September 23, 2016

Final Rule Expands US Requirements


On September 16, 2016, the Department of Health and Human Services (HHS) issued a final rule implementing section 402(j) of the Public Health Service Act (the Final Rule).1 The Final Rule, which comes two years after HHS’ initial Notice of Proposed Rulemaking, clarifies and expands clinical research sponsor responsibilities for drug and device research information on Most notably, the Final Rule broadens the range of studies that must be registered, requires submission of additional registration and summary results information, and sets forth legal consequences for non-compliance. The regulations become effective on January 18, 2017, and responsible parties will then have 90 days to comply. Pharmaceutical and medical device manufacturers and researchers should carefully review the rule and revisit internal policies and procedures governing the timing and content of posting to

A.        What Types of Research are Within the Scope of the Reporting Requirements?

The Final Rule specifies which clinical trials must be registered and articulates a set of criteria for determining whether a trial will be an applicable drug or device clinical trial moving forward. According to the Final Rule, any “applicable clinical trial” that was initiated after September 27, 2007, or was initiated before September 27, 2007, but was ongoing on December 26, 2007, must be registered. As the preamble suggests, most clinical trials will meet the definition of either an “applicable device clinical trial” or an “applicable drug clinical trial”—the Final Rule applies to most interventional studies of drug, biological, and device products that are regulated by the FDA. It notably excludes expanded access use from the definition of “applicable clinical trial.”

A study qualifies as an “applicable device clinical trial” if it is: (i) a pediatric postmarket surveillance of a device product required by FDA under section 522 of the Federal Food, Drug, and Cosmetic Act, (FD&C Act) or (ii) a clinical trial with one or more arms that meets the following criteria: (1) it is interventional; (2) the primary purpose is not a feasibility study; (3) the trial studies a FDA-regulated drug device; and, (4) one or more of the following applies: at least one Facility Location is within the US or one of its territories, the device is a product manufactured in and exported from the US for study in another country, or the clinical trial has an IND Number. “Applicable drug clinical trial” is similarly defined, except that the trial must be out of phase I, as opposed to having a primary purpose other than feasibility.2

The Final Rule also significantly broadens the scope of results information reporting. Unless a waiver is granted, the Final Rule requires submission of results information for studies where the product is approved, licensed, or cleared by the FDA and where the product is unapproved, unlicensed, or uncleared, regardless of whether FDA approval, licensure, or clearance is or will be sought. Thus for the first time, extensive results information must be posted even for drugs that do not make it to market, raising a need for sponsors to consider what information they are publicizing on their product development programs. As explained in more depth below, responsible parties must provide detailed reporting on statistical methodology, adverse events (including information about how adverse events were tracked), and baseline data on subjects’ race and ethnicity.

B.        What Information Must be Submitted?

1.        Registration Information

The Final Rule clarifies the requirements for clinical trial registration information. It should be noted that trials initiated prior to the effective date of this rule remain governed by the specifications contained in the Public Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)). For trials initiated on or after the effective date, however, responsible parties must now list numerous types of general descriptive information, trial subject recruitment information, location and contact information, and administrative data as outlined in section 11.28(a). This includes such items as brief and official titles, a summary, a primary purpose, a study design, eligibility criteria, the name of the sponsor, and human subjects protection review board status.

In the case of applicable clinical trials of unapproved drugs and biologics, a key portion of the Final Rule involves the reporting or creation of an expanded access record. The responsible party must specify whether there is expanded access to the drug under section 561 of the FD&C Act for those who do not qualify for enrollment in the clinical trial and, if so, how to obtain information about expanded access. Section 11.28(c) sets out in greater detail what is required when expanded access is available for an intermediate-size patient population and what is required when expanded access is available only for individual patients (somewhat less extensive for the latter than for the former).

Lastly, the Final Rule also contains requirements for reporting both registration and results information for applicable device clinical trials of unapproved or uncleared device products for which clinical trial registration information has not been posted publicly (described in section 11.48(a)(7)). Similar but more general registration and results information is required for pediatric postmarket surveillances of device products.

2.        Results Information

The Final Rule features expanded results reporting requirements, which have been a focus of debate and discussion among regulators, industry, and the provider community. Particularly noteworthy are the requirements for submission of the full trial protocol and statistical analysis plans (SAPs), reporting of adverse events, and inclusion of race and ethnicity data in analysis of baseline measures. Also required are details as to participant flow, comparison groups/arms used, and outcome measures collected. Responsible parties must provide point of contact information and indicate the existence of any agreement between the sponsor or its agent and the principal investigator that restricts the principal investigator’s ability to discuss or publish the results of the clinical trial.

