Posted: 11 Oct 2016 06:36 PM PDT
By James E. Valentine & David C. Clissold –
Nearly two years after releasing its Notice of Proposed Rulemaking (“NPRM”), and with about 900 comments from the public to consider, the National Institutes of Health (“NIH”) has published its Final Rule on clinical trials registration and results reporting. These regulations provide specificity and expand upon the self-implementing requirements that have been in effect since the Food and Drug Administration Amendments Act (FDAAA) was passed in 2007. The Final Rule largely maintains the proposed rule’s requirements for submitting registration and summary results information, including adverse event information, for specified clinical trials for drugs, biological, and device products to ClinicalTrials.gov (for a detailed overview of these requirements, see our previous coverage here).
However, FDAAA Section 801 delegated decision-making on several key issues to NIH’s rulemaking, including expansion of results reporting for unapproved drugs and the submission of summary narratives and trial protocols (see our previous discussion of deferred topics here). While there is much to digest in the 177-page Final Rule, this blog post will highlight how the Final Rule addresses these previously unanswered questions, as well as other key changes from the NPRM.
Submission of Results Information for Products Unapproved, Unlicensed, or Uncleared for Any Use
FDAAA Section 801 requires the submission and posting of registration information and results information for applicable clinical trials of approved, licensed, or cleared products (“approved products”), as well as the submission of registration information and posting requirements for an applicable clinical trials of unapproved, unlicensed, or uncleared products (“unapproved products”). In addition, the statute deferred to NIH as to whether to require the submission of results information from applicable clinical trials of unapproved products, whether or not approval was sought. The Final Rule maintains the NPRM’s proposal to require the submission of results information for applicable clinical trials of products unapproved for any use (i.e., any indication), regardless of whether FDA approval is or will be sought or obtained.
The Final Rule does make a change to the NPRM regarding the applicability of this requirement to applicable clinical trials of unapproved products with a primary completion date before the effective date (January 18, 2017) that are subsequently approved for the use studied in the applicable clinical trial. Under the proposed rule, results reporting was required if the results submission deadline due to FDA approval was after the effective date of the rule. This proposal was scaled back so that, now, such trials are not subject to the new results reporting requirements.
Submission of Technical and Non-Technical Results Summaries Not Required
FDAAA Section 801 required NIH to determine whether a summary of the clinical trial and its results in a technical or non-technical summary could be included as part of required results reporting on ClinicalTrials.gov “without being misleading or promotional.” In response to public comments expressing concerns regarding the difficulty of trial sponsors to write accurate, non-promotional, and non-misleading summaries, NIH decided to not require either type of narrative summary of results in the Final Rule. NIH notes that future rulemaking may be warranted if additional research can determine a way for such summaries to be produced reliably and consistently.
Submission of Protocols and Statistical Analysis Plans
FDAAA Section 801 instructed NIH to require a full protocol or information on the protocol for the trial to the degree it “may be necessary” to help evaluate the results of the trial. While the NPRM laid out several ways this could be achieved, NIH was compelled by public comments arguing that protocols provide information to better contextualize the reported results information. For example, protocols provide more detail about methods of participant selection, randomization, masking, and assignment to arms; methods of collecting data; specific information about clinical trial interventions, such as other elements of care provided; and assessment of adverse events. Thus, the Final Rule requires submission of the full protocol and the statistical analysis plan (“SAP”), if it is a separate document, as part of the results reporting, and both will be posted with the results.
NIH also recognized some concerns raised in public comments about protecting personally identifiable information about individuals participating in or involved in conducting the clinical trials. To address these, the Final Rule allows the responsible party to redact information about individual clinical trial participants. In addition, the trial allows redaction of identifying information about individuals involved in conducting the trial, as long as it is not otherwise required to be submitted as part of the clinical trial information.
Potential Legal Consequences of Non-Compliance
While not addressed in the NPRM, the Final Rule includes a new section that addresses the legal consequences of non-compliance. This new section describes potential civil or criminal actions, civil monetary penalties, grant funding actions, and judicial remedies that may be pursued as a result of a responsible party’s failure to comply with the regulations. In addition, this section describes certain non-compliant activities that will be considered prohibited acts under the Federal Food, Drug, and Cosmetic Act that can result in certain of the various types of enforcement action against the responsible party.
Although not included in the text of the regulation, the preamble to the Final Rule specifies that, under the statute, NIH will include notices on ClinicalTrials.gov denoting non-compliance. These notices include: failure to submit required information; submission of false or misleading information; penalties imposed, if any; whether the information has been corrected; and, failure to register the primary and secondary outcomes.
Effective Date, Compliance Date, and Applicability Determinations
The Final Rule extends the effective date proposed in the NPRM from 45 calendar days to 120 calendar days from the date the Final Rule was filed for public inspection in the Federal Register, or January 18, 2017. However, the compliance date remains the same in the Final Rule, at 90 calendar days after the effective date, or April 18, 2017.
To aid in determining the applicability of the requirements set out in the Final Rule, the process for making this determination was clarified. Specifically, the registration requirements that apply to an applicable clinical trial are determined by the date on which the trial is initiated (i.e., the actual start date). Meanwhile, the results reporting requirements that apply to an applicable clinical trial are determined by the date on which the trial reaches its actual primary completion date. Lastly, the marketing status of a product will be determined based on its marketing status on the primary completion date.
NIH also announced, in conjunction with the Final Rule, a final policy that would extend similar registration and reporting requirements to all clinical trials funded by NIH, regardless of whether they are subject to FDAAA.
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