Clinicaltrials.gov Registration and Results Reporting for Investigator-initiated Trials

Kate Anderton, MPH, CCRP

Clinical Trial Lead Firststring Research Inc.

Abstract: Trial registration and results reporting is an important aspect of investigator-initiated trials. This article provides an overview of ClinicalTrials.gov, the purpose of clinical trial registration and results reporting, and how to register and report results for investigator-initiated trials. The new ClinicalTrials.gov requirements and the meaning of the changes are also covered.

Background and Progress of ClinicalTrials.gov

ClinicalTrials.gov is a:

“Web-based resource that provides patients, family members, health care professionals, researchers, and the public with easy access to information on publicly- and privately-supported clinical studies on a wide range of diseases and conditions.”

(https://clinicaltrials.gov/ct2/about-site/background)

In 1997, Section 113 of the FDA Modernization Act of 1997 (FDAMA 113) was released. FDAMA 113 required the National Institutes of Health (NIH) to create a public information resource for federally- or privately -funded clinical trials conducted under an Investigational New Drug (IND) application that were looking at efficacy for life-threatening or serious diseases or conditions. ClinicalTrials.gov was made public in February 2000, but the initial scope of the public information resource was very narrow.

At first, only clinical trials funded by the NIH were registered on ClinicalTrials.gov. In 2002, the U.S. Food and Drug Administration (FDA) released a guidance for industry that provided recommendations for submitting industry-sponsored studies to ClinicalTrials.gov (this was retracted in 2017 after the Final Rule was published). In 2005, the International Committee of Medical Journal Editors (ICMJE) began requiring clinical trial registration.

The FDA Amendments Act (FDAAA 801) passed in 2007 and expanded the types of clinical trials that required registration. Under FDAAA 801, registration was required for controlled clinical investigations of any FDA-regulated drug or biologic product for any disease or condition and for certain studies of FDA-regulated medical devices.

FDAAA 801 included a major change that required clinical trial results reporting for applicable clinical trials (ACTs) of approved, licensed, or cleared products that reached a primary completion date after December 26, 2017. This law included civil money penalties (up to $10,000 per day) for non-compliance.

When an IND or New Drug Application (NDA) or a new protocol to an existing IND or NDA is submitted to the FDA, a certification of compliance (Form FDA 3674) is also required. The certification of compliance states that the sponsor or sponsor-investigator will register the clinical trial on ClinicalTrials.gov. The National Clinical Trial (NCT) number must be included on Form FDA 3674, which is not submitted for device studies.

Form FDA 3674 requires the inclusion of a statement in the informed consent form for applicable clinical trials that a description of the clinical trial will be available on ClinicalTrials.gov and that the description may include a

summary of the results, but it will not include identifiable information. The FDA is also involved in compliance and enforcement activities.

The results database was released in 2008, the year after the passage of FDAAA 801. Changes were made in 2014 to clarify FDAA 801. A notice of proposed rulemaking for FDAA 801 was issued for public comment. The same year, a draft policy on registration and results submission was issued for public comment until March 2015.

Primary Changes in the Final Rule

The Final Rule (42 CFR Part 11) was issued in 2016, clarifying and expanding the registration and results requirements in FDAAA 801. The effective data was January 18, 2007 with compliance required by April 18, 2017. Table 1 provides an overview of the primary changes in the Final Rule, which cover:

· Required data elements

· Applicable clinical trial determination

· Expanded access

· Frequency of updates

· Record corrections

· Results reporting

There are more required data elements under the Final Rule than before. The required data elements are the primary purpose, the study start date and completion date, whether the study involves an FDA-regulated device or drug, the study model, the number of arms, and a description of the intervention. To help sponsors and sponsor-investigators determine whether the clinical trial is an applicable clinical trial, questions have been added.

Registration is required if an investigational product in an applicable clinical trial is available through expanded access. Only one record will be created, and multiple applicable clinical trials will link to the same expanded access record.

The Final Rule provides more guidance about the frequency of updates. Amendments to the protocol that change the registration information (e.g., eligibility or the study drug) must be updated within 30 days. Study status updates, such as closing enrollment or adding a new clinical research site, must also be updated within 30 days. Clearance of the device under study must be updated within 15 days.

