Advocates push for access to secret clinical data, while FDA drags its feet

Mary Chris Jaklevic has freelanced for since 2016 and recently joined the staff as a full-time health care journalist. She tweets as @mcjaklevic.

Reams of clinical data that could improve treatment decisions are kept secret by regulators, transparency advocates say.

A recent analysis of once-secret clinical trial data concluded that a popular morning sickness drug, Diclegis, doesn’t actually work.

That surprising finding, made possible by the release of previously undisclosed data by Canadian regulators, drew a barrage of headlines, including coverage by Reuters, Healthline, and HealthDay.

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.”

More details could improve clinical guidelines

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.

Media coverage is ‘very, very important’

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.

Published data ‘cannot be trusted’

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

FDA lags behind other regulators

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.”

Voluntary pilot leaves out some useful data

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.

Open data movement has attracted coverage

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. 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.

Back in 2013, the New York Times highlighted the need for clinical data disclosure and ran an editorial calling for companies to release their data.

Not as much scrutiny of the FDA’s role

But the role of the FDA and other regulators in promoting transparency has largely escaped scrutiny from U.S. news outlets.

A Google search turned up a short story about the new FDA pilot in the Washington Post and an article in STAT News.

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.”

Canadian journalists put regulators in the spotlight

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.

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Comments (4)

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Larry Sasich

February 19, 2018 at 8:55 am

These comments are limited to human drugs.

Additional context and detail about the drugs mentioned in this article would be helpful to both patients and prescribers. Diclegis is a combination of the over-the-counter antihistamine doxylamine and vitamin B-6. Diclegis, originally sold in the US as Bendectin, was voluntarily withdrawn from the market in 1983. The drug was re-approved in 2013.

The assertions that the FDA drags it feet in releasing data and that Diclegis does not work are inaccurate. The Freedom of Information Act requires the FDA to release its detailed analyses of studies submitted by manufacturers in support of all new drug approvals (called “Approval Packages”). Quickly accessing the professional product label, or package insert, or the Approval Packages available for free on the Internet shows that the drug does have an effect and the extent to which it works is small.

Approval packages may contain the results of unpublished clinical trials that have been used to keep potentially dangerous drugs off the market.

Scientific disagreement is certainly possible and appropriate about the outcome measure that was used to assess the effect of Diclegis, and if this effect is important to patients. Those who disagree with the FDA may petition the agency for changes and the agency is required to respond by regulation.

This article mentions the flu drug Tamiflu (oseltamivir) and a 2014 Cochrane review showing the drug has a minimal effect on the duration of flu symptoms, and that the drug does not prevent the bacterial complications of the flu. Patients and prescribers could find the same information in the professional product label and approval package that were available more than 10 years before the 2014 Cochran review.

This article mentions the drug Neurontin (gabapentin). What is not mentioned is that the drug’s manufacturer created a publication strategy to do an end run around the FDA’s approval. The drug was widely used because prescribers did not take the time to read Neurontin’s package insert to see that many of the uses the drug was being prescribed for had not been approved by the FDA (so-called “off-label” prescribing).

Missing from the discussion of the non-steroidal anti inflammatory drug (NSAID) Vioxx (rofecoxib) are the facts that there are no claims in the drug’s professional product label that it is either safer concerning serious GI events, or more effective than other NSAIDs that were already on the market.

A major shortcoming of the FDA is that details for the reasons that a drug is not approved are not made available to the public.

Many preventable adverse drug effects and the economic losses from prescribing drugs without clear evidence of a meaningful benefit to patients would also be prevented if journalists encouraged the public, including prescribers, to consult FDA information before taking or recommending a drug.

    Mary Chris Jaklevic

    February 19, 2018 at 10:36 am

    Thank you for this context, Larry. You make a good point that the FDA does make available a lot of data that may not be fully utilized by clinicians and others. However, the characterization of foot-dragging pertains specifically to the FDA’s policy of holding back on detailed clinical reports that would allow for independent analyses. Also, the story does state that the independent analysis on the effectiveness of Dicelgis isn’t definitive, although admittedly that point might be lost on some readers.

Larry Sasich

February 19, 2018 at 5:00 pm

To the best of my knowledge, the data submitted to the FDA by drug manufacturers for new drugs belongs to the manufacturer and is not released by the FDA under Exemption 4 of the Freedom of Information Act that covers confidential commercial information. There is a balance between protecting manufacturers’ ability to profit and the publics’ right to know. Releasing confidential commercial information may be a disincentive to developing new drugs.

Data submitted to the FDA and other drug regulatory authorities that are members of the International Conference on Harmonization (ICH) are done through a Common Technical Document (CTD) and should be the same for all member regulatory agencies.

The prohibition against releasing manufacturer information is avoided by the release of FDA Approval Packages. Regulations require the preparation of Approval Packages, originally called the Summary Basis of Approval, that are released to the public at the time of or shortly after a new drug is approved.

Important information potentially including unpublished trials from manufacturers applications are made available rapidly in Approval Packages. A time lag between the release of European and FDA information, if any, is unknown.

Proponents of releasing Clinical Study Reports (CSRs) frequently use independent analyses as a positive. This is done without definition. All research groups and individual investigators self describe themselves as independent. How would a reader know if a group or individual was truly independent?

Having been able to utilize manufacturers Clinical Study Reports (CSRs) and FDA Drug Approval Packages in a drug regulatory authority outside the US, Approval Packages are much more useful than CSRs in general.

Till Bruckner

February 21, 2018 at 11:47 am

This is an excellent article.

Some additions:

1. The AllTrials campaign has explicitly called for Clinical Study Reports to be made public:

2. The world’s largest anti-corruption organization, Transparency International, recently released a study documenting the dangers of not releasing CSRs and – together with Cochrane, CRIT and TranspariMED – called on governments to ensure that CSRs are made available to researchers:

3. In-depth case studies of past harms caused by concealed CSRs can be found here:

Please keep reporting on this important issue.