Guidelines for Clinical Trial Registration

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Guidelines for Clinical Trial Registration

Background. In 2005 the International Committee of Medical Journal Editors (ICMJE) announced that in order for clinical trial results to be considered for publication in journals that adhere to ICMJE standards, all clinical trials that start recruiting patients or volunteers must be registered with a public registry before the enrolment of the first subject. Details of the ICMJE requirement are described at the ICMJE website at http://www.icmje.org/. At this point the requirement for trials covered what was typically understood as a randomized clinical trial; so did not include phase I, or early proof of concept trials or observational type studies. These requirements have now changed. This document explains what trial registration is, which studies need to register, what register to use and how to go about registering your study.

Why the need to register? As outlined by the ICMJE, the purpose is "to promote the public good by ensuring that everyone can find key information about every clinical trial whose principal aim is to shape medical decision-making" and to foster conditions in which decisions about care "rest on all of the evidence, not just the trials that authors decided to report and that journal editors decided to publish".

How is "clinical trial" defined? Initially, the ICMJE required registration of all clinically directive trials, which it defined as "any research project that prospectively assigns human subjects to intervention or comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome". In May 2005, the ICMJE clarified this definition to exclude preliminary trials designed to study pharmacokinetics or major unknown toxicity (phase 1 trials).

However, in June 2007 the ICMJE expanded this definition and adopted the WHO’s definition of a clinical trial:
"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. As previously, purely observational studies (those in which the assignment of the medical intervention is not at the discretion of the investigator) will not require registration. The ICMJE member journals apply this expanded definition of clinically directive trials to all trials that began enrollment on or after July 1, 2008.

Note this important advice from the ICMJE:
"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".

In summary: Any trial where interventions are assigned by the investigator should be registered, including health related measures and phase I studies. So this includes observational trials unless there is no assigning of interventions OR the observations are with the health worker rather than subject. If you are not sure: register!

What about registering clinical trial results? Over the time during which registration of trial methods has become common practice, several forces have begun advocating for registration of trial results. The ICMJE recognizes that the climate for results registration will probably change dramatically and unpredictably over coming years.

Since September 27, 2008 any trial that has at least one site in the United States, must comply with 2008, US Public Law (110-85, Title VIII), that mandates the submission of “basic results” data for certain clinical trials of drugs, biologics, and devices. ICMJE states that “The law applies to trials that are not Phase 1 or small device feasibility studies, and that have at least one site in the US, regardless of who sponsors, finances, or conducts the trial. Certain other trials may also be covered by the law. In general, these summary results data must be submitted within 12 months of the completion of data collection for the primary outcome measure. The law also requires submission of results for pre-specified secondary outcome measures registered at ClinicalTrials.gov. Delays in submitting results may be granted for certain reasons, but not generally for journal submission. There could be significant penalties for failure to comply with this law. These “basic results” include summary data tables of baseline characteristics, participant flow, outcomes, and adverse events. With the exception of several brief free-text fields for providing descriptions of the data, no narrative information is included (e.g., there is no discussion or conclusion section). There will be no patient level data”.

Currently, for all other trials conducted outside of the US, results submission does not apply and is not required by the ICMJE. However, if trial results are required to be submitted by US Law, ICMJE will not consider results posted in the same primary clinical trials register in which the initial registration resides (e.g. ClinicalTrials.gov) as previous publication, if the results are presented in the form of a brief, structured (<500 words) abstract or table. The ICMJE favors a standard abstract format for results reporting, and the CONSORT (Consolidated Standards for the Reporting of Trials) group’s guidelines for abstracts related to trials may be one such option (see http://www.consort-statement.org/consort-statement/overview0/).

For further clarification visit http://www.icmje.org/update_fdaaa.html.

The ICMJE believes that parties interested in results registration should consider requiring the deposition of such an abstract in the registry 24 months after closure of data collection if results are not published in a peer-reviewed venue by that time. The registered abstract should either cite any related full, peer-reviewed publications or include a statement that indicates that the report has not yet been published in a peer-reviewed journal. Researchers should be aware that editors may consider more detailed deposition of trial results in publicly available registries to be prior publication. When submitting a paper, authors should fully disclose to editors all posting in registries of results of the same or closely related work.

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.

Which trials registries are acceptable to the ICMJE?

The ICMJE accepts registration in the following registries:

www.actr.org.au
www.clinicaltrials.gov
www.ISRCTN.org
www.umin.ac.jp/ctr/index/htm
www.trialregister.nl

In addition to the above registries, the ICMJE will also accept registration in any of the primary registries that participate in the WHO International Clinical Trials Portal (see http://www.who.int/ictrp/about/details/en/index.html). However, the ICMJE will only accept those trials registered in the primary registry and not those in associate registries because the associate registries may be run on a for-profit basis.

