V.B.6. RMP part III “Pharmacovigilance plan (including post-authorisation safety studies)”

The purpose of the pharmacovigilance plan in part III of the RMP is to present an overview and discuss how the applicant/marketing authorisation holder plans to further characterise the safety concerns in the safety specification. It provides a structured plan for:

• the investigation of whether a potential risk is confirmed as an identified risk or refuted;
• further characterisation of safety concerns including severity, frequency, and risk factors;
• how missing information will be sought;
• measuring the effectiveness of risk minimisation measures.

It does not include actions intended to reduce, prevent or mitigate risks; these are discussed in RMP part V.

The pharmacovigilance plan should focus on the safety concerns summarised in RMP module SVIII of the safety specifications and should be proportionate to the benefits and risks of the product. Early discussions between competent authorities and the applicant/marketing authorisation holder are recommended to identify whether, and which, additional pharmacovigilance activities are needed and consequently milestones should be agreed.

Pharmacovigilance activities can be divided into routine and additional pharmacovigilance activities.

V.B.6.1. RMP part III section “Routine pharmacovigilance activities”

Routine pharmacovigilance is the primary/minimum set of activities required for all medicinal products as per the obligations set out in DIR and REG. Signal detection, which is part of routine pharmacovigilance, is an important element in identifying new risks for all products. The descriptions of these activities in the pharmacovigilance system master file (see GVP Module II) are not required to be repeated in the RMP.

The Pharmacovigilance Risk Assessment Committee (PRAC), the Committee for Medicinal Products for Human Use (CHMP), the Coordination Group for Mutual recognition and Decentralised Procedures – Human (CMDh), or national competent authorities may make recommendations for specific activities related to the collection, collation, assessment and reporting of spontaneous reports of adverse reactions which differ from the normal requirements for routine pharmacovigilance (see GVP Module I). If these recommendations include recording of tests (including in a structured format) that would form part of standard clinical practice for a patient experiencing the adverse reaction, then this requirement would still be considered routine. The routine pharmacovigilance section of the pharmacovigilance plan should be used in these circumstances to explain how the applicant will modify its routine pharmacovigilance activities to fulfil any special PRAC, CHMP, CMDh, and national competent authority recommendations on routine pharmacovigilance.

However, if the recommendation includes the submission of tissue or blood samples to a specific laboratory (e.g. for antibody testing) that is outside standard clinical practice, then this would constitute an additional pharmacovigilance activity.

This RMP section should describe only the routine pharmacovigilance activities beyond adverse reaction reporting and signal detection.

V.B.6.1.1. Specific adverse reaction follow-up questionnaires

Where an applicant/marketing authorisation holder is requested, or plans, to use specific questionnaires to obtain structured information on reported suspected adverse reactions of special interest, the use of these materials should be described in the routine pharmacovigilance activities section and copies of these forms should be provided in RMP annex 4.

Without prejudice to the originality of the format of the questionnaire(s), it is in the interest of public health that questionnaire(s) used by different applicants/marketing authorisation holders for the same adverse event should be kept as similar as possible, in order to deliver a consistent message and to provide useful data for the analysis of the reports, which are relevant for regulatory decisions, while decreasing the burden on healthcare professionals. Therefore, marketing authorisation holders are strongly encouraged to share the content of their questionnaire(s) upon request from other marketing authorisation holders.

V.B.6.1.2. Other forms of routine pharmacovigilance activities

The description of the planned other forms of routine pharmacovigilance activities should be described in this section, e.g. the high level description of the enhanced passive surveillance system, observed versus expected analyses, cumulative reviews of adverse events of interest.

V.B.6.2. RMP part III section “Additional pharmacovigilance activities”

The applicant/marketing authorisation holder should list in this RMP section their planned additional pharmacovigilance activities, detailing what information is expected to be collected that can lead to a more informed consideration of the risk-benefit balance.

Additional pharmacovigilance activities are pharmacovigilance activities that are not considered routine. They may be non-clinical studies, clinical trials or non-interventional studies. Examples include long-term follow-up of patients from the clinical trial population or a cohort study to provide additional characterisation of the long-term safety of the medicinal product. When any doubt exists about the need for additional pharmacovigilance activities, consultation with a competent authority should be considered.

