Team:LMU-Munich/Application/Legal Issues

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BaKillus as a medical product

Approval process and costs (alt.: Research and Development)

BaKillus is intended to be used as a medical product in the treatment or prevention of MRSA infections. Hence, it is strictly regulated by national laws to protect and promote public health. Like every new drug, it would first have to be approved by the national regulatory agency by fulfilling certain requirements during the research and development (R & D) process. Generally, the process can be divided up into three parts: pre-clinical development, clinical trials and registration (Fig. 1A). The costs for the R & D process of a new drug have been estimated to be around $ 1.5 billion [1], where the major costs (>50%) account for the clinical trials (Fig. 1B). To guarantee funding, development of a promising drug candidate typically starts with a patent application. Depending on the product and the desired market, different authorities are responsible for the approval procedure.

Typical time frame for the development of new drug applications [http://www.efpia.eu/uploads/Figures_2014_Final.pdf]

Distribution of costs for development of a new drug application[http://www.phrma.org/sites/default/files/pdf/2014_PhRMA_PROFILE.pdf]

Authorities

To get the marketing authorisation for a new medical product in Germany, there are two possibilities: either a centralised procedure via the European Union (EU) or a national procedure, submitting the application to German authorities. For the first case the application has to be submitted to the European Medicines Agency (EMA) with the application being simultaneously valid in all EU member states (Fig 2A). However, it is important to note that the centralised procedure via the EU only facilitates the formal administration, since the EMA is neither responsible for scientific assessment nor entitled to grant marketing authorisations. Thus, marketing authorization has still to be obtained from the national authorities for every particular desired country. In Germany there are three major institutions responsible for market authorisation: the BfARM, being responsible for chemical medicinal products, the PEI, responsible for Vaccines and biologicals, and the BVL, responsible for veterinary medical products (Fig. 2B). As BaKillus is a cell therapeutical application authority in charge would most probably be the PEl. However, the legal details are not fully clear for this specific case, as the application of engineered microorganisms for disease treatment is a relatively new prospect. The general situation in the USA is mostly similar to the European/German system. Authority is given to the Federal Drug Administration (FDA) by the Federal Food, Drug, and Cosmetic Act (1938) (FD&C). However the FDA represents a centralized institution in order to guarantee drug quality and safety.

Institutions responsible for registration on centralized and decentralized procedure

Distribution of responsibilities for the decentralized procedure in Germany

Legal directives affecting BaKillus

According to the EU-directive 2001/83/EG Appendix I Part IV, BaKillus is a medicine for new therapies (“Arzneimittel für neuartige Therapien”) because it contains biologically altered cells as the active component for the therapeutic purpose (“biologischen zu therapeutischen Zwecken veränderten Zellen als Wirkstoffe oder Wirkstoffbestandteile”). The medicines for new therapies are divided into two groups: gene therapeutics (“Gentherapeutika”) and somatic cell-therapeutics (“Somatische Zelltherapeutika”), with BaKillus belonging to the latter one. Although being covered up to this point by the directive, a subsequent paragraph (Part IV 2.) further classifies three types of somatic-cell therapeutics: autolog (from same patient), allogen (from another human) and xenogen (animal) cell-therapeutics. Although the term “animal” is very unprecisely defined, it probably applies in its broadest meaning to the class of Metazoa, if not just to Mammalia. Thus, in its current form the directive does not consider microbials as a medical treatment. This not only represents an incomplete status with regard to future treatments, but is even insufficient for current applications, since microbials are already used e.g. in fecal transplants [3]. Thus, an update of the directive for engineered microorganisms would be important to account for this new class of therapeutics. In the USA, the FDA has made first approaches towards creating guidances for innovative pharmaceutical products to enter the market. For instance, a draft guidance for sponsors has been published which deals with alternative therapies of fecal microbiota transplants against infections of Clostridium difficile that are not responsive to standard treatment. As BaKillus has a similar intention of treatment, such legislation would benefit our product. (5) Additionally an approach has been made targeting viral or bacterial-based gene therapy. (6) Furthermore, with respect to the release of microbial strains into the environment, a new draft guidance has been published by the FDA. Remarkably, the current design of BaKillus would fulfil most of the criteria listed therein (Fig. ?).(4)

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BaKillus as a diagnostic device

Besides its primary use as a medical product, BaKillus can also be applied as a diagnosis tool (link zu Application/Diagnosis&Treatment/Diagnostic Device). Therefore it is a medical device and no longer affected by the drug law. Since the device is designed as a closed system there won’t be any contact between BaKillus and the environment. For this reason a request for relase, according to the law on genetic engineering, is not necessary. For placing the BaKillus diagnosis device on the (European) market it first has to be tested in the laboratory and to fulfill all requirements of the In-vitro Diagnostic Directive (IVDD) to receive the CE-certification. Unfortunately the listed testing criteria for genetically modified organisms (GMOs) are primarily designed for plants and not for bacteria. It must be assumed that the IVDD will be updated in the near future since there already have been alterations in the Directive 2001/18/EC Article 11 regarding the release of GMOs other than higher plants.