By Allison Proffitt

September 19, 2016 | The Department of Health and Human Services and the National Institutes of Health issued corresponding efforts on Friday to bring transparency to the clinical trials process. 

HHS released a 710-page final ruling on clinical trials registration and the results information submission process. The rule is the final outcome on a draft ruling first published on November 21, 2014 on which HHS received more than 900 comments. The regulations go into effect on January 18, 2017.

At the same time, NIH released a complementary policy on the dissemination of NIH-funded clinical trial information. The NIH’s 26-page document applies to all NIH-funded trials, including those not subject to the HHS final rule.

“Access to more information about clinical trials is good for patients, the public and science,” said NIH Director Francis S. Collins in a press statement. “The final rule and NIH policy we have issued today will help maximize the value of clinical trials, whether publicly or privately supported, and help us honor our commitments to trial participants, who do so much to help society advance knowledge and improve health.”

HHS Final Rule Details

The HHS rule applies to all interventional clinical trials with one or more arms, and with one or more pre-specified outcome measures, even for drugs and devices not yet approved, licensed, or cleared by the FDA, or for which no approval will be sought. This excludes phase 1 trials of drug and biological products, or small feasibility studies of device products.

The rule authors were particularly concerned with avoiding bias. “This rule’s requirements that responsible parties submit results information from clinical trials of unapproved, uncleared, or unlicensed products regardless of whether approval, clearance, or licensure is sought, as well as the public posting of this information, are expected to alleviate the concerns regarding bias in the literature and selective publication,” the rule reads (emphasis ours).

There is an intent throughout the rule to respect clinical trial participants and honor their contributions (though the term “human subjects” is still used).

“The public record also ensures that each individual’s participation in a trial is appropriately respected by preventing the conduct of “secret” trials, for which their existence is not publicly known [or] their results are never publicly reported,” the rule reads. 

Trials must be listed on ClinicalTrials.gov within 21 days of enrolling the first patient by either the sponsor or another designated “responsible party”. Registered clinical trials must include the full study protocol and statistical analysis plans, but the ruling doesn’t dictate the design or conduct of trials or how data should be collected or analyzed. 

Some opposed to sharing full study protocols argued that the documents will be confusing to the public and detrimental to recruitment, because they are technical, not standardized, and may have multiple amendments. Others pointed out that protocols may contain proprietary details that would put business interests at risk.

The rule authors were unconvinced.

Protocols help provide a more nuanced understanding of key trial methods including detailed eligibility criteria, how data were collected for key outcome measures and adverse events, and detailed methods of statistical analyses, they wrote. In addition, statistical analysis plans are necessary to describe the analyses to be conducted and the statistical methods to be used.

Actual results must be submitted no later than one year after the final data collection for the primary outcome measure of the trial, with some exceptions. Results should be submitted as a table; HHS purposefully chose not to allow “technical or non-technical narrative summaries” in hopes of avoiding bias. Tables must summarize participant flow; patient demographic and baseline characteristics including race and ethnicity; primary and secondary outcomes, as well as results of any scientifically appropriate statistical tests; and adverse event information by arm or group of the study.

The required adverse event reporting is extensive. Sponsors must submit three tables of adverse event information: one summarizing all serious adverse events; another summarizing other adverse events that occurred with a frequency of 5% or more in any arm of the clinical trial; and finally, a table summarizing all-cause mortality data by arm or group. Adverse event tables must include information about events that occurred, regardless of whether or not they were anticipated, but it does not require the responsible party to collect adverse event material not specified in the protocol. Adverse event reporting must be updated at least annually if there are changes.

The authors recounted numerous public comments objecting to results submission, including an assertion that required trial results to be made public is tantamount to “a regulatory taking of property without just compensation, in violation of the Fifth Amendment of the U.S. Constitution.”

 But the authors of the ruling disagreed.

“We do not believe that drug and medical device manufacturers have a reasonable expectation at this time that the results information described in the final rule will be kept confidential. This is because (1) the field of drug and device development is highly regulated, (2) there has been robust public debate over the need for greater transparency of clinical trial results, and (3) it has been clear since the proposed rule was issued in 2014… that such information can and may be made available to the public.”

More complete information about clinical trials has both scientific and public health benefits, the rule authors wrote. This greater transparency, “may help potential clinical trial participants to better understand their options for participating in new trials; to better enable funders and clinical researchers to determine the need for new trials; to provide more complete information for those who use evidence from clinical trials to inform medical and other decisions; and to better enable the scientific community to examine the overall state of clinical research as a basis for engaging in quality improvement (e.g., with regard to research methods).”

NIH Policy Details

In conjunction with the HHS rule, the National Institutes of Health issued its own policy.

The NIH Policy is broader than the HHS rule, encompassing all clinical trials funded in whole or in part by the NIH, including types of trials not subject to the HHS rule: phase 1 trials of FDA-regulated drug and biological products, small feasibility studies of FDA-regulated device products, and studies of any intervention not regulated by the FDA like behavioral interventions.

All of these trials are expected to be registered and results submitted to ClinicalTrials.gov under the same parameters and deadlines laid out in the HHS ruling.

The NIH Policy is not a rule, but rather an expectation. Applicants and offerors for NIH funding will submit a plan outlining how they will meet the policy’s expectations, and upon receipt of an award, an awardee will be obligated to adhere to their plan.

Like the HHS, NIH submitted a draft policy in November 2014. NIH received 240 public comments. Most supported the proposed policy and great clinical trial transparency, but some suggested that the benefit of greater transparency was outweighed by the burden and cost to those who conduct clinical trials and that the NIH’s proposal was not evidence-based.

NIH rejected that assessment. “We believe that the work should not be seen as a burden, but, rather, an inherent part of an investigator’s commitment to the advancement of science,” the policy authors wrote.

HHS authors agreed.

“The scientific benefits relate to the prevention of incomplete and biased reporting of individual trials, and the provision of information about a more complete and unbiased set of trials;” they wrote, “the resulting set of data about clinical trials can form a more robust basis for current medical decision making and future research planning.”