XVI.C.2. Responsibilities of the applicant/marketing authorisation holder in the EU

The RMM in the marketing authorisation pose an obligation on the marketing authorisation holder in the EU (see XVI.C.1.1.), and the marketing authorisation holder shall by means of its pharmacovigilance system evaluate all information scientifically, consider options for risk minimisation and prevention and take appropriate measures as necessary [DIR Art 104(2)].

The applicant for a marketing authorisation shall submit the application accompanied by the RMP [DIR Art 8(3)(iaa)]. The RMP shall describe the risk management system [DIR Art 1(28c)] and also contain a documentation of the RMM, including an assessment of their effectiveness [IR Art 30(1)(c), DIR Art 1(28b)]. The marketing authorisation holder shall operate the risk management system, monitor the outcome of RMM which are contained in the RMP and/or laid down as conditions of the marketing authorisation (pursuant to DIR Art 21a, 22 or 22a), and update the risk management system [DIR Art 104(3)(c)-(e)] (see (see XVI.C.1.2.).

Therefore, when proposing initial or adapted RMM, the applicant/marketing authorisation holder should follow the guidance in XVI.B.1, XVI.B.2., XVI.B.3. and XVI.B.6.

The marketing authorisation holder should develop the required additional RMM materials and a dissemination plan following the guidance in XVI.B.4., addressing the needs for national tailoring (see XVI.C.3.1.), and submit to the competent authorities in Member States the draft materials in the official language(s) as required by the respective Member State and the draft national dissemination plan (see XVI.C.2.1.). For a risk minimisation control programme (see XVI.B.2.3.2.), the marketing authorisation holder should discuss the development, dissemination and maintenance of the RMM and the RMM materials required for the programme with the competent authorities in Member States. The marketing authorisation holder should inform the competent authorities in Member States about any important changes or issues which impact on the previously agreed dissemination plan, together with an updated plan addressing the encountered changes or issues. If amendments to additional RMM materials have been agreed (see XVI.B.6.), a national dissemination plan to replace the existing with the amended materials at the level of the target populations should be submitted by the marketing authorisation holder to the competent authorities for agreement.

The additional RMM materials should have been approved by the competent authorities in Member States before dissemination by the marketing authorisation holder in accordance with the agreed national dissemination plan. If the medicinal product is not placed on the market in a Member State, dissemination of the materials in that Member State is usually not required, but this should be discussed with the competent authority of each Member State as the materials may still be needed, e.g. for imported medicinal product for named patient use.

For the evaluation of RMM effectiveness, the marketing authorisation holder should follow the guidance in XVI.B.5. and XVI.B.6.1.. When requested, the draft protocols of the studies in the RMP for evaluating RMM effectiveness should be submitted by the marketing authorisation holder for regulatory assessment. The process for submission of the study results depends on the study category and should follow the guidance in GVP Modules V and VIII, the EMA Guidance on Post-Authorisation Safety Studies15 and the EMA Post-Authorisation Guidance16 . The results of any assessments of RMM effectiveness shall be contained in the PSUR [IR Art 34(3)], to be submitted by the marketing authorisation holder for the medicinal product [DIR Art 107b, REG Art 28 (2)] (see XVI.C.1.3.).

If the marketing authorisation holder becomes aware of information regarding the risk and/or the RMM that may impact the risk-benefit balance and/or the RMM of the medicinal product in a way that may constitute an emerging safety issue (ESI), this should be reported as an ESI (see GVP Module IX).

For further specific operations in the EU, the marketing authorisation holder should follow other applicable guidance in XVI.C., and for specific operations in Member States additionally the national guidance in Member States where such guidance is available.

Overall, the marketing authorisation holder should follow the guidance on the principles for risk minimisation in XVI.B.1., in particular regarding the non-promotional nature of the RMM as well as their studies evaluating RMM effectiveness (see XVI.B.1.5.). For the quality systems requirements, the marketing authorisation holder should follow the guidance in XVI.B.7.

