V.C.1. Requirements for the applicant/marketing authorisation holder in the EU

For all new marketing applications, the applicant shall submit the risk management plan describing the risk management system, together with a summary thereof [DIR Art 8(3)(iaa)].

In the post-authorisation phase, an RMP update or a new RMP may need to be submitted at any time:

• At the request of the Agency or a competent authority in a Member State when there is a concern about a risk affecting the risk-benefit balance.
• With an application involving a change to an existing marketing authorisation when the data included leads to a change in the list of the safety concerns, or when a new additional pharmacovigilance activity or a new risk minimisation activity is needed or is proposed to be removed. The RMP update may be warranted as a result of data submitted with applications such as new or significant change to the indication, a new dosage form, a new route of administration, a new manufacturing process of a biotechnologically-derived product.

The need for an RMP or an update to the RMP should be discussed with the Agency or a competent authority in a Member State, as appropriate, well in advance of the submission of an application involving a significant change to an existing marketing authorisation.

V.C.1.1. Risk management plans with initial marketing authorisation applications

For full initial marketing authorisation applications, all parts of an RMP should be submitted (see V.B.4.). For other types of initial marketing authorisation applications, the requirements for the RMP content follow the concept of proportionality to the identified risks and potential risks of the medicinal product, and the need for post-authorisation safety data [DIR Art 8(3)]; therefore certain parts or modules may have reduced content requirements or may be left empty, where not applicable.

Table V.5. Summary of minimum RMP requirements for initial marketing authorisation applications (for full description see text below)

Product	Part	Part II						Part	Part	Part	Part
	I							III	IV	V	VI
		SI	SII	SIII	SIV	SVII	SVIII
0. Full MA application	√	√	√	√	√	√	√	√	√	√	√
1. Generic product	√					‡	√	√	*		√
2. Informed consent product	√	√	√	√	√	√	√	√	√	√	√
3. Hybrid product	√	†		†		†	√	√	√	∫	√
4.a. Fixed combination product – new active substance	√	₸	₸	₸	₸	₸	√	√	√	√	√
4.b. Fixed combination product – no new active substance	√		†	†		‡	√	√	*	∫	√
5. Well established medicinal use product	√					√	√	√	√	√	√
6. Biosimilar product	√		√	√	√	√	√	v	√	√	√

 

√ = applicable/relevant

‡ = relevant only if “originator” product does not have an RMP and its safety profile is not published on CMDh website

* = relevant only when a PAES was imposed for the “originator” product

∫ = statement of alignment of safety information in PI is sufficient

† = requirements based on risk proportionality principle, addressing new data generated or differences with the “originator” product

₸ = focus on the new active substance

V.C.1.1.1. New applications under Article 10(1), i.e. “generic”

The elements for new applications under DIR Art 10(1) are as follows:

• RMP part I: The elements are the same as for initial marketing authorisation application for a full application;
• RMP part II: there are 3 situations possible:

1. The originator product has an RMP: RMP modules SI-SVII may not be applicable. Module SVIII should include the summary of the safety concerns, in line with the originator product. If the applicant considers that the available evidence justifies the removal or the change of a safety concern, then data in module SVII should also be included to address the safety concern and detailing the applicant’s arguments. Similarly, if the applicant has identified a new safety concern specific to the generic product (e.g. risks associated with a new excipient or a new safety concern raised from any clinical data generated), this should be discussed and the new safety concern detailed in module SVII.
2. The originator product does not have an RMP but the safety concerns of the substance are published on the CMDh website (9) . The elements under point 1 above should be followed. If more than one list of safety concerns published on CMDh website apply for the same active substance, the applicant should justify the choice of proposed safety concerns in module SVIII.
3. The originator product does not have an RMP and the safety concerns of the substance are not published on the CMDh website: Full modules SVII and SVIII should be included in the RMP. Module SVII should critically analyse available relevant information (e.g. own pre-clinical and clinical data, scientific literature, originator product’s product information) and propose a list of important identified and potential risks as well as missing information.

• RMP part III: This should include a description of the routine pharmacovigilance activities, as detailed in V.B.6.1.

The applicant is strongly encouraged to contribute to and participate in the planned or ongoing studies performed by the marketing authorisation holder of the originator product, when it is important that all available (prospective) data are collected in one study. This may be the case for instance when data from patients using the new product are important to further characterise the safety profile of the substance and enrolling patients in separate studies with the same or similar objectives creates an unnecessary burden on patients, clinicians or investigators (e.g. pregnancy registries, disease registries, any PASS evaluating long-term use).

