CHAPTER § 1.02 Clinical Trials Registration and Results Disclosure Requirements

• Jurisdiction: United States

§ 1.02 Clinical Trials Registration and Results Disclosure Requirements

[1] Introduction

In 1997, the Food and Drug Administration Modernization Act ("FDAMA")¹⁶² established data bank and registration requirements for clinical trials testing the effectiveness of drug treatments for life-sustaining diseases or conditions.¹⁶³ The National Institutes of Health ("NIH") developed the data bank, www.ClinicalTrials.gov, through the National Library of Medicine in collaboration with FDA. The data bank was intended to be a central resource, providing current information on clinical trials to individuals with serious or life-threatening diseases or conditions, to other members of the public, and to health care providers and researchers.¹⁶⁴ In 2007, Section 801 of the FDA Amendments Act ("FDAAA")¹⁶⁵ expanded the data bank and associated requirements to apply to trials for all diseases and conditions, and to include information concerning clinical trial results.¹⁶⁶ In 2016, the Department of Health and Human Services ("HHS") issued final regulations for Clinical Trials Registration and Results Information Submissions, codified at 42 C.F.R. Part 11, that clarify and expand the regulatory requirements and procedures for submitting clinical trial registration and results information on ClinicalTrials.gov, in accordance with the requirements in FDAAA Section 801 (the "Final Rule").¹⁶⁷ The expanded requirements are intended to: increase the public repository of clinical trials information; help patients find trials for which they might be eligible; enhance the design of clinical trials; prevent duplication of unsuccessful or unsafe trials; improve the evidence base that informs clinical care; increase the efficiency of drug- and device-development processes; improve clinical research practice; build public trust in clinical research; and help eliminate the selective reporting of trial results. The Final Rule applies to the "responsible party" of an applicable clinical trial that is required to be registered, a clinical trial for which clinical trial registration or results information is submitted voluntarily, or an applicable clinical trial that is required by the NIH Director to have clinical trial information submitted to protect the public health.¹⁶⁸

[a] Applicable Clinical Trials

Under FDAAA, clinical trial registry requirements apply to certain trials associated with any drug, biologic, or device subject to the FDCA or Public Health Service Act ("PHSA")¹⁶⁹ that meet the definition of an applicable clinical trial and are initiated after, or ongoing as of, December 26, 2007, regardless of the condition the product is intended to treat.¹⁷⁰ A trial is "ongoing" if at least one patient is enrolled and the trial's "completion date" (the date the final subject was examined or received an intervention for the purposes of final data collection for the primary outcome) has not yet passed.¹⁷¹ For trials involving drugs or biologics, registry requirements apply to any trial that is a controlled clinical investigation,¹⁷² other than a Phase 1¹⁷³ clinical investigation, of a product subject to Section 505 of the FDCA or Section 351 of the PHSA.¹⁷⁴

The Final Rule defines an "applicable clinical trial" to include both an "applicable drug clinical trial" and an "applicable device clinical trial."¹⁷⁵ An "applicable clinical drug trial" includes Phase 2 and Phase 3 interventional clinical investigations of FDA-regulated drugs and biologics that are conducted in at least one site in the United States, are conducted under an IND, or involve a drug manufactured in and exported from the United States.¹⁷⁶ However, a drug or biologic product manufactured outside of the United States that is undergoing clinical investigation at sites that are all outside of the United States, without an IND, would not be subject to FDCA Section 505 or PHSA Section 351, and thus the clinical investigation would not be an applicable drug clinical trial.¹⁷⁷ In addition to these definitions, the regulations specify in detail the conditions under which applicable clinical trials initiated on or after January 18, 2017, are subject to the registration requirements.¹⁷⁸ To assist responsible parties in evaluating whether their clinical trial or study is an applicable clinical trial in accordance with the definitions and the extensive conditions outlined in 42 C.F.R. § 11.22(b), NIH created a checklist-based tool with a series of questions and general and specific considerations.¹⁷⁹ More generally, applicable clinical trials under the Final Rule include interventional¹⁸⁰ studies (with one or more arms and with one or more pre-specified outcome measures) of FDA-regulated drug, biological, or device products¹⁸¹ that meet one of the following conditions:

(1) The trial has one or more sites in the United States;¹⁸²
(2) The trial is conducted under an IND application or investigational device exemption ("IDE"); or
(3) The trial involves a drug, biological, or device product that is manufactured in the United States or its territories and is exported for research.¹⁸³

The Final Rule also explains that no expanded access use is considered an applicable clinical trial under Section 402(j) of the PHSA.

