Clinical Trial Registration Audit Report

The requirement to register

The UK policy framework for health and social care research expects information about all research studies to be in the public domain before the research starts:

Whilst this is good practice for all research, there are stronger requirements for clinical trials. Clinical trials are:

• Clinical trials of investigational medicinal products (CTIMPs)
• Clinical investigations or other studies of medical devices
• Combined trials of investigational medicinal products investigational medical devices
• Other clinical trials to study novel interventions or randomised clinical trials to compare interventions in clinical practice

It is a condition of the Research Ethics Committee (REC) favourable opinion that a clinical trial is entered onto a publicly accessible register. Registration should occur before, or no longer than six weeks after, the first participant is recruited.

A ‘public register’ is defined as any register on the World Health Organisation list of primary registers or the list of registers accepted by the International Committee of Medical Journal Editors.

For some research there may be reasonable grounds, such as commercial sensitivity around early phase trials, to defer registration. Researchers may apply to the HRA for permission to defer registration provided there is no legal requirement to register.

It is also a condition of the REC favourable opinion that research tissue banks are registered on a publicly accessible database.

Applicants for research ethics review can register their study before making their application and provide registration details in the application. If they register the study after they receive a final opinion from the REC, they should provide registration details in their next correspondence with the REC.

About the audit

This audit was undertaken in 2021. The purpose of this audit was to determine the number of clinical trials, given a favourable opinion between 1 January 2019 and 30 June 2019, that met the condition to register on a publicly accessibly database. Additionally, it was hoped that this audit would provide reasons for non-compliance. The audit was not designed to increase compliance although it did prompt some researchers to register their studies. Previous audit reports are available on the HRA website.

The audit followed the same methodology as the previous audits in 2019 (looking at studies that received a favourable opinion January – June 2017) and 2020 (looking at studies that received a favourable opinion January – June 2018). The audit consisted of three main steps:

• Step 1: Data collection
• Step 2: Registration search
• Step 3: Follow-up emails to researchers

Step 1: Data collection

To identify studies for the audit, data was extracted from the HRA Assessment Review Portal (HARP). HARP is a database which records and tracks the progress of research applications submitted to the HRA. The following data was extracted from HARP on 11 December 2020:

Studies that received a REC favourable opinion between 1 January 2019 and 30 June 2019 (UK wide) and fell into one of the following categories:

• clinical trial of investigational medicinal product (CTIMP) – limited only to Phase one trials involving healthy volunteers.
• clinical investigation or other study of a medical device
• combined trial of an investigational medicinal product and an investigational medical device
• other clinical trial to study a novel intervention or randomised clinical trial to compare interventions in clinical practice.

The data did not include:

• studies that received an unfavourable or provisional opinion
• all other CTIMPs. We only looked at Phase one CTIMPs because prior to 1 January 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) registered all CTIMPs, with the exception of phase one clinical trials in adults which do not form part of an agreed paediatric investigation plan, onto the EU Clinical Trials Register.

The extract contained basic details about each study as well as any available registration details. Where a registration number was present in HARP, this was recorded on the audit log.

There were 506 studies included in the audit.

Step 2: Registration search

For studies without a registration number in HARP, registration details were searched for online using the Google search engine. Searches took place between 12 January and 22 January 2021 using full title, short title and REC reference.

Where registration details were located, the registration number and registry name were recorded on the audit log as well as updated in HARP.

Where no registration details were located online, the study entry in HARP was further reviewed to look for evidence of a valid registration deferral or evidence that the study was closed early prior to recruitment. The audit log was updated accordingly.

Step 3: Follow-up emails to researchers

Where no registration details could be found for a study and no valid reason for this could be found in HARP records, the Chief Investigator (for Phase one CTIMPs) or sponsor and Chief Investigator (for all other studies) were contacted via email.

All emails were sent out on 26 or 27 January 2021 with response deadlines of 9 or 10 February 2021. A reminder was sent one week after the first email was sent. All responses were recorded on the audit log. Responses received after the deadline were not included in the audit findings.