After the sponsor-investigator or other responsible party approves and releases the record, someone at ClinicalTrials.gov will review it and issue corrections. The expected date for completing the corrections (15 days for registration and 25 days for results) will be part of the record.

Results reporting is required for all applicable clinical trials that require registration. The Final Rule contains changes to required results reporting.

Results Reporting Changes in the Final Rule

Results reporting requirements differ depending on whether the primary completion date was before or after January 18, 2017. Before that date, reporting must include:

· Demographic and baseline characteristics

· Primary and secondary outcomes

· Serious adverse events

· Frequent adverse events.

If the primary completion date is after January 18, 2017, reporting must also include all-cause mortality and submission of the full protocol and the statistical analysis plan. The primary and secondary outcomes that are registered must match the outcomes in the protocol. If the statistical analysis plan is included in the protocol, it does not need to be submitted separately.

The Purpose of Clinicaltrials.gov Reporting

Registration and reporting on ClinicalTrials.gov is necessary in order to meet ethical, legal, and professional obligations (Table 2). Registration and results reporting increase transparency in research. While reporting on ClinicalTrial.gov is a great deal of work, patients are using ClinicalTrials.gov to find available clinical trials. The author works in South Carolina, yet she has gotten calls from patients in Canada, Utah, and Kansas about trials at the Hollings Cancer Center. Registration informs patients and clinicians across the country about available clinical trials. The information is in somewhat lay language. Registration also decreases clinical trial duplication. Investigators can review Clinical Trials.gov before developing a clinical trial to see if similar trials are already underway.

Some clinical trials, especially small trials and those that close early or have negative or unfavorable results, may not publish results. Requiring results reporting provides information that is important to the public and to other researchers. Publishing negative or unfavorable results is important in preventing other researchers from conducting similar studies and putting more patients at risk. Access to journal articles by the public is limited. Since the results are in the same format, it is easy to compare results across studies.

Registration and reporting is required by the federal government under FDAAA 801, Final Rule for Clinical Trials Registration and Results Information Submission (42 CFR Part 11). The International Committee of Medical Journal Editors requires trial registration and recommends that all medical journals follow this requirement. Thus, if investigators want to publish results, they must register their clinical trials on ClinicalTrials.gov. The committee defers to regulatory and funding agency requirements on results reporting.

Enforcement is done through the Final Rule and NIH policy. Civil penalties under the Final Rule against the responsible party listed in the record can be as high as $10,000 per day until the violation is corrected. In an investigator-initiated trial, the penalty will be imposed upon the sponsor-investigator. Under the Final Rule, the NIH can suspend or terminate the grant or contract funding, identify the clinical trial as non-compliant in ClinicalTrials.gov, and consider problems with registration and reporting in future funding decisions.

Registration and Results Reporting Overview

Table 3 highlights which clinical trials must be registered and which clinical trials must report results. Applicable clinical trials must be registered as per 402(j) of the Public Health Service Act. For trials of drugs and biologics, controlled clinical investigations of products that are subject to FDA regulation, other than Phase I studies, must be registered. The requirements are similar for device trials; however, small feasibility studies and pediatric post-market surveillance studies are excluded from registration.

The International Committee of Medical Journal Editors requires registration for any clinical trial that prospectively assigns people or a group of people to an intervention to study the relationship between a health-related intervention and a health-related outcome. Thus, if investigators want to publish results of a Phase I drug study, a small device feasibility study, or a pediatric post-market surveillance study, the study must be registered.

The Final Rule added a few clarifications of applicable clinical trials. If the trial meets one or more of the following requirements, then it must be registered:

§ One or more sites in the United States

§ Conducted under an IND or Investigational Device Exemption (IDE)

§ Product is manufactured in the United States and is exported for research.

ClinicalTrials.gov has a checklist for determining whether a clinical trial is an applicable clinical trial. If the sponsor-investigator decides not to register a trial, it is important to document this decision and maintain the documentation.

FDAAA 801 outlines clinical trial reporting requirements. If the trial’s primary completion date was between December 27, 2007 and January 17, 2017, and it is an applicable clinical trial of an approved, licensed, or cleared product, results must be reported. If the primary completion date was on or after January 18, 2017, then the Final Rule added results reporting for unapproved, unlicensed, or un-cleared products.

There are many considerations in registering and reporting clinical trials. The system will provide guidance on what is required for registration and what is not required. The person handling registration and reporting should not do more than is required.

