The aim of the Medicines and Healthcare products Regulatory Agency MHRA and Research Ethics Service (RES) combined ways of working pilot is to test a single application submission route which will incorporate both the RES and MHRA Clinical Trial Authorisation (CTA) application submission.
Below are our answers to questions received from clinical trial sponsors and Contract Research Organisations (CROs) to help you prepare for, and submit applications into, the pilot.
These FAQs will be updated on an ongoing basis.
Scope of the pilot
1. First in the UK trials.
First in the UK trials (where the compound is being used in a trial for the first time in the UK) are now included in the pilot. Applicants should confirm at the point of reservation if the trial is the first in the UK so that the MHRA multi-disciplinary team can be made aware pre-submission. If you are unsure whether a trial is using a compound for the first time in the UK then you should ask the sponsor.
2. Is there an end date for submissions into the pilot?
No, the initial phase of the pilot is inviting applications from sponsors and CROs who have expressed an interest in being involved. However, the aim of the pilot is to develop the process for combined ways of working between the MHRA and the REC as we believe that this approach is beneficial, regardless of the future regulatory landscape. The expectation therefore is that the pilot phase will prepare for a future combined way of working between the MHRA and the REC.
Once we have received sufficient applications to effectively test the process and develop our communications and guidance then the pilot will move to the next stage which will accept applications from all Sponsors and CROs.
3. Will the combined ways of working pilot adhere to the expedited timelines which are currently applied by the MHRA to Phase 1 trials?
The MHRA currently aims to undertake the initial review of phase 1 applications within a maximum of 21 days (and 14 days on average). The expectation is that the timeline of 21 days for the initial review will be achievable under the combined ways of working pilot. The aim will be for the MHRA and REC reviews to be undertaken and an initial outcome, whether confirming approval or a request for further information, to be issued within a maximum of 21 days.
However, to achieve this timeframe it will be necessary for Sponsors and CROs to submit their application on a pre-agreed date to a pre-agreed REC and the application must be valid on receipt. Where this will not be possible, and should an application not be valid on receipt, then the 21 day timeline cannot be guaranteed and it may be necessary to transfer the application to the next suitable and available REC.
These conditions are necessary because the process of allocating applications to a REC and also REC review are different to the process which the MHRA follow for the CTA application assessment. To align the timelines for these processes to be combined means that some flexibility which currently exists in the REC application process may not be possible.
Choosing a REC
4. Can we choose the REC which we submit to?
Not all RECs will be involved with the early phase of the pilot and therefore it may not be possible to submit to the REC which you usually submit to (the number of RECs involved will increase as the pilot develops). The RECs involved will be listed in a separate document, along with the submission periods for each REC. It would be possible to choose a REC which is involved in the pilot as long as the application is received within the submission period for that REC. If the application cannot be submitted within the submission period for your chosen REC then it will be allocated to the next suitable and available REC meeting.
If an application is submitted without agreeing a REC and submission period in advance, then the application can only be allocated to a REC which corresponds to the period in which the application has been submitted. This may involve minimal choice of RECs or possibly just one REC which the application will be allocated to.
This approach is necessary because the process of allocating applications to a REC and undertaking REC review are different to the process which the MHRA follow for the CTA assessment. To align the timelines for these processes to be combined means that some flexibility which currently exists in the REC application process may not be possible. For example, currently a specific REC can be chosen when booking an application because if the first available REC meeting is not selected by the applicant, the 60 day clock does not commence until the cut off date for that meeting (14 days before the meeting).
Under the combined ways of working process, the clock must always commence on receipt of a valid application as there will need to be one clock for one submission. Therefore, to achieve the 60 day timeline, applications can only be allocated to a REC which corresponds with the submission period when the application is submitted.
What to submit
5. Is there guidance which sets out what should be submitted as part of the application dossier for the pilot?
Yes, we have developed a comprehensive document which provides the full details of what is expected which is available in a separate document (Application Dossier Guidance).
6. What are the costs for submission?
There is no change to the current procedure; namely that MHRA charges will apply as now.
7. What needs to be submitted in relation to compliance with data protection legislation?
The expectation is that details of how data protection legislation and data standards (for NHS-based trials) are being met will be clearly described in the protocol. However, the sponsor should also submit a statement that data will be collected and processed in accordance with the General Data Protection Regulation. This may be a separate document or may be included in either the covering letter or the protocol.
8. How will applications involving Administration of Radioactive Substances Advisory Committee (ARSAC) be handled?
One of the reasons IRAS form is also required at this stage is to cover elements, such as ARSAC review, which would otherwise not be picked up. For the moment, the process for ARSAC review will remain as at present.