The email requested that they either provided registration details or a reason why registration had not taken place. Responses were categorised by:

a) registration status:

• registered (despite not being found in steps 1 and 2 of the audit)
• registration in progress (registered but pending registration number)
• registered during the audit (audit email acting as a prompt)
• registered on a database outside of the HRA’s requirements (e.g. not on a WHO or ICJME listed register)
• not registered
• no response

b) reason for non-compliance (if provided):

• did not know about registration requirements
• oversight/forgotten to register
• did not consider the study to be a clinical trial
• commercial sensitivity or intellectual property concerns (but no HRA-agreed deferral in place)
• study closed soon after recruitment

Responses were categorised based on the last correspondence received from the Chief Investigator (CI) or sponsor.

Results

Overview of study categories

There were 506 studies included in the audit, covering all four clinical trial categories. For simplicity, this report uses abbreviations for the four clinical trial study categories, as outlined in table 1 below.

Summary of table 1: The table shows that there were 506 studies included in the audit. Of these, 66 were Phase 1 clinical trial of investigational medicinal products (Phase 1s), 131 were clinical investigations or other studies of a medical device (devices), one was a combined trial of an investigational medicinal product and an investigational medical device (combined) and 308 were other clinical trials to study a novel intervention or randomised clinical trial to compare interventions in clinical practice (other CT).

Overall compliance

In this audit of 506 studies, 445 were confirmed as compliant, giving a compliance rate of 88%. 26 studies (5%) were confirmed as non-compliant. The remaining 35 studies (7%) did not respond to audit emails before the audit closed, it could not be confirmed as to whether these studies were compliant or not.

What does ‘compliant’ mean?

In this report, ‘compliant’ refers to studies that had:

• registered
• registration in progress (i.e. registered but pending registration number)
• not registered because there was a valid registration deferral agreed by HRA in place
• not registered because the study had not started recruitment or was closed before recruitment.

The date of registration (i.e. whether a study was registered within six weeks of recruitment of first participant as per the requirements) was not taken into consideration as this date is not recorded in HARP. It therefore means that some studies that had registered are categorised as ‘compliant’ but may have registered later than six weeks after recruitment of the first participant.

What does ‘non-compliant’ mean?

In this report, ‘non-compliant’ refers to studies that had:

• not started the registration process at the time of the audit (though some of these did go on to register after the audit)
• registered on a database outside of the HRA’s requirements e.g. on a university website

Summary of figure 1: The pie chart shows that of all 506 studies included in the audit, 88% were confirmed as compliant with the registration requirements and 5% were confirmed as non-compliant. The remaining 7% of studies represent those that did not respond to the audit emails and it was unknown whether they are compliant or not at the time of the audit.

Download a csv file for data from figure 1.

Compliance compared to previous years

Compared to the previous two annual audits, the percentage of studies confirmed as compliant has increased each year. This is outlined in Figure 2, which shows that compliance has increased from 81% when looking at studies that received a favourable opinion (FO) between January and June 2017, to 88% when looking at studies that received a favourable opinion between January and June 2019.

Summary of figure 2: The bar chart shows the compliance rate compared to the previous two annual audits. Compliance has increased from 81% in 2019 (2017 studies), to 84% in 2020 (2018 studies), to 88% in 2021 (2019 studies).

Download a csv file for data from figure 2.

Compliance according to study type

Compliance was investigated per study type. The majority of Phase 1s, 94%, were compliant, with only one study confirming non-compliance. For other CTs and devices, compliance was 87%. 18 other CTs (6%) confirmed non-compliance and seven devices (5%) confirmed non-compliance. There was only one combined study in the audit and it was compliant. Compared to the previous annual audit, the increase in compliance rate can mostly be seen in the other CTs and devices categories. Compliance in other CTs has increased from 81% to 87% and for devices, from 82% to 87%.

