ClinicalTrials.Gov

Your study involves a drug or device:

FDAAA (U.S. Public Law 110-85, Food and Drug Amendments Act of 2007) requires registration of all Applicable Clinical Trials in ClinicalTrials.gov

• Applicable clinical trials generally include interventional studies (with one or more arms) of drugs, biological products, or devices that are subject to FDA regulation, meaning that the trial has one or more sites in the U.S, involves a drug, biologic, or device that is manufactured in the US (or its territories), or is conducted under an investigational new drug application (IND) or investigational device exemption (IDE).

• FDAAA establishes penalties for failure to comply with registration or results submission requirements. Penalties include civil monetary penalties and, for federally funded studies, the withholding of grant funds.

The NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information (effective January 2017) establishes the expectation that all investigators conducting clinical trials funded in whole or in part by the NIH will ensure that these trials are registered and results information is submitted to ClinicalTrials.gov.

All competing applications (new and renewal) and progress reports for NIH grants (including cooperative agreements) supporting applicable clinical trials must include a certification of compliance with FDAAA.  This includes applications where the trial has not yet begun (e.g. is proposed) or is not yet required to be registered (e.g. less than 21 days since first subject was enrolled), as well as applications and progress reports that include an on-going trial that is already registered in ClinicalTrials.gov.

• Required for Journal Publication: You intend to publish an article about your study methods and/or outcomes. The International Committee of Medical Journal Editors (ICMJE) requires, and recommends that all medical journal editors require, as a condition of consideration for publication, registration of [all] clinical trials in a public trials registry at or before the time of first patient enrollment.

• 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 cause-and-effect 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, behavioural 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.”

For a Qualifying Clinical Trial (QCT): You intend to bill insurance for routine costs of care for study participants.

The Center for Medicare and Medicaid Services (CMS) requires a clinical trial identifier (NCT#) be reported on all billing claims for items/ services related to a qualifying clinical trial. If your study will bill routine costs to Medicare or any other insurer, the study must be registered on ClinicalTrials.gov to obtain the NCT#.

Qualifying Criteria (All three criteria must be "Yes"):

1. Evaluates a medicare benefit
2. Has therapeutic intent
3. Enrolls diagnosed beneficiaries

Deemed Automatically Qualifying Trial (Any one criteria must be "Yes"):

• Is funded/supported by NIH, CDC, AHRQ, CMS, DOD or VA
• Is supported by centers or cooperative groups that are funded by the NIH, CDC, AHRQ, CMS, DOD and VA
• Has an IND number: Trial conducted under an investigational new drug application (IND) reviewed by the FDA
• Trial is exempt from having an IND

Deemed Automatically Qualifying Trial (Any one criterion must be "Yes"):

• Is funded/supported by NIH, CDC, AHRQ, CMS, DOD or VA
• Is supported by centers or cooperative groups that are funded by the NIH, CDC, AHRQ, CMS, DOD and VA
• Has an IND number: Trial conducted under an investigational new drug application (IND) reviewed by the FDA
• Trial is exempt from having an IND

Qualifying Criteria (All three criteria must be "Yes"):

• Evaluates a Medicare benefit
• Has therapeutic intent
• Enrolls diagnosed beneficiaries

*Some commonly ordered tests may not be considered “reasonable and necessary” under the NCD, or may be reasonable and necessary at some frequency less than that required by the sponsor in a protocol. See the NCD Alphabetical Index for CMS’ indications and limitations for common procedures.

• Items or services required solely for the provision of the investigational item or service (e.g., infusion)
• Items or services typically provided absent a clinical trial
• Clinically appropriate monitoring of the effects of the item or service (e.g., monitoring side effects or complications)
• Prevention of complications
• Items or services needed for reasonable and necessary care arising from the provision of an investigational item or service (e.g., hydration fluids as part of chemotherapy treatment)

• Items or services provided solely to satisfy data collection and analysis needs that are not used in the direct clinical management of the patient or not used to monitor the effects of the item or service (e.g., plasma biomarkers)
• An investigational item or service itself if used in a non-FDA approved way
• Items or services customarily provided by the sponsors free of charge
• Items or services provided solely to determine trial eligibility
• Treatment of healthy volunteers unless used as controls
• Cosmetic surgery, some prosthetics, herbal remedies, relaxation therapies, etc.