HRA (England) / HCRW (Wales) Approval (NHS only)
9. How will HRA / HCRW assessment be incorporated into the pilot? (NHS only)
HRA / HCRW assessment will be undertaken for trials involved in the pilot in the same way as other trials and research in the NHS. During the initial phase of the pilot you will also be expected to submit the IRAS form which will ensure that all of the information which is needed for HRA / HCRW assessment will be received and can therefore be assessed. As the pilot develops, consideration will be given to what information needs to be submitted for this purpose and what is the most efficient way to do this.
The HRA / HCRW assessment will be undertaken in parallel with the MHRA and REC reviews with the aim of having combined communications and a single approval which means that a trial can commence. However, issuing HRA / HCRW Approval along with the MHRA and REC decisions will be reliant on other regulatory approvals being in place (please refer to question 11 below)
10. Will we continue to receive an initial assessment letter? (NHS only)
Yes, an initial assessment letter will continue to be issued (where this can be issued prior to the HRA / HCRW Approval letter being issued, otherwise it will just be the Approval letter). We endeavour to issue the initial assessment letter as expeditiously as possible but this is often dependent on the quality of the application which is submitted.
Where the initial assessment letter cannot be issued until further information or points of clarification have been received, this will not impact on the progress of the application in the pilot process.
11. Will contract negotiations still begin at receipt of a HRA / HCRW initial assessment letter? (NHS Only)
As now, joint assessment of capacity and capability by applicant and participating organisation transitions to joint arrangement of capacity and capability once the local information pack is shared with the participating organisation. As the Initial Assessment Letter comprises part of the local information pack, the earliest the pack can be shared is the date that the letter is issued.
This is not to say that early conversations between sponsor and participating organisation as to budget and contract cannot commence during the assess stage but we appreciate that in most cases final contract negotiation is indeed part of the arrange phase.
12. Will we still be expecting a separate HRA / HCRW Approval? (NHS Only)
The HRA / HCRW approval is the final approval for research being conducted in the NHS to confirm that your study may start in England and Wales. It is however broader in scope than what is being reviewed under the Combined Ways of Working Pilot. What this means is that there may be approvals, for example, ARSAC and the Confidentiality Advisory Group (CAG), which are still outstanding after the MHRA, REC and HRA assessment have completed their approvals process.
As there are statutory timelines within which the MHRA and the REC are expected to issue their final decisions (60 days), where additional approvals cannot be provided within the 60 days, it would be necessary to issue the MHRA and REC decisions. This would be followed up with a HRA Approval once the other approvals have been confirmed as in place and the trial will then be able to start in the NHS.
13. Will the costings template still require validation prior to the submission? And if so, I assume that this pilot will have no impact on the NIHR CRN portfolio applications/CPMS? (NHS only)
Where the study is intended to be on the NIHR CRN portfolio it should, as now, be validated by the lead LCRN prior to submission for HRA / HCRW Approval. Where the study is not intended for the NIHR CRN portfolio, validation of the costing templates takes place within the HRA subsequent to submission. Portfolio inclusion applications/CPMS are unaffected by the pilot.
14. Will the roll out of the Radiation Assurance review, which has been rolled out to all oncology studies, impact the pilot?
The ‘Radiation Assurance’ is not currently mandatory but is strongly advised; as it means that the radiation element of the study will not usually need to be considered again when the application is going through the review and site set up process. The benefits of going through the ‘Radiation Assurance’ process will continue to apply for applications which are submitted via the pilot.
The process of requesting a ‘Radiation Assurance’ requires an application to be made to the HRA (further information on the application process can be found here on the Applying for Radiation Assurance page of the HRA website) before the application is submitted to the REC.
Therefore for the purposes of the pilot, this would still need to be done in advance of the combined submission. If you have a radiation expert with whom you currently work to assess the radiation elements of your trials then this is fine as long as they are registered with the HRA. Registration is easy and free to do. Sponsors can request up to three NHS Trust reviewers with whom they have a vendor agreement.
Requests for further information/issuing a decision
15. In assessing applications and requesting further information, how will comments be delivered?
Requests for further information will be issued in the current format to ensure that the process is compliant with current legislation. Where further information or action is required before confirming a final decision, you will receive a ‘grounds for non-acceptance’ letter from the MHRA and also a ‘provisional opinion’ letter from the REC. These two letters will however be issued together as attachments to the same email.
With regards to the GNA letter, this will have been produced in liaison with the REC so elements of the review covered in the GNA letter will not be duplicated in the REC letter. In England and Wales, requests for further information which relate to the HRA / HCRW assessment will also be included where possible so that there is a single, coordinated communication.