XVI.C.2.1. Submission of materials and dissemination plan for additional risk minimisation measures to the competent authorities in Member States

Draft additional RMM materials should be submitted by the marketing authorisation holder to the competent authorities in Member States for approval after the conclusion of the regulatory procedure through which the additional RMM has been required or amended, together with the draft national dissemination plan for agreement.

If no other national requirements apply, the submission should contain the following:

• Cover letter and/or national request form including the following information:
  • the contact details of the marketing authorisation holder and, if applicable, another organisation to which it has subcontracted the submission (with the names and e-mail addresses of the contact persons);
  • the regulatory procedure which has led to the additional RMM materials being submitted with supportive documents (e.g. PRAC recommendation, CHMP opinion, CMDh position, European Commission decision with relevant annexes, national competent authority opinion, approved RMP)
  • the applicable SmPC text;
• Draft additional RMM materials in a common open text-processing electronic format in the official language(s) required by the respective Member State;
• Sample of the intended layout of the additional RMM materials, including where applicable, tables, graphics or other visualisations and enhancements;
• Results from user-testing of draft additional RMM materials, where applicable; and
• Draft national dissemination plan

If the submission concerns an amendment of an existing RMM material, the changes to the material should be highlighted.

XVI.C.2.2. Coordination of activities for risk minimisation measures across medicinal products containing the same active substance

The marketing authorisation holder for a biosimilar, hybrid or generic medicinal product should have in place the same RMM as required for the marketed reference medicinal product, unless requested otherwise by the competent authorities.

When the marketed reference medicinal product does not have additional RMM, a statement that the safety information in the product information of the biosimilar, hybrid or generic medicinal product is aligned with the reference product is sufficient for the RMP part V.

Where additional RMM materials for a generic, biosimilar or a hybrid medicinal product are identical to the user-tested materials for the reference product, no further user-testing is needed for the generic, biosimilar or hybrid product, unless testing in a not yet tested language is requested by the competent authorities. The marketing authorisation holder for a biosimilar, hybrid or generic medicinal product should develop and agree with the competent authorities national dissemination plans for the RMM materials applicable to their product (see XVI.B.4.2.).

When several medicinal products containing the same active substance, such as generic, biosimilar and hybrid products, have been authorised and require the same additional RMM, their marketing authorisation holders are encouraged to collaborate for fulfilling the responsibilities applicable to each individual marketing authorisation holder (see XVI.C.2.) through coordination of a consistent approach to developing, disseminating, evaluating and adapting RMM materials. Without prejudice to the originality of the format of a RMM material, it is in the interest of patient safety that RMM materials disseminated by different marketing authorisation holders for the same active substance should be kept consistent and as similar as possible, to avoid confusion in the target population.

When a common additional RMM material is developed for more than one medicinal product containing the same active substance, the material may refer only to the name of active substance, and not to all invented names of the concerned medicinal products. Where additional RMM are fully identical with the one for the marketed reference product, there is usually no need for the marketing authorisation holder of the generic, biosimilar or hybrid product to conduct a study evaluating RMM effectiveness for their product, if such a study is already ongoing for the reference product. However, if a considerable proportion of medicines use is expected to possibly be contributed by (a) generic, biosimilar or hybrid product(s), the respective marketing authorisation holder(s) may be requested to conduct a study evaluating RMM effectiveness.

Where a study evaluating RMM effectiveness is conducted jointly by several marketing authorisation holders for their products containing the same active substance or covers otherwise more than one medicinal product containing the same active substance, data collection may be independent of the (invented) names of the medicinal products (e.g. based on the anatomical-therapeutic-chemical (ATC) code of the active substance17).

Where the marketing authorisation holder for a generic, biosimilar or hybrid medicinal product is not required to conduct a study to evaluate RMM effectiveness, updates on the dissemination of the additional RMM materials by the marketing authorisation holder and results from RMM effectiveness evaluations through routine pharmacovigilance activities should still be included in the PSURs for the concerned product (see XVI.C.1.3.).