In an effort to make information about clinical trials widely available to the public, HHS issued an Advance Release of a Final rule that specifies requirements for registering certain clinical trials and submitting summary results information to ClinicalTrials.gov, which is operated by the National Library of Medicine (NLM) of the National Institutes of Health (NIH). The Final rule expands the requirements for submitting registration and results information for clinical trials involving FDA-regulated drug, biological and device products. The rule does not impose requirements on the design or conduct of clinical trials or on the data that must be collected during clinical trials, and no patient-specific data are required to be submitted by the rule. The rule officially publishes in the Federal Register on September 21, 2016. The Final rule will be effective January 18, 2017, and responsible parties will have 90 calendar days after the effective date to come into compliance with rule’s requirements.
Contemporaneously with the issuance of the Final rule, the NIH issued a complementary policy for registering and submitting summary results information to ClinicalTrials.gov for all NIH-funded trials, including those not subject to the rule.
Statutory basis. The Final rule implements the provisions of section 402(j) of the Public Health Service Act (PHS Act) (42 U.S.C. §282(j), as amended by Title VIII of Food and Drug Administration Amendments Act of 2007 (FDAAA) and including technical corrections made to FDAAA under P.L. 110-316). The provisions were intended to improve public access to information about certain clinical trials of FDA-regulated drugs, biological products, and devices and certain pediatric postmarket surveillances of a device.
Section 402(j) of the PHS Act also requires the HHS Secretary to use rulemaking to expand the requirements for submission of summary results information, and authorizes the Secretary to use rulemaking to make other changes that enhance, but do not decrease, the available information about the specified trials.
Under section 402(j) of the PHS Act, those responsible for specified clinical trials of these FDA-regulated products have been required to submit registration information to ClinicalTrials.gov since December 26, 2007, summary results information for clinical trials of approved products as of September 27, 2008, and certain adverse events information since September 27, 2009.
The Final rule was informed by nearly 900 comments received during the public comment period on the Notice of Proposed Rulemaking (November 21, 2014, 79 FR 69566) (see HHS proposes new requirements for submissions to ClinicalTrials.gov, November 21, 2014).
Applicable clinical trials. The Final rule considers all interventional clinical trials with one or more arms and with one or more pre-specified outcome measures to be controlled clinical trials. The rule does not consider any expanded access use (e.g., access under treatment investigational new drugs (INDs) or treatment protocols, which provide widespread access, access for intermediate-sized patient populations, or access for individual patients) to be an applicable clinical trial. The rule also describes an approach for evaluating, prior to registration, whether a particular clinical trial or study is an applicable clinical trial.
Responsible party. The Final rule specifies that there must be one (and only one) responsible party for purposes of submitting information about an applicable clinical trial. Under the rule, the sponsor of an applicable clinical trial will be considered the responsible party, unless and until the sponsor designates a qualified principal investigator as the responsible party. The rule also specifies (1) the approach for determining who will be considered the sponsor of an applicable clinical trial under various conditions; (2) what qualifies a principal investigator to be designated a responsible party by a sponsor; and (3) how responsibility reverts to the sponsor if a designated principal investigator is unable to fulfill the requirements.
Registration. The Final rule requires that the responsible party register an applicable clinical trial with ClinicalTrials.gov not later than 21 calendar days after enrolling the first human subject, and it specifies the data elements of clinical trial information that must be submitted at the time of registration. These data elements include the descriptive information, recruitment information, location and contact information, and administrative data elements, as well as additional required data elements as long as such elements improve, and do not reduce, the clinical trial information available to the public in ClinicalTrials.gov.
Expanded access information. Section 402(j) of the PHS Act requires the submission of information regarding whether, for an applicable drug clinical trial of an unapproved drug product (including an unlicensed biological product), expanded access to the investigational product being studied in the applicable clinical trial is available under section 561 of the federal Food, Drug, and Cosmetic Act (21 U.S.C. §360bbb). Under the Final rule, if the responsible party for an applicable clinical trial of an unapproved drug product (including an unlicensed biological product) is both the sponsor of the applicable clinical trial being registered and the manufacturer of the unapproved product, the rule requires the submission of a separate expanded access record containing details about how to obtain access to the investigational product.
Clinical trial results. The Final rule addresses the statutory requirement for the submission of summary results information for applicable clinical trials of drug products (including biological products) and device products that are approved, licensed, or cleared by FDA. It also extends the requirement for results information submission to applicable clinical trials of drug products (including biological products) and device products that are not approved, licensed, or cleared by FDA. The rule generally requires the submission of results information not later than one year after the completion date of the clinical trial, which is defined as the date of final data collection for the primary outcome measure.
The rule requires the submission of data in a tabular format summarizing: (1) participant flow; (2) demographic and baseline characteristics; (3) primary and secondary outcomes, as well as results of any scientifically appropriate statistical tests; and (4) adverse event information. The rule also requires the submission of the full protocol and statistical analysis plan, if contained in a separate document.
Adverse events. The Final rule requires the responsible party to submit information summarizing the number and frequency of adverse events experienced by participants enrolled in a clinical trial, by arm or comparison group, as well as a brief description of each arm or group as a component of clinical trial results information. It also requires submission of three tables of adverse event information: (1) one summarizing all serious adverse events; (2) another one summarizing other adverse events that occurred with a frequency of 5 percent or more in any arm of the clinical trial; and (3) one summarizing all-cause mortality data by arm or group.
Updating information. The Final rule requires that all submitted information be updated at least annually if there are changes to report. More rapid updating is required for several data elements to help ensure that users of ClinicalTrials.gov have access to accurate, up-to-date information about important aspects of an applicable clinical trial or other clinical trial. The rule also requires timely corrections to any errors discovered by the responsible party or the agency during quality control review of submissions or after the information has been posted.
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