Primary and secondary outcome measures are based on the primary and secondary endpoints in the protocol. Working with the investigator at the beginning of the study to designate secondary outcome endpoints with results reporting in mind is recommended. Results must be reported for every secondary outcome measure. It may be better to classify some of the secondary outcomes as exploratory outcomes or tertiary outcomes.

Endpoints with multiple parts need to be split up into individual outcomes for reporting. For example, the endpoint “To define the progression-free survival, overall survival, and duration of response of all treated patients” is one objective, but it has three outcome measures:

· Progression-free survival

· Overall survival

· Duration of response.

The second example is more difficult. The endpoint, “Identify correlations between AGE level changes and baseline, changes in clinical parameters (BMI, PSA, insulin resistance (HOMA-IR), A1C, testosterone, lipids, diet), and quality of life measures (AUA symptom index, FACT-P)” is eight outcome measures.

When registering the clinical trial, the anticipated primary completion date is entered. The anticipated primary completion date is never the actual primary completion date, and it must be updated as it changes. The primary completion date is based on the protocol, including any amendments. It is the date of the final visit for collection of data for the primary outcome. The 12-month reporting period starts at the actual primary completion date. Data should be entered in a timely manner so that investigators and research staff know what is happening with the study.

For studies with more than one outcome measure, the date on which all data collection for all primary outcomes is completed should be used. For example, if primary outcome #1 for a Phase I study is the presence or absence of DLT in ALT-803+Nivo, and primary outcome # 2 for Phase II is the response rate, the 12-month clock starts with the Phase II outcome measure.

The study completion date is the date that the final visit for collection of data for primary and secondary outcomes is completed. Phase I/II trials are considered Phase II trials when it comes to results reporting. If the study terminates before reaching Phase II, the study phase data field should be updated to indicate that the trial is a Phase I trial. Then, it is not considered an applicable clinical trial and results reporting is not necessary.

Reporting results can be delayed for good cause or waiver of results for extraordinary circumstances for two years from the date of a certification that the unapproved, unlicensed, or un-cleared product under study is still under development if approval will be sought within one year after the primary completion date for the product or for a new use of the product. The author has never done this and does not know of any circumstances that would qualify for delayed results reporting.

Partial results can be submitted if data for secondary outcomes have not been collected by the primary completion date. For example, say that safety is the primary outcome measure and overall survival is the secondary outcome measure. Adverse events will be documented for 30 days after the last dose of the drug; however, overall survival will be measured for five years. The 12-month clock starts at the primary completion date. In this situation, partial results would be reported. Final results must be added when they become available. If the protocol is amended between the time of the primary completion date and the study completion date, the amendment must be submitted to ClinicalTrials.gov.

Table 4 highlights the timeline for clinical trial registration and results. The trial must be registered within 21 calendar days of the first subject enrollment. As per the Final Rule, enrollment is the date that the subject signs the informed consent form. If the trial will be conducted under an IND, FDA Form 3674 has been submitted before enrollment starts and the study has been registered. If the study is IND-exempt or is not an applicable clinical trial,

the International Committee of Medical Journal Editors wants the trial to be registered before the first subject is enrolled.

Registering the clinical trial before it is activated is recommended. It is easier to do this while doing other administrative work for the trial. If the person handling registration is not in the clinic, he/she will not know when the first subject is enrolled.

Corrections to trial registration must be made within 15 days of receiving comments from staff at ClinicalTrials.gov. Changes in approval or clearance status of a device must also be made within 15 days. Amendment changes and status changes must be made within 30 days. The record must be verified every 12 months. This basically entails stating that the record is correct. Within one year of the primary completion date, results must be reported. Corrections to the results record must be made within 25 days of receipt.

Clinicaltrials.gov in the News

The New England Journal of Medicine published an article where researchers analyzed 13,327 highly-likely applicable clinical trials. Researchers found that 13.4% of trials reported results within 12 months, and 20.2% of these trials were academic or non-NIH funded trials (Anderson ML, Chiswell K, Peterson ED, Tasneem A, Topping J, Califf RM. Compliance with Results Reporting at ClinicalTrials.gov. N Engl J Med 2015 03/12; 2018/06;372(11):1031-1039).

