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Sept. 19 — The NIH may freeze future grant funding if a research institution fails to follow final clinical trial registration and reporting requirements released Sept. 16.
The potential hold is a move by the National Institutes of Health to address low compliance rates—particularly by scientists at academic institutions—for registering studies and reporting their results on ClincalTrials.gov. It's part of the enforcement arm of an NIH final policy that expands the requirements to agency-sponsored clinical trials.
That NIH policy complements a separate but related Department of Health and Human Services final rule, which requires registration and results reporting for clinical trials submitted to the Food and Drug Administration for the approval of new medical products.
The clinical trial process is a major contributor to growing drug development costs. There's been a push on many levels to improve the efficiency of clinical trials, including:
“This is an important day,” NIH Director Francis S. Collins said during a press briefing. “This development means that public benefit will be further optimized from the very large investment in clinical research. That is our goal.”
The NIH is the nation's largest public funder of clinical trials, spending more than $3 billion annually on these studies, according to a Sept. 16 viewpoint by Collins and his colleagues in the Journal of the American Medical Association explaining the new policy.
Collins cited a study published in the BMJ in February that found results of 43 percent of clinical trials at academic medical centers were unpublished two years after the study ended.
“Such low reporting of clinical trial information is simply not acceptable,” he said.
FDA Commissioner Robert M. Califf said at the press briefing that the final rule and policy hold scientists to the goal of research, which is to produce generalizable knowledge that should be publicly available.
“This is fundamentally an ethical issue, and it’s a legal approach to making it happen.” Califf said. “I think a lot of major universities just miss the point that if you do an experiment on a person and get consent, you really have an obligation to make your results known.”
A 2015 New England Journal of Medicine study—which Califf co-authored when he was a cardiologist and researcher at Duke University—found that studies funded by industry are more likely to report results in a timely fashion compared with NIH-funded trials.
Mark Grayson, spokesman for the Pharmaceutical Research and Manufacturers of America said the association's 2014 principles on clinical trial data sharing reflect the pharmaceutical industry commitment to responsible clinical trial data sharing.
“While we are still reviewing the new Rule issued today, we note that biopharmaceutical companies are committed to enhancing public health through responsible sharing of clinical trial data in a manner that is consistent with the safeguarding the privacy of patients; respecting the integrity of national regulatory systems; and maintaining incentives for investment in biomedical research,” Grayson said in a Sept. 16 e-mail.
The final rule is effective Jan. 18, 2017, but the compliance date is 90 days later. The NIH policy also takes effect on Jan. 18, and applies to grant applications and proposals received and intramural clinical trials submitted for institutional review board review on or after that date.
The new rule and accompanying NIH policy finalize draft versions issued in December 2014 (8 LSLR 1173, 11/28/14).
“We’re glad that it’s here. Having finality and clarification knowing that it was coming is a good thing,” Heather H. Pierce, senior director on science policy and regulatory counsel for scientific affairs at the Association of American Medical Colleges, told Bloomberg BNA in a Sept. 16 interview. “It provides real needed clarification on some definitions and some requirements.”
At the same time, Pierce said, the new requirements come at a time when there is already a heavy compliance burden related to the research enterprise as a whole.
“New requirements, new processes, additional data elements are not costless to institutions, so implementing this rule and preparing for the compliance date and the effective date will take some time, some new resources, some new infrastructure both on the part of the institutions and on the part of the NIH as well. In order for this process to be successful, to be useful to the public and to be accomplished in a way that really accomplishes the ultimate goals of the rule, there will need to be a lot of work done.”
Specifically, she said that over the next few months, ClinicalTrials.gov administrators, the NIH and institutions will need to make sure that the rules, guidance and educational materials are clear and that the interface itself is workable.Comparison of HHS Final Rule, NIH Policy Provisions ElementFinal RuleNIH Policy Scope/Applicability Applicable clinical trials of FDA-regulated drug, biological and device products and pediatric post-market surveillance studies of devices required by the FDA under the FD&C Act. Doesn't apply to phase I trials or small feasibility device studies. Applies to public and private sector sponsors and other entities who meet the definition of a responsible party. All clinical trials funded wholly or partially by NIH. Includes phase I clinical trials and trials that don't involve any FDA-regulated product such as trials involving only behavioral interventions. Applies to NIH-funded clinical trials where applications or proposals are received by NIH on or after the policy's effective date. Applies to NIH-conducted clinical trials initiated on or after the policy's effective date. Time frame for registration on ClinicalTrials.gov Not later than 21 days after enrollment of the first participant. Same Registration data elements to be submitted to ClinicalTrials.gov Elements defined in the final rule. Consists of descriptive information, recruitment information, location and contact information, and administrative data. Same Time frame for results information submission to ClinicalTrials.gov Not later than 12 months after primary completion date; possible delay of up to an additional two years for trials of unapproved products or of products for which initial FDA marketing approval or clearance is being sought, or approval or clearance of a new use is being sought Same Results information data elements to be submitted to ClinicalTrials.gov Elements defined in the final rule. Includes participant flow, demographic and baseline characteristics, outcomes and statistical analyses, adverse events, the protocol and statistical analysis plan, and administrative information. Same Potential consequences of noncompliance •Identifying clinical trial record as noncompliant in ClinicalTrials.gov •For federally funded trials, grant funding can be withheld if required reporting cannot be verified. •Civil monetary penalties of up to $10,000/day (amount to be adjusted going forward) •May lead to suspension or termination of grant or contract funding •Can be considered in future funding decisions •Identifying clinical trial record as noncompliant in ClinicalTrials.gov Effective Date Jan. 18, 2017. Compliance date is 90 days later. Jan. 18, 2017
Deborah Zarin, director of ClinicalTrials.gov at the NIH's National Library of Medicine, said during the press briefing that in general, the proposed versions of the rule and policy were accepted. But she said the HHS added a requirement to submit the clinical trial protocol and statistical analysis plan at the time of results information submission. There also are new requirements for reporting adverse events and study subject race and ethnicity, Zarin said.
