With the new regulation on advanced therapy medicinal products, the European Union has the goal to establish legal certainty with regard to gene therapy, somatic cell therapy and tissue engineering products. However, Dr. Heinz W. Joseph of TETEC AG is sure that the new guidelines will lead to difficulties for small and medium-sized companies.
Research in the area of biology, medicine and biotechnology has made considerable progress over the last few years and might soon be able to provide new solutions for the prevention and treatment of diseases and functional disorders of the human body. Products arising from this research, tissue engineering products in particular, are already frequently used in the treatment of patients.For the last few years, numerous gene therapy and somatic cell therapy products have entered clinical trials, including products for the treatment of Parkinson’s disease and cancer. Consequently, the EU has sought to put in place regulations that take these developments into account. With the regulation on advanced therapy medicinal products, the EU is seeking to provide an EU-wide regulatory framework to replace diverse national approaches, particularly with regard to tissue engineering products. The regulation was designed to ensure the free movement of advanced therapy products within Europe, to facilitate access to the European market and to boost the competitiveness of European companies in this field, at the same time as guaranteeing the highest level of health protection for patients.
According to the new regulation, the medicinal advanced therapy products, i.e. gene therapy, somatic cell therapy and tissue engineering - are classified as medicinal drugs and need to fulfil the same approval conditions as traditional drugs. Authorisation for marketing new drugs in the EU is given by the EMEA - European Medicines Agency. Dr. Heinz Joseph of TETEC AG and chairman of the BPI e.V. Biopharm (special interest group of the biotechnology industry within the German Pharmaceutical Industry Association) envisages numerous problems, in particular for small and medium-sized companies (SMEs). "Initially, many SMEs do not want to obtain marketing authorisation for the EU as a whole because the costs associated with this are still too high, even though the EU grants SMEs' fee reductions and exemptions," explains Joseph. "In addition, SMEs often lack the regulatory know-how that is required to successfully apply for marketing authorisation. They have to turn to expensive consulting companies. TETEC AG is lucky in that it is part of Aesculap AG."
In contrast to the traditional pharmaceutical industry, human tissue engineering medicinal products (hTEPs) are often developed at universities and research laboratories. Small companies, which have produced and marketed products according to GMP standards, are increasingly spun out of universities. It had not previously been necessary to obtain marketing authorisation for these products. However, from the end of 2012, EU-wide marketing authorisation will have to be obtained from the EMEA for all hTEPS already on the market. National approval procedures will no longer be valid. “This might result in many products disappearing from the market from 2012 because many SMEs will not have the financial means to comply with the EMEA requirements, which include the carrying out of expensive and time-consuming clinical trials. This will of course also affect the treatment of patients,” said Joseph.
Clinical trials involve the testing of medicinal products on humans and are carried out according to strict scientific regulations. The trials are classified in four phases. Phase I clinical trials are the first stage of medicinal product testing in human subjects and normally only involve a small number of healthy volunteers in the assessment of potential side effects of a drug. Phase II clinical trials are designed to assess how well the drug works for a certain disease. Phase III clinical trials are aimed at enabling the definitive assessment of how effective the drug is by comparing it to current ‘gold standard' therapies. Marketing authorisation is usually given after the successful completion of phase III trials, which are randomised multicentre trials involving large groups of patients.
"Randomised trials carried out to assess the safety and tolerability of already marketed drugs and involving already successful therapeutic procedures are questionable from both a financial and ethical point of view," said the biochemist, using autologous chondrocyte transplantation as an example: Autologous chondrocyte transplantation (ACT) has been applied since 1994 to treat focal cartilage damage using autologous cartilage cells. The procedure is superior to traditional treatments (microfracturation and autologous osteochondral cylinder transplantation, OCT), in particular with regard to tissue damage affecting an area larger than four cm².
Classical ACT involves the removal of cartilage tissue from the knee joint; the tissue is processed and expanded in the laboratory. The cartilage cells produced are then injected into the defective cartilage during open knee surgery. Novel ACT involves carrier materials that facilitate the transplantation of cells. TETEC AG's NOVOCART 3D is such a medicinal product. Undesired secondary transplant hypertrophy occurs very rarely in ACT grown on a scaffold, but occurs frequently in classical ACT which then has to be treated in a second, complex surgical intervention. "Although the procedure of scaffold-coupled ACT has been applied for years in many European countries, the new regulation and the resulting additional regulatory requirements might lead to the disappearance of this method from the market, despite the fact that it is associated with far fewer side effects," said Joseph explaining that "the new regulation will potentially require the combination of autologous chondrocytes on a three-dimensional scaffold to be tested in randomised clinical trials and to be compared to classical surgical cartilage treatment, something which I regard as highly problematic and inconsistent with ethical principles. In addition, the efficacy of a medicinal product is being compared with a surgical procedure."
However, Joseph knows of a potential solution for German companies. The 15th amendment of the German Medicines Act mentions the possibility of having this product group approved in Germany by the Paul Ehrlich Institute (PEI). It is currently assumed that the 15th German Medicines Act amendment will come into force in this legislation period. It is also foreseeable that a national consulting agency will be established at the PEI, providing support for small and medium-sized companies in solving questions relating to regulatory and reimbursement issues. “However, this is currently in a very early phase of preparation,” said Joseph. It is also foreseeable that the problem may be solved by taking into consideration the known clinical observations for such a therapeutic procedure. However, such large-scale observational studies are currently only seen as the equivalent of additional scientific findings and cannot replace classical clinical testing. However, there is growing resistance to such rigidity. The British NICE (National Institute for Clinical Excellence) has ruled that large-scale observational studies must be given greater significance and it has also found that these so-called “real life data” come closer to describing the true efficacy of a product than classical clinical trials. Joseph also believes that the extension of the transition period for products already on the market might also help the SMEs. However, we will have to wait and see how the politicians react to the doubts raised by institutions and associations. It remains to be seen whether further regulations will be issued to specify the marketing authorisation procedure for advanced medial therapy products, at the same time as hoping that this will not lead to further overregulation, in particular in the area of tissue engineering.