Strict requirements for the market approval of tissue engineering products
New regulations for the marketing approval of advanced therapy medicinal products have applied in the EU since December 2008. Prof. Sabine Kloth from TÜV SÜD Product Service GmbH is an expert in materials of animal origin and has been closely following the formulation of the ATMP Regulation.
Which products are part of the so-called advanced therapies?
As I see it, the majority of products launched within the scope of the ATMP Regulation are combination products. Under the ATMP Regulation, the end product is in any case considered to be a drug. However, there will be many products with a medicinal product component. These include for example collagen fleece. Collagen fleece has already been certified as a medicinal product for a broad range of applications, in the case where it is made from animal material. If cells were applied to this carrier matrix, then it would be regarded as a simple combination product. A more complicated example is a hip implant that is coated with a layer of human cells. In this case, it is considered to be a medicinal product as specified by the ATMP Regulation, but nevertheless it clearly has a medicinal product component. Another very complex example would be a liver support system involving human hepatocytes embedded in a filter unit. Patients' blood flows through this filter unit. Such a filter unit is assembled in a similar way to a dialysis device. In contrast to the evaluation of traditional medicinal products, the evaluation of such devices requires special engineering know-how. Dialysis devices are complex active medicinal products.
ATMP Regulation: The new European Regulation on Advanced Therapy
Medicinal Products (ATMP) (Regulation No. 1394/2007/EU) came into force
in December 2008. The ATMP Regulation regulates the market approval of
advanced therapy medicinal products (gene therapy products, somatic cell
therapy products and tissue engineering products) in the EU and
overrides national law. The central approval procedure is coordinated by
the European Medicines Agency EMEA.
Do you regard the consideration of products as medicinal products as useful?
The debate on whether it is useful to consider the aforementioned products as medicinal products is still ongoing. We have to live with this fact. The problem is that a traditional medicinal product is a chemical. An ATMP is not a chemical but a viable material. Therefore, it is very difficult to use the regulations that are valid for traditional medicinal products for ATMP products. The same is true for requirements relating to clinical trials. A simple translation of regulations from one field to the other is not feasible. However, since ATMPs are medicinal products, we need authorisation regulations and export regulations that take these issues into account.
During the formulation of the new ATMP Regulation it was considered important that the assessment of the medicinal product part of combination products was carried out by qualified experts who are trained to do such assessments. These kinds of specialists are not found in public authorities, but in so-called notified bodies. The notified bodies are bodies that are in charge of the assessment and certification of medicinal products, such as for example TÜV SÜD Product Service GmbH. There are about 80 notified bodies that deal with such assessments in Europe.
Have guidelines been published detailing how ATMP products must be dealt with?
Two guidelines came into force in 2008 (EMEA/149995/2008: Guideline on safety and efficacy follow-up – risk management of advanced therapy medicinal products and EMEA/CHMP/410869/2006: Guideline on human cell-based medical products). These are the first positive steps towards supporting the manufacturers, but this is not enough by far. There are no regulations dealing with the application of ATMP in clinical studies. Guidelines on the procedure and content of applications submitted to EMEA would also be very helpful.
What must a German company do if it wants to launch an ATMP product on the EU market?
The company must contact the EMEA. It is always advisable to talk with EMEA representatives or obtain what is known as scientific advice. If the product is a new innovative one, advice can also be obtained from the Innovation Task Force.
Do you have any idea of the potential cost of launching a combination product?
Details are provided by the EMEA. The cost for the market authorisation of a highly complex medicinal product is somewhere between 20,000 and 50,000 euros. The costs for a marketing authorisation of a medicinal product start at 200,000 euros and can be considerably higher.
Are German companies aware of these costs and the extra administrative work associated with obtaining the marketing authorisation for ATMP products?
Small start-up companies or university spin-offs require in any case further know-how in order to be able to effectively launch an ATMP. And they will probably be able to obtain the necessary know-how by working with consultants. I also come from a university research background, I have worked for many years at a university and I am therefore fully aware that it is perfectly possible to do excellent scientific work without having the slightest idea about the regulations. But regulatory know-how is important for launching medicinal products. The companies will then either have staff with this special know-how or work with excellent consultants. This will most likely be a somewhat painful experience for small companies because regulatory knowledge is essential and communicating this knowledge is a very important task. On this subject, this is one of my objectives: to take the knowledge from TÜV SÜD Product Service GmbH to universities by holding lectures on regulatory aspects.
Was the EU able to achieve its goal, i.e. to provide patients with safer access to ATMP products at the same time as reducing the paperwork?
It is difficult to say if the new Regulation has led to a reduction in bureaucracy. What we have achieved is regulatory safety and harmonised market access. In Germany, market authorisation was already well regulated, however, producers were only able to sell their product on the German market, and this is of course small. The ATMP Regulation is a solid foundation for manufacturers interested in selling their product on the European market, and many companies are quite happy to take on the "extra" work in order to gain access to the European market as a whole. The approval procedures for chemical medicinal products and the market access for medicinal products are well established. With regard to this new type of products, it is worth noting that Germany and Europe can look back on 40 years' work with cell-based products. Blood products have been used for more than 40 years. There have been some painful experiences and the safety standards have been further developed. This has meant that we are more aware of the risks of such products. And this awareness must now be transferred to ATMP products. This will be achieved by working closely together with institutions such as the Paul Ehrlich Institute in Berlin.
But who determines whether a product can be launched or not?
The final decision is made by the EU Commission. The Committee for Advanced Therapies (CAT) comes up with a suggestion on whether the said product is an acceptable product or not. This suggestion is submitted to the Committee for Medicinal Products for Human Use (CHMP). The CHMP assesses the suggestion and forwards it, together with a positive statement, to the EU Commission.
How long does this take?
The hours of work required by the EMEA is regulated by law. 210 working hours are foreseen for traditional medicinal products. Prior to these 210 working hours, the full application must be in the hands of the EMEA. If for example, the assessment of the medicinal product component through a notified body were missing, then the EMEA might ask for it. However, there is currently no information available on how the EMEA will proceed in such cases.
Another aim of the EU was the traceability of products? Do you believe that the new Regulation guarantees this?
The EU Commission has set up a work group that deals exclusively with the traceability and coding of cells. The work group has so far not been able to agree on a coding system because the system is required to guarantee the traceability of cells at the same time as being relatively cheap. Therefore, the results of this work group have not become part of the guidelines on the general procedure. The same is true for the field of pharmacovigilance. In case of doubt, the EMEA will follow the regulations for traditional medicinal products. In my opinion, this is a very difficult constellation because traditional medicinal products are based on chemical substances that have completely different requirements from ATMP products.
The interview was conducted by Dr. Ariane Pott on behalf of BIOPRO Baden-Württemberg.