The World Health Organization (WHO) defines a clinical trial as “any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. Interventions include but are not restricted to drugs, cells and other biological products, surgical procedures, radiological procedures, devices, behavioural treatments, process-of-care changes, preventive care, etc.”

The U.S. National Institutes of Health (NIH) defines a clinical trial 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.”

Consistent with the definition developed by the WHO, The International Committee of Medical Journal Editors (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 cause-and-effect 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, behavioural 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.”

The FDA defines an Applicable Clinical Trial (ACT) as follows:

• Trials of drugs and biologics: controlled clinical investigations, other than Phase 1 investigations, of a product subject to FDA regulation.
• Trials of biomedical devices: controlled trials with health outcomes of devices subject to FDA regulation, other than small feasibility studies, and pediatric post-market surveillance.

For complete statutory definitions and more information on the meaning of Applicable Clinical Trial, see Elaboration of Definitions of Responsible Party and Applicable Clinical Trial (PDF).Definition of a Clinical Trial

Under the National Coverage Decision (NCD), Medicare will cover those routine costs of qualifying clinical trials and the costs of items and services that are reasonable and necessary to diagnose and treat complications arising from participation in all clinical trials (Centers for Medicare and Medicaid Publication 100-3, Ch 1, Part 4, Section 310.1).

The trial may be “Qualifying” if it:

• Is funded/supported by NIH, CDC, AHRQ, CMS, DOD or VA
• Is supported by centers or cooperative groups that are funded by the NIH, CDC, AHRQ, CMS, DOD and VA
• Has an IND number
• Is conducted under an IND/IDE reviewed by the FDA
• Is exempt from having an IND/IDE
• Is conducted an abbreviated IDE

-OR-

Your trial (All three criteria must be "Yes"):

• Evaluates a Medicare benefit
• Has therapeutic intent
• Enrolls diagnosed beneficiaries

For additional information regarding “Qualifying Trials” please refer to Qualifying Clinical Trials on ResearchGO.

Yes, your trial must be registered in ClinicalTrials.gov if it is a “qualifying trial” even if it doesn’t meet the definition of an “Applicable Clinical Trial.” According to a recent CMS mandate, a clinical trial number must be reported on claims for items and services provided in clinical trials that are qualified for coverage as specified in the “Medicare National Coverage Determination (NCD) Manual, “ Section 310.1.

The clinical trials number to be reported is the number assigned by the National Library of Medicine (NLM) http://clinicaltrials.gov website (an 8-digit # preceded by “NCT”, a.k.a. “the NCT #”) when a study appears in the NLM Clinical Trials database.

Your “Qualifying Trial” must be registered in ClinicalTrials.gov prior to IRB approval
 

According to the ICMJE:

Unregistered trials will not be considered for publication in journals that adhere to ICMJE standards. This penalty has not changed over time.

According to the FDA/NIH (Food and Drug Amendments Act of 2007):

Penalties may include civil monetary penalties up to $10,000 fine for failing to submit or for submitting fraudulent information to ClinicalTrials.gov. After notification of noncompliance, the fine may go up to $10,000 per day until resolved. For federally funded grants, penalties may include the withholding or recovery of grant funds.

Applicable Clinical Trial (ACT) is the term used in Title VIII of the Food and Drug Administration Amendments Act of 2007 (FDAAA) (PL 110-85) to designate the scope of trials that may be subject to the registration and reporting requirements in FDAAA. FDAAA defines the term using two other terms defined in the Act, namely an “applicable drug clinical trial” or an “applicable device clinical trial.”

Detailed definitions can be found in the Elaboration of Definitions of Responsible Party and Applicable Clinical Trials document.

In general, a study is likely subject to the requirements of FDAAA if YES is answered to all five questions below:

1. Was the study initiated after September 27, 2007 (OR ongoing as of December 26, 2007)?
2. Is the study ‘interventional’ (i.e., participants are assigned to interventions by protocol)?
3. Does the study intervention include a ‘drug’, ‘biological product’, or ‘medical device’ (whether or not approved for marketing in the United States)?
4. Is the study not considered a phase I clinical investigation (e.g., a phase 2 study) OR not considered a ‘small feasibility’ device trial (e.g., a pivotal study)?
5. Does the study have at least one site located in the United States OR is the study conducted under an IND or IDE?

Yes, investigator-initiated trials are applicable clinical trials if they meet the criteria outlined above.

