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Final Rule Confirms, Posting of Study Results on ClinicalTrials.gov Will be Required for Unapproved Products

November 29, 2016 | Hazar Awad Granko, RPh, PhD, Senior Director, Regulatory Affairs | Regulatory Affairs

In a previous post, we told you about the National Institutes of Health’s (NIH) Notice of Proposed Rulemaking (NPRM) on expanded clinical trial registration and results submission on ClinicalTrials.gov. The Final Rule has now been issued and significantly expands the registration and results reporting requirements for clinical trials.

Background
The Food and Drug Administration Amendments Act of 2007 (FDAAA) required Sponsors of certain clinical trials to register on ClinicalTrials.gov, but only required results reporting for trials of drugs, biologics, or devices that were approved, licensed, or cleared by the FDA.

In a push for expanding transparency and advancement of public health, the NIH issued an NPRM in November 2014 proposing to expand these requirements. After receiving over 900 comments from various companies, organizations, and individuals, and nearly 2 years later, the NIH has now issued a Final Rule on clinical trials registration and results reporting.

Results Posting Required, Even for Unapproved Products
As outlined in the NPRM, the Final Rule expands the requirement for submission of results information to studies where the drug, biologic, or device is unapproved, unlicensed, or uncleared by FDA, regardless of whether FDA approval, licensure, or clearance is being or will be sought.

So, for the first time, results information must be posted on ClinicalTrials.gov, even for products that do not ever make it to market (eg, including results of negative or failed clinical trials and clinical trials that are part of abandoned clinical programs).

As drug development professionals who often assist our clients with designing and implementing their clinical development programs, we see this as a very positive change. Having visibility into drugs that have been unsuccessfully studied for particular indications, as well as the trial designs that were utilized, can provide valuable lessons for other programs.

On the flip side, the new requirement has implications for companies who have undertaken lengthy clinical development programs and are faced with having to disclose proprietary results data (whether positive or negative) before they might want to (more on this below).

What Kind of Trials Require Results Information to be Posted?
Posting of results information is required for all “applicable clinical trials,” which can be either an applicable drug clinical trial (including biologics) or an applicable device clinical trial.

chart

What Results Information Must be Posted?
As already required for approved products, the rule requires the submission of data in a tabular format summarizing participant flow; demographic and baseline characteristics; primary and secondary outcomes, as well as results of any scientifically appropriate statistical tests; and adverse event information.

Also particularly noteworthy, the full protocol (including all amendments) and Statistical Analysis Plan (if a separate document) will now be required to be submitted at the time of results information submission for all applicable clinical trials (for both approved and unapproved products) and will be posted with the results.

When Must Results be Posted?
Submission of results information is required no later than 1 year after the primary completion date of the clinical trial, which is defined as the date of final data collection for the primary outcome measure.

Results information submission can be delayed for up to 2 additional years from the date of submission of a certification that either of the following apply (the certification must be submitted prior to the results information submission deadline):

  1. an unapproved, unlicensed, or uncleared product studied in the trial is still under development by the manufacturer, or
  2. marketing approval will be sought within 1 year after the primary completion date of the trial for a new use of an approved, licensed, or cleared product that is being studied in the trial.

Following this potential extension of up to 3 years after the primary completion date of the clinical trial, results must be posted regardless of whether the product is approved or is being sought for approval.

Further extensions to the results information submission deadlines may be granted for “good cause” (eg, the need to preserve the scientific integrity of a trial for which data collection is ongoing or emergencies, such as natural disasters of catastrophes, that would prevent timely submission of results information).

A permanent waiver of results information submission requirements may also be granted for extraordinary circumstances, consistent with the protection of the public health or in the interest of national security, but are expected to be exceedingly rare.

What Else Has Changed Regarding Results Reporting?
Other significant changes to results information reporting implemented by the Final Rule include:

  • Requires additional summary results information data elements to be submitted (some that are new and some that were previously optional), including the race and ethnicity of trial participants, if collected.
  • Requires 3 tables of adverse event (AE) information:
    • Summary of all serious AEs
    • Summary of other AEs that occurred with a frequency of 5% or more in any arm
    • Summary of all-cause mortality by arm

Are There Any Other Important Changes I Should Know About?
Other significant changes implemented by the Final Rule include:

  • Provides a checklist for evaluating which clinical trials are subject to the regulations and who is responsible for submitting required information.
  • Requires additional registration information data elements to be submitted (some that are new and some that were previously optional).
  • Requires some data elements to be updated more frequently than the standard 12 months (several data elements must be updated within 30 days of a change, and one within 15 days).
  • Following NIH’s quality-control (QC) review of submitted information:
    • Corrections to submitted information will be required within 15 days (for registration information) and 25 days (for results information).
    • NIH will be required to publicly post all submitted information within 30 days after receipt, even if there are outstanding issues with the QC review (with a disclaimer and, possibly, a general explanation of the concerns about quality).
  • Requires an expanded access record to be created if an investigational drug product studied in an applicable drug clinical trial is available through an expanded access program.

Additional details on these and other changes can be found in the extensive 177-page Final Rule.

Effective Date
The Final Rule will be effective January 18, 2017. As of that date, the ClinicalTrials.gov’s Protocol Registration and Results System (PRS) will allow responsible parties to comply with the rule.

Whether results information submission is required for an applicable clinical trial of an unapproved, unlicensed, or uncleared product depends on the primary completion date for that trial, as shown below:

Primary Completion Date of Trial for Unapproved Product Results Information Requirement
Before January 18, 2017 No results information is required to be submitted for that applicable clinical trial, regardless of whether the product studied in that clinical trial is later approved, licensed, or cleared
On or after January 18, 2017 Results information submission is required as specified in the final rule

Responsible parties will have 90 calendar days after the effective date (ie, until April 18, 2017) to come into compliance with the requirements of the rule.

What Happens if I Don’t Comply with these Requirements?
The Final Rule includes a new section outlining the 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.

IMPACT Can Help!
IMPACT’s team of experienced regulatory experts and medical writers can help you make sense of the new requirements and ensure that you are compliant with clinical trial registration and results information submission requirements. Send us an email or give us a call today at (919) 899‑9248.

 

Category: Regulatory Affairs
Keywords: clinical trials, registry, ClinicalTrials.gov, NIH, FDA, Federal Register

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