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Information for marketing authorization holders on the transitional arrangements of the new pharmacovigilance legislation July 2012

Information for marketing authorization holders on the transitional arrangements of the new pharmacovigilance legislation

1. Adverse drug reaction reporting

National Institute of Pharmacy (hereinafter referred to as the Institute) requests the spontaneous adverse reaction reports to be submitted to the Institute during the transitional period of the new pharmacovigilance legislation (2/21 July 2012 – 2/21 July 2015) as follows:

Please be informed that the requirements of the different national competent authorities in the EU in relation to adverse reaction reporting may vary during the transitional period.

1.1 Serious cases

Serious suspected adverse reactions that occur within the territory of Hungary

The reports shall be submitted via EudraVigilance (EV) to the ID OGYIP and to the ID EVHUMAN as well. It means that unlike up to the present, the marketing authorization holders (MAH) should send the reports directly to the EV database along with a notification to the Institute (which is to submit the reports to the ID OGYIP). The Institute will not forward the reports originating from MAHs to the central EV database from now on.

The Institute will introduce a 3 months transitional period starting from 21 July 2012 till 21 October 2012 to make sure that MAHs are able to switch to the new reporting procedure smoothly. From 21 October, it will be the MAH's sole responsibility to make sure that the reports arrive to the central EudraVigilance database. Adherence to the new requirements will be monitored by NIP.

Serious suspected adverse reactions that occur in the territory of a European Union Member State other than Hungary

The Institute does not require these reports to be submitted to OGYIP. For serious adverse reactions occurring in the territory of a European Union Member State other than Hungary, the reporting requirement of the competent authority shall be followed. For further information on this topic will be available on the EV website.

Serious suspected adverse reactions from outside the European Union

The Institute does not require these cases to be submitted to OGYIP either. Serious cases originating from outside the EU shall be submitted directly to the central EV database to the ID EVHUMAN. Furthermore, certain Member States shall also be informed. Please refer to the EV website for further guidance.

1.2 Non-serious cases

The Institute does not require non-serious cases to be submitted to OGYIP. The requirements of non-serious adverse reaction reporting may vary during the transitional period among Member States of the EU, please refer to the EV website for further information.

Please note that irrespective of the differing reporting requirements of the Member States, all adverse reactions (serious and non-serious as well) occurring anywhere in the world should be recorded in their database and should be analyzed and evaluated in the respective PSURs. When considered necessary, the Institute may request an analysis of non-serious adverse reactions or a line listing of the individual cases. All cases that are not accompanied by the development of adverse reactions, but may provide important information during the assessment of the risk-benefit balance of the products should also be recorded (e.g. drug exposure during pregnancy, medication errors, inappropriate use, abuse, overdose etc.)

2. Periodic safety update reports (PSUR)

2.1 Derogation from the submission of PSURs

The requirement to submit PSURs is waived for generic medicinal products (authorized under the legal basis of Article 10(1) of Directive 2001/83/EC), WEU products (Article 10a), traditional herbal medicinal products (Article 16a) and homeopathic medicinal products (Article 14). However, if considered necessary by the authority, PSURs for several certain active substances will continue to be required, e.g. because the original drug was withdrawn from the market or safety issues emerged with the active substance. The EURD (European Union Reference Date) list will indicate the active substances for which PSURs shall continue to be submitted on the above mentioned grounds. Until the EURD list becomes legally binding – which is expected to take place in April 2013 – an upcoming publication of the European Medicines Agency (EMA) will substitute the list in this context.

2.2 Deadline for PSUR submission

PSURs will be submitted during the transitional period irrespective of whether they follow the old or the new format according to the following schedule:

· within 70 calendar days of the data lock point for PSURs covering intervals up to 12 months;

· within 90 calendar days of the data lock point for PSURs covering intervals in excess of 12 months;

· the timeline for the submission of ad hoc PSURs requested by the national authority will be normally specified in the request, otherwise the ad hoc PSURs should be submitted within 90 days of the data lock point.