The rule and policy essentially have the same requirements on trial registration deadlines, what information must be included in the registration and when study results must be posted. The key differences depend on whether the study meets the FDA's definition of a regulated trial, the NIH has provided funding for the study, or both. There are also different enforcement mechanisms.
The final rule (RIN:0925-AA52) carries out a statutory requirement under Section 801 of the 2007 Food and Drug Administration Amendments Act (Pub. L. No. 110-85).
Mark Barnes, a research attorney with Ropes & Gray who is also the co-chairman of a Harvard University project to improve multinational clinical trials, said the final rule continues to expand the coverage and the detail required for registering trials and reporting results under FDAAA.
“This expansion of authority has been gradual but inexorable in the continuing guidance documents and regulatory revisions issued by NIH, and this expansion is consistent with international trends toward transparency of clinical trial processes and data,” Barnes said in a Sept. 19 e-mail.
Under the rule, applicable clinical trials must be registered on ClinicalTrials.gov no later than 21 days after enrollment of the first participant. The rule defines applicable clinical trials as:
The rule includes a checklist for determining which clinical trials are subject to the regulations and who is responsible for submitting the required information.
The NIH final policy essentially extends the registration and results reporting requirements to all clinical trials the NIH funds, either in full or partially. Unlike the rule, the policy includes phase I clinical trials backed by the NIH, along with clinical trials that don't involve an FDA-regulated product, such as studies of behavioral interventions.
The policy also applies to NIH-funded clinical trials where applications or proposals are received by the NIH on or after the policy’s effective date.
Under the final rule, results must be submitted no later than a year after the “primary completion date,” which the rule defines as “the date that the final subject was examined or received an intervention for the purpose of collecting the data for the primary outcome measure.”
But the rule includes a provision to delay results submission for as long as two years if the responsible party certifies that the product being studied isn't yet approved, licensed or cleared for marketing by the FDA and is still under development by the manufacturer; or if the manufacturer is the sponsor of the clinical trial and has sought or will seek approval, licensure or clearance for a new use of a product studied in the trial within one year.
The final rule also permits responsible parties to request extensions to the results information submission deadline for good cause.
Failure to comply with the rule could result in civil monetary penalties of up to $10,000 a day, and the clinical trial record will be listed as noncompliant in a section on ClinicalTrials.gov which has been dubbed “the wall of shame.”
For NIH-supported trials, the agency can withhold funding if the required reporting can't be verified. The NIH also may move to suspend or terminate grant or contract funding, and factor this noncompliance into future funding decisions.
“This is not a rule that lacks compliance [enforcement provisions]. It does, in fact, have some teeth,” Collins said. “Remember that for NIH, the grantee is not the investigator, it’s the institution. And so the institution then shares this responsibility and all compliance consequences would fall upon the institution.”
The NIH director said the agency would consider placing a hold on future grant funding in circumstances in which a clinical trial is ongoing and out of compliance, and the institution has failed to respond to notifications and follow up with corrective actions.
“We have trouble getting various cats to be herded. You can move their food or you can actually take away their food,” Collins said, adding that the NIH wouldn't stop other clinical trials in progress. “That would be unethical. But we would have the ability to withhold future funding until the problem has been corrected.”
An FDA-regulated clinical trial that also received NIH funding essentially could be subject to both NIH and FDA penalties if there is noncompliance, Collins said.
“Hopefully this will not become necessary,” Collins said.
Califf said the FDA and the NIH will continue to work closely together to ensure the compliance and enforcement activities are coordinated.
“The real purpose of this is to hold true to the pledge that we make to people when we do human research—providing this information to the public gives us a tremendous chance to improve the entire system and do a better job with diagnostics and therapeutics,” Califf said.
Pierce of the AAMC said the new compliance measures underscore the need for these agencies to engage with stakeholders to ensure complying with these requirements isn't hindered by confusion, a lack of resources or an unusable interface or infrastructure.
“It’s clear that the NIH and the FDA are taking these requirements very seriously. Our institutions do as well,” she said.
In response to a question of whether the new posting requirements could discourage some clinical trials from getting done, Califf noted that public outcry back in 2004 that drug companies hide negative results that could hurt product sales led to these requirements in the first place.
He said the new results reporting requirements are expected to improve the quality of clinical trials.
“One type of research that I hope will not get done are trials that are not very well designed in the first place,” Califf said.
“We’re at this amazing time of biotechnology and health services delivery where we’re learning at such a rapid pace now,” he said. “The money that we have to spend on research needs to be spent doing really good research. And if it's not a good clinical trial, and we’re saying you’ve got to put it out there anyway, I think that’s going to lead people to do things more thoughtfully.”
Barnes of Ropes & Gray expressed similar thoughts, citing the requirement that at the time of results reporting, the full protocol and statistical analysis plan also must be provided and presumably will be posted on ClinicalTrials.gov.
“This level of transparency—posting of full protocols—is groundbreaking and may, in the end, greatly affect the care with which some protocols are drafted,” Barnes said.
He added that among the more remarkable expansions in reporting requirements is the addition of race and ethnicity information on enrolled subjects. This requirement coincides with the issuance of the draft guideline developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use , which addresses potential racial and ethnic differences in drug effects in clinical trials.
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