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In 1998, the US Food and Drug Administration (FDA) approved an antimicrobial solution called Sulfamylon to stave off infections in people with severe burns. Because the drug, manufactured by Mylan, a company based in Canonsburg, Pennsylvania, qualified for accelerated approval, the agency required the company to conduct a post-approval trial to confirm the efficacy of the medicine, which also goes by the generic name mafenide acetate. But 16 years later, that trial has yet to be completed. As of July—the most recent date for which information was available as Nature Medicine went to press—the company hadn’t even finished enrollment, according to an FDA database. Mylan did not respond to Nature Medicine's requests for comment, but the database describes the study, which was due in 2010, as “delayed.”

The Sulfamylon trial is just one of the approximately 150 required post-approval drug studies that are incomplete and past their original due date. In some cases, the manufacturers have valid reasons for the delays: enrollment is lagging, or they’re working to revise the study protocol. In other cases, there is no publicly available explanation for the delay, or the company has refused to do what was required of them. And some of the same problems that plague post-market drug studies appear to extend to post-approval studies of medical devices. An analysis published in late September found that 18% of the 223 post-approval studies ordered between 2005 and 2011 for medical devices had made “inadequate progress” and that, for a third of these, it was impossible to determine the reason for the delay1.

“In some settings, companies face tremendous disincentives to complete these studies,” says Caleb Alexander, co-director of the Johns Hopkins Center for Drug Safety and Effectiveness in Baltimore, Maryland.

New authority, lingering problemsConcerns about post-approval safety began to mount after the pain medication Vioxx was pulled from the market in 2004. A 2006 investigation by the US Government Accountability Office found that the FDA had little authority to require drug manufacturers to conduct observational studies or clinical trials aimed at investigating post-market safety concerns. “[The] FDA often relies on drug sponsors voluntarily agreeing to conduct such postmarket studies. But the postmarket studies that drug sponsors agree to conduct

have not consistently been completed,” the authors wrote.

Today, however, the FDA has far more power. The Food and Drug Administration Amendments Act (FDAAA), which went into effect in 2008, gave the agency the authority to require post-market studies to assess known or suspected safety issues and the ability to enforce its authority through penalties and misbranding charges. However, the agency’s expanded authority has not done away with delays. “What I’m seeing is that [post-approval] studies are often either not completed on time or not completed at all. And even when they are completed, the information that’s available for researchers and the general public regarding the results of the study often are not easy to come by,” Alexander says. “This is bad news—bad news for patients, bad news for the general public.”

Last year, Alexander and his colleagues examined the status of all post-approval studies reported by the FDA between 2007 and 2011. The researchers found that the percentage of post-market studies that had not yet begun fell during this five-year period, and the percentage of studies completed grew. But the results were still somewhat disheartening. In 2011, of 1,781 post-market studies that were established or tracked during that year by the FDA, 44% had yet to begin. What’s more, the number of delayed studies grew from 7% in 2007 to 14% in 2011 (ref. 2). “Our analysis called into question the degree to which the changes in the FDA’s regulatory authority in 2008 really have put this issue [of delays] to bed,” says Alexander, one of the authors of the study.

The numbers didn’t change much in 2012, the most recent year for which data were available. Of 1,781 studies—coincidentally the same number as in 2011— 40% had not yet begun and 17% were delayed. In many cases, the reasons for the delays are unclear. “The concern is that the manufacturer is delaying it until the patent runs out anyway, so it’s going to have no impact on their actual sales,” says Joseph Ross, a physician at the Yale University School of Medicine in New Haven, Connecticut. Even research that isn’t delayed may take years or even decades to complete. The problem is exacerbated for rare diseases for which patient recruitment can be a challenge. For example, NPS Pharmaceuticals, based in Bedminster, New Jersey, is required to create a registry to assess the long-term safety of Gattex (teduglutide), a drug that was approved in 2012 to treat a

rare condition called short bowel syndrome (SBS). “Given [that] prevalence data for SBS is uncommon and only a few thousand adult patients are believed to be in the US, enrolling 1,300 patients will take time,” says NPS spokesperson Scott Santiamo. The company has five years to enroll patients and must track their health for at least ten years. The completion deadline is 2029.

Shifting burden of proofIn many cases, the post-approval data provides crucial safety and efficacy information about a medicine or device. “The FDA is under a lot of pressure to approve drugs and devices sooner and sooner on the basis of less and less evidence and to push the evaluation to the post-approval period,” says Aaron Kesselheim, a physician and lawyer at Brigham and Women’s Hospital in Boston who studies the impact of regulatory policies on the drug approval process.

A study from Ross and his colleagues published in January found that between 2005 and 2012, the FDA authorized about a third of 188 new therapies on the basis of a single efficacy trial. And nearly half of the trials relied on surrogate endpoints3. One such study assessed the efficacy of Sirturo (bedaquiline), a drug approved in 2012 to treat multi-drug-resistant pulmonary tuberculosis when other alternatives will not work. A phase 2 trial showed that 79 patients with tuberculosis who received a drug cocktail

FDA’s post-approval studies continue to suffer delays and setbacks

Matter of time: Follow-up trials lag.

