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Pharmaceutical Companies Face New Pharmacovigilance Obligations in the EU

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10 November 2013

Amendments to the EU pharmacovigilance legislation that were adopted in October 2012 (through Directive 2012/26/EU) came into force on Monday 28 October. From now on, pharmaceutical companies withdrawing medicines from the EEA or a third country (i.e., non-EEA) market for safety or other product-related reasons must notify the competent authorities, and state why they are doing so. Additionally, the 2012 amendments clarify the scope of, and strengthen the EU safety referral procedures, and now permit urgent action (such as a suspension of a medicine) by EU Member States in the course of an Article 31 referral.

Beginning 28 October 2013, pharmaceutical companies are now required to notify the relevant authorities of the withdrawal (or other similar actions described below) of a medicinal product from the EEA or a third country market, together with the reason for this action. While the same requirements for centrally approved medicines came into effect on 5 June, they now apply to all medicinal products, counting nationally authorised medicines (including those authorised through the mutual recognition and decentralised procedures). The notification requirements are intended to enable the European medicines network to respond promptly where there are safety issues and to prevent companies from withdrawing products for supposedly commercial or other reasons where there might in fact be underlying safety issues.

WHAT ACTIONS? – Notification must be made where (i) the marketing of a medicinal product is temporarily or permanently discontinued or suspended; (ii) if the medicine is withdrawn from the market; (iii) if a company requests to withdraw the marketing authorisation (MA); or (iv) states that it has no intention to renew the marketing authorisation for a specific medicine.

ON WHAT GROUNDS? – If any of the above listed actions involve the EEA market, notification is mandatory regardless of the reasons for the (intended) action.

However, with respect to third countries, companies must notify the authorities only if the action is taken for any of the five following reasons:

The medicine is harmful;
The medicine lacks therapeutic efficacy;
The benefit-risk balance of the medicine is not favourable;
The medicine’s qualitative and quantitative composition are not as declared; or
Manufacturing or inspection issues have been identified.

TO WHOM? – For centrally authorised medicines, notifications must always be sent to the European Medicines Agency (EMA).

For those actions involving nationally authorised medicines companies must notify the competent authorities of the Member States concerned. In addition, if the action is taken on the basis of any of the five aforementioned grounds, notification must be made to the EMA as well.

WHEN? – Pharmaceutical companies must notify the EMA or competent authorities no less than two months before the temporary or permanent interruption in the placing on the market of the product, except under exceptional circumstances.

However, for both EEA and third countries, if the action is taken on the basis of the five grounds mentioned above, notification must be forthwith.

HOW? – The notification should clearly state the action intended to be taken and the reason for such action (in particular when these are based on the aforementioned grounds). Notifications should be sent to the EMA using a specific template and cover letter, available via the EMA website, to, and to the relevant national authorities’ respective requirements.

PUBLICATION? – Beginning in 2014, the EMA intends to regularly publish a list of medicines for which a marketing authorisation has been refused, revoked or suspended in the EU, whose supply has been prohibited or which have been withdrawn from the market. This list will include the reason for the actions taken.

In addition to setting forth new notification requirements, the 2012 amendments also clarify and strengthen the main EU safety referral procedures (for non-centrally authorised medicines), with the goal of allowing swift assessment and subsequent action where safety problems are identified, and facilitating enhanced coordination amongst regulatory authorities.

A “referral” is a procedure during which specific (usually safety or quality) issues related to a medicine or a class of medicines are ‘referred’ to the EMA for a scientific assessment in order to obtain a harmonised EU-wide recommendation. As a general rule, an Article 31 referral (the Normal Procedure) should be initiated for matters concerning quality, safety or efficacy of medicinal products where the interests of the Union – in particular interests of public health – are involved. The Urgent Union Procedure, as set forth by Article 107i, on the other hand, will be triggered when there is a need to swiftly assess safety concerns resulting from the evaluation of data from pharmacovigilance activities.

2.1 The Urgent Union Procedure (Article 107i referral)

REINSTATE AUTOMATIC CHARACTER – The amendments to Article 107i of Directive 2001/83/EC aim at reinstating the “automatic” character of the so-called “Urgent Union Procedure” which had been lost during the 2010 revision of the legislation.

