FDA Grapples With Lesser-Known Costs of Clinical Trials Transparency

Regulatory NewsRegulatory News | 14 July 2014 |  By 

US medical device regulators soon plan to hold a public hearing to discuss how the results of cardiovascular outcomes trials (CVOTs) can be kept confidential until they are completed.


The meeting, previewed by the US Food and Drug Administration (FDA) in a 14 July 2014 Federal Register notice, comes after years of the agency placing more of an emphasis on mandatory post-market approval trials.

Those trials are meant to assuage outstanding regulatory concerns about the safety of a product. Traditionally, regulators would have required a company to conduct additional clinical trials to assess those risks—trials which can take years to finish and cost tens, if not hundreds of millions of dollars. But since the mid-2000s, FDA has increasingly shifted those trials to postmarket settings, allowing companies to market their products on the condition that they finish the mandatory trials by pre-specified dates.

Some trials, FDA notes, "are not large enough to assess the risk of rare serious events such as heart attacks, strokes or death." Large CVOTs are therefore commonly used to assess those risks as a condition of approval.

Large CVOTs are especially common for certain classes of drugs, including diabetes medications. For example, Afrezza, a diabetes drug approved in June 2014, was approved on the condition of it conducting a trial to "assess cardiovascular risk and the long-term effect of Afrezza on pulmonary function."

Farxiga, another diabetes medication approved in January 2014, was approved on the condition that Bristol-Myers Squibb, its sponsor, conduct a CVOT to evaluate cardiovascular risk in patients with an elevated risk of cardiovascular disease. And a third diabetes medication approved this year, Tanzeum, was also approved on the condition of conducting a CVOT.

Lingering Concerns About Cost of Transparency

And it is these trials, and the trials of other drugs, that have left FDA with some lingering concerns—and not just about the safety of the drugs.

Because the trials are meant to assess serious risks which could lead to new safety restrictions or even the removal of a drug from the market, companies regularly conduct so-called "interim" analyses of the data which are meant to generate preliminary findings. Those findings might constitute early evidence that a drug is safe for use, or conversely might generate evidence that the risks of a drug outweigh its benefits in certain populations.

But in its Federal Register notice, FDA indicated that the publication of interim data can prove problematic.

Globally, regulators have expressed a unified view that "all staff involved in the conduct of the trial should remain blind to the results of such [interim] analyses because of the possibility that their attitudes to the trial will be modified and cause changes in the characteristics of patients to be recruited or biases in treatment comparisons," FDA wrote, quoting the International Conference on Harmonization's (ICH) E9 Statistical Principles for Clinical Trials.

To guard against interim results interfering with ongoing care, FDA recommends that an Independent Data Monitoring Committee (DMC) review the results instead of trial investigators.

But even then, sometimes interim results are widely published, and FDA has expressed concern that investigators could learn of a trial that way. "Sponsors and other interested parties with access to interim data may have difficulty managing the remainder of the trial in an objective manner, particularly if changes to the trial protocol are needed for other reasons," the regulator wrote.

Perils of Public Data

And therein lies the trouble for FDA, it said. Because the Federal Food, Drug and Cosmetic Act (FD&C Act) calls for summaries of the interim data conducted for postmarketing studies to "be made available immediately for public disclosure," keeping those results from investigators is harder than ever.

Trickier still are cases when a single ongoing trial is used both to substantiate approval and generate post-approval data on cardiovascular risks. In such cases, some information will become available to investigators by default, such as the drug's relative risk ratio.

Explained FDA: "Disclosure of detailed and more extensive information or analyses from an ongoing trial—that is, the results of an interim analysis—could undermine the integrity of the trial and jeopardize its continuation, which could delay or even prevent obtaining the safety data about serious risks that were required to be assessed at the time of approval."

Accordingly, FDA has taken to releasing only high-level summary conclusions about approved drugs subject to ongoing trials, it said.

Meeting Questions

All of this raises questions about the nature of transparency, FDA said in its Federal Register notice. In announcing an upcoming meeting, regulators say they want to solicit public input on how and when to disclose data to the public, and whether alternative trial designs might be appropriate for use in postmarket settings.

A full list of questions presented by FDA is as follows:

  • When a trial to evaluate CV safety of a new treatment is ongoing at the time a drug is approved, do stakeholders agree that disclosure of detailed analyses (such as point estimates of hazard ratios and the associated confidence intervals) could undermine the integrity of an ongoing trial and jeopardize its continuation, potentially eliminating or substantially delaying the Agency’s ability to obtain needed long-term safety information?
  • What interim findings, if disclosed, would represent the greatest risk to trial integrity or jeopardize trial continuation?
  • Can partial disclosure of interim findings at the time of approval, essentially disclosing only that the standard for approval has been met, offer protection of trial integrity and also provide health care practitioners with the essential scientific information needed to inform their use of the drug?
  • If the detailed interim results were disclosed at the time of approval, and the ongoing study was discontinued at that time, would it be feasible to conduct a new large trial as a postmarketing requirement that would fulfill the original study objective?
  • Are there other, alternative trial designs that would allow for disclosure of interim results on safety risks at the time of product approval while also allowing for further information to be obtained postmarket?

The meeting is set to take place on 11 August 2014 at FDA's White Oak campus in Silver Spring, MD.


Federal Register Notice


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