Peter O'Donnell
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The European attempt to boost the emergence of new therapies is starting to gain momentum. The EU rules that agreed in 2007
to create a standardized and centralized authorization process for advanced therapy medicinal products are coming into full
effect, and the procedures that applicants have to follow are being more clearly defined.
A further directive setting out the requirements in detail is in the final stages of approval in Europe's byzantine legislative
machinery, and should come into force at the start of June.
These new detailed requirements are a response to the specific nature of these products, in which a risk-based approach may
be applied to determine the extent of quality nonclinical and clinical data to be included in the marketing authorization
application.
So, for instance, for all products where the clinical application of advanced therapy medicinal products requires specific
concomitant therapy and involves surgical procedures, the therapeutic procedure as a whole has to be investigated and described.
And since it is the nature of advanced therapy medicinal products that their manufacturing process may change during clinical
development, additional studies to demonstrate comparability may be required. Risks arising from potential infectious agents or the use of material derived from animal sources during clinical development
will have to be addressed, along with measures to reduce the risks. Dose selection and schedule of use will have to be defined
by dose-finding studies. And the efficacy of the proposed indications will have to be supported by relevant results from clinical
studies using clinically meaningful endpoints for the intended use.
In some clinical conditions, evidence of long-term efficacy may be required, and the strategy to evaluate long-term efficacy
will have to be provided, along with a strategy for the long-term follow-up of safety and efficacy. Further specific provisions
are imposed on gene therapy and somatic cell therapy products and on tissue engineered products.
At its third meeting in March, the Committee for Advanced Therapies (CAT), created at the heart of the new system within EMEA,
adopted its own rules of procedure and also provided an update of what it has so far done—which is to start evaluation of
the three applications it has received thus far.
The CAT wants to raise its profile and awareness of its role, and is seeking collaboration with academia. It has also held
discussions with representatives of the Japanese health authorities "with a view to...exploring potential opportunities for
cooperation."
During April 2009, a workshop explained the system to potential applicants and provided further information on the classification
of advanced therapies, dossier requirements for applications, procedures for postauthorization follow-up and traceability,
and how the CAT interacts with EMEA's principal scientific committee for assessing marketing authorizations for medicines.
CAT is already focusing on advanced products already on the market with authorizations granted under national or earlier EU
legislation, and that will have to comply with the new rules by the end of 2012. It is stressing the importance of early contacts.
Viral vectors
Meanwhile, work continues at the coalface, as it were, where industry and regulators work together on designing guidelines
for the development of specific advanced products. The latest output is a draft reflection paper on quality nonclinical and
clinical issues relating to recombinant adeno-associated viral vectors, of particular interest for gene therapy application
due to their long-term persistence.
The document was generated in EMEA's gene therapy working party and has been reviewed by CAT. It is open for consultation
until September.
"The development of these vectors as medicinal products is at a relatively early stage, and both pharmaceutical companies
developing the products and the regulatory agencies involved in giving advice and assessing marketing authorization applications
have much to learn," the document remarks.
It reviews production systems—virus-containing and virus-free, as well as self-complementary recombinant adeno-associated
virus—choice of animal model, vector persistence, tissue tropism, reactivation of productive infection, germ-line transmission,
and environment risk considerations. And in clinical terms, it assesses biodistribution and shedding studies, immunogenicity,
germ-line transmission and long-term follow-up.
Determining what sampling/analysis is included or excluded from protocols on the basis of nonclinical data will need to be
scientifically justified, says the guideline.
"The extrapolation of biodistribution data from animal models to humans is not straightforward. It is recommended that wherever
possible an investigation into the biodistribution of the vector, by screening for DNA sequences in the first instance, should
be included within a clinical trial protocol," it says.
Similarly, the extrapolation of immunogenicity data for therapeutic applications from animal models to humans "is not simple,"
and the route of administration may also impact on the immunogenic profile of the product.
"It is recommended therefore that consideration is given to the potential of subjects having pre-existing antibodies to the
serotype under investigation, and that evaluation of the immunogenicity of both the vector and the transgene is assessed in
terms of neutralizing and non-neutralizing antibody formation during clinical trials."
Nor has the question of germ-line transmission in humans been fully resolved, and since short-term DNA persistence has been
observed in semen, it is recommended that germline transmission is investigated during clinical studies and that the use of
barrier contraception for individuals enrolled in clinical trials is included in study protocols.
If nonclinical studies indicate long-term persistence of the vector, due to viral DNA integration or episomal maintenance,
long-term follow-up of the patients treated "could be necessary, not only in terms of safety evaluation but also efficacy.
It should also be considered that where these vectors are being investigated for preventive vaccination uses, long-term expression
of the antigenic proteins may be a safety risk rather than a desired outcome."
