Clinical Trial Registration

In September 2004, the International Committee of Medical Journal Editors (ICMJE) stated that “the research enterprise has an obligation to conduct research ethically and report it honestly. Honest reporting begins with revealing the existence of all clinical studies, even those that reflect unfavorably on a research sponsor’s product”. The ICMJE instituted rules for all clinical trials that started recruiting patients or volunteers on or after July 1, 2005 that they must be registered with a public registry before the enrolment of the first subject, and indicated that trial results would not be published if not registered (N Engl J Med 2004; 351 :1250-1 ). Ongoing trials not registered at inception will be considered by the ICMJE for publication if they are registered before September 13, 2005. All trials with recruitment completed before July 1, 2005 need not register. Details of the ICMJE requirement are described at the ICMJE website at www.icmje.org

Addtionally, the ICMJE has stated that purely observational studies (those in which the assignment of the medical intervention is not at the discretion of the investigator) will not require registration. However, ”Those who are uncertain whether their trial meets the expanded ICMJE definition should err on the side of registration if they wish to seek publication in an ICMJE journal”.

New legislation was put in place in the US through the Fair Access to Clinical Trials (FACT) Sec 113 of the FDA Modernization Act which mandated registration of clinical trials through the www.clinicaltrials.gov website for all IND and efficacy trials. Most recently, the FDA has instituted an amendment to the Act which requires sponsors to expand the types of clinical trials are required to be registered, and to enhance the amount of information submitted to the registry. Additional information now required includes an estimated closure date for each study and the posting of clinical trials results as they become publicly available.

Health Canada has required the registration of trials since 2006 under the legislation entitled “Registration and Disclosure of Clinical Trials Information”.

Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council, Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans,- December 2018 (TCPS2). – Article 11.10 states “All clinical trials shall be registered before recruitment of the first trial participant in a publicly accessible registry that is acceptable to the World Health Organization (WHO) or the International Committee of Medical Journal Editors (ICMJE).

TCPS2 states that there are compelling ethical reasons for the registration of all clinical trials:

Registration improves researchers’ awareness of similar studies so that they may avoid unnecessary duplication and thereby reduce the burden on participants.
Registration also improves researchers’ ability to identify potential collaborators and/or gaps in research so that they may pursue new avenues of inquiry with potential benefits to participants and to society.
To prevent researchers or sponsors from reporting only those studies with favourable outcomes. When all studies must be registered, it is easier to identify those studies where outcomes have not been reported or findings have been withheld.”

In accordance with TCPS2, researchers must provide the REB with evidence of clinical trial registration (e.g., registration number).

What is the Definition of a Clinical Trial for Registration Purposes?

Three similar definitions of a “clinical trial” are provided below. If your study meets any one of these definitions, the trial must be registered.

TCPS 2 defines a clinical trial as:

A form of clinical research (also known as patient-oriented research), is any investigation involving participants that evaluates the effects of one or more health-related interventions on health outcomes. Interventions include, but are not restricted to, drugs, radiopharmaceuticals, cells and other biological products, surgical procedures, radiologic procedures, devices, genetic therapies, natural health products, process-of-care changes, preventive care, manual therapies and psychotherapies. Clinical trials may also include questions that are not directly related to therapeutic goals – for example, drug metabolism – in addition to those that directly evaluate the treatment of participants.

FDA (Food and Drug Administration) requires registration of applicable “clinical trials” defined as follows:

For any trials of drugs and biologics: controlled clinical investigations, other than Phase I investigations, of a product subject to FDA regulations
For 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.

ICMJE definition of a clinical trial includes:

“Any research study that prospectively assigns human participants or groups of humans to one or more “health-related interventions” to evaluate the effects of health outcomes.”
“Health-related interventions” include any intervention used to modify a biomedical or health-related outcome (for example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-of-care changes). Health outcomes include any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events.