Summary of figure 3: The bar chart shows that for Phase 1s: 94% were compliant, 2% non-compliant and 5% did not respond to the audit emails. For devices: 87% compliant, 6% non-compliant and 7% did not respond to audit emails. For other CTs: 87% were compliant, 6% non-compliant and 7% did not respond to audit emails. There was only one combined study in the audit, and as it was compliant, this gives a compliance rate of 100%.

Download a csv file for data from figure 3.

Responses to follow-up emails

Following steps 1 and 2 of the audit, registration details or a valid reason for not registering, was found for 358 of the 506 studies. An email was sent to the CI and/or sponsor of the remaining 148 studies. The following results relate to the responses received to these follow-up emails.

Of the 148 emails sent, responses were received for 113, leaving 35 (24%) with no response. Of the 148 emails, around a quarter (26%) confirmed that they had already registered their studies, but the registrations had not been found during the audit search. This is most likely because a different study title was used in the registry compared to the REC application or HARP record.

An additional 20% confirmed that they had either registered during the audit or were in the process of registering their study. A further 19 studies (13%) stated that they had not registered their studies, but as the studies had not started recruitment yet or had closed before recruitment began, they were classed as compliant. Of these 19 responses, 12 stated that the COVID-19 pandemic was the reason for recruitment not starting.

This leaves 26 studies (18% of those emailed) confirming that they had not registered their studies on a publicly accessible register, and therefore confirming non-compliance. Of these that confirmed non-compliance, 10 stated that they would register as soon as possible after the audit.

Although the purpose of the audit was not to enforce compliance, at least 40 studies were registered or going to be registered because of receiving the audit follow-up email, which seemed to act as a prompt to register studies.

Summary of figure 4: The bar chart shows the number of responses to follow-up emails that fall into each registration status category. The graph also shows an additional breakdown for each study type. Of the 148 emails sent, 26% stated that their study was registered despite the registration not being found in the audit search. A further 20% confirmed that they registered or were in the process of registering during the audit. An additional 13% stated that the study never started recruitment, some of these were due to the COVID-19 pandemic. A further 18% confirmed that their study was not registered and the remaining 24 % did not receive a response. Most of the non-responses were within the ‘other CT’ study category, which has the largest number of studies.

Download a csv file for data from figure 4.

Reasons provided for non-compliance

Respondents gave several different reasons as to why registration had not occurred at the time of the audit. Some of these studies went on to register during the audit. Of those who gave a reason for not registering, 32% reported that they had forgotten to register, which is in line with previous audits. Some went on to explain that there had been changes of staff and roles within the research team and that registration had been overlooked during the handover process. Most of these went on to confirm that the email had prompted them to begin the registration process.

A further 30% of respondents said that they did not consider the study to be a clinical trial. Most of these responses were regarding other CTs with one being a device. As per previous audits, common reasons for not considering the studies as clinical trials were because they were student, feasibility or non-interventional studies.

An additional seven responses (19%) stated that they did not know about the registration requirements. Some of these emails specified that it was their first time conducting a clinical trial, they were ‘clinicians’ rather than ‘researchers’, and some thought that the publication of the research summary on the HRA website, or registering on a registry outside of the WHO and ICJME list, was sufficient. There were also comments that the HRA or REC never mentioned registration requirements to them.

Other responses included: not registering due to commercial sensitivity whilst also not knowing about the HRA deferrals policy, and not registering as the study closed shortly after recruitment.

Summary of figure 5: The bar chart shows that the most common reasons for non-compliance were: oversight/forgetting to register at 32%, not considering the study to be a clinical trial at 30% and not knowing about the registration requirements at 27%. Finally, two studies stated that they did not register because the study was terminated shortly after recruitment and two studies did not register due to commercial sensitivity or intellectual property concerns.

Download a csv file for data from figure 5.