The government has never enforced compliance measures, including imposing fines, related to clinical trials registration and results reporting. In “Failure to report: A STAT investigation of clinical trials reporting,” STAT News analyzed registration and results reporting by pharmaceutical companies and found a potential $25 billion in fines for unreported results (https://www.statnews.com/2015/12/13/clinical-trials-investigation/). Only two organizations met the reporting requirements more than 50% of the time. Ninety percent of academic institution records were late or unreported. Six organizations did not report any results.

Conclusion

Clinical trial registration and results reporting is an administrative burden; however, once staff on investigator-initiated trials learn how to do this and make it part of their regular procedures, it is not that difficult. Table 5 has resources related to ClinicalTrials.gov, which is a user-friendly system. ClinicalTrials.gov has many definitions, and users can email staff with specific questions about the study and receive answers within a day.


TABLE 1. Primary Changes in the Final Rule

  • Required Data Elements
    • Primary Purpose
    • Study start date/completion date
    • FDA regulated device/drug
    • Study model
    • Number of arms
    • Intervention description
  • Applicable clinical trial determination
    • Required fields will help determine this
  • Expanded access
    • Required if an investigational product in an applicable clinical trial is available through expanded access
    • Only one record will be created
    • Multiple application clinical trials will link to the same expanded access record
  • Frequency of updates
    • Amendments: 30 days
    • Status updates: 30 days
    • Clearance of device under study: 15 days
  • Record Corrections
    • 15 days for registration
    • 25 days for results
    • Record will reflect the expected correction date
  • Results reporting
    • Required for all applicable clinical trials that require registration
    • Changes to require results reporting




TABLE 2. Purpose of ClinicalTrials.gov Reporting

  • Ethical obligations
    • Registration
      • Informs patients and clinicians about available clinical trials
      • Trial information in lay language
      • Decreases trial duplication
    • Results Reporting
      • Trials may not be published without results reporting
      • Reporting negative results
      • Available to people with limited access to journal articles
      • Easily compare results across studies
  • Legal Obligations
    • Required by the federal government:
      • FDAAA801, Final Rule for Clinical Trials Registration and Results Information Submission (42 CFR Part 11)
  • Professional Obligations
    • Required for publication
      • International Committee of Medical Journal Editors required trials registration
      • Recommends all medical journals follow this requirement
      • Defers to regulatory and funding agency requirements for results reporting

TABLE 3. Clinical Trial Registration and Results Reporting

  • Clinical trial registration
    • Applicable clinical trials (402(j) of the Public Health Service Act):
      • Trials of drugs and biologics:
        • Controlled, clinical investigations, other than Phase I studies, of a product subject to FDA regulations
      • Trials of devices
        • Controlled trials with health outcomes, other than small feasibility studies and pediatric post-market surveillance studies
    • Include interventional trials of FDA-regulated drug, biologic, or device products (Final Rule) if:
      • Trial has one or more sites in the U.S.
      • Trial is conducted under an IND or IDE
      • Product is manufactured in the U.S. and is exported for research
  • Clinical trial results Reporting
    • Primary Completion date on or after 12/27/07 to 1/17/17
      • Applicable clinical trials of approved, licensed, or cleared products
    • Primary completion date on or after Jan 18, 2017:
      • Applicable clinical trials of approved, licensed, or cleared products and
      • Applicable clinical trials of unapproved, unlicensed, or un-cleared products

TABLE 4. Timeline for Registration and Results Reporting

  • Within 21 calendar days of first subject enrollment:
    • Register trial
  • Within 15 days of receiving comments:
    • Make corrections to trial registration
  • Within 15 days:
    • Change in approval or clearance status of devise product
  • Within 30 days:
    • Submit amendment changes
    • Submit status changes
  • Every 12 months:
    • Verify record
  • Within 1 year of primary completion date:
    • Deadline for results reporting
  • Within 25 days:
    • Make correction to results record

TABLE 5. Resources Related to ClinicalTrials.gov

  • FDAAA 801 and the Final Rule:
    • clinicaltrials.gov/ct2/manage-recs/fdaaa
  • International Committee of Medical Journal Editors recommendations:
    • icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration
  • Final Rule information page:
    • prsinfo.clinicaltrials.gov
  • Clinicaltrials.gov support materials:
    • clinicaltrials.gov/ct2/manage-recs/resources
  • PRS Users Guide:
    • prsinfo.clinicaltrials.gov/prs-users-guide.html

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