Clinical trials results reporting requirements apply to all applicable clinical trials associated with an FDA approved, licensed, or cleared drug, biologic, or device, unless a waiver is granted under the regulations.¹⁸⁴ NIH used discretionary authority granted under FDAAA to also require submission of clinical trial results from applicable clinical trials of products that are unapproved, unlicensed, or uncleared, whether or not approval, licensure, or clearance was sought.¹⁸⁵ The Final Rule requires the submission of clinical trial results for any applicable clinical trial with a primary completion date on or after January 18, 2017, for which clinical trial registration information is required to be submitted and for which the studied product is not approved, licensed, or cleared by FDA unless a waiver is granted.¹⁸⁶ Results are not required to be submitted for applicable clinical trials of unapproved products with a primary completion date before January 18, 2017. For applicable clinical trials of a device product not previously approved or cleared by FDA for any use and that are required to be registered, full posting of the clinical trial information on ClinicalTrials.gov ordinarily is delayed until after the device product has been approved or cleared. The Final Rule states that the responsible party may authorize NIH to publicly post clinical trial registration information for an applicable device clinical trial of a device product that has not been previously approved or cleared by FDA.

[b] Responsible Party

The Final Rule requires the Responsible Party for an applicable clinical trial to register the trial with NIH and submit required results information.¹⁸⁷ Responsible Party is defined as either the trial sponsor, as defined in 21 CFR § 50.3,¹⁸⁸ or the principal investigator, if so designated by the sponsor, grantee, contractor, or awardee, so long as the principal investigator is responsible for conducting the trial, has access to and control over the data from the clinical trial, has the right to publish the results of the trial, and has the ability to meet all of the requirements under this subsection for the submission of clinical trial information.¹⁸⁹ For a pediatric postmarket surveillance of a device product that is not a clinical trial, the Responsible Party is the entity that FDA orders to conduct the pediatric postmarket surveillance of the device product.

Section 11.4(c) of the Final Rule requires every applicable clinical trial have one, and only one, Responsible Party and one sponsor and specifies the approach for determining who will be considered the sponsor of an applicable clinical trial under various conditions, what qualifies a principal investigator to be designated a responsible party by a sponsor, and how responsibility reverts to the sponsor if a designated principal investigator is unable to fulfill the requirements for submitting information to ClinicalTrials.gov unless and until the sponsor designates another principal investigator as the responsible party.¹⁹⁰ If an applicable clinical trial or other clinical trial is conducted under an IND or IDE, the IND or IDE holder will be considered the sponsor.¹⁹¹ For clinical trials not conducted under an IND or IDE, the single person or entity who initiates the trial, by preparing and/or planning the trial, and who has authority and control over the trial, will be considered the sponsor.¹⁹²

[2] Registering Trials on ClinicalTrials.gov

[a] Required Clinical Trial Registration Information That Must Be Reported

ClinicalTrials.gov publicly discloses that a registered applicable clinical trial exists and is enrolling patients, or that it previously existed and was completed or terminated. The Responsible Party for applicable clinical trials that must be registered (other than postmarket surveillance of a device product that is not a clinical trial) that are initiated on or after January 18, 2017, must submit the following data elements information:¹⁹³

(1) Descriptive Information—brief title, official title, brief summary, primary purpose, study design, study phase (drugs), study type, pediatric postmarket surveillance of a device product (if applicable), primary disease or condition being studied or focus of the study, intervention name(s) for each intervention studied, other intervention name(s) for each intervention studied, intervention description for each intervention studied, intervention type for each intervention studied, indicate if studies an FDA-regulated device product or an FDA-regulated drug product, indicate if device product is not approved or cleared by FDA, indicate if post prior to FDA approval/clearance for applicable device clinical trial that studies at least one device product not

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