Regulation of Gene Transfer Medicinal Products in Germany

• I. Introduction
• II. Preclinical Research
• III. Manufacture
• IV. Clinical Trial („Klinische Prüfung")
• V. Marketing Authorisation (Drug Licensing)
• VI. Additional information on clinical trials and future regulatory changes
• VII. Contacts for further information
• VIII. Overviews are given in

I. Introduction

Definition: Gene therapy and somatic cell therapy products used in or on humans (in vivo) are termed gene transfer medicinal products (GT-MPs). They are medicinal products (drugs) according to § 2 (1) of the German Drug Law (AMG; „Arzneimittelgesetz") and include DNA, viral or non-viral vectors and genetically modified autologous, allogeneic or xenogeneic cells (used in vivo). No official definition of GT-MPs is given in the AMG. GT-MPs are either vaccines or blood products according to § 4 (4) and § 4 (2) AMG, respectively, or other drugs. According to § 77 AMG, the Paul-Ehrlich-Institut, Langen, is the competent higher authority for those GT-MPs which are vaccines and blood products, whereas the Federal Institute for Drugs and Medical Devices (BfArM, Bonn) is the competent higher authority for other GT-MPs.

As for other medicinal products regulations relevant for the manufacture and clinical trial of GT-MPs are provided by the AMG and the professional law of physicians. Application of GMOs and therefore of respective GT-MPs in humans is not regulated by the German Gene Technology Law (GenTG). Approval of deliberate release according to the GenTG is not required. In contrast to other medicinal products, an appraisal of the central Commission Somatic Gene Therapy of the Scientific Board of the German Medical Association ("Kommission Somatische Gentherapie" des Wissenschaftlichen Beirates der Bundesärztekammer; KSG-BÄK) is required for clinical trials involving the use of GT-MPs (see below) according to the professional law of the physicians.

II. Preclinical Research

Experimental pre-clinical work in gene therapy including the construction, use, storage and inactivation of vectors, genetically modified bacterial or mammalian cells or animals has to be conducted according to the German Law on Gene Technology (GenTG; „Gentechnikgesetz"; transformation of the relevant Council Directives).

Experiments involving the use of genetically modified organisms (GMOs) have to be performed in laboratories or animal facilities of one of four safety levels (S1 to S4), which are accordingly equipped.

Laboratory approval is given by the competent authority of the Federal Land for the GenTG. Experiments in safety level 1 laboratories only have to be documented and the competent authority has to be notified, whereas experiments falling under higher safety levels need additional approval by the same authority (3 months or less).

The Central Commission for Biological Safety (ZKBS; „Zentrale Kommission für die Biologische Sicherheit", Robert Koch-Institut, Berlin) provides a list containing the safety level classifications of „standard" vectors or plasmids and GMOs and is in some cases (e.g. approval of safety level 3 operations) to be consulted by the competent authority of the Federal Land for the GenTG.

Other laws and regulations that may apply (which are executed by different competent authorities of the Federal Land where the laboratory or clinic is located):

• The law on epidemics („Infektionsschutzgesetz"),
• the law on animal protection („Tierschutzgesetz"),
• the law on human embryo protection („Embryonenschutzgesetz"),
• the radiation protection ordinance („Strahlenschutzverordnung")
• the ordinance on the use of hazardous substances („Gefahrstoffverordnung").

