An internal FDA email chain from 2007 obtained by POGO provided a glimpse of the time pressures. Following up on a staff meeting at which employees reportedly voiced concern about PDUFA deadlines, John K. Jenkins, director of the Office of New Drugs, thanked employees for “your candor in expressing your concerns about the pressures you are facing every day.”

“I agree that the competing pressures, workload, and goals we face today are daunting and that we don’t have nearly enough staffing and resources to do our work to the level we strive for as stewards of the public health,” Jenkins wrote. “We clearly cannot do all that we are being asked to do,” he added.

Meanwhile, the Institute of Medicine conducted a sweeping assessment of the FDA at the agency’s request and issued its findings in a watershed 2006 report.

“For some staff and policy analysts, user-fee funding, combined with industry’s considerable role in shaping PDUFA-associated goals and expectations, further reinforces the perception that the industry has become a primary driver of the agency’s priorities and performance,” the Institute of Medicine reported. “The notion of ‘regulatory capture’ has been employed to describe the state of affairs created or, more likely, exacerbated by the user fee system, namely that powerful industry interests control or strongly influence the regulatory agency’s decision making.”

Criticizing the FDA’s “overdependence on PDUFA funding with the strings that are attached,” the Institute of Medicine recommended that new FDA safety functions be funded through Congressional appropriations rather than user fees.

The following year, at a George Washington University panel discussion, former FDA commissioners unanimously agreed that appropriations would be better than user fees, the FDA history recounts. “Appropriations, no question,” Kessler said.

“User fees may appear to save the taxpayers money, but at an unacceptable cost to public health,” 22 academic experts, former FDA officials, and others said in a 2007 open letter to the FDA’s Congressional overseers.

In a 2008 study published in The New England Journal of Medicine, Harvard scholar Carpenter and his co-authors found that PDUFA deadlines appeared to be causing safety problems. Under PDUFA, drug approval decisions tended to take place in the two months before their deadlines, and drugs approved just before the deadlines tended to have more safety problems after they were approved. For example, they were more likely than other drugs to be withdrawn from the market or to have major warnings added to their labels, the study found.

For much of the user-fee era, the FDA was allowed to spend the user fee revenue only on activities leading up to drug approval—thereby hastening approvals but limiting the FDA’s ability to monitor the safety of drugs once they were in widespread use. In time, that changed, and the focus on postmarket surveillance increased. Postmarket surveillance is important in part because even the largest clinical trials may not reveal what will happen when drugs are used over the long term by much larger numbers of people.

Nonetheless, tracking the performance of drugs once they are on the market continued to be a weakness at the FDA.

“FDA’s lack of reliable, readily accessible postmarket safety data has prevented the agency from publishing required reports in a timely manner and has restricted its ability to conduct systematic oversight,” the Government Accountability Office said in a December 2015 report. As of October 2015, the FDA had not published required annual reports containing data on postmarket studies for fiscal years 2013 or 2014, the GAO said.

The FDA lagged in tracking postmarket safety even as it was approving many new drugs on an expedited basis under programs for drugs deemed worthy of “fast track” and other special consideration, the GAO said.

Whether drugs approved on an expedited basis have deserved the shortcuts is a separate question.

At an FDA meeting last year, Aaron Kesselheim, who runs a program on regulation, therapeutics, and law at Harvard Medical School, noted that a program created in 2012 for so-called “breakthrough therapies”—drugs that, based on preliminary data, have the potential to substantially improve the treatment of serious or life-threatening diseases—was the fifth pathway created for drug companies to get products approved on an expedited basis. Others bear such names as “accelerated approval” and “priority review.”

“I think what these data show is over time, an increase and creep of designations towards drugs that may not be truly the most transformative products,” Kesselheim said.

In a study published last year in The BMJ, formerly known as British Medical Journal, Kesselheim and co-authors said special pathways were meant as exceptions to the standard FDA review process. As it turned out, “the exceptions had become more common than the rule.”

