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Changing rules on advanced therapy medicinal products to require more from clinical studies.
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.
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."
By coincidence, the EMEA has also published its 2008 Public Status Report on implementation of the European risk management strategy, aimed at an advanced quality of risk assessment, not just for advanced therapies but all meds.
Its goal is to improve the evidence for safety monitoring, ensure more proactive pharmacovigilance, and find what it calls "the right balance between timely access to medicines and the knowledge on the safety profile needed at the moment of licensing."
The latest conclusion of this in a series of annual reports is that good progress has been made, particularly in strengthening the science and methodology that underpins the safety monitoring. It attributes much of the success to an advanced level of collaboration between all EU regulatory authorities.
Nowadays everyone is vying for transparency prowess. EMEA is elaborating its new policy. And already the guiding principles in its mission statement say: "We communicate in an open, transparent manner with all of our partners, stakeholders, and colleagues."
So when this columnist received a press release on the March meeting of the agency's committee for orphan medicinal products (COMP), it seemed logical to follow-up on what looked like an interesting detail. The release said: "The main topics addressed during...the meeting related to...discussion on the 9th Workshop of the Eurordis Round Table of Companies on 'Significant Benefit of Orphan Drugs: Impact on Clinical Development and Assessment' held on December 12, 2008, in Paris."
An email went to the agency (and Eurordis) on March 8, expressing interest in learning more about this. Not until March 23 did the agency reply.
It said: "First of all I would like to apologize for the late reply. Unfortunately, we do not have more information we can disclose on this and Eurodis (sic) was better choice to contact."
Eurordis wasn't in fact a "better choice to contact." It had already replied on March 17, stating that "the 9th ERTC Workshop we organized in Paris on December 12, 2008, was actually on 'Significant Benefit of Orphan Drugs: Impact on Clinical Development and Assessment,' not on clinical trials."
Helpfully, if somewhat confusingly, it added: "If you can confirm the name of the workshop, I am happy to send you the concept paper for it."
ACT readers won't be getting an update on this workshop. Don't blame me. Blame transparency.
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.