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:

To avoid waste, information about research projects (other than those for educational purposes) is made publicly available before they start, unless a deferral is agreed by or on behalf of the Research Ethics Committee (REC).

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 and 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 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.

The purpose of this audit was to determine the number of clinical trials, given a favourable opinion between 1 January 2021 and 30 June 2021, 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 implementation of the HRA’s 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 a similar methodology to the previous year’s audit of 2020 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 24 March 2023:

Studies that received a REC favourable opinion between 01 January 2021 and 30 June 2021 (UK wide) and fell into one of the following categories:

• clinical trial of investigational medicinal product (CTIMP)
• clinical investigation or other study of a medical device
• combined trial of an investigational medicinal product and an investigational medical device
• other clinical trials to study novel interventions or randomised clinical trials to compare interventions in clinical practice.

Previously, 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.

Since January 2021 the MHRA no longer has access to the EU Clinical Trials Register or its replacement, the Clinical Trials Information System.

In December 2020, MHRA and HRA published guidance to trial sponsors stating that they should use existing and established international registers such as the ISRCTN registry, or ClinicalTrials.gov, to ensure the public is aware of their trial.

For the purposes of the 2023 audit, HRA categorised studies registered on the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) before 2021 as compliant.

Studies with a EudraCT 2021 pre-fix number i.e. those studies which entered the database system after 31 December 2020 were contacted via email to check registration compliance.

The data did not include studies that received an unfavourable or provisional opinion.

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 27 March – 31 March 2023 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 04 - 07 April 2023 with response deadlines of 24 – 27 April 2023.

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.

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

Overview of study categories

There were 754 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 754 studies included in the audit, 59 were phase 1 clinical trial of investigational medicinal products (Phase 1s), 148 were clinical investigations or other studies of a medical device (Devices), 543 were other clinical trials to study a novel intervention or randomised clinical trial to compare interventions in clinical practice (Other CT) and 4 were a combined trial of an investigational medicinal product and an investigational medical device (Combined).

Overall compliance

In this audit of 754 studies, 687 were confirmed as compliant, giving a compliance rate of 91%.

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

The 43 remaining studies (6%) 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 754 studies included in the audit, 91% were confirmed as compliant with the registration requirements and 3% were confirmed as non-compliant.

The remaining 6% 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.

Five 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 increased.

*Please note: the number of studies analysed in the 2023 audit is considerably higher than those looked at in the 2022 audit (438). For the purposes of the 2023 audit, the HRA categorised studies entered on the EudraCT database before 2021 as compliant. This includes 88 studies (3 Combined, 85 Other CTs). Eleven studies with a EudraCT 2021 pre-fix number were contacted via email to check registration compliance. Five Other CTs were contacted regarding compliance but there was no response.

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 2021.

Summary of Figure 2:

The bar chart shows the compliance rate compared to the previous two annual audits. Compliance decreased from 88% in 2021 (for 2019 studies), to 86% in 2022 (for 2020 studies) and increased by 5% in 2023 (for 2021 studies).

Download a csv file for data from Figure 2.

Compliance according to study type

Compliance was investigated per study type:

Combined

Of the 4 combined studies included in the audit, 3 (75%) were compliant. One study (25%) was non-compliant.

Device

Of the 148 Device studies included in the audit, 128 were compliant (86%). Four studies (3%) were non-compliant. For 16 studies (11%), the Sponsor did not respond to email correspondence, therefore, compliance could not be determined.

Other CTs

Of the 543 Other CTs included in the audit, 499 were compliant (92%). Nineteen studies (3%) were non-compliant. For 25 studies, (5%) the Sponsor did not respond to email correspondence, therefore, compliance could not be determined.

Phase 1

Of the 59 Phase 1 studies included in the audit 57 were compliant (97%) including 5 deferral agreements. For 2 studies (3%) the Sponsor did not respond to email correspondence, therefore, compliance could not be determined.

Summary of Figure 3:

The bar chart shows that for combined studies 75% were compliant and 25% were non-compliant. For device studies, 86% compliant, 3% non-compliant and 11% did not respond to audit emails. For Other CT studies, 92% were compliant, 3% non-compliant and 5% did not respond to audit emails. For phase 1 studies, 97% were compliant, 0% non-compliant and 3% did not respond to the 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 165 studies.

Of the 165 emails sent, responses were received for 122 studies, leaving 43 studies with no response (16 Device, 2 Phase 1, 25 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 the HRA at the appropriate time.

Two Other studies were registered on a database outside of HRA's requirements and therefore considered non-compliant.

