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Investigational medicinal products, trial sponsors, and registration all impacted by UK exit.
Following the United Kingdom’s exit from the European Union on Jan. 31, 2020, revisions were applied to the regulations concerning clinical trials, and which have ramifications for sponsors of clinical trials run in the UK. The following article aims to address key aspects around the importation of investigational medicinal products to the UK, sponsors of clinical trials, registration of a clinical trial in a publicly accessible database and requests for authorization of a clinical trial.
Per regulation 3 of The Medicines for Human Use (Clinical Trials) Regulations 20041 as amended by The Medicines for Human Use (Clinical Trials) (Amendment)(EU Exit) Regulations 20192, a sponsor of a clinical trial is defined as the person who takes responsibility for the initiation, management and financing (or arranging the financing) of that trial. A sponsor of a clinical trial must further be established in the United Kingdom or a country that is included in an approved country list5 or have a legal representative who is so established. Those countries on the current approved list are summarized below. The regulation permits for co-sponsorship of a given clinical trial if two or more persons take responsibility for a given trial.
For sponsor organizations that are not established entities in the UK or in a country listed in Table 1 there shall remain the requirement to appoint a legal representative to serve on their behalf. It is however not implicit that a legal representative need be established in the UK if the nominated individual/entity is established in one of the approved countries.
On Oct. 21, 2021 the MHRA announced that the pilot Combined Ways of Working (CWoW) review service, in operation since March 2018, will become the new standard approach for seeking clinical trial authorizations in the UK from Jan. 1, 2022. With its announcement the name of the process has been revised to “Combined Review” and will apply to both investigational medicinal products and medical devices.
Through the Combined Review service applicants for clinical trial approval will have a single application route and coordinated review by MHRA, HRA and REC leading to a single opinion for a UK trial. Applications are managed electronically via the Integrated Research Application System (IRAS), for which sponsor organizations should register.
Timelines for review under the combined review service are consistent with those as stipulated in regulations 15, 18, 19 and 20 of The Medicines for Human Use (Clinical Trials) Regulations 20041 as amended by The Medicines for Human Use (Clinical Trials) (Amendment)(EU Exit) Regulations 2019.2 As such an opinion can be expected in 60 days from the date of valid receipt of an application in the case of general medicinal products or medicinal products with special characteristics, or 90 days in the case of gene therapy, somatic cell therapy (including xenogenic cell therapy) or products containing genetically modified organisms. In the case of medical device investigations the timeline for review will be 60 days from the date of valid receipt of an application. In all cases an initial assessment can be expected within 30 days of a submission being validated with a deadline for responses to any grounds for non-acceptance expected within 14 days (30 days in the case of gene/cell therapy or GMO products).
Although the combined review service will be mandatory from Jan. 1, 2022 it is noteworthy that both MHRA and HRA recommend that any sponsors wishing to seek approval for a clinical trial prior to the formal implementation date should do so through the combined review service.
From the changes implemented to regulation 36 of The Medicines for Human Use (Clinical Trials) Regulations 20041 by The Medicines for Human Use (Clinical Trials) (Amendment)(EU Exit) Regulations 20192 it is a requirement of sponsors of clinical trials being conducted that a UK Manufacturing and Import Authorization (MIA(IMP)) holder, with an appropriate qualified person, be employed to implement an assurance system that verifies that investigational product batches are appropriately certified before these are distributed to sites for use in a given clinical trial. Sponsor organizations who are holders of a UK MIA(IMP) may perform the verification process themselves assuming that the MIA(IMP) held appropriately covers the required activities. Alternatively, this responsibility can be outsourced to a third party who is a UK MIA(IMP) holder. In the case of the latter, it will be important to ensure that written agreements describing the assigned responsibilities and provision of relevant information between sponsor and the third party(ies) are in place. This requirement will formally apply from Jan. 1, 2022.
It should, however, be noted that there is no expectation that a UK QP recertifies IMP that has already been batch released in an approved country. For any IMP that is being shipped directly to the UK from a non-approved country for import will require QP certification in the UK by a MIA(IMP) holder. In the case of comparator products that are imported from outside the UK and subject to a marketing authorization granted by a country on the approved country for import list or Northern Ireland, no recertification will be required by a UK QP however there must be evidence to demonstrate that the comparator product has been appropriately QP certified in a country on the approved list. Those countries on the current approved list are summarized below.
The MHRA foresees two routes for IMPs to be imported for use in UK clinical trials when coming from a country on the approved list, namely direct to site or alternatively via a storage and distribution hub in the UK. In both cases the oversight of a UK MIA(IMP) folder and QP is required and must ensure the following:
In the case of non-investigational medicinal products importation from a listed approved country should be performed under a wholesale dealer’s license (WDA(H)) and overseen by a Responsible Person (import) (RPi).4 Responsibilities of the RPi include implementing a system to confirm that required QP certification has taken place and/or that the required independent batch release certificate for biological products is available. This approach would also apply in the case of unmodified comparators (marketed products) to be labelled in the UK prior to QP certification and release to a given clinical trial.
In addition to the requirements around MIA(IMP), QP and WDA(H) it should also be noted that for the purposes of importing goods into the United Kingdom the responsible party must be in possession of an Economic Operators Registration and Identification number.
In accordance with paragraph 35 of the World Medical Association Declaration of Helsinki5, every research study involving human subjects must be registered in a publicly accessible database
before recruitment of the first subject. Consequently, registration of a clinical trial is a formal condition of any favorable opinion issued by a UK Research Ethics Committee (REC).
The present expectation of Health Research Authority (HRA)6 is that registration should occur before the first participant is recruited and no later than six weeks after recruitment of the first participant. As such it is important factor in trial registration as part of overall study start up planning for any trial that may be conducted in the UK.
Recognized registries include the International Standard Randomized Controlled Trial Number (ISRCTN), ClinicalTrials.gov, EU Clinical Trials Register, or those cited on the World Health Organization (WHO) list of primary registries or the International Committee of Medical Journal Editors (ICMJE) list of registries.
Of note, should a given clinical trial involve sites in both the UK and EU a record in the EU Clinical Trials Register will satisfy the favorable opinion condition. It is however important to recognize that the EU Clinical Trials Register does not include adult Phase I studies and consequently for these trials an alternative registry must be considered.
HRA have further recently announced a partnership with ISRCTN to automatically register new clinical trials following a favorable REC opinion being issued. Whilst targeted towards improving visibility of UK-based research the automatic registration of trials within the ISRCTN registry will negate any specific actions on the side of study sponsors to ensure registration in accordance with the time limits set. Automatic registration of trials is expected to apply from the point of implementation of the Combined Review process on Jan. 1, 2022.
Chris Ingram, Bsc(Hons), Head of Regulatory Consultancy (Europe) for Precision for Medicine