Registering an Investigator-Initiated Clinical Trial in a Public Registry
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 Marie Malikowski (email@example.com) 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.
Guidance on ICMJE Data Sharing Statements for Investigator-Initiated Research
Effective July 1, 2018 manuscripts submitted to ICMJE journal members must contain a data sharing statement. In connection with this requirement, a related field exists within ClinicalTrials.gov records (i.e., “IPD Sharing Statement”) wherein the applicable sharing plan should be indicated.
The data sharing statement needs to indicate:
- Whether individual deidentified data will be shared;
- What data will be shared;
- Availability of related documents (e.g., study protocol, statistical analysis plan);
- When the data will be available and for how long;
- Criteria for obtaining the data.
UNC recommends the following data sharing statement:
Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.
When data sharing is permitted, a Data Use Agreement (DUA) specifying the uses of such data to be shared must be in place before any data is shared. The Principal Investigator should submit a request to the Office of Industry Contracting for processing. For further information on DUAs, please refer to the Data Use Agreement Guidance.
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.
Protocol Registration and Results Reporting Overview
It is the responsibility of the Principal Investigator to ensure that registration, results reporting, and updating are performed within the specific timelines required by each applicable rule body for all new and ongoing clinical trials.
The Principal Investigator or designee is responsible for performing the following functions:
- Identify studies requiring registry in a publically accessible database;
- Request user account set-up within UNC organization account;
- Create records on ClinicalTrials.gov;
- Confirm accuracy of record content;
- Change ClinicalTrials.gov Record Status following edit completion to trigger release process;
- Ensure ClinicalTrials.gov notification emails are addressed within 15- and 25-day timelines (registration and results records, respectively);
- Maintain records on ClinicalTrials.gov in accordance with all regulatory and policy driven requirements;
- Notify the Office of Clinical Trials of receipt of any correspondence from an external agency regarding Final Rule (42 CFR Part 11) requirements, NIH policy requirements, ClinicalTrials.gov record: registration, results, and/or record maintenance requirements;
- Notify the Office of Clinical Trials within 30 days of an expected and 15 days following an unexpected Principal Investigator/Responsible Party personnel change. All changes in Study Official (Principal Investigator), their official title, and/or contact information must be updated in the ClinicalTrials.gov record within 30 days of the change.
The Office of Clinical Trials offers support, guidance, and assistance including user account set-up, clinicaltrials.gov record creation; record maintenance/updates, and results reporting.
New faculty coming in or faculty leaving may need to transfer their ClinicalTrials.gov records with them. The Office of Clinical Trials can assist with this as well.
Trial Registry Overview Chart
|Register WHEN?||Phase 1||Phases 2-4||Device||Other Interventional*||Observational||Post Results?|
|ICMJE||Before enrollment of 1st subject||Yes||Yes||Yes||Yes||No||No|
|NIH||Within 21 days of 1st subject’s enrollment||Yes||Yes||Yes||Yes||No||Yes|
|FDA||Within 21 days of 1st subject’s enrollment||No||Yes||Yes||No||No||Yes|
|CMS||Prior to claims submission (for Qualifying Clinical Trials)||Yes (if qualifying)||Yes||Yes||No||No||No|
* Health-related or Behavioral Interventional Trials. Go back.
Depending on the reason for registering and associated requirements, ClinicalTrials.gov Records consist of 1-3 sections: Protocol (initial registration record), Results, and Document Sections. The Protocol (initial registration) is the minimum registration requirement for those studies being registered to meet ICMJE and CMS rules. While permissible to enter results for such trials, it is not required. Records registered to meet Final Rule and/or NIH Policy requirements, must report results within ClnicalTrials.gov no later than 12 months of reaching the “Actual” Primary Completion. These studies must add and complete a results record and upload a protocol in Portable Document Format Archival (PDF/A) format. If the Statistical Analysis Plan (SAP) is included within the protocol, the protocol including SAP is the only item required for upload. However, if a stand-alone SAP exists, then it must be uploaded too. Each document must include a cover sheet indicating the Official Study Title, NCT number, and date of document.
The process for registering individual studies at ClinicalTrials.gov is described below. This pertains only to investigator-initiated studies.
- A study must have been submitted to an IRB for review prior to registry although actual approval is not required prior to ClinicalTrials.gov protocol record creation/
UNC’s IRB does not review the data registered for a given trial. Ultimate responsibility for record accuracy lies with the Principal Investigator (PI) although a preliminary quality control (QC) review is performed by UNC’s ClinicalTrials.gov account administrator before release to ClinicalTrials.gov where a separate QC review is conducted.