III. Manufacture

• GMP (Good Manufacturing Practice) is generally required for the manufacture of medicinal products for human use on the grounds of ethical considerations (see: GMP guidelines by the WHO and EC). If a manufacturing authorisation is required (see below), the „Operation Ordinance for Pharmaceutical Entrepreneurs" (PharmBetrV; „Betriebsverordnung für pharmazeutische Unternehmer") applies (transformation of Commission Directive 91/356/EEC).
• For pharmacological-toxicological tests the results of which are to be used in an application for a marketing authorisation, GLP (Good Laboratory Practice) according to the German law on the use of chemical substances (§ 19a ChemG; „Chemikaliengesetz") has to be used (transformation of Council Directives 87/18/EEC and 88/320/EEC). This is specified in the Directive 75/318/EEC and the German Directive termed Official Drug Testing Guidelines („Arzneimittelprüfrichtlinien").
• Manufacturing authorisation is necessary for manufacturers who intend to commercially or professionally manufacture the drug (and/or the active ingredient) with the intention to commercially or professionally distribute it to others. It is granted by the authority of the Federal Land, where the facility is located, competent for the AMG (§ 13 AMG). This authority is also responsible for inspections and supervision (§ 64 AMG).
• Import authorisation is required for parties wishing either commercially or professionally to bring finished (ready-prepared) medicinal products, test sera, test antigens, active ingredients which are of human or animal origin or which are gene-technologically manufactured into Germany from countries not being member states of the European Union or Contracting States of the European Economic Area Agreement (§ 72 AMG). For Germany, this is granted by the competent authority of the Federal Land into which the product is imported.
• Notification of the competent authority of the Federal Land for the AMG is necessary beforehand for companies and establishments (also clinical departments) which develop, manufacture, test, package drugs or subject them to clinical trials (§ 67 AMG).
• Laboratory and approval of experiments according to the GenTG (see above) is required for experimental work with GMOs.

IV. Clinical Trial („Klinische Prüfung")

Prior to licensing, gene transfer medicinal products are to be used in or on humans during clinical trials only (according to the appraisal of the KSG-BÄK). Very few exceptions require special consideration by the KSG-BÄK. The guidelines „Richtlinien zum Gentransfer in menschliche Körperzellen", published by the German Medical Association (see below), specify the necessary ethical considerations and are guidelines for clinical trial applications. Clinical trials can only be conducted, if certain requirements are met (see §§ 40, 41 AMG).

Positive appraisal of the local ethics committee formed according to the law of the Federal Land and competent for the principal clinical investigator, is required before initiation of a clinical trial (see § 40 (1) AMG). No approval by a competent authority is necessary, if a positive appraisal is given and submitted to the competent higher authority (see chapter: "submission of documents").

• Notification of the authority of the Federal Land competent for the AMG and deposition of the clinical study plan is required (§ 67 (1) AMG). This authority is also responsible for inspections and supervision of the trial.
• Submission of documents to the competent higher authority (presentation according to § 40 AMG; forms ("Vorlageblatt Klinische Prüfung") available by Internet including the positive appraisal of the local ethics committee relevant for the principal clinical investigator and the pharmacological-toxicological data (see Directive 75/318/EEC- Annex- and the German Directive „Arzneimittelprüfrichtlinien" for content) to the federal higher authority competent for the AMG. The competent higher authority is either the Paul-Ehrlich-Institut, Langen, for those gene transfer medicinal products which are vaccines or blood preparations, or the Federal Institute for Drugs and Medical Devices (BfArM), Bonn, for other gene therapy drugs (see § 77 AMG). The trial can be initiated after submission of the documents. A written confirmation of the competent higher authority stating that the required documents have been received is usually returned within a week.
• Positive appraisal is given by the "Commission Somatic Gene Therapy" of the Scientific Board of the German Medical Association (KSG-BÄK, „Kommission Somatische Gentherapie", Köln (required according to the professional law of physicians; see „Richtlinien zum Gentransfer in menschliche Körperzellen", Deutsches Ärzteblatt 92, Heft 11, B-583-B588 (1995)). The KSG-BÄK can be contacted by the local ethics committee, the sponsor or the clinical investigator.
• Registration of the clinical trial and patients involved with the German Register for Somatic Gene Transfer Studies (DeReG, "Deutsches Register für somatische Gentransferstudien") at the University of Freiburg, Germany (address see below), and the publication of the protocol via the German Working Group for Gene Therapy (DAG-GT) are recommended.
• Registration of the patient treatment room or description of the transport, storage and inactivation of GT-MPs containing or consisting of GMOs according to the GenTG (see above) is required for experimental work with GMOs.
• The relevant European guideline termed "Note for guidance on the quality, preclinical and clinical aspects of gene transfer medicinal products (CPMP/BWP/3088/99)" should be consulted and is available by Internet (Notes for Guidance -> Biotechnology -> Adopted Guidelines). FDA Points to consider can also be consulted.

