Hessen – Gateway to Contract Research in Europe a Practical Guide to Sites and Services, Second Edition

Hessian Ministry of Economics, Transport, Urban and Regional Development www.hessen-biotech.de

Hessen – Gateway to Contract Research in Europe A practical Guide to Sites and Services, second edition

Volume 8 of the Brochure Series Aktionslinie Hessen-Biotech Imprint Brochure Series

Hessen – Gateway to Contract Research in Europe Brochure Series of the Aktionslinie Hessen-Biotech of the Hessian Ministry of Economics, Transport and Volume 8 of the series Aktionslinie Hessen-Biotech of Regional Development the Hessian Ministry of Economics, Transport, Urban and Regional Development Volume 1 | Förderoptionen Für technologie-orientierte Unternehmen in Hessen Publisher HA Hessen Agentur GmbH Volume 2 | Werkzeuge der Natur Dr. Detlef Terzenbach Weiße Biotechnologie in Hessen 4 Abraham-Lincoln-Str. 38-42 65189 Wiesbaden | GERMANY Volume 3 | Hessen: Gateway to Biomanufacturing in Europe Phone +49 611 774-8613 A pracitcal Guide to Sites and Services for GMP-Production – Fax +49 611 774-58613 Quality Management – Contract Manufacturing [email protected] www.hessen-biotech.de Volume 4 | Hessen – Your Gateway to the Diagnostics Market in Europe Listing of a company profile within this publication is strictly A pracitcal Guide to Services and Technology for voluntary, all Contract Research Organizations in Hessen have the Diagnostic Industry the opportunity of being entered in this database since its online version is being continually expanded and updated. Volume 5 | Medizintechnik in Hessen – The publisher does not take any responsibility for correctness Strukturen und Potenziale and preciseness of the give information. Ergebnisse einer Unternehmensbefragung

Editorial Ofﬁ ce Volume 6 | Competence Atlas Hessen-Biotech 2007 TransMIT Gesellschaft für Technologietransfer mbH, Gießen The Spectrum of Biotechnology Companies in Hessen

© Hessian Ministry of Economics, Transport, Volume 7 | Hessen – Urban and Regional Development das Tor zum europäischen Diagnostikmarkt Jens Krüger Wegweiser für Dienstleistungen und Technologien Kaiser-Friedrich Ring 75 in der hessischen In-vitro-Diagnostik-Industrie 65185 Wiesbaden | GERMANY www.wirtschaft.hessen.de Volume 8 | Hessen - Gateway to Contract Research in Europe Reproduction and reprint – even in parts – A practical Guide to Sites and Services. Second edition subject to prior written approval.

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May 2009 www.hessen-biotech.de Content

Foreword | 6-7 Clinical Research in Hessen

Hessen | 8-10 Gateway to Clinical Research in Europe

Paul-Ehrlich-Institut | 11-13 A Federal Research and Regulatory Institute with International Competence for Vaccines and Biomedicines 5

Yes Pharma | 14-16 Regulatory Compliance as a Prerequisite for Lean Drug Development

Sterna | 17 Biotech Start-ups and Contract research Organizations Forming winning teams

ZAFES | 18-20 Investigator-initiated trials

Ethics Committees | 21-22 The Work of the Ethics Committees in Hessen

RP Darmstadt | 23-24 Competence and Communication Mission Statement of the Monitoring Authority