Studies in the pharmacovigilance plan aim to identify and characterise risks, to collect further data where there are areas of missing information or to evaluate the effectiveness of additional risk minimisation activities. They should relate to the safety concerns identified in the safety specification, be feasible and should not include any element of a promotional nature.

Studies in the pharmacovigilance plan should be designed and conducted according to the respective legislation in place, and recommendations in the GVP Module VIII.

Study protocols may be included for evaluation in an RMP update only when the studies are included in the pharmacovigilance plan and the protocols submission has been requested by the competent authority. Reviewed and approved protocols for studies in the pharmacovigilance plan should be provided in RMP annex 3 – part C (or electronic links or references to the protocol included in other section of the eCTD dossier). Other category 3 studies protocols, submitted for information only, may also be included in RMP annex 3 – part C. Protocols of completed studies should be removed from RMP annex 3 once the final study reports are submitted to the competent authority for assessment and the study is removed from the parmacovigilance plan (see V.B.10.3.).

The milestones for the final study report submission to the competent authority should be included for all studies in the pharmacovigilance plan.

Marketing authorisation holders may also submit to EMA or national competent authorities protocols of post-authorisation safety studies (PASS) for scientific advice.

V.B.6.3. RMP part III section “Summary table of additional pharmacovigilance activities”

This RMP section outlines the pharmacovigilance activities designed to identify and characterise risks associated with the use of a medicinal product. Some may be imposed as conditions to the marketing authorisation, either because they are key to the risk-benefit profile of the product (category 1 studies in the pharmacovigilance plan), or because they are specific obligations in the context of a conditional marketing authorisation or a marketing authorisation under exceptional circumstances (category 2 studies in the pharmacovigilance plan). If the condition or the specific obligation is a non-interventional PASS, it will be subject to the supervision set out in DIR Art 107m-q and the format and content of such non-interventional PASS should be as described in IR Annex III (see GVP Module VIII).

Other studies might be required in the RMP to investigate a safety concern or to evaluate the effectiveness of risk minimisation activities. Such studies included in the pharmacovigilance plan are also legally enforceable (category 3 studies in the pharmacovigilance plan). The summary table of the pharmacovigilance plan should provide clarity to all stakeholders as to which category an activity in the pharmacovigilance plan falls under (see Table V.3.).

Table V.3. Attributes of additional pharmacovigilance activities

	Type of activity	In annex II of MA (CAPs only)	Study category (PhV plan)	Status	Supervised under
					Article 107m	Article 107 n-q
Imposed PASS	“Interventional”*	Yes, in annex IID	1	Mandatory and subject to penalties	No	No
	Noninterventional	Yes, in annex IID			Yes	Yes
Specific obligation	“Interventional”*	Yes, in annex IIE	2	Mandatory and subject to penalties	No	No
	Noninterventional	Yes, in annex IIE			Yes	Yes
Required	“Interventional”*	No	3	Legally enforceable	No	No
	Noninterventiona	No			Yes	No

*Clinical interventional studies are subject to the requirements of Directive 2001/20/EC. Non-clinical interventional studies are subject to the legal and ethical requirements related to the protection of laboratory animals, and Good Laboratory Practice as appropriate.Studies required in jurisdictions outside the EU should not be included in the RMP unless they are also imposed as a condition to the marketing authorisation or as a specific obligation, or required by the Agency or a national competent authority. Studies not required by the EMA or a national competent authority should not be included in the pharmacovigilance plan in the RMP. This is without prejudice to safety concerns arising from any such studies, which should be reported as per the applicable legislation.For generic products, the pharmacovigilance plan will reflect the outstanding needs for pharmacovigilance investigations at the time of their approval. In some cases, ongoing or planned PASS for the originator product would also be required to be conducted for the generic products (e.g. registries may need to be in place to include most/all patients treated with the medicine, be it generic or originator products). Where applicable, the marketing authorisation holders are encouraged to set up joint PASS, for instance in the case of registries or when a referral has resulted in an imposed PASS for all authorised medicinal products containing a named substance in a specified indication.