The competent authority may also consider imposing studies to be conducted for generic products as applicable (e.g. within the context of referrals when generic products are involved or as consequence of the outcome of a referral imposing a study to the originator product).

• RMP part IV: This part of the RMP may be left empty unless a PAES has been imposed to be conducted for the generic product (e.g. following a referral).
• RMP part V: When the originator product does not have additional risk minimisation activities, a statement that the safety information in the product information of the generic product is aligned with the originator product is sufficient for RMP part V. Where new risks have been identified for the generic product, the risk minimisation activities for such safety concerns should be presented in part V, following the same elements as for a full marketing authorisation application. If the originator product does have additional risk minimisation activities, a full part V is required for the generic product.
• RMP part VI: The elements are the same as for a full initial marketing authorisation application, to the extent of data requested and provided in other parts of the RMP, as per above.
• RMP part VII: The elements are the same for a full initial marketing authorisation application. For RMP annexes 4 and 5, the applicant is strongly encouraged to use materials as similar, in content, as possible to the originator product.

V.C.1.1.2. New applications under Article 10c, i.e. “informed consent”

For new applications under DIR Art 10c, the RMP should be the same as the RMP of the cross-referred medicinal product. An RMP will still be required even if the cross-referred product does not have an RMP. If the marketing authorisation holder is the same as for the authorised product, the marketing authorisation holder is encouraged to put in place only one RMP document for their products with the same active substance.

V.C.1.1.3. New applications under Article 10(3), i.e. “hybrid”

For new applications under DIR Art 10(3), the RMP elements are the same as for a generic product. However, for changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, the applicant should discuss in RMP module SVII whether this results in the addition or deletion of a safety concern. Clinical trial data generated to support the application should be discussed in the RMP, as appropriate (e.g. RMP part II, modules SI, SIII). Other parts of the RMP should also be aligned (e.g. parts V and VI).

V.C.1.1.4. New applications under Article 10b, i.e. involving “fixed combination” medicinal products

For new applications for fixed dose combinations, there are two situations:

4. The combination contains a new active substance: A full RMP, following the elements as for full initial marketing authorisation application, should be submitted. RMP modules SI-SVI should focus on the new active substance.

5. The combination does not contain a new active substance: The RMP should follow the elements for a generic product. For the purpose of establishing the elements of RMP part II, “the originator product” should be read as “any/all authorised products containing the same active substances included in the new product”.

In addition, new data generated with the fixed combination should be provided in modules SII and SIII.

V.C.1.1.5. New applications under Article 10a, i.e. “well established medicinal use”

For new applications under DIR Art 10a, RMP elements are as follows:

• RMP part I: The elements are the same as for a full initial marketing authorisation application.
• RMP part II: Only RMP modules SVII and SVIII might be applicable. The applicant is required to justify the proposed safety concerns, or the lack of any thereof, using available evidence from published scientific literature (information available in the public domain).
• RMP parts III-VII: The elements are the same as for a full initial marketing authorisation application.

V.C.1.1.6. New applications under Article 10(4), i.e. “biosimilar products”

For new applications for biosimilar products, the RMP elements are described in GVP P.II.

V.C.1.1.7. New applications for homeopathic and herbal products not falling within the scope of the simplified registration

New applications for homeopathic and herbal medicinal products not falling within the scope of the simplified registration are subject to standard marketing authorisation; therefore the RMP elements are the same as defined by the type of the marketing authorisation application (i.e. legal basis).

V.C.1.2. Risk management plans first submitted post-authorisation

V.C.1.2.1. New risk management plans at the request of a competent authority to address one or more safety concerns

The elements are the same as those applicable to a generic product where the originator product does not have an RMP (see V.C.1.1.1.).

Two possible scenarios are envisaged:

1. Marketing authorisation holders may be requested to submit an RMP with a RMP module SVII focused on the safety concern(s) evaluated in the procedure. Other safety concerns should be included as needed.
2. Marketing authorisation holders may be requested to submit an RMP based on a comprehensive identification of safety concerns.

It is left to the discretion of the competent authority, which is the most appropriate in given circumstances.

V.C.1.2.2. Unsolicited risk management plan submission in post-authorisation phase

This RMP follows the elements of the type of marketing authorisation under which this medicinal product was initially submitted (i.e. full marketing authorisation application, generic medicinal products, “informed consent” applications, etc., see V.C.1.1.).