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The Department of Health and Human Services has issued a new regulation and the ľ��ֱ�� (NIH) has issued a new policy to increase the availability of information about clinical trials via ClinicalTrials.gov, a publicly accessible database operated by the National Library of Medicine (NLM), part of the NIH.  The Final Rule, promulgated in accordance with section 402(j) of the Public Service Health Act, describes requirements for registering and submitting summary results information for certain clinical trials to ClinicalTrials.gov.  The Final Rule will be codified at 42 CFR part 11.  A complementary NIH policy applies to all clinical trials funded by NIH, regardless of whether they are subject to the Final Rule.

Both initiatives aim to increase the availability of information to the public about clinical trials – information that is not systematically available from other public sources. The regulation and NIH policy do not affect the design or conduct of clinical trials or define what type of data should be collected during a clinical trial. Rather, they aim to help ensure that information about clinical trials and their results are made publicly available in a timely manner.

The Final Rule and the Final NIH Policy will be made publicly available on September 16, 2016.  The NIH Policy is also published in the NIH Guide for Grants and Contracts at:  .

Key provisions of the Final Rule and NIH Policy are summarized below.

General scope of the Final Rule

The Final Rule applies, in general, to “responsible parties” for “applicable clinical trials.” A responsible party is the sponsor of the clinical trial or a designated principal investigator. The responsible party could be an organization (such as a drug or device manufacturer, a university or academic medical center, or a government research organization such as the NIH), or an individual. The Final Rule specifies the approach for determining who is the sponsor of a clinical trial and explains how a sponsor can designate a principal investigator as the responsible party [see 42 CFR § 11.4(c)].

The Final Rule applies to trials that meet the legal definition of an applicable clinical trial and certain other clinical trials for which information is voluntarily submitted. Applicable clinical trials include certain interventional studies of drug, biological, and device products that are regulated by the FDA. Phase 1 trials of drug and biological products and feasibility studies of device products are excluded from the definition of an applicable clinical trial.  A pediatric post-market surveillance study of a device product required by the FDA is also subject to the regulation. In general, to be considered an applicable clinical trial, one or more of the following criteria also must be met.  The clinical trial must include one or more sites in the United States; study a drug, biological, or device product that is manufactured in the United States or its territories and is exported for use in a clinical trial outside the United States; or be conducted under an FDA investigational new drug application (IND) or investigational device exemption (IDE). The Final Rule provides an approach, using specific data elements submitted at the time of registration, for evaluating whether a particular clinical trial or study is an applicable clinical trial [see § 11.22(b)].

Registration Information

The Final Rule requires that, in general, a responsible party register an applicable clinical trial at ClinicalTrials.gov no later than 21 days after enrolling the first participant (see § 11.24). Registration consists of submitting four categories of data elements:  1) descriptive information, 2) recruitment information, 3) location and contact information, and 4) administrative information.

If a drug or biological product studied in an applicable clinical trial is available under expanded access, the Final Rule requires the responsible party, if both the manufacturer of the drug product or biological product and the sponsor of the clinical trial, to also submit a separate expanded access record (or link to an existing expanded access record) containing certain details about how patients may obtain access to the investigational product.  Expanded access is the use outside of a clinical trial of an investigational product (i.e., one that has not been approved by FDA). FDA’s statute and regulations provide various mechanisms under which patients may be able to access investigational products outside of a clinical trial.

Results Information

The Final Rule requires a responsible party to submit summary results information to ClinicalTrials.gov for any applicable clinical trial that is required to be registered, regardless of whether the drug, biological, or device products under study have been approved, licensed, or cleared for marketing by the FDA (see § 11.42). This represents an expansion of the statutory requirement, which requires the submission of summary results information only for applicable clinical trials of drug, biological, or device products that have been approved, licensed, or cleared by the FDA. The clinical trial results information submission requirements in the Final Rule apply to an applicable clinical trial with a primary completion date on or after the effective date of the Final Rule.

In general, results information must be submitted no later than one year after the primary completion date of the applicable clinical trial. Primary completion date is the date that the final subject was examined or received an intervention for the purpose of collecting the data for the primary outcome measure. Results information submission may be delayed for as long as two additional years if the responsible party submits a certification to ClinicalTrials.gov that either:  1) a drug, biological, or device product studied in the clinical trial is not yet approved, licensed, or cleared for marketing by the FDA and is still under development by the manufacturer; or 2) that 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” (See § 11.44).