Yes – non-randomized trials can be “Applicable Clinical Trials” if they meet the other criteria. In non-randomized trials, participants are expressly assigned to intervention groups through a non-random method, such as physician choice. Keep in mind, a single –arm study often uses a historical comparison. See below for details regarding ‘controlled’ studies.

A study where a control is not expressly outlined in the protocol may still be considered an applicable clinical trial if it meets the other criteria outlined above. A controlled clinical investigation is one that is designed to permit a comparison of a test intervention with a control to provide a quantitative assessment of the drug effect. The purpose of the control is to distinguish the effect of a drug from other influences. The control provides data about what happens to human subjects who have not received the test intervention or who have received a different intervention. Generally, the types of control that are used in clinical investigations are (1) placebo concurrent control; (2) dose-comparison control; (3) no intervention concurrent control; (4) active intervention concurrent control; and (5) historical control.
 

• Phase 0 and phase I drug trials (however, these trials may still require registration per FDAMA Section 113).

• Small feasibility device trials and larger clinical trials of prototype devices with a primary measure of feasibility rather than health outcomes.

• Trials that include only de-identified human specimens and do not include human subjects.

Additional information can be found in the Elaboration of Definitions of Responsible Party and Applicable Clinical Trials document.

The “Responsible Party” is the entity or individual responsible for meeting FDAAA requirements for registering protocols and reporting results of ACTs. The responsible party is generally either the regulatory sponsor or the principal investigator. Note that the regulatory sponsor and financial sponsor are sometimes the same entity (i.e., a pharmaceutical company).

Generally speaking, the regulatory sponsor of an ACT will register and report the results of the trial if they:

• Are the company/organization that initiates the trial (multicenter or otherwise) and its employees conduct the trial;
• Are an individual who initiates a trial, but has someone else conduct the investigation;
• Hold the IND or IDE.

Generally speaking, Principal Investigators of applicable clinical trials will register and report the results of the trial if:

• The obligation is delegated to the principal investigator by the regulatory sponsor;
• The principal investigator is responsible for conducting the trial, analyzing the data, has rights to publish results and has the ability to meet all of FDAAA’s requirements for the submission of clinical trial information.

Note: For investigator-initiated ACTs, where a UCLA PI holds the IND/IDE, the IND/IDE holder (sponsor-investigator) must serve as the responsible party. For investigator-initiated ACTs where there is no IND or IDE holder and UCLA is the regulatory sponsor, the PI will be the designated responsible party. [UCLA Policy Pending]

Investigators and institutional officials associated with the trial should work together to determine the Responsible Party and ensure that the other grantees are aware of the designation. For assistance in these situations, please contact the UCLA PRS Administrator.

Yes, you can! ClinicalTrials.gov will allow registration of the study prior to getting IRB approval if the Overall Recruitment Status of the study is “Not yet recruiting.” IRB approval must be obtained before the study’s Overall Recruitment Status is changed to “Recruiting”. When IRB approval is obtained, update the protocol registration and release the study to ClinicalTrials.gov for review and processing.

As of January 18, 2017, the NIH requires registration and results reporting for all NIH supported clinical trials, regardless of whether or not they are required to do so under FDAAA. Results submission for non-applicable clinical trials is not required (for example, a behavioral study) by FDAAA 801. 

If no participants were ever enrolled in the trial, no results must be reported. Remember to change the Overall Recruitment Status to “Withdrawn.”

For a trial that terminated early after participants were enrolled, provide any available data for Participant Flow, Baseline Characteristics, Outcome Measures, and Adverse Events. If no data are available for any of the Outcome Measures, specify zero (“0”) for the Number of Participants Analyzed in each Arm/Group, and leave the data fields blank. Provide an explanation in the Analysis Population Description for why zero participants were analyzed and, if appropriate, provide information in the Limitations and Caveats module. You must still provide data for Participant Flow, Baseline Characteristics, and Adverse Events.

The data must be reported on ClinicalTrials.gov as soon as possible. The International Committee of Medical Journal Editors has indicated that they do not consider publishing to ClinicalTrials.gov as “pre-publication.” Here’s a link to their FAQs that may be useful. 

One can ask for an extension/delay in disclosing results by contacting the ClinicalTrials.gov staff (register@clinicaltrials.gov), but the request would need to meet their definition of “good cause” and publication issues are generally excluded from that definition.

