Registering an Investigator-Initiated Clinical Trial Overview
ClinicalTrials.gov is a web-based registry maintained by the National Library of Medicine which was originally created in response to the 1997 FDA Modernization Act (FDAMA) and has been publically available since February 2000. ClinicalTrials.gov — also known as the Protocol Registration and Results System (PRS) — contains both federally and privately supported clinical trials.
There are four principal drivers for registering a trial in a public registry. These are: (1) International Committee of Medical Journal Editors (ICMJE); (2) National Institutes of Health (NIH) policy, (3) Title VIII of the Food and Drug Administration Amendments Act of 2007 (FDAAA 801) and Final Rule (42 CFR Part 11) addressing Applicable Clinical Trials (ACTs) and (4) the Centers for Medicare and Medicaid Services (CMS). Each entity has distinct requirements and is discussed separately below. In determining the need to register, each organization’s rules should be considered independently.
The study “Sponsor” has overall responsibility for registering the trial. The Sponsor of industry-initiated single and multi-center studies is the pharmaceutical company whose protocol you are following. For investigator-initiated studies that are initiated and overseen by our faculty, without regard to funding source, UNC is considered the Sponsor and the University is therefore responsible for registering those studies. All registration, results reporting, and updating tasks are delegated by the University to the Principal Investigator.
The University is a registered Sponsor at ClinicalTrials.gov and holds two separate accounts: one for oncology and another for non-oncology trials. Monica Coudurier (firstname.lastname@example.org) from the Office of Clinical Trials, is the designated Administrator for the University’s non-oncology ClinicalTrials.gov account and Mary O’Dwyer (Mary_ODwyer@med.unc.edu) is the designated Administrator for the oncology ClinicalTrials.gov account. All clinical trials requiring registration must be registered through one of UNC’s organizational accounts accessible at: https://register.clinicaltrials.gov.
As a prerequisite of publication consideration, the ICMJE requires all studies meeting their definition of “clinical trial” to be entered in a public registry before the onset of subject enrollment. Further details regarding the ICMJE’s trial registration policy can be found at: icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html.
Although the ICMJE did not endorse a specific registry, they did describe criteria for a qualifying registry. ClinicalTrials.gov meets those criteria and has become the most widely used registry to meet the ICMJE requirement. Other ICMJE-approved registries are: http://www.anzctr.org.au/, http://www.isrctn.org, http://www.umin.ac.jp, http://www.trialregister.nl. Note that while the ICMJE does not mandate a specific registry, each of the other key drivers (shown below) specifically requires registration at www.ClinicalTrials.gov.
ICMJE defines a “clinical trial” as: “any research project that prospectively assigns people or a group of people to an intervention, with or without concurrent comparison or control groups, to study the relationship between a health-related intervention and a health outcome.
- Health-related interventions are those used to modify a biomedical or health-related outcome; examples include drugs, surgical procedures, devices, behavioral treatments, educational programs, dietary interventions, quality improvement interventions, and process-of-care changes.
- Health outcomes are any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events.”
Study registration should be complete by the time of first participant consent.
The NIH requires registration and results reporting for all studies receiving NIH funding, either in whole or in part, and meeting their clinical trial definition that were initiated on or after the effective date, January 18, 2017. For the extramural program, this applies to grant applications, contracts, and other transactions submitted on or after the effective date requesting support for a trial initiated on or after the effective date. For the intramural program, the policy applies to clinical trials that were initiated on or after the effective date. Clinical trials using NIH-supported infrastructure, but not receiving direct NIH funds for conduct are not subject to the policy. If required, registration should occur within 21 days of the first participant’s enrollment and results reporting within 1 year of the “Actual” Primary Completion date.
A short description must be included in NIH award applications explaining measures that will be taken to assure trial registration and results reporting at ClinicalTrials.gov will occur within the required timelines, informed consent documents will include a statement advising public trial posting, and confirmation of an existing institutional policy to ensure compliance with policies pertaining to trial registration and results reporting. For more details, see NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information NOT-OD-16-149 and General Application Guide for NIH and Other PHS Agencies, Section 4.7 Dissemination Plan. See also UNC Policy Statement.
Per the revised version (NOT-OD-15-015 issued on October 23, 2014), the NIH defines a “clinical trial” as:
“A research study1 in which one or more human subjects2 are prospectively assigned3 to one or more interventions4 (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.”5
1 See Common Rule definition of “research” at 45 CFR 46.102(d). Go back.
2 See Common Rule definition of “human subject” at 45 CFR 46.102(f). Go back.
3 The term “prospectively assigned” refers to a pre-defined process (e.g., randomization) specified in an approved protocol that stipulates the assignment of research subjects (individually or in clusters) to one or more arms (e.g., intervention, placebo, or other control) of a clinical trial. Go back.
4 An “intervention” is defined as a manipulation of the subject or subject’s environment for the purpose of modifying one or more health-related biomedical or behavioral processes and/or endpoints. Examples include: drugs/small molecules/compounds; biologics; devices; procedures (e.g., surgical techniques); delivery systems (e.g., telemedicine, face-to-face interviews); strategies to change health-related behavior (e.g., diet, cognitive therapy, exercise, development of new habits); treatment strategies; prevention strategies; and, diagnostic strategies. Go back.
5 A “health-related biomedical or behavioral outcome” is defined as the pre-specified goal(s) or condition(s) that reflect the effect of one or more interventions on human subjects’ biomedical or behavioral status or quality of life. Examples include: positive or negative changes to physiological or biological parameters (e.g., improvement of lung capacity, gene expression); positive or negative changes to psychological or neurodevelopmental parameters (e.g., mood management intervention for smokers; reading comprehension and /or information retention); positive or negative changes to disease processes; positive or negative changes to health-related behaviors; and, positive or negative changes to quality of life. Go back.
The NIH definition of a clinical trial is broader than the term “Applicable Clinical Trial” or ACT described in the Final Rule and includes Phase 1 trials of FDA-regulated products as well as non FDA-regulated interventions such as behavioral interventions.
Ensure entry of the NIH Grant/Contract award number as a Secondary ID within the ClinicalTrials.gov record’s Study Identification field.
Under FDAAA, the operative term is “Applicable Clinical Trial” (ACT). Trials meeting the definition of an ACT are required to register (within 21 days of the 1st participant’s enrollment) and report results (i.e., complete and publically posted by no later than 1 year of the “Actual” Primary Completion date) within the ClinicalTrials.gov registry. ACTs are divided into two categories: Applicable Clinical Drug Trials and Applicable Clinical Device Trials.
ACT—Drug (or Biologic)
Controlled investigation, other than Phase 1, using a drug or biologic intervention subject to FDA regulation. This pertains to both those interventions with and those without marketing approval.
Controlled investigation with health outcomes evaluating a device subject to FDA regulation other than a small (early) feasibility study or pediatric postmarket surveillance study. For help in understanding the difference between “early” and “traditional” device feasibility, see FDA Guidance Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies.
Recent regulation changes clarify the definition of “Control or “Controlled” to include all single or multi-arm interventional studies with a pre-specified outcome measure. Data may be compared to concurrently collected or non-concurrently collected data, including (historical) baseline data collected as a part of the trial.
Since January 1, 2014 CMS requires the National Clinical Trial (NCT) number on all clinical trial-associated claims submitted and is available only by registering at ClinicalTrials.gov. Claims submitted to CMS without the NCT number will be rejected.