An individual user account must be established at ClinicalTrials.gov by the University Administrator for the study Principal Investigator (PI) and all designees requiring record access as user accounts should not be shared among users. To request a user account, send an e-mail to firstname.lastname@example.org or email@example.com providing the user’s name, department, telephone number, and e-mail address. The user account will be created within ClinicalTrials.gov the same day if at all possible, and usually within minutes of account set-up, the new user will receive an e-mail from ClinicalTrials.gov providing the login details and a temporary password.
The PI or the PI’s designee will complete the required record fields by entering study-specific details into the ClinicalTrials.gov website. The ClinicalTrials.gov Protocol Registration Data Element Definitions for Interventional and Observational Studies is available from the Help ‘pull-down’ menu on the ClinicalTrials.gov/PRS Home page upon log in and is also accessible by using the ‘Definitions’ hyperlink found in each edit module. This document can be used to identify which fields are (*) required, (*§) required if Study Start Date is on or after January 18, 2017, or ([*]) conditionally required.
When creating a new record, enter the 6-digit, hyphenated, IRB number (i.e., XX-XXXX) into the first entry field as the “Unique Protocol ID” since UNC has no overall protocol numbering convention. For those using a department or other protocol identifier, this can be entered into the Secondary ID field (found within the Study Identification section).
Unreleased records cannot be seen outside the University’s PRS account. Records must progress from “In Progress” to “Entry Complete” to “Approved” and then to “Released” in order to be reviewed by ClinicalTrials.gov staff and updated on the ClinicalTrials.gov public website. This applies to initial record creation and subsequent record updates (e.g., after making edits based on ClinicalTrials.gov review comments or any future registration or results record updates).
Once editing is complete and the ClinicalTrials.gov Record Status is changed from “In Progress” to “Entry Complete,” an automated system e-mail is sent to the University Administrator (Office of Clinical Trials) advising that the record is ready to review and edit (or facilitate editing), if necessary. Upon review completion, the administrator will then approve and release the record for review by ClinicalTrials.gov. Until this release occurs, no one outside of UNC can see the record (new registrations) or updated information (existing record edits). Once released, ClinicalTrials.gov will perform a system validation and QC review. For protocol records this usually occurs within 2 to 5 days of release. For records containing results, each review may take 30 or more days.
If ClinicalTrials.gov identifies questions or requests additional information/clarification, they will send notification via email to the Record Owner (for registration records) or Results Point of Contact (for records with results) which contains instructions for accessing comments within the record. To remain compliant, records must be edited to address issues identified by ClinicalTrials.gov notification within 15 calendar days for protocol/registration records and within 25 calendar days for records with results. Upon completion of their review, ClinicalTrials.gov will assign an NCT number and publically post the new registration record, record maintenance updates, or results record.
In order to qualify for publication consideration, enrollment should not begin until the NCT number assignment is received as studies are not officially considered to be registered until the NCT number is received. The NCT number is not provided until the ClinicalTrials.gov QC review process has been completed. Please allow adequate time this process.
The Principal Investigator is responsible for maintaining the accuracy of the registration record information in accordance with regulations. This includes information updates as applicable, no less than once every 12 months and within 30 calendar days of the occurrence of a significant change. Some examples of a “significant” change include: Study Start Date, Overall Recruitment Status, Human Subjects Protection Review Board Status, Primary Completion Date, and Principal Investigator change. For specific details, see Changes from Current Practice Described in the Final Rule (Table 3).
During each record update, the Record Verification date field should be revised to reflect the current Month/Year attesting to the record’s accuracy. If no changes are needed at the time of the required annual update, the Record Verification field should be updated regardless and the record re-released for public update.
The obligation to submit updates and corrections ends on the date that all required data elements have been submitted for all primary and secondary outcomes and all adverse events collected in accordance with the protocol, and the QC process has concluded.
Results must be entered for studies that fall under the Final Rule and/or NIH Policy requirements no later than 12 months after the “Actual” Primary Completion. The Primary Completion date is defined as the date of final data collection for the primary outcome measure(s). The results record can be created once an “Actual date has been entered into the Primary Completion date field within the ClinicalTrials.gov protocol record. Much of the results record is constructed using information within the protocol record, especially the outcome measures which will be pulled into the results record to become the labels for the data reporting tables. Prior to creating the results record, ensure that the protocol section is accurate especially the outcome measure titles, descriptions, and time frames such that these will be meaningful to people who are unfamiliar with the study. Narrative conclusions are not allowed within the results record. A results record is comprised of: Participant Flow, Baseline Characteristics, Outcome Measures, Adverse Events,
Additional registration and results reporting tools provided by ClinicalTrials.gov are available by clicking the ‘Help’ menu on the PRS homepage to better understand, prepare, and organize registration and results reporting. Included there are results data preparation checklists and simple results templates and examples.
Please do not hesitate to contact Monica Coudurier (firstname.lastname@example.org) should you have any questions about this important procedure.