Principles and Practice of Pharmaceutical Medicine

packages (addressing blister packs, ampoules,
etc.).

34.13 Marketing authorization

variations, renewals and

reclassification

License variations

Most of the work of the national regulatory autho-
rities concern license variations, line extensions
and license renewals. The application will follow
the same approval procedure in which the original
authorization was obtained. As many products cur-
rently licensed have been licensed through national
procedures, before the mutual recognition or CP
were available, many of the applications are still
undergoing the national approval process in each
MS separately.
Since October 1, 2003, the European variations
regulations came into force, which introduced a
newly revised Annex I to Directive 2001/83. The
relevant Commission regulations 1084/2003/EC
and 1085/2003/EC concern mutual recognition
and CPs, respectively. The MRFG has issued a
Best Practice Guide, which implements the direc-
tive and gives guidance to MA holders on how to
apply for the variations under national or MRP.
Guidance on variations in the CP can be found in
the CPMP document on post-authorization gui-
dance (human medicinal products), February 2004.
License variations are divided into three main
categories termed ‘Type I variation’, ‘Type II var-
iation’ and ‘extensions’. The main changes intro-
duced by the new legislation are

a new category of minor variation (Type IA
notification) with a 14-day timeline and requir-
ing only scientific validation;

the former revised Type I minor variation cate-
gories are now classed as Type IB notifications,
and have a 30-day review timeline;

RMS act on behalf of all CMS for products
approved by the MRPs for Type I minor variations;

flexibility of timelines for Type II variations

(extension for new indications and reduction

for safety variations);

introduction of a process of appeal by MA

holders when Type IB and Type II variations

are rejected;

streamlined decision making for centralized

notifications;

new Annex II of the variations regulations and

definition of extension applications.

Frequently, MA holders find it difficult to classify

the requested labeling change into Type IA, IB and

so on. The ‘Notice to applicants of the EU Commis-

sion – Guideline on the categorisation of new

applications versus variations applications, Jan

2002 ’aims to clarify these issues, and it has now

been supplemented (July 2003) by the ‘Guidance

on dossier requirements for Type IA and IB notifi-

cations’ which lists of all foreseen variations, their

classification and the documentation required.

Revisions of the former are expected in late 2005.

In general, Type IA and IB variations are, for

example, changes of administrative nature like the

address of the MA holder; changes in batch sizes

within limits; minor changes in test procedures.

These contrast with ‘Extension’ applications,

which are necessary when the following has

occurred:

changes to the active substance(s);

changes to the indications;

changes to strength, pharmaceutical form and

route of administration;

changes specific to veterinary medicinal pro-

ducts.

Any of these changes have to undergo a full scien-

tific evaluation as for any new marketing applica-

tion. An exception to this rule is the annual human

influenza vaccine, which, although a change to the

34.13 MARKETING AUTHORIZATION VARIATIONS, RENEWALS AND RECLASSIFICATION 473