Clinical Trial Registration Audit Report

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 with their next correspondence with the REC.

About the audit

The purpose of this audit was to determine the number of clinical trials given a favourable opinion between 1 January 2020 and 30 June 2020, that met the condition to register on a publicly accessibly database. Additionally, it was hoped that this audit would provide reasons for non-compliance, and therefore highlight any areas that could be considered during the implement our research transparency strategy. It 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 year’s audit of 2019 data.

There were 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 January 2022:

Studies that received a REC favourable opinion between 1 January 2020 and 30 June 2020 (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 01 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.

Step 2: Registration search

For studies without a registration number in HARP, registration details were searched for online using the search engine ‘Google’.

Searches took place between 12 January and 22 January 2022 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 22 to 27 January 2022 with response deadlines of 8 to 11 February 2022.

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 audit steps 1 and 2)
• 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
• not registered but intend to register (audit acting as a prompt)
• not registered and no confirmation whether registration is intended
• no response

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

• did not know about requirement to register
• forgot to register/oversight
• did not consider study to be a clinical trial
• technical issue with registry website

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

Overview of study categories

There were 438 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:

Of the 438 studies included in the audit, 57 (including one combined trial of an investigational medicinal product and an investigational medical device) were phase 1 clinical trial of investigational medicinal products (Phase 1s), 126 were clinical investigations or other studies of a medical device (Devices), and 255 were other clinical trials to study a novel intervention or randomised clinical trial to compare interventions in clinical practice (Other CT).

*Please note, one study was recorded on HARP as both an ‘Other CT’ and ‘Device’ study incorrectly. For the purposes of this audit, the study was classified as a Device.

Overall compliance

In this audit of 438 studies, 375 were confirmed as compliant, giving a compliance rate of 86%.

Thirteen studies (3%) were confirmed as non-compliant.

The 50 remaining studies (11%) did not respond to audit emails before the audit closed, as such, it could not be confirmed if these studies were compliant or not.

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

• registered
• registration in progress (registered but pending registration number)
• a valid registration deferral in place
• not registered because the study had not started 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.

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)

Figure 1 pie chart showing the percentage of studies that were confirmed compliant with the registration requirements.

Summary of figure 1:

The pie chart shows that of all 438 studies included in the audit, 86% were confirmed as compliant with the registration requirements and 3% were confirmed as non-compliant.

The remaining 11% of studies represent those that did not respond to the audit emails; it was unknown whether they are compliant or not at the time of the audit.

Fourteen studies had a deferral agreement in place with HRA and therefore were considered compliant.

Download a csv file for data from figure 1.

Compared to the previous two annual audits, the percentage of studies confirmed as compliant has decreased.

This is outlined in Figure 2, which shows that compliance has decreased when looking at studies that received a favourable opinion (FO) between January and June 2019.

Summary of figure 2:

The bar chart shows the compliance rate compared to the previous two annual audits. Compliance increased from 84% in 2020 (for 2018 studies), to 88% in 2021 (for 2019 studies), and decreased by 2% in 2022 (for 2020 studies).

Download a csv file for data from figure 2.

Compliance according to study type

Compliance was investigated per study type:

Phase 1

Of the 57 Phase 1 studies included in the audit (including one combined study) 53 were compliant (93%). For four studies (7%) the Sponsor did not respond to email correspondence, therefore, compliance could not be determined.

Device

For Device studies included in the audit, 106 of 126 were compliant (84%). For 16 studies (13%), the Sponsor did not respond to email correspondence, therefore, compliance could not be determined. Four studies (3%) were non-compliant.

Other CTs

For the 255 Other CTs included in the audit, 216 were compliant (85%). For 30 studies (12%), the Sponsor did not respond to email correspondence, therefore, compliance could not be determined. Nine studies (3%) were non-compliant.

Summary of figure 3:

The bar chart shows that for phase 1 studies, 93% were compliant, 0% non-compliant and 7% did not respond to the audit emails. For device studies, 84% compliant, 3% non-compliant and 13% did not respond to audit emails. For Other CT studies, 85% were compliant, 3% non-compliant and 12% did not respond to audit emails.

Download a csv file for data from figure 3.

Responses to follow-up emails

Following steps 1 and 2 of the audit, where registration details could not be located either in HARP records or following an online search, an email to determine compliance was sent to the Chief Investigator and/or Sponsor for 188 studies.

Of the 188 emails sent, responses were received for 138 studies, leaving 50 studies with no response (16 Device, four Phase 1, 30 Other CTs).

The following results relate to the responses received to these follow-up emails.

