Pharmaceutical legislation on notice to applicants and regulatory guidelines for medicinal products for human use.

Notice to Applicants

The European Commission in tandem with proficient authorities from the Member States, the European Medicines Agency along with interested parties created the Notice to Applicants (NTA). This was done with the objective to fulfil the obligations of the commission with regards to article 6 of Regulation (EC) No. 726/2004, and with regards to the Annex I to Directive 2001/83/EC as per the amendments. One of the first editions of the Notice to Applicants (which is volume 2 in the series “The Rules governing medicinal products within the European Union) was initially published in the year 1986. This notice was subject to further revisions following which a completed version was issued i.e., the second edition was published in 1989(European Commision, 2020). Later, during 1993, the processes related to applications for marketing authorizations were modified and the mutual as well as centralized regulation procedures came into force from 1995. Decision was then taken to segregate the presentational and procedural aspects of this guidance as volume 2A and 2B. Later on in 2000, a necessity was felt for further particular regulation based guidelines, which was acknowledged and a Volume 2C was created. Publication of the NTA is now under the following volumes:

• Volume 2A deals with all processes pertaining to marketing authorization.
• Volume 2B handles every format and presentation of application dossier.
• Volume 2C tackles issues pertaining to regulatory guidelines.

However, it needs to be taken into consideration that this notice is devoid of any legal force and does not essentially project the final perspectives of the Commission. In the event that any doubt arises, it would be appropriate to draw reference to the suitable Union Directives and Regulations.

Volume 2

As per volume 2 of the publication, the rules that oversee medicinal products within the European Union comprise of a list of regulatory guidelines that is linked with regulatory and procedural requirements like; procedures related renewal, dossier requirements for Type IA/IB variation notifications, summary of product characteristics, package information and classification for supply, label readability and requirements for package leaflets(European Commision, 2020).

Volume 2A – Marketing Authorization

A medicinal product can only be placed in the market within the European Economic Area (EEA) in the event marketing authorization has been duly issued by a competent authority from a member state for their own region (national authorization) or when the grant of authorization has been in tandem with Regulation (EC) No 726/2004 for the whole Union (union authorization). It is essential that the holder of the marketing authorization has been established in the EEA(European Commision, 2006). Pertinent responsible authorities from member states would be responsible for providing marketing authorization for medicinal products that are placed within the markets, other than medicinal products that have been authorized as per Regulation (EC) No 726/2004(European Commision, 2006).

Volume 2B: Format and Presentation

Volume 2B is associated with the presentation and application dossier and it was initially made public as a distinct volume during 1998. It offers guidance with regards to dossier compilation in order to apply for European marketing authorizations and is applicable for the centralized process and nationalized processes. This is inclusive of procedures that are decentralized and mutual recognition(CTD, 2003). This update takes into consideration the international agreements related to the format and structure of the Common Technical Document (CTD) on which an agreement was reached during November, 2000 at the time of the international Conference on Harmonization (ICH) framework and additional documents and modified guidelines that have been agreed upon from then onwards.

The present requirement for the content of the dossier for European application are outlined as per the Annex I to Directive 2001/83/EC as modified, and as mentioned in Article 8.3 “this application would be accompanied with the following documents and particulars, as submitted according to Annex I, Annex I of the Directive 2001/83/EC which outlines the legal provisions for executing the CTD format. The provision of this update from Volume 2B (EU-CTD), which considers the ICH agreements, substitutes the earlier structure of the European marketing authorization dossier as it has been elucidated within the 1998 edition of Volume 2B. From July, 1^st 2003 onwards, every application was supposed to be made as per the EU-CTD presentation as mentioned during the July, 2003 edition of the NTA, Volume 2B or any later updates. With a view to also consider experience with regards to the structure of CTD and modifications of a scientific or technical nature, it is anticipated that NTA, Volume 2B would be subject to regular updates and extra guidance would be provided in the manner of Question & Answer 2 documents on the basis of experience that has been achieved.

Volume 2C: Regulatory Guideline

Following 1^st of July, 2003, every application for variation needs to be presented using the EU-CTD format. Nonetheless, any cross-references to ‘old’ EU format documentation will be accepted as the content would be more or less the same. Any clear reference to any ‘old’ format documentation is necessary. For instance;

• Any new (either revised or additional) data in support of the variation is supposed to be submitted utilizing the CTD format.
• In case any data is supposed to be submitted which is not changed, for instance, the Type I variation guideline might specify the necessity for submitting a copy of the approved specifications, then the marketing authorization holder needs to update the said specifications within the new CTD format. The holder of marketing authorization is also supposed to offer a declaration which would imply that the content of any document that has been reformatted is unchanged. Any kind of variation in the future application would then be in a position to utilize such updated (CTD) specifications).

Here only a cross-reference to an authorized data that already existed is needed. Cross-references of such kind could still be made to the pertinent ‘old’ format dossier (part and section). Nonetheless, if the holder of the marketing authorizations opts to take the opportunity to present the (unaltered) data in the format of the new CTD instead, this would be acceptable as well. This is because that it would enable any variations in future to be handled. In addition, the holder of the marketing authorization is also expected to offer a declaration which would state that the content of all documents that have been reformatted would remain unaltered.

References

1. (2003). Volume 2B Notice to Applicants Medicinal products for human use. 2. Retrieved from https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-2/b/update_200805/ctd_05-2008_en.pdf
2. European Commision. (2006). Procedures for marketing authorisation. Retrieved from https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-2/vol2a_chap1_rev6_201612.pdf
3. European Commision. (2020). EudraLex – Volume 2 – Pharmaceutical legislation on notice to applicants and regulatory guidelines for medicinal products for human use. Retrieved from https://ec.europa.eu/health/documents/eudralex/vol-2_en