[Special considerations for the regulation of biological medicinal products in individualised medicine. More than stratified medicine].

The term individualised medicine, also called personalised medicine, is commonly used as an equivalent to stratified medicine. However, this is erroneous since quite often it is forgotten that especially biological medicinal products have other aspects of individualization that go beyond mere stratification. The principles of stratified medicine have been applied for biological medicinal products for many years. A historical example is diphtheria antitoxin made from horse serum, while current examples are transfusion of red blood cells and the administration of factor VIII in haemophilia A. The stratifying aspects of these medicinal products are given by the following considerations: diphtheria antitoxin is only administered after a diagnosis of diphtheria and not in other forms of tonsillitis, red blood cells should only be transfused once blood group compatibility as been established and factor VIII replacement is only administered in haemophilia A as opposed to other acquired or hereditary disease of the coagulation system. The peculiarities of biological medicinal products, in particular the inherent variability of the drug, are especially important for autologous cellular medicinal products. In addition to the expected variability of the biological source material there is interindividual variability of patients as cell donors, which make definition of specifications and determination of criteria for pharmaceutical quality and potency tests difficult. Therapy with modified autologous cells, a common and important application of advanced therapy medicinal products, is exemplary for the special considerations that must be made when evaluating pharmaceutical quality, mode of action and toxicological properties of the biological medicine. The clinical investigation of advanced therapy medicinal products with the intent of demonstrating safety and efficacy is particularly challenging because of the complexity of therapy, which often involves invasive interventions. The development of biomarkers accelerates the process towards stratified or individualised therapies. Increased requirements for companion diagnostics are a possible consequence. Progress in analytical processes and in biotechnology make a higher degree of individualization likely, possibly to the degree that medicinal products will be individually manufactured for each patient. Current principles of medicinal product testing and market authorization may be applicable only with limitations, because the individual medicinal products are not uniform and are not repeatedly manufactured. The assessment of the process, performed on several different medicinal products manufactured by the same process could potentially serve as a basis for the assessment. For the evaluation of risk for the patient in clinical trials new concepts must be considered, which can be facilitated by interaction of regulatory authorities and developers.