You must also ensure that all the minimum data elements are completed in an informative manner. Failure to do this may result in the registration not being accepted.

Who is responsible for registering a trial?

1. Industry or PPP sponsored trials Where there is a contract between the industry or PPP (such as IAVI, MMV, MVI, DNDi) sponsor and the programme. The sponsor should register the trial and this is typically the product manufacturer. This should be agreed before a contract is signed. Before enrolling study subjects, 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.

2. Investigator-initiated trials

(a) Where industry has supplied the study drug or grant funds, the trial should be registered by the lead PI, through the sponsoring institution (e.g. The University who employs the PI). OR (b) Where the trial is either unfunded or funded through a grant from non-profit sources, or internal sources, the trial should be registered by the lead PI or through the sponsoring institution (typically the PI’s employers). (c) Where there is no external sponsor (i.e. the funds came straight to the trial site and no other external body is acting as sponsor) then the PI is sponsor and can register by following the requirements for this below.

3. Multi-site trials –

Registration should be coordinated among the study sites and registered by the "lead sponsor" to avoid multiple registrations.

My trial is funded through a source where the funders are not able to register my trial?

You will need to register through ISRCTN or Clintrial.gov. ISRCTN is accessed through the on-line application at http://www.controlled-trials.com/isrctn/submission/ . You can log-in immediately and register your trials. Once the form has been submitted, you will get an email confirming receipt of your application, which you may print out for your records if you wish. The ISRCTN editorial office will then check whether the application is eligible. An administrative charge will then be requested – the current 2010 rate is £160 per trial (US$254/€183 based on October 2010 exchange rates). All users will have permanent free access to the information in the ISRCTN Register. If you have any questions about the registration process, please feel free to email info@controlled-trials.com.

The Pan African Clinical Trials Registry (PACTR) is a regional register of clinical trials conducted in Africa. The registry is an African initiative serving the needs of Africans. It provides a platform where clinical trials can be registered prospectively. In addition, it also provides a searchable, electronic database of planned trials and trials currently in progress. The PACTR is unique in recognising that African trialists face additional challenges in trial registration and seeks to provide feasible ways of overcoming these. For example, a common problem for individuals living in sub-Saharan Africa is limited, unreliable and costly internet access. With this in mind, the registry provides alternative means of trial registration for registrants who do not have reliable access to the internet. Trials may be registered manually by email, postal mail or facsimile correspondence and trial registration is free.

http://www.pactr.org/

Does the local Research Ethics Board need to approve the study before it is registered?

No. Registry allows for trials to be registered 'pending' ethics approval. However, once a trial has been approved by the REB, the registry must be updated with the REB approval number.

How can I find out more about clinical trial registration?

ICMJE - to find out more about the registration requirements of the International Committee of Medical Journal Editors (ICMJE) refer to:

• http://www.icmje.org/clin_trial.pdf (Initial ICMJE Statement)
• http://www.icmje.org/update_oct04.html - Update on Trials Registration (October 2004)
• http://www.icmje.org/update_may05.html - Update on Trials Registration: Is This Clinical Trial Fully Registered?: A Statement from the International Committee of Medical Journal Editors (May 2005)
• http://www.icmje.org/update_june07.html - Update on Trials Registration: Clinical Trial Registration: Looking Back and Moving Ahead(June 2007)
• http://www.icmje.org/update_fdaaa.html - Update on FDAAA from ClinicalTrials.gov: Basic Results Reporting at ClinicalTrials.gov and “Prior Publication” (June 2008)

What is the relationship between the ICMJE trials policy and the ongoing WHO trials registry effort?

In September 2005, the ICMJE implemented a policy that requires registration of clinically directive trials. The WHO is also working towards the implementation of an international trials registration process. Although several editors of ICMJE journals are independently involved as advisors to the WHO process, the two efforts are separate. The ICMJE welcomes the WHO initiative and is following its progress closely. When the final WHO policy is available, the ICMJE will determine whether to revise the ICMJE requirements to correspond to the WHO requirements. At present, the ICMJE expects investigators who wish to publish in ICMJE journals to adhere to the current ICMJE trials registry policy as documented on this web site (see May 2005 editorial and Frequently Asked Questions for details of the current ICMJE policy including the definition of applicable trials, acceptable registries, timing of registration and required data items).

Do I need to register my study if the subjects were health care providers and not patients?

Some trials assign health care providers, rather than patients, to intervention and comparison/control groups. If the purpose of the study is to examine the effect of the provider intervention on the health outcomes of the providers’ patients, then investigators should register the trial. If the purpose if to examine the effect only on the providers (for example, provider knowledge or attitudes), then registration is not necessary.

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