Communication with the journal regarding the legal obligatory requirements may also be useful. It’s unlikely that the journal would refuse a manuscript when the institution/investigator is mandated by law to disclose publicly. However, if the trial was not registered according to the ICMJE journal requirements (prior to enrollment of first participant), the journal may take issue with that and reject the manuscript on that basis.

The new NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information is complementary to the statutory and regulatory reporting requirements of FDAAA and establishes the expectation that all investigators conducting clinical trials funded in whole or in part by the NIH will ensure that these trials are registered and results information is submitted to ClinicalTrials.gov. See more FAQs for NIH Grantees.

Because data reviews are retrospective and largely observational in nature and, in general, exempt research studies are not controlled clinical trials, nor involving an FDA-regulated intervention, they would not need to be registered or reported on ClinicalTrials.gov.

However, the ICJME may have a different opinion if exempt research involves any of the following:

• Drugs:
• surgical procedures;
• devices;
• behavioral treatments;
• dietary interventions;
• process-of-care change.
• biomedical or health-related measures including pharmacokinetic measures and adverse events.

If the applicable clinical trial has reached the primary completion date, then results must be submitted by the Responsible Party no later than 12 months after the primary completion date. If the ACT is investigating mortality over a long period of time (e.g., 10 years) and the investigator chooses to analyze mortality trends over time during the course of the study, the outcome measures may be revised in the PRS according to the desired analysis timeframe while the study is still ongoing. If, in this example, the only primary outcome measure is mortality at 10 years and the investigator does not choose to analyze the data prior to the primary completion date, the study will still be considered ongoing. The record, however, should be updated regularly to accommodate for enrollment status and protocol/amendment verification.

The primary outcome measure should have an estimated time frame.
Many times studies include a mortality endpoint and could remain open for several years following the completion of the intervention under investigation. Should we wait until study is closed to enter results?

If the applicable clinical trial has reached the primary completion date, then results must be submitted by the Responsible Party no later than 12 months after the primary completion date. If the ACT is investigating mortality over a long period of time (e.g., 10 years) and the investigator chooses to analyze mortality trends over time during the course of the study, the outcome measures may be revised in the PRS according to the desired analysis timeframe while the study is still ongoing. If, in this example, the only primary outcome measure is mortality at 10 years and the investigator does not choose to analyze the data prior to the primary completion date, the study will still be considered ongoing. The record, however, should be updated regularly to accommodate for enrollment status and protocol/amendment verification.

Yes, but you may ‘delay results posting’ until 30 days after the product receives FDA approval or clearance. You do not qualify for this delay if you are using approved products ‘off-label’. Only investigational products (i.e., no FDA approvals/clearance for any indication) qualify for delayed results posting. However, the NIH requires results reporting for all NIH supported clinical trials registered in ClinicalTrials.gov, regardless of whether or not they are required to do so under FDAAA.

FDAAA requires the reporting of results for all pre-specified primary and secondary outcome measures/endpoints for applicable clinical trials. Tertiary and exploratory outcomes are not captured as part of FDAAA.

Though there is no official guidance, ClinicalTrials.gov generally advises completing data entry ASAP but not later than 12 months after data collection has ended for that measure. If data collection is ongoing, it is a good idea to provide the anticipated posting date for that measure so it is clear to the public when the information will be made available.

In a case like this, the study team may submit an extension request, indicating that the study has not been unblinded and reporting the primary outcome measure data would interfere with the scientific integrity of the study. For assistance with this request, contact the UCLA PRS Administrator.

For studies that do not involve a drug or biologic, such as behavioral interventional studies or device trials, select ‘Not Applicable’.

FDAAA does not require that patient-level data/raw data be entered into ClinicalTrials.gov. Summary data, similar to that represented in manuscripts, is entered into ClinicalTrials.gov

The ClinicalTrials.gov protocol registration/results reporting system interface was originally developed prior to 2000 when ‘results reporting’ was not a requirement. Since the implementation of the ICMJE requirements and FDAAA enactment, this system has been adapted in many ways to meet challenging data requirements. Continuous enhancement occurs as various users make suggestions to the ClinicalTrials.gov staff. It is likely, however, that the tool will continue to maintain a form/function similar to the current tool.

Trials that were “ongoing” as of December 26, 2007 (i.e., participants were being recruited, were being selected from a predetermined population, or were being treated or examined) require results reporting within one year of the Primary Completion Date. The Primary Completion Date is defined as the date the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome, whether the clinical trial concluded according to the pre-specified protocol or was terminated.