FDA Repays Industry by Rushing Risky Drugs to Market

As pharma companies underwrite three-fourths of the FDA’s budget for scientific reviews, the agency is increasingly fast-tracking expensive drugs with significant side effects and unproven health benefits.

by Caroline Chen
ProPublica

Nuplazid, a drug for hallucinations and delusions associated with Parkinson’s disease, failed two clinical trials. In a third trial, under a revised standard for measuring its effect, it showed minimal benefit. Overall, more patients died or had serious side effects on Nuplazid than after receiving no treatment.

Patients on Uloric, a gout drug, suffered more heart attacks, strokes and heart failure in two out of three trials than did their counterparts on standard or no medication.

Nevertheless, the U.S. Food and Drug Administration approved both of these drugs — with a deadly aftermath. Uloric’s manufacturer reported last November that patients on the drug were 34 percent more likely to die from heart disease than people taking an alternative gout medication. And since the FDA fast-tracked approval of Nuplazid and it went on the market in 2016 at a price of $24,000 a year, there have been 6,800 reports of adverse events for patients on the drug, including 887 deaths as of this past March 31.

The FDA is increasingly green-lighting expensive drugs despite dangerous or little-known side effects and inconclusive evidence that they curb or cure disease. Once widely assailed for moving slowly, today the FDA reviews and approves drugs faster than any other regulatory agency in the world. Between 2011 and 2015, the FDA reviewed new drug applications more than 60 days faster on average than did the European Medicines Agency.

Europe has also rejected drugs for which the FDA accelerated approval, such as Folotyn, which treats a rare form of blood cancer. European authorities cited “insufficient” evidence of health gains from Folotyn, which shrinks some tumors but hasn’t been shown to extend lives. It costs more than $92,000 for a seven-week course of treatment, according to research firm SSR Health.

As patients (or their insurers) shell out tens or hundreds of thousands of dollars for unproven drugs, manufacturers reap a windfall. For them, expedited approval can mean not only sped-up sales but also — if the drug is intended to treat a rare disease or serve a neglected population — FDA incentives worth hundreds of millions of dollars.

“Instead of a regulator and a regulated industry, we now have a partnership,” said Dr. Michael Carome, director of the health research group for the nonprofit advocacy organization Public Citizen, and a former U.S. Department of Health and Human Services official.

“That relationship has tilted the agency away from a public health perspective to an industry friendly perspective.”

While the FDA over the past three decades has implemented at least four major routes to faster approvals — the current commissioner, Dr. Scott Gottlieb, is easing even more drugs’ path to market. The FDA okayed 46 “novel” drugs — whose chemical structure hadn’t been previously approved — in 2017, the most in at least 15 years. At the same time, it’s rejecting fewer medications. In 2017, the FDA’s Center for Drug Evaluation and Research denied 19.7 percent of all applications for new drugs, biologics, and efficacy supplements, down from a 2010 peak of 59.2 percent, according to agency data.

President Trump has encouraged Gottlieb to give patients faster access to drugs.

“You’re bringing that down, right?” Trump asked the commissioner at a May 30 event, referring to the time it takes to bring drugs to market. “You have a lot of good things in the wings that, frankly, if you moved them up, a lot of people would have a great shot.”

Faster reviews mean that the FDA often approves drugs despite limited information. It channels more and more experimental treatments, including Nuplazid, into expedited reviews that require only one clinical trial to show a benefit to patients, instead of the traditional two.

The FDA also increasingly allows drugmakers to claim success in trials based on proxy measurements — such as shrunken tumors — instead of clinical outcomes like survival rates or cures, which take more time to evaluate. In return for accelerated approval, drug companies commit to researching how well their drugs work after going on the market. But these post-marketing studies can take 10 years or longer to complete, leaving patients and doctors with lingering questions about safety and benefit.

“Clearly, accelerated approval has greater uncertainty,” Dr. Janet Woodcock, head of the FDA’s Center for Drug Evaluation and Research, said in an interview. When only a single trial is used for approval, “in some cases, there may be more uncertainty about safety findings or with the magnitude of effectiveness.”

She attributed the increased use of expedited pathways to more drugmakers developing treatments for rare diseases, “where there’s unmet need, and where the patient population and providers are eager to accept more uncertainty.”

