Principles and Practice of Pharmaceutical Medicine

scientific and regulatory challenge, insofar as the
synthetic process takes place inside a living organ-
ism. The synthetic process cannot be controlled
directly and this fact alone introduces a series
of aspects linked to factors, which are certainly
more difficult to control and standardize. Years
ago the regulatory thinking for biotech products
was based on the paradigm ‘the process defines the
product’, implying that changes in manufacture
could result in changes in the product difficult
or impossible to detect, with the risk of nonther-
apeutic biological responses. This excluded, in
practice, the possibility of generic applications
for biotech products.
Now, there has been a substantial change in
attitude toward biotech products: technological
improvement and higher sophistication of analyti-
cal methodology make it possible to design inte-
grated control strategies allowing physicochemical
characterization to begin to shift the focus from the
process to the product.
In any case, Article 10 of Directive 2004/27
introduces the concept of ‘similar products’ as
follows:
‘Where a biological medicinal product, which is
similar to a reference biological product, does not
meet the conditions in the definition of generic
medicinal product, owing to, in particular, differ-
ences relating to raw materials or differences in
manufacturing process of the biological medicinal
product and the reference biological medicinal
product, the results of appropriate preclinical
tests or clinical trials relating to these conditions
must be provided. The type and quantity of supple-
mentary data to be provided must comply with the
relevant criteria stated in Annexe 1 and the related
detailed guidelines. The results of other tests and
trials from the reference medicinal product’s dos-
sier shall not be provided’.
Note that the Directive makes two important
points: (a) similar biological products are legally
admitted and (b) at least partial reference to the
originator dossier is acceptable, making it possible
to prepare a dossier based on ‘bridging studies’, to
be decided on a case-by-case basis. A correspond-
ing Guidance has also been published (EMEA/
CPMP/BWP/3207/00/Rev.1, EMEA/CPMP/3097/
02/final).

When considering how extensive the compara-

tive studies must be, the following factors are

relevant:

Stage where the manufacturing change is intro-

duced

Potential impact of the change on product char-

acterization

Suitability of analytical techniques to detect

potential modifications

Relationship between established quality cri-

teria with safety and efficacy results based on

the overall preclinical and clinical experience

Where similarity to an already authorized product

is claimed, the nonclinical and clinical data to be

submitted will probably be decided on the basis of

the following considerations:

The extent to which the product may be charac-

terized

The nature of the changes in the new product

compared to the reference product

The observed/potential differences between the

two products

The clinical experience with the particular class

of products

One critical issue may be that of immunogenicity.

This must always be investigated, and a plan for a

post-marketing monitoringmust be includedin any

‘generic biological product’ application.

34.11 Herbal medicinal products

Herbal medicinal products represent a large market

in the EU, although unevenly distributed across

MS. Although there is a separate chapter on com-

plementary medicines in this book, we must here

consider the special regulatory approach that is

taken toward these distinctive products within the

468 CH34 MEDICINES REGULATION IN THE EUROPEAN UNION