Despite the user-fee money, pressures to review drugs expeditiously have been a strain on the agency.

For example, when FDA officials met with representatives of the pharmaceutical and biotech industries last year to negotiate the renewal of PDUFA, the agency said that the breakthrough therapy program was turning out to be more work than expected. “FDA stated that because the program was not funded with new resources at its inception, the demand is currently met through either uncompensated staff overtime or by rebalancing existing priorities,” according to minutes of the negotiating session.

The FDA has pointed a finger at Congress.

When the user fees expire every five years, the bills renewing them are essentially must-pass legislation. That makes them convenient vehicles for other provisions—giving lobbyists and lawmakers an additional opening to influence the FDA’s workings.

When Congress takes up the reauthorization of PDUFA, “additional requirements are often placed on the agency without being properly resourced,” FDA spokeswoman Goodin said in an email to POGO. “This phenomenon may lead to the notion of the agency not being adequately resourced to take care of all the work that society asks us to do.”

Currently, the fees drug companies pay for the FDA to review new drugs run about $2 million each for applications that involve clinical trials. The fee doesn’t guarantee that the FDA will approve the drug. However, under PDUFA, the FDA has committed to dozens of performance goals, from how quickly it acts on different types of meeting requests from drug companies to how much time it takes to review drugs. The agency is required to measure and report its compliance with those goals.

The FDA’s latest annual “Performance Report to Congress” under PDUFA totals 64 pages. It notes that in fiscal year 2014, the FDA was supposed to review at least 90 percent of certain expedited applications within six months of their filing dates. The FDA exceeded that goal, reviewing 96 percent of them within the six-month time frame. As the document explains, activities “not captured by PDUFA goals and therefore not presented in this report include . . . the ongoing monitoring of drug safety in the postmarket setting.”

The target dates for FDA drug review decisions, known as “PDUFA dates,” focus the minds of people inside the agency and out. Investors hang on them, knowing that company fortunes can rise or fall depending on the outcomes. Hence, a constant stream of headlines such as “Egalet (EGLT) Says FDA Will Not Meet October 14 PDUFA Date” and “DVAX Vaccine Faces Crucial PDUFA Date.”

The FDA history of PDUFA—co-authored by Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research—warned that drug industry money has a price:

“The provision of industry fees to FDA has undermined public trust in the agency, which is perceived by some as having lost independence and credibility as a result of accepting industry money.”

PDUFA VI: The Latest Round of Negotiations

The latest round of PDUFA negotiations—the sixth, known as “PDUFA VI”—charted goals for the FDA through fiscal year 2022. In drafting the goals, the industry and FDA negotiators got under the agency’s hood and examined its inner-workings.

The 70 negotiating sessions were almost double the 36 sessions held five years earlier. In a change since last time, there were subcommittees to discuss each of several facets of the agency, from finances to information technology, and from pre-market oversight of drugs to postmarket oversight. To guide it all, there was a steering committee whose participants included the global head of regulatory affairs at Novartis, the senior vice president for global regulatory affairs and clinical safety at Merck, the global head of regulatory policy and intelligence at Alexion Pharmaceuticals, and lobbyists for Pharmaceutical Research and Manufacturers of America (the main trade group for drug companies) and Biotechnology Industry Organization (the main trade group for biotech firms, renamed this year as “Biotechnology Innovation Organization”).

POGO sought to observe negotiating sessions, but the FDA said they were closed to the public.

Federal law required the FDA to release minutes of the meetings to the public. The minutes the FDA posted were written in vague, general terms—descriptions such as, “Industry proposed that PDUFA VI build on the PDUFA V performance goals for further implementation of a structured benefit-risk framework to inform regulatory decision-making.” The agency gave the public meager real-time insight into the discussions.

The commitments the negotiations produced establish broad mandates for the FDA while leaving many details to be filled in later.

