New guidance has been published on the MHRA website concerning process changes for the assessment of established medicines that come into effect on 1 March 2024.
- The changes will enable the agency to assess applications more efficiently, helping to ensure a smoother and more rapid approvals process for applicants.
- At the heart of the changes are a ‘technical completeness check’ designed to ensure that the MHRA has all the necessary information to proceed with its assessment at the start of its review.
- These changes are in addition to measures already implemented.
This post is an attempt to present the guidance information in a manner that facilitates ease of understanding. Please read it in conjunction with the guidance on the MHRA website.
What are the key changes resulting from the new guidance?
The key changes resulting from the new guidance are:
- Incomplete applications will not be processed
- Only one Request for Further Information (RFI) will be sent
- Following approval, applicants will be asked to submit a template pre-populated with the Lay Summary for the UK Public Assessment Report (UKPAR). More information is provided in the section UK Public Assessment Reports (UKPAR) below.
What is considered ‘in scope’ of established medicines?
The scope of “Established Medicines” includes products that are not new active substances and line extensions to new active substances. These process changes apply specifically to ‘chemical’ products (i.e. ‘biosimilars’ are excluded).
Approaches to be adopted by the MHRA for all future established medicine applications
The approaches set out below will be adopted for all applications for established medicines until further notice and will be reviewed after three months.
- Revised process for applications received and where assessment has not started and
- Revised process for applications which are already under assessment or have received a “Request for Further Information”
Further information on the revised processes is provided below.
1. Revised process for applications received and where assessment has not started
Before assessment of an application commences
Two weeks before assessment of an application is planned to start, the MHRA will notify the applicant (by email) of its intention to begin assessment of their MAA.
- At this point, the MHRA will require the applicant to submit the following documentation (by means of a new eCTD sequence via the MHRA submissions portal):
- a marked-up comparison of the Summary of Product Characteristics (SmPC); and
- a comparison of the text contained within the Patient Information Leaflet (PIL) against the equivalent product information for the reference medicinal product (where appropriate)
- Applicants will have the opportunity to provide updated GMP certificates and/or QP Declarations at this time.
- Should the applicant consider that they have not submitted the complete documentation required to support their application, or they do not wish to have their application processed, they will have the opportunity to withdraw their licence application before assessment has started and receive a 90% refund of the application fee.
Withdrawal of an application once assessment has commenced
Once assessment of an application has commenced, if it is subsequently withdrawn by the applicant before determination, any refund on withdrawal will depend on the stage in the assessment process that has been reached in line with The Medicines (Products for Human Use) (Fees) Regulations 2016 (as amended).
The application assessment process
From 1 March 2024, the assessment process is as follows:
- When the MHRA commences assessment, it will carry out a technical completeness check of the application.
- The application will be refused if it is determined that the data required by regulations 49 – 55 and Schedule 8 of The Human Medicines Regulations 2012 (as amended) have not been submitted. (Examples of this include incomplete documentation even where there are commitments given to provide pivotal data during the assessment procedure.)
- Applications which are considered to be technically complete will be scientifically assessed.
How will the MHRA handle deficiencies in an application?
When taken together, if deficiencies are considered to present a potential serious risk to public health the application will be referred to the Commission on Human Medicines (CHM) for advice on refusal.
- In all cases where an application is referred to the CHM and their advice is to refuse it, a letter will be issued from the CHM, and the applicant will have the usual appeal rights as described in paragraph 6 of Schedule 11 of The Human Medicines Regulation 2012 (as amended).
- In other cases, where there are deficiencies, a “Request for Further Information” (RFI) will be sent to the applicant. (Note: there will no longer be more than one RFI and for these applications, the MHRA will no longer issue an assessment report alongside the RFI.)
How long will an applicant have, to respond to an RFI?
Applicants will have a maximum of 60 calendar days to respond to this request. The RFI letter will include a contact email for questions or clarifications on the questions raised.
What might be the outcome of an application following the submission of a response to an RFI letter?
There can be one of three possible outcomes:
- If the response submitted within 60 days is complete and satisfactory and, where necessary, updated documentation has been provided to address all of the questions raised in the RFI, including questions on the product information, the application will be determined as approved in line with Regulation 58(4). At this point, the applicant will be asked to provide a template pre-populated with the Lay Summary for the UK Public Assessment Report (UKPAR). More information is provided in the section UK Public Assessment Reports (UKPAR) below.
- If the response is incomplete or does not resolve the issues raised on quality, safety, or efficacy, then the application will be referred to the CHM for advice on refusal.
- If no response is received within the timeline of 60 days, then the application will be referred to the CHM for advice on refusal.
How will the MHRA deal with requests for extensions to the 60 day timeframe for an RFI response
Requests for extensions to response times will not be granted. Exceptional circumstances to meet public health needs and minimise the impact on patients will be reviewed on a case-by-case basis.
2. Revised process for applications which are already under assessment or have received a “Request for Further Information”.
One further final RFI
For all applications currently under assessment or which have been issued with an RFI, the MHRA will limit applications to one further final RFI.
What will happen if a response to the RFI has not been submitted within the 60 day timeframe?
If within the 60-day timeframe following the date of the final RFI, the MHRA has not received a response or insufficient evidence of safety, quality and efficacy to be able to approve an application, it will be referred to CHM for advice on refusal on the grounds that safety, quality or efficacy have not been demonstrated in line with Regulation 58(4).
What will happen once a response to an RFI has been assessed?
Once the response to the final RFI has been assessed a decision on approval or refusal will be made as follows:
- If the response submitted within 60 days is complete and satisfactory and, where necessary, updated documentation has been provided to address all of the questions raised in the RFI, including questions on the product information, the application will be determined as approved in line with Regulation 58(4). At this point, the applicant will be asked to provide a template pre-populated with the Lay Summary for the UK Public Assessment Report (UKPAR).
- If the response is incomplete or does not resolve the issues raised on quality, safety, or efficacy, then the application will be referred to the CHM for advice on refusal.
- If no response is received within the timeline of 60 days, then the application will be referred to the CHM for advice on refusal.
UK Public Assessment Reports (UKPAR)
When the RFI or letter from CHM is issued, this will include a request that applicants provide, with their response, a template pre-populated with the Lay Summary for the UK Public Assessment Report (UKPAR).
- Templates are available at Apply for a licence to market a medicine in the UK. The applicant should use the template that corresponds to the legal basis of their application.
- If the application is approved, the draft UKPAR supplied by the applicant will be completed by MHRA and then published on the MHRA Products website.
- Where necessary, prior to the publication of the final public assessment report, the MHRA will consult Marketing Authorisation Holders further on the text of the final public assessment report.
What are most common deficiencies associated with such applications?
According to the MHRA, the most common deficiencies concerning such applications are:
- Bioeuivalence issues and inappropriate use of biowaivers
- Product specifications, appropriateness of dissolution methods and limits, and impurities test and limits
- Including the requirement for an assessment of nitrosamines content
Remember to use the Checklists that are available to support applicants to complete ‘right first time’
Source: MHRA