GROUNDS FOR REFERRAL – The grounds that will set the Urgent Union Procedure in motion remain largely the same, with one potential addition: where a marketing authorisation holder has not applied for the renewal of the marketing authorisation. In sum, the Urgent Union Procedure is now automatically triggered if the European Commission or a Member State:

  • considers any of the following actions based on an evaluation of data resulting from pharmacovigilance activities, i.e., (i) suspension or revocation of a MA; (ii) prohibition of the supply of a medicine; (iii) refusal of the renewal of a MA; or
  • is informed by a marketing authorisation holder that, based on safety concerns, it has interrupted the placing on the market of a medicine; has or intends to take action to have a marketing authorisation withdrawn; or has not applied for the renewal of a marketing authorisation.

2.2 The Normal Procedure (Article 31 referral)

CLEAR DELINEATION OF SCOPE – First, the amendments to Article 31 clearly delineate the scope between the two safety referral procedures by stating that “where one of the criteria listed in Article 107i(1) is met, the [Urgent Union Procedure] shall apply.”

TEMPORARY URGENT ACTION PERMITTED – In addition, similar to what is set forth in the Urgent Union Procedure, a Member State or the Commission (where centrally approved medicines are involved) can now suspend or prohibit the use of a medicine at any stage of the procedure if it considers that ‘urgent action’ is necessary to protect public health, as a temporary measure until a final decision is adopted.

INCLUSION OF CENTRALLY AUTHORISED MEDICINES – Ultimately, for Article 31 referral procedures covering a range or therapeutic class of medicines, centrally authorised medicines will be included whether the grounds for the procedure are based on safety, efficacy or quality issues.

A recent EMA communication also highlights two other recent amendments to the pharmacovigilance legislation which were already in force before 28 October 2013 but may have gone unnoticed.

3.1 Extended Additional Monitoring

Earlier (2010) amendments to the EU regulatory framework introduced the “additional monitoring” list, which mandates certain medicinal products to be marked with an inverted black triangle.

EXTENSION OF MANDATORY SCOPE – Previously, this was reserved for (1) products containing a new active substance that had not been approved in the EU as of 1 January 2011 and (2) any biological products (including biosimilars) that were authorised after that date. As of 5 June 2013, the “mandatory” scope of the medicines that are automatically subject to additional monitoring has been extended to include:

  • Medicines given conditional approval or authorised under exceptional circumstances and medicines authorised with specific obligations regarding the recording or monitoring of suspected adverse reactions; and

  • Medicines for which the marketing authorisation holder is required to carry out a post-authorisation safety study (PASS).

REMAINING OPTIONAL SCOPE – Those medicines were previously included in the “optional” scope, meaning that they could be included in the additional monitoring list at the request of the European Commission or a national competent authority, following consultation with the Pharmacovigilance Risk Assessment Committee (PRAC). There remain some situations that could still form the basis for such an “optional” request, such as the granting of a MA subject to, for example, the existence of an adequate pharmacovigilance system or an obligation to conduct a post-authorisation efficacy study (PAES).

GRADUAL IMPLEMENTATION OF BLACK TRIANGLE – As of 1 September 2013, the product information for all new EU medicines (authorised after 1 September 2013) that are subject to such additional monitoring must include the inverted black triangle in the patient information leaflet and in the summary of product characteristics.

For monitored medicines authorised before September 2013, the black symbol will be introduced “gradually” meaning that companies may request authorities for a longer implementation time. However, stocks of medicinal products produced, packaged and labelled before January 2014, which do not yet include the symbol in the package leaflet, may continue to be placed on the market, distributed, dispensed, sold and used until the stocks are exhausted.

3.2 Additional Translation Exemptions

The 2010 amendments to the EU pharmacovigilance legislation have also extended the scope of the translation exemptions in order to facilitate the availability of medicines across the EU. As a general rule, the labelling of a medicinal product must be presented in the official language(s) of the Member State(s) where the product is placed on the market.

Previously, translation exemptions applied to medicines intended for the treatment of rare conditions (orphan medicines) and medicines administered to health care professionals only. Under the revised legislation, marketing authorisation holders can now also request an exemption from the requirement to translate both the package leaflet and the labelling where there are severe issues of availability, including shortage of medicines.

Allen & Overy’s life sciences practice has extensive experience in advising pharmaceutical companies on existing and new pharmacovigilance obligations. If you need assistance in this respect, please contact us.