V.B.8. RMP part V “Risk minimisation measures (including evaluation of the effectiveness of risk minimisation activities)”

Location:
V.B.
In force from:
31.03.2017

Part V of the RMP should provide details of the risk minimisation measures which will be taken to reduce the risks associated with respective safety concerns.

For active substances where there are individual products with substantially different indications or target populations, it may be appropriate to have a risk minimisation plan specific to each product. i.e. products where the indications lie in different medical specialities and have different safety concerns associated; products where risks differ according to the target population; products with different legal status for the supply of medicinal products to patients.

The need for continuing risk minimisation measures should be reviewed at regular intervals and the effectiveness of risk minimisation activities assessed (see V.B.8.). Guidance on additional risk minimisation measures and the assessment of the effectiveness of risk minimisation measures is provided in GVP Module XVI and GVP Module XVI Addendum I – Educational materials.

Routine risk minimisation activities

Routine risk minimisation activities are those which apply to every medicinal product. These relate to:

  • the summary of product characteristics;
  • the labelling (e.g. on inner and outer carton);
  • the package leaflet;
  • the pack size(s);
  • the legal status of the product.

Even the formulation itself may play an important role in minimising the risk of the product.

Summary of product characteristics (SmPC) and package leaflet (PL)

The summary of product characteristics and the package leaflet are important tools for risk minimisation as they constitute a controlled and standardised format for informing healthcare professionals and patients about the medicinal product. The Guideline on Summary of Product Characteristics provides guidance on how information should be presented.

Both materials provide routine risk minimisation recommendations; however, there are two types of messages the SmPC and PL can provide:

  • routine risk communication messages: usually found in section 4.8 of the SmPC or section 4 of the PL; these messages communicate to healthcare professionals and patients the undesirable effects of the medicinal product, so that an informed decision on the treatment can be made;
  • routine risk minimisation activities recommending specific clinical measures to address the risk: usually found in sections 4.2 and 4.4 of the SmPC but can also be found in sections 4.1, 4.3, 4.5, 4.6, 4.7 and 4.9, and sections 2 and 3 of the PL; warning and precaution messages and recommendations in the SmPC will include information on addressing the risk of the product by e.g.:
    • performing a test before the start of treatment;
    • monitoring of laboratory parameters during treatment;
    • monitoring for specific signs and symptoms;
    • adjusting the dose or stopping the treatment when adverse events are observed or laboratory parameters change;
    • performing a wash-out procedure after treatment interruption;
    • providing contraception recommendations;
    • prohibiting the use of other medicines while taking the product;
    • treating or preventing the risk factors that may lead to an adverse event of the product;
    • recommending long-term clinical follow-up to identify in early stages delayed adverse events.

Pack size

Since every pack size is specifically authorised for a medicinal product, planning the number of “dosage units” within each pack and the range of pack sizes available can be considered a form of routine risk management activity. In theory, controlling the number of “dosage units” should mean that patients will need to see a healthcare professional at defined intervals, thus increasing the opportunity for testing and reducing the length of time a patient is without review. In extreme cases, making units available in only one pack size to try to link prescribing to the need for review may be considered.

A small pack size can also be useful, especially if overdose or diversion are thought to be major risks.

Legal status

Controlling the conditions under which a medicinal product may be made available can reduce the risks associated with its use or misuse.

The marketing authorisation must include details of any conditions or restrictions imposed on the supply or the use of the medicinal product, including the conditions under which a medicinal product may be made available to patients. This is commonly referred to as the “legal status” of a medicinal product. Typically it includes information on whether or not the medicinal product is subject to medical prescription [DIR Art 71(1)]. It may also restrict where the medicinal product can be administered (e.g. in a hospital) or by whom it may be prescribed (e.g. specialist).

For medicinal products only available on prescription, additional conditions may be imposed by classifying them into those available only upon either a restricted medical prescription, or upon a special medical prescription.