For example, the FDA agreed to hold early consultations with drug companies about the feasibility of approving individual drugs on the basis of measures never used before—new types of “surrogate endpoints.” Surrogate endpoints are proxies for what the drugs are supposed to achieve. If a drug is supposed to prevent heart attacks, a surrogate might be lowering cholesterol. If a drug is supposed to save people from dying of cancer, a surrogate might be shrinking the size of a tumor.

Designing clinical trials around surrogate endpoints can be quicker and easier than waiting to track actual heart attacks or survival rates, and it can hasten the availability of new treatments. But researchers have found that surrogate endpoints are not always good predictors of the desired outcomes.

“Most trial-level meta-analyses in oncology found low correlation between a surrogate end point and overall survival,” researcher Vinay Prasad of the National Cancer Institute and his co-authors wrote in a study published last year.

“Our findings call into question the widespread use of surrogate end points in oncology as a basis for treatment decisions,” they wrote, warning that the practice “has led to use of toxic drugs that do not improve survival.”

Approving drugs on the basis of “weak surrogates” can set back the cause of helping cancer patients because it “may encourage the pharmaceutical industry to pursue even more cancer drugs with marginal to no benefits,” they said.

In another major PDUFA VI commitment, the FDA said it “recognizes the potential value of utilizing ‘real-world’ evidence in evaluating not only the safety of medications but also their effectiveness.” The term “real-world evidence” was not defined, leaving possibilities open-ended. Real-world evidence evidently differs from the kind of data that has long been the bedrock of clinical research and FDA reviews. It could include, for instance, medical data gathered from millions of health insurance claims. In a similar vein, the FDA said it will beef up its ability to consider “patient-reported outcomes,” and it said it will foster the development of “tools to collect meaningful patient input that can be incorporated into regulatory review.” Those weren’t described in any detail, either.

Kay Holcombe of BIO, the biotech industry group, provided this perspective at the August FDA forum:

“We cannot put anecdotes on the drug label. So this is all a way for us to convert what always has been an anecdote into real data that can be on the label and help people use this therapy in the way that is the safest and most effective for each individual patient.”

At the same event, Peter Pitts, president of Center for Medicine and the Public Interest and a former FDA associate commissioner, offered a cautionary word.

“When it comes to the patient voice, or any voice, the plural of anecdote isn't data,” he said.

“To evaluate the reliability of data, FDA must assess how they were collected, their adequacy for answering relevant questions, and whether they were collected in a manner that minimizes bias,” he said.

In a third commitment, the FDA said it would take steps to “facilitate the advancement and use of complex adaptive, Bayesian, and other novel clinical trial designs.” Those terms weren’t defined, either. However, to focus on the first, the term “adaptive” has been used to describe clinical trials whose procedures are changed while the trial is in progress, as information is gathered. At their best, such approaches can reduce wasted effort and increase efficiency. At their worst, they can open the door to bias and manipulation.

The FDA told POGO that the use of highly innovative trial designs should not increase the risk of bias or manipulation. In a written response to questions, the FDA gave as its reason something not promised in the PDUFA VI commitment letter: It said adaptations would be specified before trials begin.

At the August FDA forum, BIO’s Holcombe, an invited panelist, explained that “innovative trial design” was a prime topic for BIO member companies.

“I want to say a few words about innovative trial design, not because I understand what it means,” Holcombe said.

The PDUFA VI agreement calls for a “pilot program” for “highly innovative trial designs” for which “simulations are necessary.”

“It's going to allow companies to bring in creative ways of doing trials,” Holcombe said. In an apparent nod to an FDA official at the meeting named Lisa, Holcombe added, “By ‘creative’—Lisa is getting nervous about the word ‘creative’—I mean like statistically okay ones.”

Paul Brown of National Center for Health Research saw a downside. The “faster, less thorough reviews” contemplated under the agreement “will cost patients and taxpayers billions of dollars, but many will later be found to offer risks that far outweigh the benefits,” he said.