Does the Need to Register Trials Apply Only to Industry-Sponsored Clinical Trials?

No. It makes no difference who the sponsor is or whether there is an external sponsor.

Who is Responsible for Registering a Trial?

The “responsible party” must register a clinical trial. The responsible party is defined as:

The sponsor of the clinical trial

The principal investigator (PI) of the clinical trial if so designated by a sponsor grantee, contractor, or awardee.

In most cases, registration will be the responsibility of the sponsor and will not require the researcher to complete any extra work. For clinical trials that do not have a sponsor or are funded by a grant, the lead PI is responsible for registering. If the trial is a single study site, this responsibility will fall to the local PI.

In general, the following applies:

Industry-sponsored trials should be registered by the sponsor. These are trials in which there is a contract between the industry sponsor, the host institution, and the PI. Before enrolling study participants, every PI should ensure the industry sponsor has registered the trial. The PI should also check the registry to ensure that all ICMJE minimal data set elements are included in the registration.
Investigator-initiated trials, whether or not there is industry funding or, in fact, if there is no funding, the PI is considered the sponsor and is responsible for registering the clinical trial.
For clinical trials that are being performed at multiple institutions, the lead sponsor should take responsibility for registering the trial. The local PI should work with the other investigators and sponsors to ensure that the trial is registered only once for the entire project.
CIHR-funded randomized controlled trials- The PI is advised to contact CIHR. CIHR may prefer the trial be registered in the ISRCTN Registry rather than Clinical trials.gov.
NIH sponsored trials are usually registered by the Institute that is funding the research. They may delegate this responsibility to the lead PI.

Which trials registries are acceptable to the ICMJE?

Acceptable registries must

be accessible to the public at no charge
open to all prospective registrants (investigators are able to register without restriction by geographic location, academic affiliation, patient demographics, or clinical condition)
managed by a not-for-profit organization
have a mechanism to ensure the validity of the registration data
electronically searchable
must include the required data elements

ICMJE has a list of registries that meet the ICMJE criteria.

In addition, the ICMJE will also accept registration in any of the primary registries that participate in the WHO International Clinical Trials Platform (ICTRP). The mission of the WHO International Clinical Trials Registry Platform is to ensure that a complete view of research is accessible to all those involved in health care decision making. This will improve research transparency and will ultimately strengthen the validity and value of the scientific evidence base.

Most clinical trials are registered on ClinicalTrials.gov via a web-based entry system called the Protocol Registration and Results System.

When Do I Register my Clinical Trial?

Register a trial before any participants are enrolled. TCPS 2 and ICMJE require registration be completed before the first participant is enrolled to avoid publication restrictions.

Does CHIPER Need to Grant Final Approval of the Trial Before it is Registered?

The ClinicalTrials.gov registry allows for trials to be registered ‘pending’ ethics final approval. However, once a trial has been approved by the ethics board, the registry must be updated with the REB approval number.

In most instances it suggested that you wait to register the trial following initial review and receipt of your Revisions Required letter.

How to Register your Trial

Please contact your home institution to determine if they have an organizational account and for guidance on completing a registration.

Are Registration Updates Required?

In accordance with TCPS2 Article 11.11: “Following registration of their study in accordance with Article 11.10, researchers are responsible for ensuring that the registry is updated in a timely manner with:

new information (Article 11.8);
safety and, where feasible, efficacy reports (Article 11.6);
reasons for stopping a trial early; and
the location of findings.”

Clinicaltrials.gov requires that the “responsible party” must also verify, review and update the study record when any changes are made to a study protocol and/or at a minimum every 6 months. The records must also be updated when the trial is completed.

What are the Consequences of not Registering a Trial?

There are penalties for responsible parties who fail to register clinical trials, keep the information up to date, or submit false or misleading information.

The inability to publish the results of a trial in an ICMJE associated journal.
For US federally-funded trials, the penalties could include withholding or recovery of grant funds.