Proﬁ les | 25-41

Supplement | 42-47 Some basics on Clinical Research Foreword

– that is more than a quarter of the turnover of the entire German pharmaceutical industry. Of this, Clinical Research in Hessen pharmaceutical products to a value of 7 billion euros were exported throughout the world from • Health is no longer just a highly private affair, Hessen. Companies such as Sanofi -Aventis, Merck it is also a major economic factor. The health Serono, Fresenius, Novartis-Behring, CSL-Behring, business is growing at a very considerable rate. In Lilly, Merz or Abbott are just a few examples of 2007, for example, the statutory health insurance internationally successful concerns researching funds in Germany spent almost 28 billion euros and producing in Hessen. on medicaments alone. To secure a share in this Biotechnology is assuming a constantly increas- market, companies need not only good products ing share in all this. Over 200 companies are en- but also an excellent infrastructure and reliable gaged in biotechnology. Most of them are service business conditions. Unless these are available, providers, whether in contract research, produc- research-based pharmaceutical companies will tion, the growing fi eld of quality management or hardly be prepared at all to start out on the highly the performance of clinical trials. This mix, cover- long-term and cost-intensive processes culminat- ing the entire range of the pharmaceutical value 6 ing in the authorisation of a new active ingredi- chain, is unique in Europe. ent. Important factors for the growth of companies Not many regions offer excellent and reliable are also created by an attractive regulatory business conditions of this kind. The Federal State framework. The responsibilities for implementing of Hessen is with certainty one of them, with its the requirements of gene technology legislation economic centre Frankfurt/Rhine-Main and its in Hessen were centralised in a single authority, pharmaceutical industry with a tradition going with the result that companies need to approach back over one hundred years. It is not for nothing only one contact partner. The times necessary for that the region, one of the economically most approval of new plants are among the shortest in powerful centres in Europe, bears the title Germany. of “Germany’s chemist shop”. Companies benefi t from the international charac- It is now one hundred years since the fi rst Nobel ter of the Frankfurt/Rhine-Main region. No other Prize winner for medicine, Emil von Behring, region in Germany houses so many companies established the world’s fi rst “biotech start-up” – from abroad. More than 700 American fi rms are the Behringwerke AG – in Marburg and began located in Hessen, and just on 20 percent of all with the production of vaccines through the American direct investments in Germany fi nd immunisation of horses. In 1909, Paul Ehrlich, the their way here. Nobel Prize winner resident in Frankfurt, started on the production of the world’s fi rst chemical Frankfurt has the largest Korean community in therapeutic agent “Salvarsan” for the treatment Europe, the Chinese and Japanese communi- of syphilis. His success formed the basis for the ties are growing steadily. The many international rise of Farbwerke Hoechst as the world’s leading schools enable expatriates to have their children pharmaceutical concern. educated in same way as they would be in their Minister of Economics, own countries. This is one reason why employees Nowadays the pharmaceutical industry in Hes- Transport, Urban and Regional of foreign companies are so willing to live here. sen employs over 29,000 people, who in 2008 Development in Hessen generated a turnover of around 11 billion euros One factor which makes the region so attractive is the excellent transport infrastructure. The Frank- furt Rhine-Main airport, with about 54 million passengers per year, is among the largest airports in Europe after London and Paris. It offers 4,375 direct fl ights a week to all major international centres, and to many of them several times daily. Frankfurt is also Europe’s largest air freight

Dieter Posch Foreword

transhipment centre. chemicals.

These connections guarantee the opportunities Backed up by these resources, Hessen is in a for rapid travel which are so important for interna- good position to expand its position as a biotech tionally operating companies. With 40 contract reproduction industry region. The pharmaceutical search organisations (CROs), it is no coincidence concerns based here are extending their produc- that clinical research is centred in the region. tion capacities – Novartis Behring in Marburg, Abbott in Wiesbaden, and Sanofi -Aventis in It is clear that effective research, especially into Frankfurt. the development of new therapeutic active ingredients, cannot be done without academic All this speaks for the quality of Hessen in the research and training of high quality. Here, again, fi elds of pharmaceuticals and biotechnology. the excellent infrastructure in this area becomes This is doubtless one of the reasons why the evident. In less than one hour it is possible to CROs stated in their replies to a questionnaire reach a large number of maximum care hospitals that Hessen is unusually well positioned and can with about 35,000 beds. In Hessen, relevant sub- be considered as a fi rst-class competence centre jects such as human medicine, pharmacy, biology, able to stand any international comparison. chemistry or process engineering are taught at 7 I would like, therefore, to invite you to use this as many as twelve universities and high schools. brochure as a source of information about the op- More than 600 professors teach nearly 17,000 portunities for clinical testing in Hessen. I greatly students in these subjects. Every year, companies hope that you will be convinced by what we can draw on a pool of almost 3,000 highly quali- have to offer and would be very glad if we could fi ed graduates. extend a welcome to your company also. The State of Hessen has set up an Initiative for the Development of Scientifi c and Economic Excellence (LOEWE) with a view to establishing new leading-edge technology centres. Additional resources were made available with the explicit Dieter Posch intention of turning already existing strong points Hessian Minister of Economics, Transport, into real centres of excellence. The maximum Urban and Regional Development benefi t of this will accrue to the Life Sciences.