Lowering the Bar for Drug Approval

The FDA Commissioner’s September decision to approve the muscular dystrophy drug eteplirsen over the objections of FDA staff illustrates, for better or worse, where some of these commitments could lead. It also sheds light on the agency’s posture toward industry in the age of user fees.

The FDA’s review of the drug included extensive input from patients. At the direction of Janet Woodcock, head of the FDA’s Center for Drug Evaluation and Research, members of the FDA team reviewing eteplirsen joined her for meetings with patient advocacy groups “anywhere from six to twelve times,” according to an internal FDA account. The meetings frequently included boys with Duchenne muscular dystrophy and their parents. One member of the review team described the sessions as “’intense,’ ‘personal,’ and ‘intimidating,’” the internal account said.

When an FDA advisory committee held a hearing on the drug in April 2016, one of the witnesses was Pat Furlong, who lost two sons to Duchenne muscular dystrophy and founded the advocacy group Parent Project Muscular Dystrophy. Furlong recounted that, before her son Patrick died at age 15, “he couldn’t lift his hand to his mouth.”

“Your goal, the FDA, is to improve how an individual feels, functions, and survives,” she said, urging the committee to “exercise maximal flexibility” in assessing the drug.

In pursuit of a cure, Parent Project Muscular Dystrophy has joined forces with drug makers. Its website lists several pharmaceutical companies as sponsors—including Sarepta Therapeutics, maker and sponsor of eteplirsen.

At the advisory committee hearing, speakers from the public were asked “to advise the committee of any financial relationship that you have with the sponsor, its product, and if known, its direct competitors.”

When it was Furlong’s turn to speak, she began: “My name is Pat Furlong, and I am president and CEO of Parent Project Muscular Dystrophy. I have nothing financial to disclose.”

Furlong’s organization did not respond to inquiries for this story.

The scientific research that drug-maker Sarepta submitted to the FDA did not show that eteplirsen cured the disease. Rather, the case for eteplirsen hinged on an unproven surrogate endpoint: production of dystrophin, a protein that is lacking in muscular dystrophy patients. One FDA official said the increase in test subjects’ dystrophin levels was “trivial.” Another described it as “miniscule.”

Unger, director of an FDA drug evaluation office, said the case for approval was weak.

“The approval of this NDA”—new drug application—“in its present form would have far reaching negative consequences for the public health,” he wrote in a July memo.

Unger was overruled by Woodcock. He appealed to an internal FDA board responsible for resolving scientific disputes.

In a presentation to the board, Woodcock talked about the drug maker’s financial condition and stock price. “Dr. Woodcock cautioned that, if Sarepta did not receive accelerated approval for eteplirsen, it would have insufficient funding to continue to study eteplirsen and the other similar drugs in its pipeline,” Luciana Borio, the FDA’s acting chief scientist, wrote in an account of the appeal.

Woodcock also “emphasized her view that the agency needs to accept more uncertainty when granting accelerated approval,” Borio wrote.

Borio sided with Unger. “[A]pproving products based on hope, on subjective clinical judgment, or on theoretical constructs that are not anchored in data leads to irreparable damage to patients,” she wrote.

The decision fell to the FDA Commissioner.

“Major flaws in both the design and conduct of the clinical trials using eteplirsen have made it impossible to use much of the resulting trial data as reliable evidence,” Califf wrote. He also wrote that he was “troubled” to read that Woodcock’s decision “may have been inappropriately motivated by concerns over” the drug maker’s “financial well-being.”

But Califf said he spoke to Woodcock and was “satisfied that her decision is indeed based on her scientific evaluation of the evidence.”

Saying he would defer to Woodcock, he approved the drug.

“Patients with a particular type of Duchenne muscular dystrophy will now have access to an approved treatment for this rare and devastating disease,” Woodcock said in an FDA news release.

Charles R. Babcock, Halle Zander, and Lydia Dennett contributed to this report. Editing by Danni Downing.