Established Medicinesmedicines: marketing authorisation application process changes

EstablishedChanges Medicinesto the marketing authorisation application process changes

1. From 1 March 2024, new process changes are being introduced for applications for marketing authorisations for “Establishedestablished Medicines”.medicines. The scope of “Establishedestablished Medicines”medicines includes products that are not new active substances andor line extensions to new active substances. These process changes apply specifically to ‘chemical’chemical productsproducts. Biosimilars (i.e. ‘biosimilars’ are excluded).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 ‘rightright-first- firsttime time’ submissions.

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

• Bioequivalencebioequivalence issues and inappropriate use of biowaivers
• Productproduct specifications, appropriateness of dissolution methods and limits, and impurities test and limits
• Including including the requirement for an assessment of nitrosamines content

3. TheWe will take the approaches set out below –for (1)all applications until further notice, and have reviewed them and made changes clarified in this guidance after three months:

• 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 “Requestrequest for Further Information” - will be adopted for all applications, until further notice, and will be reviewed after three months.
  information

4. The keymain changes are as follows:

a. incompletewe applications will not beprocess processedincomplete applications (see 1.6.2)

b. we will only send one Requestrequest for Furtherfurther Informationinformation (RFI) will be sent (see 1.6.5)

c. following approval, applicantswe will beask askedapplicants to submit a template pre-populatedprepopulated with the Laylay Summarysummary for the UK Publicpublic Assessmentassessment Reportreport (UKPAR) (see 2.4)section 3)

5. We are committed to being transparent about our performance in reaching regulatory decisions on each type of fully compliant applicationapplication. andWe topublish 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 Our MHRA’s Regulatory Information Service (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.started

1.1. TwoPrior weeksto beforeassessing assessment of an applicationapplication, iswe plannedwill todo start,our webest willto notify the applicant (by email) of our intention to begin assessment of their MAA.

1.2. AtWe thisask pointthat weall willapplicants, requireirrespective theof applicantthis tonotification, submitprovide the following documentation (by means of a new eCTD sequence via the MHRA submissions portal):portal in MS Word rather pdf) as a matter of urgency:

• a marked-up comparison of the Summarysummary of Productproduct Characteristicscharacteristics (SmPC)(SmPC), if applicable

• a comparison of the text containedin within the Patientpatient Informationinformation Leafletleaflet (PIL) against the equivalent product information for the reference medicinal product (where appropriate)

• any additional stability data that supports an increase in shelf life since the original submission, and any updates to relevant documents to reflect this

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

1.4. ShouldIf the applicant considerconsiders 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 the 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. (ExamplesExamples of this include incomplete documentation even where there are commitments given to provide pivotal data during the assessment procedure.)procedure.

1.6.3. Applications which arewe consideredconsider to be technically complete will be scientifically assessed.

1.6.4. When taken together, if deficiencieswe areconsider considereddeficiencies to present a potential serious risk to public healthhealth, thewe application will berefer referredthe application 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, athe “Requestapplicant forwill Furtherreceive Information”a (RFI)request willfor befurther sentinformation to(RFI). theNote: 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.)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 addressrespond to 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, thenwe the application will berefer referredthe application to the CHM for advice on refusal.

1.6.7.3. If nowe responsedo isnot receivedreceive a response within the timeline of 60 days, thenwe the application will berefer referredthe application to the CHM for advice on refusal.

1.6.8. RequestsWe forwill not grant extensions to response timestimes. We will notreview beexceptional 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 “Requestrequest for Furtherfurther Information”.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 RFIRFI, we have not received a responseresponse, or insufficientif we have not received sufficient evidence of safety, quality and efficacy has been received to be able to approve it, thewe application will berefer referredthe application 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 we have assessed the response to the final RFIRFI, haswe beenwill assessedmake a decision on approval or refusal will be made using criteria detailed above under 1.6.7.

3. UK Publicpublic Assessmentassessment Reportsreports (UKPAR)

3.1. For each of the two processes described above, following an assessment decision to approve, applicantswe will beask askedapplicants to provide,provide a template pre-populatedprepopulated 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 should use the template that corresponds to the legal basis of their application.

3.3. TheWe will complete the draft UKPAR supplied by the applicant will be completed by MHRA and thenpublish publishedit on the MHRA Products website.

3.4. Where necessary, priorbefore to the publication of the final public assessment report, we will consult Marketingmarketing Authorisationauthorisation Holdersholders further on the text of the final public assessment report.

Published 28 February 2024