The FDA’s growing emphasis on speed has come at the urging of both patient advocacy groups and industry, which began in 1992 to contribute to the salaries of the agency’s drug reviewers in exchange for time limits on reviews. In 2017, pharma paid 75 percent — or $905 million — of the agency’s scientific review budgets for branded and generic drugs, compared to 27 percent in 1993.

“The virginity was lost in ’92,” said Dr. Jerry Avorn, a professor at Harvard Medical School. “Once you have that paying relationship, it creates a dynamic that’s not a healthy one.”

Industry also sways the FDA through a less direct financial route. Many of the physicians, caregivers, and other witnesses before FDA advisory panels that evaluate drugs receive consulting fees, expense payments, or other remuneration from pharma companies.

“You know who never shows up at the [advisory committee]? The people who died in the trial,” lamented one former FDA staffer, who asked not to be named because he still works in the field. “Nobody is talking for them.”

The drug industry’s lobbying group, Pharmaceutical Research and Manufacturers of America, continues to push for ever-faster approvals. In a policy memo on its website, PhRMA warns of “needless delays in drug review and approval that lead to longer development times, missed opportunities, higher drug development costs and delays in treatments reaching patients.”

The agency has internalized decades of criticism that painted it as an obstacle to innovation, said Daniel Carpenter, a professor of government at Harvard and author of a 2010 book on pharmaceutical regulation at the FDA.

“They now have a built-in fear of over-regulation that’s set in over the last 20 years.”

To be sure, nobody wants the FDA to drag out drug reviews unnecessarily, and even critics acknowledge that there’s no easy way for the agency to strike the perfect balance between sufficient speed and ample information, particularly when patients have no other treatments available, or are terminally ill.

FDA Is Approving More New Drugs and Rejecting Fewer Overall

“I think it’s reasonable to move drugs faster particularly in the case where you’re dealing with an extremely promising new product which treats a serious or life-threatening disease,” said Dr. Aaron Kesselheim, an associate professor at Harvard Medical School.

“The key, though, when you do that is that you’ve got to make sure you closely follow the drug in a thoughtful way and unfortunately, too often we don’t do that in the U.S.”

After thalidomide, taken by pregnant women to prevent nausea, caused thousands of babies in the early 1960s to be born with stunted limbs, Congress entrusted the FDA with ensuring that drugs going on the market were both safe and effective, based on “substantial evidence” from multiple trials.

Assembling this evidence has traditionally required three stages of clinical trials; the first in a small cohort of healthy volunteers to determine a safe dosage; the second to assess the drug’s efficacy and side effects; and then, if results are positive, two larger trials to confirm the benefit and monitor for safety issues. An FDA team of in-house reviewers is then assigned to analyze the results and decide whether the agency should approve the drug. If reviewers want more input, the agency can convene an advisory committee of outside experts.

As the FDA’s responsibilities expanded in the 1970s, review times began to lag, reaching more than 35 months on average in 1979. The AIDS crisis followed soon thereafter, prompting complaints from Gonsalves and other activists. Their protests spurred the Prescription Drug User Fee Act in 1992, which established industry fees to fund FDA staff salaries. In return, the FDA promised to review drugs within 12 months for normal applications, and 6 months for priority cases.

The more that the FDA relied on industry fees to pay for drug reviews, the more it showed an inclination towards approval, former employees say.

“You don’t survive as a senior official at the FDA unless you’re pro-industry,” said Dr. Thomas Marciniak. A former FDA medical team leader, and a longtime outspoken critic of how drug companies handle clinical trials, Marciniak retired in 2014.

“The FDA has to pay attention to what Congress tells them to do, and the industry will lobby to get somebody else in there if they don’t like you.”

Staffers know “you don’t get promoted unless you’re pro-industry,” he added.

This tilt is reflected in what senior officials choose to highlight. The agency’s Center for Drug Evaluation and Research gives internal awards to review teams each year, according to Marciniak and the former FDA employee who requested anonymity. Both said they had never seen an award granted to a team that rejected a drug application. The FDA did not respond to ProPublica’s request for a list of award winners.

Higher-ups would also send congratulatory emails to medical review teams when a drug was approved.

“Nobody gets congratulated for turning a drug down, but you get seriously questioned,” said the former staffer, adding that the agency’s attitude is, “Keep Congress off your back and make your life easier.”

Read the full report at ProPublica.