In addition to the universities and high schools, there are also the four Max Planck Institutes, where high-end research is carried out. Among their principal focuses are biophysics, physiologi- cal research, brain research and microbiology.

The close interlocking of business and science, of research and application, is already producing visible results in Hessen – in a nation-wide contest, Hessen was chosen to establish an excellence cluster in the promising future ﬁ eld of white biotechnology. This is now engaged in developing the most recent methods for the biotechnological production of ﬁ ne and specialty Hessen

Eastern Europe. This was made very much easier Hessen: by the history and culture shared by European countries. Next to Russian, German is the most Gateway to widespread foreign language in Eastern Europe.

Clinical Research in Europe Hessen - The centre of the CROs in Germany More than 40 CROs are based in the region Clinical research is beyond all doubt one of the • around Frankfurt. In addition, there are many most important phases in the development of a providers who help to ensure the quality of test- new medicament. Mistakes made at the being either by consultancy services in this context ginning – whether in the planning of the study, or through the provision of software and quality the choice of suitable cooperation partners or management products. the drafting of the test schedules – can lead to considerable costs and lengthen the time needed These CROs employ 1,700 people in Hessen, and 8 for registration. more than 38,000 worldwide. This indicates how well Hessen’s CROs are netted globally and what For this reason it is important for small and potentials this centre has to offer. medium-sized biotech and pharmaceutical companies to fi nd speedy and uncomplicated A look at the adjoining map (illustration with the access to networks offering high-quality advisory dots on the Hessen map) will clearly show how services in connection with clinical tests and their greatly these companies can benefi t from the performance. In this brochure you will fi nd a list geographical nearness to the authorities and the of the Contract Research Organisations (CROs) in transport connections. Hessen and the test centres at Hessen’s university clinics. CROs give the region Access to 500 million consumers an excellent rating Hessen, with its economic centre Frankfurt, is The CROs based in Hessen have stated with one of the centres of the European chemical and conviction that they are entirely satisfi ed with pharmaceutical industry. It is ideally situated in Hessen as a location. They rate it better than the middle of a pharmaceutical market with 500 other German regions and consider it to be fully million consumers. These are joined by just on competitive at international level. Hessen scores another 300 million consumers in the non-EU very well most especially for qualifi ed personnel Eastern European states. These countries, which and for cooperation with the authorities. It is the include Russia and the Ukraine, are noted for their internationally active CROs which have given the high concentration of hospitals and practising best ratings here. They emphasise in particular physicians. the transport infrastructure and the cooperation with the ethics commissions. This can be taken as Region Consumers evidence for the high quality and professionalism USA 283 million in Hessen. European Union (27 States) 501 million Eastern Europe 300 million

All these markets can be reached from Frank- furt in less than two to three hours. Compared with the USA, a greater number of patients can be reached over a smaller area. These facts are becoming increasingly important in the growing markets of Eastern Europe because, before new medicaments are approved in these countries, the authorities expect to receive data which have been generated there.