Please note, not all responders gave a reason, as such, some studies became compliant without an explanation given for not registering the study or informing HRA at the appropriate time.

Registration was in progress (pending registration number) with the audit acting as a prompt for 16 studies (three Device, two Phase 1, 11 Other CTs).

Five studies were registered on another Registry (one Phase 1, four Other CT).

One Device study was registered on a database outside of HRA's requirements and therefore considered non-compliant. Several studies (98 in total) were registered, despite not being found in steps 1 and 2 of the audit: (22 Device, 24 Phase 1, 48 Other CTs).

Some studies (29) were not registered because the study had not started recruitment or was closed before recruitment (eight Device, one Phase 1, 20 Other CTs). With 16 studies terminated or postponed due to the COVID-19 pandemic (11 Other CTs and five Device studies).

There was a significant number of studies (71) where the sponsor had failed to inform HRA of the registration number (six Phase 1, 48 for Other CTs, 17 of Device studies).

Nine studies never commenced after REC favourable opinion (seven Other CTs, one Phase 1, one Device).

One Device study was withdrawn from HARP.

Reasons given for non-compliance

For two Other CTs, there was an oversight of the registration process which led to failure to register a study on a publicly accessible register within the appropriate timeframe.

One Device study has registered on a database outside of HRA requirements (for example, not on a WHO or ICJME listed register).

Two Other CT studies were not registered and therefore considered non-compliant.

Ten sponsors did not consider their study to be a clinical trial, with the incorrect category selected at point of submission (seven for Other CTs and three of Device studies). For the purposes of this audit, these studies are considered non-compliant as registration was expected due to the initial study categorisation selection.

Sponsors for 50 studies did not respond to emails (16 Device, four Phase 1, 30 Other CTs).

Summary of figure 4:

The bar chart shows that the most common reason for non-compliance was that researchers did not consider the study to be a clinical trial. This is closely followed by an oversight of the registration process and registering on a publicly accessible register outside of HRA requirements.

Download a csv file for data from figure 4.

Types of registries

As per the previous audits, the results show that ClinicalTrials.gov is the most widely used registry with a total of 200 studies registered.

The second most widely used registry was ISRCTN with 99 studies.

Several studies, six in total, were registered on both ClinicalTrials.gov and ISRCTN, a slight increase from the previous audit (four).

Summary of figure 5:

The bar chart shows that most Phase 1s, 34 of 57 were registered on the ClinicalTrials.gov registry. Three with ISRCTN.

For Devices, 70 of 126 were registered on ClinicalTrials.gov with a further 18 studies registered on ISRCTN. With three Device studies registered on both.

For Other CTs, 96 of 255 were registered on ClinicalTrials.gov with a further 78 registered on ISRCTN. With three Other CT registered on both.

Two Other CT’s studies registered with the Australia and New Zealand Clinical Trials Registry, One Other CT with Netherlands National Trial Register (NTR) and one Device study with German Clinical Trials Register (DRKS).

Download a csv file for data from figure 5.

This audit shows that there is still not complete compliance with the requirement to register a clinical trial on a publicly accessible database.

Comparisons to 2021 audit (studies that received a favourable opinion January to June 2019)

The main reasons provided for non-compliance remain the same, although 16 studies in this audit specifically stated that COVID-19 had affected 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. Other registries used included: Netherlands Trial Register, DRKS, ANZCTR and JapicCTI.

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. This audit, as seen in previous years, has been the catalyst for registration and many clinical trials would not have been registered if contact had not been made.

Studies miscategorised as clinical trials

A common reason for non-compliance continues to be applicants miscategorising the study as clinical trials. When we chase the study about registration, it becomes apparent that the study is not a clinical trial and therefore registration is not required. The HRA does not re-categorise the study, so it gets recorded as non-compliant when the study hasn’t been registered. In the future, we intend to highlight how many studies classed as non-compliant for this audit fall under this category.

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.

There remains a clear need to increase awareness amongst researchers of the requirement to register clinical trials.

HRA has clarified its guidance as part of its work to implement the Make it Public research transparency strategy. One aspect of the HRA’s transparency strategy commitment which, as of 1 January 2022 is now in operation, is for the HRA to register clinical trials of medicine and combined trials of medicine and device on ISRCTN on behalf of the Sponsor. If a Sponsor informs HRA that they have or will register on ClinicalTrials.gov then the study will not be automatically registered on ISRCTN. Both ClinicalTrials.gov and ISRCTN registry feed in to Be Part of Research if UK locations are included, bringing us closer to having a full record of all UK clinical trials in one single place.

Benefits of this 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 can 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