Ethics, safety and regulations

Ethical review of clinical research

We contacted Prof. Jože Trontelj, MD, PhD, a neurologist, the president of the Slovenian Medical Ethics Committee and Slovenian Academy of Sciences and Arts. Based on the brief information on our project he expressed his enthusiasm for this type of medical therapy and noted that for clinical studies the board will have to study the complete documentation.

Since the 1960s there has been a formal system for ethical review of medical research in Slovenia. Slovenia was one of the first five countries to ratify the Council of Europe’s Convention for the protection of human rights and dignity of the human being with regard to the application of biology and medicine (the Oviedo Convention). Most provisions of EU Directive 2001/20/EC of good clinical practice in the conduct of clinical trials on medicinal products for human use have already been incorporated into the Slovenian regulation of clinical studies. The Slovenian Act on Clinical Drug Testing, regulating good clinical practice in the field of pharmaceutical research and research on medical appliances, is based on this Directive.

In general an approval by the Slovenian Medical Ethics Committee is sufficient, and necessary, for the clinical research to go ahead. However in clinical drug studies (phase I–III), an approval of the Agency for Medicinal Products and Medical Devices of the Ministry of Health is also required.

Environmental regulations and biosafety

Figure 1. Meeting of the team members with Dr. Ruth Rupreht (second from the right) from the Ministry of Agriculture and Environment.

Dr. Ruth Rupreht from the Environment Directorate of the Ministry of Agriculture and the Environment of the Republic of Slovenia visited our team on the National Institute of Chemistry (Figure 1). The ministry is national competent authority for the notification of contained use systems and work with genetically modified organisms (GMOs) in the contained use as well as for deliberate and market release of GMOs. EU Directive 2009/41/EC lays down common measures for the contained use of GMOs and EU Directive 2001/18/EC for the deliberate and market release of GMOs. Slovenia, as a member of the EU since 2004, has a law about the management of GMOs from the year 2002 which was amended in 2005 to implement the requirements of both directives.

We presented our proposed solution for the medical therapy, safety mechanisms that we plan to introduce for the application of microencapsulated engineered mammalian cells in therapy and our future work plans. We would like to perform exhaustive experimental work at the cellular level, followed by the animal model and at the end, if the results continue to be favorable, with clinical trials. Within the frame of iGEM competition we will perform the experiments only on cell line HEK293 in the Department of Biotechnology at the National Institute of Chemistry, Ljubljana, Slovenia, where they have registered facilities for contained use of GMOs issued by the Ministry of Agriculture and the Environment of the Republic of Slovenia. In the near future we plan to continue and expand this research on a laboratory animal model (mouse or rat). The final experimental phase should be a double-blind, placebo-controlled clinical trial with patients.

We discussed with Dr. Ruth Rupreht the procedures for the notification of contained use systems (experiments on animals) and deliberate release (clinical trials) as well notification of activities involving GMOs in both cases. She first explained to us that researchers must never weigh the risks and benefits. We always must first assess the risk that our work represents for humans, animals and for the environment. Only after this assessment we can perform our research, whose results we believe could improve the quality of patient's life. All experimental procedures with laboratory mice involving GMOs are regulated as contained use of GMOs. We will have to assess risk for the application of microencapsulated cells into mice and request the Veterinary Administration of the Republic of Slovenia for the permission for the animal experiments. Clinical trials with GMOs are defined as deliberate release of GMOs into the environment (EU Directive2001/18/EC). The EU has several directives and guidelines for conducting clinical gene therapy trials (EU Directive 2001/83/EC, EU Directive 2001/20/EC). Before clinical trials preclinical testing of several cell lines will be performed in order to find the best engineered, optimized and tested cell line for the clinical trial. Mandatory requirement for the environmental risk protection is the registration of an outpatients’ clinic department, as the facility for the contained use of GMOs where the cells will be administered to the patients, which will participate in the clinical trial. We have already established contacts with physicians at the University Medical Centre Ljubljana, a leading medical institution in Slovenia. Next steps of our project will include risk assessment for the deliberate release of microencapsulated cells, administered to the patients, into the environment and application for the permission to perform clinical trials which is issued by the Slovenian Medical Ethics Committee.

Our strategy of medical treatment, where microencapsulated cells will produce sufficient local concentration of the therapeutic agent in the affected tissue while enabling low systemic concentration, will not only minimize the systemic side effects in the patients and eliminate the need for the repeated invasive administration of therapeutics, but will also reduce the effects on the environment due to the excreted therapeutics.