Thanks to the numerous local CROs, and also to transport facilities unequalled anywhere in Europe, 800 million consumers/patients can be reached by air in less than three hours. The CROs based here already have very close contacts with Hessen

The region offers the best conditions for fi nding industry. The CROs have given Hessen a very high qualifi ed and well-trained personnel. The long- rating at international level for cooperation with standing structures of medium-size and large the authorities. companies, together with the high concentration of research facilities, are constantly producing Frankfurt – Germany’s centre for CROs a large number of highly qualifi ed employees. Coordination centres for clinical research which The highest concentration of CROs in Germany have been set up at the universities act as direct lies within a one hour’s drive from Frankfurt. The contact partners. New study courses have been companies in this area are distinguished by their initiated for qualifying as study nurses or research great variety and by the comprehensive range of physicians. The universities in Hessen have adapt- services they have to offer. Practically all use areas ed their courses to fi t in with the internationally are covered, and many of the companies are customary master and bachelor degrees. This will highly specialised. This high degree of profes- ensure greater relevance for everyday practice. sionalism is enhanced by the close networking of the CROs. More than half of the CROs work on a Hessen is one of the fi rst German states to have cooperative basis. reorganised and simplifi ed the work of the As the most important customer group, the 9 ethics commissions. Multicentric studies can be large pharmaceutical concerns play a major role. set in motion much more rapidly through the However, the small pharmaceutical and biotech binding vote of an executive committee. A stand- fi rms are becoming an increasingly important ard format has been agreed on, and the work is target group. In the meantime, more than half of closely supervised by Hessen’s Ministry of Health. the CROs have gained intensive experience with small biotech fi rms. Operating conditions like Unbureaucratic access to authorities these are highly useful especially for biotech fi rms newly breaking into the European market. Hessen’s central situation makes it an ideal location for clinical tests. The Hessen-based CROs are innovative, and they are striking out on new paths. A service offered The Paul Ehrlich Institute (PEI), one of Germany’s by one third of the CROs is to take over the entire leading authorisation authorities and at the preparation and handling of the CTD (Common same time an internationally renowned research Technical Document) and forward it to the regula- centre, is situated very near to Frankfurt airport. tory authorities in electronic form (eCTD). It is competent for the particularly innovative recombinant drugs, for gene therapy and stem cells. This close vicinity is of great advantage for the CROs. The PEI actively seeks contact with the CROs and sponsors, it offers advice at every stage of the application process, and provides training Hessen – Gateway to Europe programmes for research physicians. The PEI is integrated in the work of the German and Euro- pean regulatory authorities by voicing recom- mendations and also by offering advisory support for the legislature.

Bonn, just over an hour’s journey from Frankfurt, is the seat of the Federal Institute for Drugs and Medical Devices (BfArM), the German regulatory authority,. The European regulatory authority EMEA, based in London, can be reached by air in just under one and a half hours.

Once the studies have been authorised, they are supervised by a central authority in Hessen with experts of its own who have themselves gath- ered extensive experience in the pharmaceutical Hessen

A large number of companies, engaged up to The central contact partner for the university clin- now in the classical tasks of supporting clinical ics in Marburg and Giessen is the Coordination studies for new medicaments, have now turned Centre for Clinical Trials (KKS), which also makes additionally to medical products or even special- important contributions in the area of personnel ised in them. These new ﬁ elds of business also training. The most recent legal and professional include studies for the food industry to deal with aspects are integrated in the training of research health claims in connection with functional foods. physicians, study directors or study nurses.

