotherapeutics agreed that there is a firm basis for this conclusion, pointing to the fact that 57% of “fast-track molecules received a black box warning” from 2011-2015 and furnishing a lengthy table of significant adverse event alerts issued for products with fast-track designations.

Implications for children and adolescents

From 1998 to 2018, states the JAMA review, the FDA approved 42 new vaccines, which fall under the even less stringent category of biologics. A number of these vaccines received expedited approval, including Merck’s disastrous Gardasil vaccine—fast-tracked in six months in 2006. In 2014, the FDA granted a Breakthrough Therapy designation and then quickly approved Pfizer’s meningococcal group B (MenB) vaccine, a vaccine now widely administered to college students despite “limited quantifiable safety data.” In the context of hype about potential pandemics, vaccine scientists continue to push for more fast-track approvals. Others argue that biologics need longer review times, speculating that “[e]xpedited approval may cure an autoimmune disorder and incite another one.”

As the most vaccinated generation of American children ever has developed historically unprecedented levels of chronic illness, the FDA continues to bestow its regulatory largesse on drugs designed to profitably manage these chronic conditions, including drugs for vaccine-linked conditions such as atopic dermatitis and asthma. In 2018, for example, the FDA granted a Breakthrough Therapy designation to the Genentech and Novartis biologic omalizumab (marketed as Xolair)—already approved for young people ages 12 and up for severe asthma (2003) and chronic hives (2014)—to extend the drug’s indications to life-threatening food allergies. This, despite prior safety review warnings that prompted the FDA, in 2014, to approve label changes to describe Xolair’s “slightly higher risk of heart and brain adverse events.” The FDA also noted at that time that it could not rule out a potential risk of cancer. In 2016, Genentech paid user fees to the FDA when it submitted a request to extend Xolair’s target population to 6- to 11-year-olds.

Putting the public last

The fact that the public’s health seems to occupy last place on the FDA’s priority list is, in some respects, unsurprising, particularly to those who have followed the agency’s behavior with regard to vaccine approvals and regulation (see list of further reading below). Other recent reports paint an equally unflattering picture of the FDA and its dereliction of duty. For example, a 2015 discussion in Slate described the agency’s shocking “pattern of burying the details of [scientific] misconduct” and mused, “For an agency devoted to protecting the public from bogus medical science, the FDA seems to be spending an awful lot of effort protecting the perpetrators of bogus science from the public.” Reuters was no less scathing when it published a special report in December 2019 about the FDA’s half-century-long efforts to minimize the dangers of asbestos in talc-based baby powders and cosmetics; Reuters concluded, “Again and again since at least the 1970s, the agency has downplayed the risk of asbestos contamination and declined to issue warnings or impose safety standards.”

In 2018, The New Republic shed light on another aspect of the FDA’s and U.S. government’s close relationship with the pharmaceutical industry, pointing to the government’s central role in drug development and the boondoggle that this represents for taxpayers. According to TNR:

Of the 210 medicines approved for market by the FDA between 2010 and 2016, every one originated in research conducted in government laboratories or in university labs funded in large part by the National Institutes of Health [emphasis added]. Since 1938, the government has spent more than $1 trillion on biomedical research, and at least since the 1980s, a growing proportion of the primary beneficiaries have been industry executives and major shareholders. Between 2006 and 2015, these two groups received 99 percent of the profits, totaling more than $500 billion, generated by 18 of the largest drug companies. This is not a “business” functioning in some imaginary free market. It’s a system built by and for Wall Street, resting on a foundation of $33 billion in annual taxpayer-funded research.

A 2020 letter in JAMA Internal Medicine calls attention to the fact that when the FDA allows drugs or medical products to proceed to market without thorough premarketing clinical studies, postmarketing studies become “the principal way [that] adverse events and risks become apparent.” Yet here, too, the FDA is falling short, they state, with a high rate of misclassification of adverse events, including deaths. The letter-writers also refer to recent news reports “that the FDA allowed [medical] device manufacturers to file reports of malfunctions in a hidden database.” What is the result of this type of nontransparent behavior? At a minimum, the JAMA Internal Medicine writers warn, public and physician perceptions of safety will be “inaccurate”—increasing the odds of adverse events befalling an unsuspecting public.

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