Mary Chris Jaklevic has freelanced for HealthNewsReview.org since 2016 and recently joined the staff as a full-time health care journalist. She tweets as @mcjaklevic.
A recent analysis of once-secret clinical trial data concluded that a popular morning sickness drug, Diclegis, doesn’t actually work.
But those news reports didn’t mention a much bigger issue: the push to release comparable clinical data for thousands of other drugs and medical devices — data that has been kept under wraps by the FDA and other regulatory bodies.
Detailed data that companies submit to regulators when they seek a product’s approval — known as a clinical study report, or CSR — could enable researchers and clinicians to get a fuller picture of its benefits and risks.
Those reports haven’t been made public, often because manufacturers won’t sanction their release. A physician-researcher in Canada was able to obtain data about Diclegis from Canadian health authorities only after a four-year battle, helped along by some media publicity.
“It is practically impossible to do this type of work now,” said the researcher, Nav Persaud, MD, a family physician at St. Michael’s Hospital in Toronto. “Regulators have to make it easier for researchers to access this information.”
It’s not the first time independent scrutiny of comprehensive trial data has contradicted published research.
For example, a 2014 Cochrane review used CSRs to show that the benefits of Tamiflu to treat flu symptoms are smaller than previously believed and may not outweigh the harms. A 2013 review of the data behind Medtronic’s Infuse spinal implant concluded it was actually no better than an older treatment and may carry additional risks.
In both cases manufacturers voluntarily released the data under pressure from the research and medical community, but that’s unusual.
Some advocates say it’s time to uncork CSRs for all drugs and devices, which can amount to thousands of pages per product, including descriptions of every adverse event and the minutiae of how a trial was performed. They argue these nitty-gritty details could improve the quality of clinical practice guidelines and systematic reviews, which try to aggregate all evidence about a medical intervention.
“Transparency of clinical trial data is a no-brainer,” said Peter Doshi, PhD, an assistant professor of pharmaceutical health services research at the University of Maryland and associate editor of The BMJ, in an email. “It just requires reflecting on the fact that there is more to the trial than the 10-page report we see published in journals.”
Releasing the FDA’s trove of evidence could foster a “cascade” of better information to help clinicians, patients and policymakers make decisions about medical treatments, said Kay Dickersin, PhD, director of the U.S. Cochrane Center and a professor at the Johns Hopkins Bloomberg School of Public Health.
“Public awareness and media coverage is very, very important to promoting data transparency,” Dickersin said via email.
Tianjing Li, PhD, an associate professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, argued in a recent BMJ editorial that “information in the public domain cannot be trusted at face value” because companies can downplay adverse events and switch outcomes.
For example, a 2000 examination of 12 clinical trials of the drug gabapentin (brand name Neurontin) concluded that in eight of the studies researchers changed the primary outcome from what was stated in the original trial description, most often to indicate a more favorable result for the drug.
Advocates for disclosure also cite the 2004 Vioxx case, in which tens of thousands of people died from taking the painkiller after it was approved by regulators. If comprehensive trial data had been available for independent review, they argue, its safety problems could have been detected much earlier.
A sweeping Blueprint for Transparency by researchers and academics recommended the FDA take a number of steps including releasing CSRs to advance innovation, improve the design of clinical studies, and avoid exposing patients to drugs that have been shown to cause harm.
Broader transparency can empower patients, clinicians, researchers, and others to use information more effectively for a broad range of goals. For example, knowledge that a product failed because of problems with kidney toxicity may help patients and clinicians to understand the need for alternatives and lead researchers to focus on new assays of kidney function or develop new compounds that work through different mechanisms.
That document was supported by the Laura and John Arnold Foundation, as is Doshi’s project to collect data from unpublished or misreported trials. The foundation also funds HealthNewsReview.org.
But while European and Canadian regulators have committed to releasing CSRs, the FDA has dragged its feet.
The European Medicines Agency (EMA) began routinely publishing CSRs in 2016. Health Canada announced in March 2017 that it would work to make clinical data for all drugs and medical devices public, including products that were rejected or are already on the market.
In January the FDA announced a pilot to release portions of CSRs for as many as nine approved drugs.
However, critics say the pilot is so narrow in scope it might not benefit consumers. It will include only drugs whose corporate sponsors volunteer to participate, and only parts of the evidence deemed “most important to the FDA’s assessment of the safety and efficacy of the drug.”
There’s no plan to release data that could prove more useful, such as CSRs for drugs that were not approved or were withdrawn, or for so-called “legacy drugs” that have been on the market for decades and make up the bulk of prescribing.
Nor are there plans to release data pertaining to unapproved “off-label” uses of drugs, or to medical devices.
Doshi said there’s “no real sign that the pilot reflects a change in FDA’s long-held view” that CSRs are protected by laws governing trade secrets.
“The real test will come if the FDA ever attempts to implement a CSR release program that is not voluntary for industry,” he said. “That is when things can get more confrontational.”
In Europe, some pharmaceutical companies brought legal challenges to block the release of CSRs, claiming they contain proprietary information. The EMA has maintained that clinical data isn’t proprietary.
The issue of open data in general is gaining some traction among journalists.
For example, the AllTrials campaign has focused media attention on the issue of unpublished clinical trials, showing how missing data from those studies — which may be shelved by drug company researchers because of negative results — can skew the medical literature and affect clinical decision-making.
There has also been some coverage of efforts to get drug companies and medical journals to share the underlying data from clinical studies that do get published. HealthNewsReview.org wrote about how lack of access to such data hampered the ability of the U.S. Preventive Services Task Force to issue optimal guidance on the use of statins.
But the role of the FDA and other regulators in promoting transparency has largely escaped scrutiny from U.S. news outlets.
A Times profile of FDA Administrator Scott Gottlieb, entitled, “FDA Chief Goes Against the Administration Stereotype,” offered an upbeat take.
Jennifer Miller, an assistant professor and clinical trials transparency expert at New York University School of Medicine, said a pilot program started by Dr. Gottlieb, in which pharmaceutical firms voluntarily release information about their clinical studies for approved drugs, was a step in the right direction.
“The industry is already trending toward releasing them,” Dr. Miller said. “It’s a safe time to roll out a pilot. I think he’ll likely be successful and learn what works and what didn’t.”
By contrast, some Canadian journalists focused on the refusal of Health Canada to release clinical evidence on Diclegis. The Toronto Star ran a 2015 investigation that it called it “a story about secrecy,” documenting how drug companies wielded control over what data the government shared with the public.
Eventually Persaud, the Toronto doctor, obtained the CSR for the company-sponsored trial, after agreeing to keep it confidential. “I think people are shocked that this type of information was hidden,” he said.
His team concluded that selective reporting of outcomes in the published study had made the drug seem effective; measures that showed a benefit, such as time lost from employment due to nausea and vomiting, were included in the results while measures that did not show a benefit, such as time lost from household tasks, were left out.
While some observers caution that his analysis isn’t definitive, Persaud has called for regulators to reconsider their approval of the drug and for doctors to stop prescribing it.
Diclegis manufacturer Duchesnay Inc. has said more than a million prescriptions have been written for the pill, which costs about $430 for 60 tablets with a coupon, according to web site GoodRx.
Meanwhile, the FDA hasn’t responded to Persaud’s plea, made years ago, for its own data on Diclegis. “They are still processing my request,” he said.