V. Marketing Authorisation (Drug Licensing)

GT-MPs are medicinal products derived by recombinant DNA technology and fall under the scope of Council Regulation (EEC) 2309/93. Marketing approval is granted by the European Commission via the centralised procedure initiated by sending an application to the Committee for Proprietary Medicinal Products (CPMP) at the European Agency for the Evaluation of Medicinal Products (EMEA) in London. The application must be accompanied by the particulars and documents referred to in Articles 4 and 4a of the European Directive 65/65/EEC, in the Annex of Directive 75/318/EEC and in Article 2 of Directive 75/319/EEC. Additional documents are required for a GT-MP containing or consisting of GMOs for the environmental risk asessment. Notice for Applicants for medicinal products for human use is available.

Scientific Advice with a view to marketing authorisation is given by the CPMP at the EMEA. One of the relevant European guidelines is the "Note for guidance on the quality, preclinical and clinical aspects of gene transfer medicinal products (CPMP/BWP/3088/99).

VI. Additional information on clinical trials and future regulatory changes

Information about clinical trials in Germany is available (only in german). Additional information is currently being prepared by the German Register for Somatic Gene Transfer Studies and will also be available by Internet. Unfortunately, the gene therapy websites of the European Society for Gene Therapy and of the Office of recombinant DNA Technology at the NIH, USA, do not contain sufficient information about clinical trials involving the use of GT-MPs in Germany.

Following the transformation of the European Directive 2001/20/EC, the positive opinion of the local ethics committee, advised by the Commission Somatic Gene Therapy (KSG), and a written approval by a competent authority will be necessary prior to initiation of clinical trials involving the use of gene transfer medicinal products in all European member states, including Germany. In Germany, this will require an adoption of the German Drug Law which is expected to be finalised in 2002 or 2003.

Currently, the guideline "Richtlinien zum Gentransfer in menschliche Körperzellen" of the German Medical Association is also being revised and the new version will be published in 2002.

VII. Contacts for further information

• Section Gene Therapy, Department of Medical Biotechnology, Paul-Ehrlich-Institut, Dr. C. Buchholz
• Deptartment of Medical Biotechnology, Paul-Ehrlich-Institut, Prof. Dr. K. Cichutek
• Federal Institute for Drugs and Medical Devices (BfArM), Friedrich-Ebert-Allee 38, 53113 Bonn, Tel. +49-228 207 30, Fax +49-228 207 5207
• Commission for Somatic Gene Therapy (KSG-BÄK), Wissenschaftlicher Beirat der Bundesärztekammer, Herbert-Lewin-Str. 1, 50931 Köln, Germany, Tel. +49-221-4004-0, Fax +49-221-4404-386, email dezernat6@baek.dgn.de
• Deutsches Register für somatische Gentransferstudien, ZKS - Zentrum Klinische Studien, Universitätsklinikum Freiburg, Hugstetter Straße 55, 79106 Freiburg, Tel.: +49-761/270-7384
• German Working Group for Gene Therapy, (contact: Dr. M. Hallek, Muenchen, email hallek@lmb.uni-muenchen.de)

VIII. Overviews are given in

• Guidelines for the design and implementation of clinical studies in somatic cell therapy and gene therapy, A. Lindemann et al., J. Mol. Med. 73, 207-211 (1995);
• Abschlußbericht der Bund/Länder-AG „Somatische Gentherapie", in: Eberbach/Lange/Ronellenfitsch (Hrsg.), Recht der Gentechnik und Biomedizin, GenTR/BioMedR, Teil II, F., Loseblattwerk, Heidelberg, Stand: 19. Erg.Lfrg., Dezember 1997).
• Gene therapy in Germany and in Europe: Regulatory Issues, K. Cichutek and I. Krämer, Qual. Assur. J. 2, 141-152 (1997).
• Bundesgesundheitsblatt, Jahrgang 44, Heft 11, November 2001.
• Somatische Gentherapie: Stand der klinischen Forschung und Regularien in Deutschland, K. Cichutek, in: Recht der Gentechnik und Biomedizin, GenTR/BioMedR,Eberbach/Lange/Ronellenfitsch, Verlag C. F. Müller (2001).

author: Klaus Cichutek