Separately, the Final Rule also describes how responsible parties can satisfy a preexisting statutory requirement for submission of the full protocol or such information on the trial protocol as may be necessary to evaluate the results of the trial. As specified in section 11.48(a)(v), a statistical analysis must be submitted if it: (1) has been pre-specified in the protocol and/or statistical analysis plan for the trial and was performed on the outcome measure data; (2) was made public by the sponsor or responsible party prior to the required submission date for primary outcome measures information; or (3) was conducted on a specific primary outcome measure in response to a request made by FDA prior to the date required for submission of that primary outcome measure. Responsible parties must provide a statistical analysis overview, complete with identification of arms or comparison groups, information as to the type of statistical analysis conducted, and specific information for non-inferiority or equivalence tests relating to the power calculation and non-inferiority or equivalence margin. In addition, responsible parties must provide information, as applicable, regarding either the statistical test of hypothesis used (including the p-value and procedure used for statistical analysis) or the method of estimation (including estimation parameter, estimated value, and confidence interval, if calculated).

Beyond requirements relating to statistical analysis and outcome measures, the Final Rule greatly enhances requirements for reporting adverse events, whether anticipated or unanticipated. Responsible parties must now provide three tables, summarizing: (1) information collected about serious adverse events occurring during the clinical trial; (2) information relating to other adverse events that exceed a frequency of five percent within any trial arm; and (3) all-cause mortality data. Information in the first two tables must be grouped by organ system, and information in all three tables must also include number or frequency within each comparison group used. Notably, information provided as to adverse events must include the time frame for collection and whether the collection approach was systematic (based on checklists, questionnaires, or tests) or non-systematic (based on spontaneous reporting and recording). The requirement for adverse event reporting, which relies on the Adverse Event Reporting Description data element on, is meant to closely parallel the previously optional data element that was operational on the site prior to issuance of the Final Rule. Adverse event reporting is now considered part of the results information that responsible parties must submit; thus, penalties related to failure to submit information, or submission of false or misleading information would likely be categorially applicable.

One final noteworthy addition is the requirement of race and ethnicity data. This information must be captured in Baseline Measure Information, alongside sex/gender, age, and other information collected as part of the baseline for the study.

3.        Corrections and Updates

Responsible parties should take note of the Final Rule’s requirements for corrections and updates of information previously submitted. These apply in cases of changes made to the study itself, or to incorrect information previously submitted. In general, registration information must be updated not less than once every 12 months. Depending on the reporting requirement to which the update pertains, updates typically must occur within a 30-day window (e.g., from the advent of the change in information, the date of enrollment of the first human subject, availability of an expanded access record, or primary completion date). In certain instances, such as when a device product has not been approved or cleared by the FDA, a 15-day window is required instead, to provide notice to HHS that it must publicly post clinical trial registration information in conformity with statutory requirements.

Corrections, distinguished from updates, relate to notification of apparent errors, deficiencies, or inconsistencies under quality control procedures specified at On notification, responsible parties have 15 days to correct clinical trial registration information and 25 days to correct clinical trial results information. Potential penalties for non-compliance are discussed below.

C.        When Must the Information be Submitted?

The Final Rule requires there to be one “responsible party” who must submit information about applicable clinical trials to The responsible party will generally be the sponsor of the clinical trial, unless and until a principal investigator has been designated as such. In accordance with the Final Rule, the responsible party must submit clinical trial registration information 21 calendar days after the first human subject is enrolled in the clinical trial (or the FDA approves the postmarket surveillance plan), unless the trial meets a narrow exception for serious or life-threatening diseases.

Submission requirements for results information vary according to the trial’s primary completion date. Generally, clinical trial results information must be submitted no later than 1 year after the primary completion date. However, delayed submission is allowable for up to two years if the drug or device product studied in the trial is not yet approved or the manufacturer is the sponsor and is seeking approval of a new use. In these instances, the deadline will be 30 calendar days after the earliest of the following events: (1) the FDA approves, licenses, or clears the drug product; (2) the FDA issues a letter that ends the regulatory review cycle (for previously approved drugs and devices); or (3) the application or premarket notification seeking approval, licensure, or clearance of the new use is withdrawn without resubmission.  