Types of registries

As per the previous audits, the results show that clinicaltrials.gov is the most widely used registry with 98% of Phase 1s, 77% of devices and 57% of other CTs registered there. The second most widely used registry was ISRCTN. A small number of studies, four in total, were registered on both clinicaltrials.gov and ISRCTN. Furthermore, a small number of studies were registered on ‘other registry’ such as the EU Clinical Trials Register (EU CTR), Netherlands National Trial Register (NTR) and German Clinical Trials Register (DRKS). Figure 6 shows the registries used by each study category. There was only one combined study included in this audit, which was registered on clinicaltrials.gov.

Summary of figure 5: The bar chart shows that most Phase 1s (98%) were registered on the clinicaltrials.gov registry with the remaining studies on other registry such as EU CTR, NTR or DRKS. For devices, 77% were registered on clinicaltrials.gov and the remaining 23% on ISRCTN. For other CTs, 57% were registered on clinicaltrials.gov, 41% on ISRCTN, 2% on both and the remaining 1 % on other registry. The one combined study included in the audit was registered on clinicaltrials.gov

Download a csv file for data from figure 5.

Observations

Although registration rates continue to increase, this audit shows that there is still not complete compliance with the requirement to register a clinical trial on a publicly accessible database. The main reasons given for non-compliance were not recognising that the study was a clinical trial, not knowing about the registration requirements, or forgetting to register.

Comparisons to 2020 audit (studies that received a favourable opinion January – June 2018)

The findings are very similar to the previous year’s audit, although compliance rate has improved from 84% to 88%. This increase is mainly seen in devices and other CTs, where compliance has increased from 82% and 81% respectively, to 87%.

The main reasons provided for non-compliance remain the same, although 12 studies in this audit stated that COVID-19 had affected their study recruitment, meaning that some studies did not begin recruitment on time and had therefore not yet registered.

The type of registry being used remains the same, with clinicaltrials.gov being the most widely used, particularly by Phase 1s, and ISRCTN being the second most used registry.

Willingness to register

As per the previous audit, most responses to the audit follow-up emails were apologetic and researchers showed eagerness to register as soon as possible or had already registered the study before the audit deadline. The majority of those that responded indicated that they would be willing to pay a registration fee, this had not been a reason for not complying. This audit has been the catalyst for registration and many clinical trials would not have been registered if contact had not been made.

Registration requirements not made clear

Two of the most common reasons for non-compliance were a) not knowing about the requirements, and b) not considering the study a clinical trial. This highlights that the registration requirements are not set out clearly enough for researchers. Some responses stated that the HRA or REC had never ‘mentioned registration’ and that the REC final opinion letters did not make this clear. It is also apparent that it is not clear which study types are ‘clinical trials’ and what additional requirements are involved in clinical trial studies.

Responsibility for registration

One of the other common reasons for non-compliance was an oversight or forgetting to register. Just like the previous audits, some responses went on to explain that there had been changeover in staff and that the task of registration had not been handed over. This highlights that registration is not always well prioritised within research teams and there appears to be a lack of certainty regarding which individual or team is responsible for registration.

Identifying registration entries

Searching for studies using Google proved challenging as study titles are often different in the registry from their IRAS application and HARP. It was noticed that the REC reference number was usually included in the ISRCTN registry, which helped with the search, but was often not included in other registries.

Actions

There remains a clear need to increase awareness amongst researchers of the requirement to register clinical trials. We have begun to clarify our guidance as part of our work to implement our research transparency strategy.

One aspect of the HRA’s transparency strategy is for the HRA to register clinical trials on behalf of the sponsor. Benefits of this will include:

• all clinical trials taking place in the UK are visible to the public
• data can be shared with recruitment services, such as Be Part of Research, so that more people are able to join research studies
• sponsors and researchers will be able to spend more time on keeping study information up to date because they will no longer need to register the study themselves
• the HRA will be able to focus on ensuring reporting at the end of the study because we will no longer need to chase sponsors to register.