Restricted medical prescription

This may be used to control who may initiate treatment, prescribe the medicinal product and the setting in which the medicinal product can be given or used. According to EU legislation, when considering classification of a medicinal product as subject to restricted medical prescription, the following factors shall be taken into account [DIR Art 71(3)]:

  • The medicinal product, because of its pharmaceutical characteristics or novelty or in the interests of public health, is reserved for treatments which can only be followed in a hospital environment.
  • The medicinal product is used in the treatment of conditions which must be diagnosed in a hospital environment or in institutions with adequate diagnostic facilities, although administration and follow-up may be carried out elsewhere.
  • The medicinal product is intended for outpatients but its use may produce very serious adverse reactions requiring a prescription drawn up as required by a specialist and special supervision throughout the treatment.

Special medical prescription

For classification as ‘subject to special medical prescription’, the following factors shall be taken into account [DIR Art 71(2)]:

  • the medicinal product contains, in a non-exempt quantity, a substance classified as a narcotic or a psychotropic substance within the meaning of the international conventions in force, such as the United Nations Conventions of 1961 and 1971;
  • the medicinal product is likely, if incorrectly used, to present a substantial risk of medicinal abuse, to lead to addiction or be misused for illegal purposes, or
  • the medicinal product contains a substance which, by reason of its novelty or properties, could be considered as belonging to the group envisaged in the second indent as a precautionary measure.

Categorisation at Member State level

There is the possibility of implementing sub-categories at Member State level, which permits the Member States to tailor the above-mentioned classifications to their national situation. The definitions and therefore also the implementation vary in those Member States where the sub-categories exist.

Additional risk minimisation activities

Additional risk minimisation activities should only be suggested when essential for the safe and effective use of the medicinal product. If additional risk minimisation activities are proposed, these should be detailed and a justification of why they are needed provided. The need for continuing with such measures should be periodically reviewed.

Where relevant, key messages of additional risk minimisation activities should be provided in RMP annex 6 – Details of proposed additional risk minimisation activities.

For medicinal products approved non-centrally, in situations where the need for additional risk minimisation may vary across Member States, the RMP can reflect that the need for (and content of) additional risk minimisation can be agreed at a national level.

Further guidance on additional risk minimisation measures is provided in GVP Module XVI.

Evaluation of the effectiveness of risk minimisation activities

When the RMP is updated, the risk minimisation plan should include a discussion of the impact of additional risk minimisation activities. Where relevant, such information may be presented by EU region.

A discussion on the results of any formal assessment(s) of risk minimisation activities should be included when available. If a particular risk minimisation strategy proves ineffective, or to be causing an excessive or undue burden on patients or the healthcare system then consideration should be given to alternative activities. The marketing authorisation holder should comment in the RMP on whether additional or different risk minimisation activities are needed for each safety concern or whether in their view the (additional) risk minimisation measures may be removed (e.g. when risk minimisation measures have become part of standard clinical practice).

If a study to evaluate the effectiveness of risk minimisation activities is required or imposed by the competent authority, the study should be included in the pharmacovigilance plan, part III of the RMP.

Guidance on monitoring the effectiveness of risk minimisation activities is included in the GVP Module XVI.

V.B.8.1. RMP part V section “Risk minimisation plan”

In the RMP section on the risk minimisation plan, for each safety concern in the safety specification, the following information should be provided:

  • routine risk minimisation activities, including details of whether only inclusion in the SmPC and PL is foreseen or any other routine risk minimisation activities are proposed;
  • additional risk minimisation activities (if any), including individual objectives and justification of why needed, and how their effectiveness will be measured.

V.B.8.2. RMP part V section “Summary of risk minimisation measures”

A table listing the routine and additional risk minimisation activities by safety concern should be provided in this RMP section (e.g. the SmPC section number where the risk appears in the SmPC, the list of educational materials). A further summary of pharmacovigilance activities should be included, as described in the EMA Guidance on Format of the Risk Management Plan in the EU(6).