There was a significant number of studies (67) where the sponsor had failed to inform the HRA of the registration number (13 of Device, 52 for Other CTs, 2 Phase 1).

Seven studies never commenced after REC favourable opinion was given (5 Other CTs, 2 Device).

Six studies were terminated after REC favourable opinion was received and recruitment was never commenced (2 Device, 3 Other CTs, 1 Phase 1).

Thirteen studies (4 Devices, 9 Other CTs) confirmed there had been an oversight, and a failure to register at the correct time, registration is now in progress for all 13 studies and therefore considered compliant (registered but pending registration number).

Reasons given for non-compliance

Twenty four studies in the audit (3%) were confirmed as non-compliant.

For 16 studies (1 Combined study, 4 Device studies and 11 Other CTs), the sponsor stated that they did not consider the study to be a clinical trial, and/or was miscategorised at the point of submission as a clinical trial and are therefore considered non-compliant.

Five Other CTs were registered on the European Union Drug Regulating Authorities Clinical Trials Database with a 2021 pre-fix EudraCT number and did not respond to HRA correspondence asking if they study was registered elsewhere and therefore considered non-compliant.

Two Other CTs were registered on a database outside of the HRA’s requirements and therefore considered non-compliant.

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 such as the European Union Drug Regulating Authorities Clinical Trials Database only post 2021.

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 431 studies registered.

The second most widely used registry was ISRCTN with 136 studies registered.

Several studies, 4 in total, were registered on both ClinicalTrials.gov and ISRCTN, a slight decrease from the previous audit (6).

One Other CT study was registered on the Australia and New Zealand Clinical Trials Register.

One Phase 1 study was registered on the Netherlands Trial Register.

Summary of Figure 5:

The bar chart shows that most Phase 1s, 49 of 59 were registered on the ClinicalTrials.gov registry. Two with ISRCTN.

For Devices, 103 of 148 were registered on ClinicalTrials.gov.gov with a further 16 studies registered on ISRCTN.

For Other CTs, 279 of 543 were registered on ClinicalTrials.gov with a further 118 registered on ISRCTN. With 4 Other CT registered on both.

One Other CT’s studies registered with the Australia and New Zealand Clinical Trials Registry. One Phase 1 study was registered with Netherlands National Trial Register (NTR).

All 3 Combined studies analysed had a EudraCT registration number that predates 2021.

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 2022 audit (studies that received a favourable opinion January – June 2020)

The main reasons provided for non-compliance remain the same. There is also a significant number of sponsors (43 studies) that continue not to respond to HRA correspondence.

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, many 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.

Registration requirements not made clear

A common reason for non-compliance continues to be not considering the study a clinical trial. This highlights that the registration requirements are not set out clearly enough for researchers. It is apparent that it is not clear which study types are ‘clinical trials’ and what additional requirements are involved in clinical trial studies. It is also apparent that it is not clear that HRA should be notified of registration compliance.

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.

The HRA has begun to clarify 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 the HRA that they have or will register on ClinicalTrials.gov then the study will not be registered on ISRCTN through the HRA. 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

Previous clinical trials registration audits only reported Phase 1 CTIMPs.[1] To be able to compare this audit data with previous years, it was necessary to therefore also audit the dataset with CTIMPs removed.

In the audit of 405 clinical trials excluding CTIMPs that are not phase 1 CTIMPs, 345 studies were confirmed as compliant, giving a compliance rate of 85%.

19 studies (5%) were confirmed as non-compliant.

41 studies (10%) did not respond to audit emails before the audit closed, as such, it could not be confirmed if these studies were compliant or not.

[1] See Step 1: Data collection: prior to 01 January 2021, the MHRA registered all CTIMPs (except Phase 1 clinical trials in adults which do not form part of an agreed paediatric investigation plan) onto the EU Clinical Trials Register.

Figure 6: Pie chart showing the percentage of non-CTIMP studies that were confirmed compliant with the registration requirements

The percentage of compliant studies in 2021 was 85%, compared to 86% (2020), 88% (2019) and 84% (2018). Overall this figure is stable.

The percentage of non-compliant studies in 2021 was 5%, compared to 3% (2020), 5% (2019) and 10% (2018). Overall this figure has halved since 2018 and remained fairly stable, give or take 1-2%.

The percentage of no responses in 2021 was 10%, compared to 11% (2020), 7% (2019) and 6% (2018). Overall this figure has increased since 2018.

Download a csv file for data from Figure 6

Figure 7: Line chart showing trends in compliance, non-compliance, and no responses over the four years between 2018 and 2021