Medicines Healthcare Products Regulatory Agency
Legal background and scope
Regulation 78A(13) and (14) of the Human Medicines Regulations 2012, as inserted by the Human Medicines (Amendment etc.) (EU Exit) Regulations 2019, requires that holders of a UK marketing authorisation who sponsor a study which involves use in the paediatric population in respect of the medicinal product to which that authorisation relates must submit to the Medicines and Healthcare products Regulatory Agency (MHRA) results of the study within the period of six months beginning with the day on which the trial ended.
This applies irrespective of whether or not:
the studies are conducted in accordance with an agreed paediatric investigation plan (PIP); or
the?MAH?intends to apply for a marketing authorisation for a paediatric indication in relation to the product.
These provisions replace Article 46 of Regulation (EC) No 1901/2006 (the Paediatric Regulation).
MHRA?will also consider the outcome of?CMDh?paediatric work-sharing procedures (PdWS) reviewed under Article 45 of Regulation (EC) No 1901/2006 (as amended). If required,?MHRA?will request updates to the product information (PI) for UK Marketing Authorisations.
1. Submission of information
The?MAH needs to submit a cover letter ( email@example.com.?) within 6 months of completion (i.e. date of last visit of last subject undergoing the trial, unless otherwise justified in the protocol) of the concerned paediatric studies to the?MHRA?in eCTD format to this mailbox:?
The?MAH?should indicate in the cover letter whether the study(ies):
1.1. are linked to other paediatric studies which have been or will be the subject of other submissions under?Regulation 78A of the Human Medicines Regulations 2012, as inserted by the Human Medicines (Amendment etc.) (EU?Exit) Regulations 2019.
If this is the case, the?MAH?should provide the study title(s) with approximate date of completion. If the study(ies) relate to a UK?PIP, the?MAH?should provide the?PIP?number.
1.2. have been or will be submitted in the UK as part of a variation/extension or any other application including this paediatric study. If this is the case, the?MAH?should:
specify the UK procedure number, if available or the type of application this will be submitted under
confirm that the application will be submitted within the next 6 months
confirm that, based on the results of the study, no urgent safety update of the product information is required
The MAH?should provide any relevant information about any related Article 46 of Regulation (EC) No 1901/2006 procedure(s) or?EU?agreed?PIP(s).
The?MAHs?should also state whether as a result of the paediatric study there is a need to update the product information.
2. Initial appraisal
On receipt of the cover letter,?MHRA?will carry out an initial appraisal of whether an assessment procedure is required at this stage. One of the following may apply:
2.1. Assessment of the data is not required at this stage and?MHRA?will maintain records including justification for the decision, e.g. that a regulatory submission to vary the Marketing Authorisation is planned in the next 6 months, or any other agreed reason(s) to defer the procedure.
2.2. Limited evaluation of the study data may be undertaken if the MAH provides robust justification that the study data are unlikely to warrant product information (PI) changes. The MAH will need to state in the cover letter that one or more of the following criteria are met:
- the same data have been reviewed in another regulatory procedure by MHRA or another competent authority and the review has not led to PI changes
- the study was conducted mainly in adult patients with limited paediatric patients included
- the drug is already licensed in the paediatric population and the study does not provide new PK, efficacy or safety data
- the study, due to its design, limited number of paediatric patients, discontinuation or other reason does not allow drawing conclusions on efficacy or safety that would impact on the drugs benefit:risk ratio or be useful to prescribers and patients
- only interim results from an ongoing study are available which will be assessed later in their totality
- the study has been conducted in populations and/or diseases that are not applicable to UK (for example hay fever to specific seasonal pollen found in non-UK countries)
- other justification as to why a detailed assessment is not required at this stage
If one or more of the above criteria are met, the MAH should submit the study report and a short clinical overview (as in 2.3) including justification why PI changes are not necessary. A variation application will not be requested if MHRA agrees with the MAHs justification not to update the PI.
2.3. If review of the data is required?when the MAH proposes a PI update or when MHRA concludes after the initial appraisal, that a full assessment is needed to robustly conclude on prospective PI updates, MHRA?will notify the?MAH?to submit the paediatric data within 60 days as a type II variation application (change code C.I.13 - complex type II variations fees will be applicable). The?MAH?should submit the following:
Final clinical study report
A short clinical overview clarifying the context of the data, including information on the pharmaceutical formulation used in the study, the existence of a suitable paediatric formulation and if relevant, conditions for an extemporaneous formulation.
A summary of Product Characteristics/ Patient Leaflet (SmPC/PL) proposal to update the paediatric information, or when none is considered required, justification that changes are not necessary.
For a paediatric study that is part of a development program including a?PIP, a line listing of all relevant studies.
If the?MAH?holds other paediatric studies for the same active substance falling under the scope of?EU?Article 45 of Regulation (EC) No 1901/2006 which have not yet been assessed by a competent authority, these should be submitted along with a clinical overview clarifying the context of the data.
If the?MAH?is unable to submit the type II variation within the 60-day timeframe, they must justify t