The data lock point for PSURs will remain the same until the EURD list comes into force. It is expected that following April 2013, the EURD list will determine the data lock points. In case the PSUR cycle specified in the marketing authorization is different from the one indicated in the EURD list, it will need to be brought in line with the EURD list through submission of a variation. Guidance on the submission of such a variation is expected to be published in due time.

2.3 Submission of PSURs to the national competent authorities

Until the EMA delivers the new PSUR repository, marketing authorization holders shall submit the PSURs to all competent authorities of the Member States in which the medicinal product is authorized, and in case of centrally authorized medicinal products to the EMA.

The Institute requests PSURs to be submitted according to the following:

· Via e-mail, to the e-mail address adr.box@gyemszi.hu. Should the size limit of electronic transmission be exceeded, 1 copy of a CDROM should be sent to the Institute, with a simultaneous notification of the submission in e-mail.

· Required format: 1 copy of a pdf file. In case Hungary is the reference member satet [(Co)-Rapporteur, RMS or PSUR-RMS], an additional copy in word format is also required.

Please note that the requirements of PSUR submissions may vary among Member States as detailed on the EMA website.

2.4 Format of PSURs

Commission Implementing Regulation published by the European Commission on 19 June 2012.

The new format of PSURs can be found in the

A 6-month transitional period came into force on the day of the publication of the Commission Implementing Regulation, during which, applicants and marketing authorization holders can either use the old (Volume 9A) or new (Commission Implementing Regulation) format and content for the PSUR irrespective of the type of the authorization procedure.

PSURs submitted in accordance with the old format (Volume 9A) during the 6-month transitional period, will have to incorporate a critical evaluation of the benefit-risk balance either in the PSUR or in an attachment to the cover letter. The 6-month transitional period will apply according to the PSUR submission date and not to the data lock point.

PSURs prepared under the new format and content will not contain line listings. However, the MAH may have to provide them upon request of the EMA or the national competent authorities.

3. Risk Management Plan (RMP)

3.1 Submission of a Risk Management Plan in a marketing authorization application

All applicants submitting an initial marketing authorization application (MAA) after 2/21 July 2012 irrespective of the legal basis of their MAA are required to submit an RMP.

For initial marketing authorization applications pending on 2/21 July 2012 and not containing an RMP, there is no obligation to submit an RMP during the course of the evaluation procedure. The submission of an RMP is not required for an application for a traditional herbal medicinal product, nor for a homeopathic medicinal product. For other herbal or homeopathic medicinal products not falling within the scope of the traditional use registration or simplified registration respectively, an RMP will be required for any initial marketing authorization applications after 2/21 July 2012.

3.2 Format of the RMP

The new format of RMPs can be found in the Commission Implementing Regulationpublished by the European Commission on 19 June 2012. A 6-month transitional period came into force on the day of the publication of the Commission Implementing Regulation, during which, applicants and marketing authorization holders can either use the old (Volume 9A) or new (Commission Implementing Regulation) format. The template for the RMP will be updated and this is expected to be available around September 2012.

3.3 Publication of the summary of RMP on the national web-portal and the European medicines web-portal

Marketing authorization holders are reminded that a summary of the RMP will be published on the national or the European medicines web-portal. This requirement also applies to existing medicinal products with an RMP. After the RMP gained acceptance during the evaluation procedure, applicants shall submit the Hungarian summary of the RMP. The time of submission must be before the end of the evaluation procedure. As for already existing RMPs, MAHs are requested to submit a Hungarian summary thereof to the Institute by 31 December 2012 at latest.

The summary of the RMP will follow the new format and content as set out in the Commission Implementing Regulation and as detailed in the relevant GVP module.

