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 2018 and 30 June 2018, 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 2017 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 December 2019:

Studies that received a REC favourable opinion between 01 January 2018 and 30 June 2018 (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.

There were 513 studies included in the initial data collection, but one study was mistakenly not included in the audit, so due to this oversight, 512 studies were included in the audit.

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 15 January and 20 January 2020 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 or 05 February 2020 with response deadlines of 18 or 19 February 2020. 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 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.

Results

Overall compliance

The results show that the overall rate of compliance for the 512 studies involved in this audit was 84%.

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)

Summary of figure 1: The pie chart shows that of all 512 studies included in the audit, 84% were confirmed compliant with the registration requirements, 10% were confirmed non-compliant with the requirements and 5 %did not respond to the audit emails. These findings are similar to the previous audit report that looked at 2017 data.

Download a csv file for data from figure 1.

Compliance according to study type

Compliance was also analysed per study type. For simplicity, this report uses abbreviations for the four clinical trial study types as follows:

• ‘Phase 1’: CTIMPs limited to Phase 1 trials involving healthy volunteers
• ‘Devices’: Clinical investigation or other study of a medical device
• ‘Combined’: Combined trial of an investigational medicinal product and an investigational medical device
• ‘Other’: Other clinical trial to study a novel intervention or randomised clinical trial to compare interventions in clinical practice

Looking at compliance rate according to clinical trial study category, the results show that almost all the phase 1 studies 1 (97%) were compliant with registration.

Summary of figure 2: The bar chart shows that for phase 1 studies, 97% were compliant, 1% non-compliant and 1% did not respond to the audit emails. For device studies, 82% compliant, 12% non-compliant and 7% did not respond to audit emails. For other studies, 81% were compliant, 11% non-compliant and 8% did not respond to audit emails. None of the 512 studies included in the audit were combined trials.

Download a csv file for data from figure 2.

Responses to follow-up emails

Following steps 1 and 2 of the audit, there were 154 studies where registration details could not be located either in HARP records or following an online search. The following results relate to the responses received to follow-up emails that were sent to these 154 studies (email sent to CI and/or Sponsor). The results show that 12% of respondents confirmed that the study was not registered but that they intended to register the study after the audit, an additional 16% of respondents did not confirm if they would register their study and another 16% reported that they had already registered the study before the audit although the registration details had not been found during the online search. This is most likely because a different study title was used in the registry compared to the REC application or HARP record.

Although the purpose of the audit was not to enforce compliance, at least 30 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 3: 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 154 emails sent, 16% stated that their study was registered despite the registration not being found in the audit search. A further 16% confirmed that their study was not registered but did not confirm whether they intended to register whereas 24% stated that they intended to register their study after the audit or were in the process of registering at the time of the audit. Of the 154 emails sent, 21% (33 emails) did not receive a response. Most of the non-responses were within the ‘other’ study category.

Download a csv file for data from figure 3.

Reasons given for non-compliance

Those respondents who reported that the clinical trial had not been registered gave several different reasons for non-compliance. Of those who gave a reason for not registering, 32% reported that they had forgotten to register, some explained 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 total of 56% of respondents said that they did not consider the study to be a clinical trial. Most of these responses were regarding ‘other’ types of clinical trials. Common reasons for not considering the studies as clinical trials were because the they were student, feasibility or non-interventional studies.

Of the 23 responses that stated that they did not consider the study to be a clinical trial, 6 responses went on to explain that in hindsight the wrong study category had been selected in their IRAS application form and 2 responses referred to the favourable opinion letter not being clear about the registration requirements.

Summary of figure 4: The bar chart shows that the most common reason for non-compliance (56%) was that researchers did not consider the study to be a clinical trial. This is closely followed by 32% forgetting to register, 7% stating that they did not know about the registration requirements and 5 % stating that technical issues with registry websites had prevented them from registering.

Download a csv file for data from figure 4.

Types of registries

As per the previous audits, the results show that clinicaltrials.gov and ISRCTN were the two main registries used.

Summary of figure 5: The bar chart shows that most Phase 1 studies (98%) were registered on the clinicaltrials.gov registry. For device studies, 79% were registered on clinicaltrials.gov, 17% on ISRCTN and 3% on other registries. For other clinical trials, 54 % were registered on clinicaltrials.gov, 44% on ISRCTN and 2% on other registries. Some ‘other’ clinical trials confirmed that they were registered on multiple registries. These findings are very similar to the findings of the previous audit.

‘Other’ registries’ include German Clinical Trials Registry (DRKS) and Research Registry.

Download a csv file for data from figure 5.

Observations

The results of this audit show that there is not full 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 or forgetting to register.

Comparisons to 2017 data

The findings are very similar to the previous year’s audit, showing that the compliance rate has slightly improved from 81% to 84%. This increase is mainly seen in the ‘Other’ clinical trials studies, where compliance has increased from 77% to 81%. The compliance rate in Phase 1 studies and Device studies remained the same. The reasons provided for non-compliance and the types of registries being used have not changed from the previous year’s audit findings.

Willingness to register

Of the 512 studies involved in the audit, 88% were either compliant with the requirement to register or had made plans to become compliant. Of the remaining 12%; 6% did not confirm whether they would register their study and 6% did not respond to the audit emails.

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 audit has been the catalyst for registration and many clinical trials would not have been registered if contact had not been made.

Registry type

As per the previous year’s audit findings, this audit showed that some Sponsors and Chief Investigators were aware that they needed to register but were not aware of which registries to use.

Definition of a clinical trial

The most common reason for non-compliance was because the Chief Investigator or Sponsor did not consider the study to be a clinical trial, even though a clinical trial category had been selected in IRAS and the REC final opinion letter included wording that stated that the study was a clinical trial requiring registration. Some responses stated that this information had not been clear in the REC final opinion letter. Some responses acknowledged that in hindsight they should have selected a different study category type in their IRAS application form.

Responsibility for registration

The second most common reason for non-compliance was oversight or forgetting to register. Just like the previous audit looking at 2017 data, 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 may again highlight that registration is not prioritised well 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 in 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 Sponsors and Chief Investigators of the requirement to register clinical trials. We will clarify our guidance and introduce new learning 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.

Post publication changes:

Version 1 published 15 February 2021

Version 1.2 published 01 March 2021: typographical corrections made to labels on figure 5

Version 1.3 published 18 March 2021: typographical corrections made to labels on figure 4 and figure 5.