Consistent with current practice, the Final Rule requires that results information consist of tables of information summarizing: 1) participant flow information, 2) demographics and baseline characteristics of the enrolled participants, 3) primary and secondary outcomes, including results of any scientifically appropriate statistical tests, and 4) adverse events.  Adverse event information consists of one table that summarizes all serious adverse events experienced by participants enrolled in the clinical trial, and a second table that summarizes other adverse events that exceed a frequency of 5 percent in any arm of the clinical trial. The Final Rule adds a third table for summarizing all-cause mortality, with the number and frequency of deaths due to any cause by arm. All results information is aggregated, summary level data, not data for the individual subjects who participated in the clinical trial. The Final Rule also adds a requirement to submit the clinical trial protocol and statistical analysis plan at the time of results information submission. Personally identifiable information and trade secret and/or confidential commercial information may be redacted from the protocol, unless such information is required to be submitted by the regulation. Section 11.48 provides a listing of all required results information data elements.

The Final Rule does not require the submission of narrative summaries.

Updates and Other Required Information

The Final Rule requires all submitted information to be updated at least once a year.  More frequent updating is required for some data elements to help ensure that users of ClinicalTrials.gov have access to accurate, up-to-date information about important aspects of a clinical trial (see § 11.64). The Final Rule also requires the responsible party to address any apparent errors, deficiencies, and/or inconsistencies identified by NIH as part of the quality control review process and any other errors identified by the responsible party within the timeframes set forth in the Final Rule. (see § 11.64).  

Posting Submitted Information

The Final Rule specifies that the NIH generally will post registration and results information no later than 30 days after it is submitted to ClinicalTrials.gov (see § 11.35 and § 11.52). The posting provisions differ for trials of unapproved and uncleared device products.  The statute prohibits NIH from posting registration information for those trials; however, the final rule specifies that registration information from those trials will be posted if the responsible party authorizes NIH to do so.

General Scope of the NIH Policy

The final NIH Policy complements the Final Rule in that the NIH Policy applies to all clinical trials funded in whole or in part by NIH, regardless of study phase, type of intervention, or whether they are subject to the Final Rule. The NIH Policy applies to clinical trials which are defined as “a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.” In addition to the types of trials covered by the Final Rule, the NIH Policy applies to all other trials funded by NIH, including phase 1 trials of drug and biological products, small feasibility studies of device products, and clinical trials of behavioral, surgical, and other types of health and medical interventions. Clinical trials that use NIH-supported infrastructure, but receive no other NIH funds for the conduct of a specific clinical trial are not subject to the NIH Policy.

Applicants for NIH funding are required to submit a plan outlining how they will comply with the clinical trial information dissemination expectations of the policy.  Consistent with the terms and conditions of their NIH funding, awardees undertaking clinical trials covered by the NIH Policy must ensure the submission and updating of the same type of registration and results information, and in the same timeframes, as responsible parties whose trials are subject to the Final Rule.  An NIH-funded clinical trial that is also subject to the Final Rule should only have one entry in ClinicalTrials.gov containing its registration and results information.  The policy takes effect on the effective date of the final rule, and applies to applications and proposals received and intramural clinical trials submitted for Institutional Review Board review on or after that date.

Compliance

The Final Rule has a compliance date of 90 days after January 18, 2017, meaning that a responsible party has until that date to come into compliance with the requirements of the Rule.  Failure to comply with the regulation may have legal consequences, which are described in the Final Rule. In addition, the NIH is required to make a responsible party’s non-compliance public through a posting on the clinical trial record. If the applicable clinical trial is funded in whole or part by HHS, failure to submit all required registration and results information can jeopardize grant funding and future funding to the grantee.

The FDA has the authority to issue a Notice of Noncompliance to a responsible party who has failed to comply with the requirements for registering and submitting results information for an applicable clinical trial. The FDA may also impose civil monetary penalties for such violations. Additionally, a responsible party who commits a prohibited act(s) may be the subject of an injunction action or criminal prosecution brought by the Department of Justice.

Compliance with the NIH policy will be via the terms and conditions of the NIH award. Failure to comply with the terms and conditions of an NIH funding award could lead to grants enforcement actions, including termination of funding.