4. Pharmacovigilance System Master File (PSMF) and the summary of the pharmacovigilance system

4.1 Submission of the summary of the pharmacovigilance system in the marketing authorization application (and introduction of the PSMF)

After 2 July 2012 (for CAPs) and 21 July 2012 (for NAPs), instead of a Detailed Description of Pharmacovigilance System (DDPS) applicants are required to include a summary of the pharmacovigilance system in the initial marketing authorization application in Module 1.8.1 of the dossier. The PSMF will take the role of the DDPS, and even if the PSMF will not be provided on a routine basis for assessment, the document itself and the system behind it must be established by the time of the submission of the initial marketing authorization application.

The new requirement (summary of the pharmacovigilance system included in the dossier and the establishment of the PSMF) will replace the old regulation (DDPS) according to the following schedule:

· An initial marketing authorization application can only be initiated according to the new requirement

· For existing and pending marketing authorizations (MAs), the switch from the DDPS to the PSMF shall take place according to the following timeline, whichever is the earlier

- At the time of submission of the renewal application,

- At time of the annual renewal for a conditional marketing authorization through the centralized procedure,

- By 2/21 July 2015 at the latest.

These requirements apply to all existing MAs with or without a detailed description of the pharmacovigilance system (DDPS) in their dossier.

Applicants or marketing authorization holders may introduce the PSMF before the aforementioned deadlines, provided that the PSMF fully complies with the new legal requirements.

For pending initial marketing authorization applications and renewal applications on 2/21 July 2012, there is no obligation to replace the DDPS with the summary of the pharmacovigilance system and introduce the PSMF during the course of the evaluation procedure.

A variation shall be submitted when introducing the PSMF and the summary of the pharmacovigilance system (except for initial MAAs and renewals), the classification of which will be defined in the revised classification guideline that will be published soon. It is expected to be a Type IAin variation.

Please be informed that the 'master file' introduced temporarily on a national level in 2010, by the Institute, does not correspond either in content, or in format to the PSMF that comes into effect on 2/21 July 2012.

4.2 Introduction of changes to the summary of the pharmacovigilance system

From those elements included in the pharmacovigilance system summary, changes to the QPPV and/or QPPV contact details and/or to the PSMF location will require the submission of a variation application in accordance with the variation classification guideline.

4.3 Introduction of the PSMF and the summary of the pharmacovigilance system for traditional herbal and homeopathic medicinal products

The requirement to operate a pharmacovigilance system and to maintain and make available on request a pharmacovigilance system master file also applies to traditional herbal and homeopathic medicinal products. However, the requirement to submit a summary of the pharmacovigilance system in the application dossier does not apply to them.

For other herbal medicinal products not falling within the scope of the traditional use registration, are not exempted from submitting a summary of the pharmacovigilance system.

5. Post Authorisation Safety Studies (PASS)

The new procedures for submission and assessment of PASS protocols, substantial amendments and final study results only apply to PASS studies which have been imposed after 2/21 July 2012 as a condition to the marketing authorization.

We hereby inform marketing authorization holders, that from 21 July 2012 the Institute will take over the authorization of non-interventional studies (therefore PASS as well). Furthermore, the Institute will contact the Ethics Committee (ETT-TUKEB) whenever necessary during the evaluation procedure of these studies. The documentation should be submitted henceforth exclusively to the Institute (Clinical Trial Unit), which will be forwarded to the Ethics Committee.

6. Renewals

The obligation to submit the renewal application 9 months before the expiry of the marketing authorization applies to medicinal products for which the marketing authorization expires after 2/21 April 2013.

The new requirements on the content and procedure for a renewal which are set out in theupdated guideline will apply as of 2/21 July 2012. Therefore any renewal applications submitted after 2/21 July 2012 will have to comply with the new requirements and will follow the new procedure.

PSUR, PSUR addendum, Summary Bridging Report and line listing should no longer be submitted as part of the renewal application. Therefore, in the first months of implementation it is particularly critical that the clinical overview includes relevant information to support the benefit-risk re-evaluation of the medicinal product.

Further information on the transitional arrangements of the new pharmacovigilance legislation can be found in the Question and Answer document of the EMA.

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