D.        What are the Penalties for Non-Compliance?

Under the Final Rule, failure to post the required information, or submission of false or misleading information, may result in civil or criminal actions, civil monetary penalties, and suspension or denial of grant funding (for HHS-funded trials). The Final Rule does not articulate new grounds for civil or criminal liability; rather it merely highlights that failure to comply with reporting requirements, as clarified under the rule, may constitute a prohibited act under section 301(jj) of the FD&C Act. As noted in the preamble, current penalties may total, for individuals, up to US$100,000 for a misdemeanor and up to US$500,000 for a felony; and, for organizations, up to US$200,000 for a misdemeanor and up to US$500,000 for a felony. Responsible parties should also be aware of the NIH’s statutory responsibility to post data regarding noncompliance, including the failure to submit the required information, submission of false or misleading information, any penalties received, corrections made, and the failure to register primary and secondary outcomes. NIH has also stated that it may freeze future grant funding if a research institution fails to follow final clinical trial registration and reporting requirements.3

Failure to certify compliance with applicable registration requirements for may constitute an independent violation of the FD&C Act, as FDA requires such certification as a condition of drug and device clearance, approval, and research exemption applications.4 Additionally, FDA requires the inclusion of a statement on informed consent in documentation submitted for applicable clinical trials.5

E.        Conclusion

The Final Rule clarifies and expands upon clinical trial transparency requirements that go well beyond the initially implemented scope of With the finalization of the HHS rule, it is likely that various parties who have raised concerns about clinical trial transparency around “negative” or “failed” studies into unapproved/uncleared uses, will be paying attention as the expanded requirements are implemented.6 It is also likely that the expanded results information will be used for various third-party analyses of drug safety and effectiveness issues, as well as for competitive intelligence purposes. In the meantime, pharmaceutical and medical device companies, as well as other regulated entities (including research institutions and certain government institutions), have until roughly the end of Q2 2017 to consider whether their policies and procedures adequately address compliance with the new requirements set forth by HHS.

*Bethan Jones and Nikki Leon contributed to this article. Ms. Jones is a graduate of University of Pennsylvania Law School employed at Arnold & Porter LLP. She is not admitted to the bar. Ms. Leon is a graduate of Stanford Law School employed at Arnold & Porter LLP. She is not admitted to the bar.

  1. See Clinical Trials Registration and Results Information Submission, 81 Fed. Reg. 64,981 (Sept. 21, 2016) (to be codified at 42 C.F.R. pt. 11). In tandem with the Final Rule, The National Institutes of Health (NIH) laid out its Policy on the Dissemination of NIH-Funded Clinical Trial Information (the Policy), which will also take effect on January 18, 2017. See 81 Fed. Reg. 64922. Most importantly, the Policy requires submission of summary results to for all clinical research supported by the agency. Thus the Policy extends not only to clinical trials falling under the auspices of the final rule, but also to experimental behavioral interventions and early-stage (Phase I) drug trials. The time frames for registration and information submission and data elements to be included in registration and results submission mirror those provisions in the Final Rule.

  2. Notably, the preamble specifies that with respect to study phase and the determination process, HHS will not consider a trial with both phase I and phase II characteristics to be a phase I trial. If a trial is initially registered as phase I/phase II trial, it will be considered to be a phase II trial.

  3. NIH grantees must separately certify to NIH their compliance with FDAAA 801. This includes submission of the grantee’s registry number to NIH. See also Summary of HHS/NIH Initiatives to Enhance Availability of Clinical Trial Information.

  4. FDA, Guidance for Industry, Certifications To Accompany Drug, Biological Product, and Device Applications/Submissions: Compliance with Section 402(j) of The Public Health Service Act, Added By Title VIII of The Food and Drug Administration Amendments Act of 2007 (Jan. 2009). See FDA, Certification of Compliance, under 42 U.S.C. § (j)(5)(B), with Requirements of Data Bank (42 U.S.C. § 282(j)).

  5. FDA, FDA’s Role: Information, (last updated Nov. 5, 2013).

  6. For example, as regulators and Congress have clarified their expectations for research transparency over the past ten years, the Office of the Inspector General for the Department of Health and Human Services has changed its approach to research transparency-related compliance requirements in Corporate Integrity Agreements—moving from a model that focused largely on requiring posting of post-marketing commitments to a model that explicitly cross-references the requirements in Section 801 of the Food and Drug Administration Amendments Act. See e.g., Johnson & Johnson CIA. The Department of Justice and State Attorneys General have also modeled research transparency requirements imposed as part of the resolution of civil or criminal cases on prior requirements. Glaxo Smith Kline’s 2014 settlement with California’s Attorney General serves as one example. See Press Release, Attorney General Kamala D. Harris Secures $105 Million Multistate Settlement with GlaxoSmithKline, (June 4, 2014).

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