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Along a stretch of road in Boston lie two hospitals within a mile of each another, Brigham and Women’s Hospital and the Beth Israel Deaconess Center. In the event that a resident nearby has a heart attack and is brought to the emergency department, the choice of hospital could determine how quickly he or she receives medications based on his or her medical history. That’s because if the patient’s electronic health record (EHR) resides at one institution, it may not be available in a format that can easily be read by the other hospital. Even if partial information is recorded about the individual in each system, “the data won’t be able to talk to each other,” says Catherine DesRoches, a senior researcher at Mathematica Policy Research, a public policy research firm headquartered in Princeton, New Jersey.

A massive push toward digitizing health records came in 2009 when lawmakers in the US passed the HITECH—short for the Health Information Technology for Economic and Clinical Health—Act. To date, $547 million

has been made available by that legislation for states to set up ‘health information exchanges’, which facilitate the transfer of electronic patient records between hospitals, diagnostic centers and pharmacies. But that money is now running out fast. And with the future of these exchanges in doubt, the prospect of harnessing them for research purposes is also under threat.

Hospitals across the country are building EHR systems to fulfill the criteria of different stages of federal guidelines in order to receive payments as a part of the Medicare EHR Incentive Program. As of September 2014, out of the 5,000 hospitals in the US eligible for the Medicare EHR Incentive Program, only 235 hospitals had demonstrated that they used certified systems that shared digital patient data continuously for 90 days in a manner that complied with the latest stage in federal guidelines, according to the US Centers of Medicare and Medicaid. However, proponents of electronic health record sharing say that more hospitals use digitized

information than ever before. A 2014 report from the US Office of National Coordinator for Health Information Technology, the agency entrusted with spearheading the government’s health information technology efforts, stated that more than 59% of hospitals in the US use some form of electronic health records that include the results of diagnostic tests, patient summaries, admission dates and other such information.

Private vendors such as Practice Fusion, Surescripts and GE Healthcare’s Centricity programs, and handful of open source solutions approved by the government, offer software packages for EHR systems. Wisconsin-based software company Epic, which sells a wide share of EHRs currently on the market, estimates that by late 2015, 51% of people in the US will have a health record stored in one of their electronic systems. But the transfer of information between hospitals can prove difficult because each vendor’s proprietary software runs differently. Even two hospitals in the same network might

As funds to sync health records dwindle, research could suffer

that included Sirturo cleared the bacteria from their sputum faster than 81 people who received the same drug regimen plus a placebo. However, those who received Sirturo also had a greater increased risk of death: nine deaths occurred in the Sirturo group compared to two deaths in the placebo group. As part of the approval, the FDA required Janssen, the drug’s manufacturer, to conduct a phase 3 trial to confirm the drug’s efficacy, but Janssen isn’t required to complete the trial until 2022. “That seems like a very long time horizon, and I don’t see the justification,” Kesselheim says. Lisa Vaga, a spokesperson for Janssen, explains that the company is looking for ways to get the information sooner: “We’ve been in active discussions with health authorities and additional external partners to identify ways to meet our post-marketing commitments and generate additional clinical data, as well as how to accelerate the outcome.”

Society may accept drug approvals based on preliminary evidence “because we want drugs to market faster,” says Ross. But “the argument then is we need to have much better data in the post-market period.”

Policing drugmakersThe FDAAA authorized the FDA to fine companies that fail to comply with post-approval requirements or charge them with misbranding, but the FDA seldom uses this

authority. The authors of the medical device study published in September found the FDA has never issued a warning letter, fined a company or withdrawn a device’s approval because of a manufacturer’s failure to meet deadlines or complete a post-marketing study. And Nature Medicine found only two instances of warning letters issued to pharmaceutical companies because of failure to begin or complete a post-approval study required under the FDAAA.

One of those went to Shionogi Inc., the New Jersey–based arm of a Japanese pharmaceutical company. In September 2012, the FDA notified the company that it would be required to conduct two clinical trials to identify an unexpected serious risk of heart problems associated with its pain medication Rybix ODT, a drug that was approved in 2005. The company told the FDA they did not intend to comply because the costs of the study “were not commercially justified based on the sales potential for Rybix.” Shionogi proposed that the FDA allow the company to sell down its remaining stock of the drug before pulling it off the market. In a warning letter sent last spring, the agency advised Shionogi that it was in violation of the FDAAA.

A month and a half after the FDA sent the letter, the company discontinued Rybix. Shionogi did not comment on its reasons for doing so when contacted by Nature Medicine.

Kesselheim suggests that drugmakers might have more incentive to complete their post-approval studies if a drug’s or device’s approval automatically expired after a certain number of years unless the required post-approval studies had been completed. “But that would require a legislative amendment,” he says.

Even when manufacturers do complete their post-approval requirements, the data can be hard to come by. Two years ago, Alexander tried to gain access to the results of a post-marketing study by filing a US Freedom of Information Act request. The FDA told him his request could take several years to process and that the agency might not be able to fulfill it because the documents could contain proprietary information regarding the manufacturer’s risk mitigation efforts. The request for information remains unfulfilled, and without access to that kind of data, Alexander says, it’s impossible to assess whether the FDA’s risk mitigation strategies are helping to make drugs safer. “The jury is out not because the data isn’t there,” he says, “but because the data isn’t available for review and evaluation.”

Cassandra Willyard

1. Reynolds, I.S. et al. J. Am. Med. Assoc. Intern. Med. doi:10.1001/jamainternmed.2014.4194 (29 September 2014).

2. Fain, K., Daubresse, M. & Alexander, G.C. J. Am. Med. Assoc. 310, 202–204 (2013).

3. Downing, N.S. et al. J. Am. Med. Assoc. 311, 368–377 (2014).

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