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Guidance: Established Medicines marketing authorisation application process changes

Medicines Healthcare Products Regulatory Agency

March 11
14:53 2024

Established Medicines marketing authorisation application process changes

1. From 1 March 2024, new process changes are being introduced for applications for marketing authorisations for 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).

2. These changes are in addition to measures already implemented:

a. Eligible national marketing authorisation applications (MAA) submitted before 1 January 2024, awaiting first assessment, may convert to the Mutual Recognition and Decentralised Reliance Procedure (MRDCRP) or European Commission Decision Reliance Procedure (ECDRP).

b. Checklists are available to support applicants to complete right first time submissions.

c. Most common application flaws, where we frequently raise deficiency points, are summarised below:

  • Bioequivalence 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

3. The approaches set out below (1) Revised process for applications received and where assessment has not started and (2) Revised process for applications which are already under assessment or have received a Request for Further Information - will be adopted for all applications, until further notice, and will be reviewed after three months.

4. The key changes are as follows:

a. incomplete applications will not be processed (see 1.6.2)

b. only one Request for Further Information (RFI) will be sent (see 1.6.5)

c. following approval, applicants will be asked to submit a template pre-populated with the Lay Summary for the UK Public Assessment Report (UKPAR) (see 2.4)

5. We are committed to being transparent about our performance in reaching regulatory decisions on each type of fully compliant application and to this end we are publishing these data on our website each month see the latest performance data.

6. Likewise, we are committed to providing applicants with information and support. The MHRAs RegulatoryInformationService (RIS)acts as the single main point of contact for marketing authorisation holders of medicines and their representatives.

Telephone (weekdays 9am to 5pm): 020 3080 7400

New licence applications: RIS.NA@mhra.gov.uk

1. Revised process for applications received and where assessment has not started.

1.1. Two weeks before assessment of an application is planned to start, we will notify the applicant (by email) of our intention to begin assessment of their MAA.

1.2. At this point we 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)

  • a comparison of the text contained within the Patient Information Leaflet (PIL) against the equivalent product information for the reference medicinal product (where appropriate)

1.3. Applicants will have the opportunity to provide updated GMP certificates and/or QP declarations at this time.

1.4. 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 as described below under 1.6, they will have the opportunity to withdraw their licence application before assessment has started and receive a 90% refund of the application fee.

1.5. Once assessment of an application has commenced, as detailed under 1.6 of the process below, 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).

1.6. From 1 March 2024, the assessment process is as follows:

1.6.1. When we begin assessment, we will carry out a technical completeness check of the application.

1.6.2. 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 have not been submitted. (Examples of this include incomplete documentation even where there are commitments given to provide pivotal data during the assessment procedure.)

1.6.3. Applications which are considered to be technically complete will be scientifically assessed.

1.6.4. 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).

1.6.5. 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 some of these applications, we will no longer issue an assessment report alongside the RFI.)

1.6.6. 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.

1.6.7. There will be three possible outcomes beyond this point:

1.6.7.1. 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).

1.6.7.2. 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.

1.6.7.3. If no response is received within the timeline of 60 days, then the application will be referred to the CHM for advice on refusal.

1.6.8. 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.

2.1. For all applications currently under assessment or which have been issued with an RFI, we will limit applications to one further final RFI.

2.2. If within the 60-day timeframe following the date of the final RFI we have not received a response or insufficient evidence of safety, quality and efficacy has been received to be able to approve it, the application 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).

2.3. Once the response to the final RFI has been assessed a decision on approval or refusal will be made using criteria detailed above under 1.6.7.

3. UK Public Assessment Reports (UKPAR)

3.1. For each of the two processes described above, following an assessment decision to approve, applicants will be asked to provide, a template pre-populated with the Lay Summary for the UK Public Assessment Report (UKPAR).

3.2.Templates are available at Apply for a licence to market a medicine in the UK. The applicant

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