Access to clinics in Hessen Hessen: Your Gateway to “Investigator-initiated trials” are assuming Clinical Research in Europe increasing importance. As many as one quarter Germany remains the European reference market of the CROs stated them to be their major focus, for therapeutic agents. It is here that the specifi ca- or have declared universities, university clinics tions for other European markets are very largely and scientifi c study groups as their clientele. This set. A number of unique advantages makes refl ects the high quality and creativity of medical Hessen the ideal starting point for access to this 10 research at Hessen’s universities and institutes. enormous market. What sets Hessen apart are the The Centre for Drug Research, Development and best travel connections in Continental Europe, Safety (ZAFES) is a model project in the southern the close cooperation with all authorities, and the region of Hessen in which 24 clinics and research wide choice of highly qualifi ed and motivated institutes and the locally based pharmaceutical employees. companies have joined forces under the aegis of In addition to its excellent resources in the area the Frankfurt University Clinic. In the fi eld of clini- of clinical research, Hessen can offer more than cal research, they offer a complete package of one hundred years of pharmaceutical experience. clinical services over all phases of the project. This And with regard to research, scale-up, produc- encompasses a variety of different things, ranging tion, distribution or marketing, there is hardly from chemical analysis to the provision of beds in another region which can bear comparison with individual clinics. Hessen.

Hessen-Biotech is your contact partner for Kassel CROs in Hessen integrating you in this network. This brochure gives you all the information you need. Dynamic companies need an environment to match, and we will open up the way for you.

Kassel

Bonn Marburg BfArM

Giessen

Wiesbaden Frankfurt PEI

Mainz Würzburg Darmstadt

Heidelberg International Competence for Vaccines and Biomedicines

• The development of a medicinal product and its establishment in standard medical use is a Paul-Ehrlich-Institut: complex process which includes research and discovery, non-clinical development, testing in A Federal Research and clinical trials, fi nally marketing authorisation and post-marketing follow-up. Regulatory Institute with The development process is legally regulated to ensure safety and effi cacy of new medicines for International Competence for maximum benefi t of the patients. Non-clinical testing allows insight into the pharmacology and Vaccines and Biomedicines toxicology of a new medicinal product. Clini- cal testing for safety, optimal or feasible dosing, Jens Reinhardt, Evelyne Kretzschmar, Klaus Cichutek environmental risks and effi cacy in controlled clinical trials provides data for a thorough risk- benefi t assessment. An acceptable risk-benefi t Regulatory activities ratio is the basis for marketing authorisation, for of the Paul-Ehrlich-Institut either Germany only or also for other EU member 11 states. Scientifi c research provides the necessary Marketing authorisation of safe know-how for the experimental testing and evalu- and effi cacious biomedicines ation of biomedicines. A modern research and The Paul-Ehrlich-Institut is the Federal Institute for regulatory institute like the Paul-Ehrlich-Institut vaccines and biomedicines in Germany. Biomedi- The Process of Drug Development therefore carries out experimental scientifi c cines are derived from biological organisms and research on an internationally competitive level include vaccines, allergens, blood products, sera Research and Discovery and is a major player in the European network of and monoclonal antibodies, gene therapy, cell Development medicinal product regulatory agencies. therapy and tissue engineered products as well - Non Clinical Tests as classical tissue preparations. The Paul-Ehrlich- In Germany, human medicinal products are (Cell Culture, Animal Studies) Institut carries out important regulatory activities regulated by authorities of the Laender and by on the national level such as authorisation of - Clinical Trials (Patients) two higher competent authorities. While the clinical trials, marketing authorisation, experi- Phase I Federal Institute for Drugs and Medical Devices mental and batch release testing of biomedicines Phase II (BfArM) is concerned with chemical medicinal and pharmacovigilance (see below). Moreover, Phase III products, many recombinant proteins, cytokines the Paul-Ehrlich-Institut plays an important role in and medical devices, the Paul-Ehrlich-Institut in Marketing Authorisation Application regulating biomedicines on the European level. Langen near Frankfurt/Main is responsible for Here, the European Medicines Agency (EMEA) in Postmarketing Activities vaccines and biomedicines. Within the network London co-ordinates the centralised procedure of EU member state agencies, the Paul-Ehrlich- for marketing authorisation and provides scien- Institut provides expertise to the European tifi c advice during medicinal product develop- Medicines Agency (EMEA), for example by ment. The scientifi c assessment of the centralized assessing centralised marketing authorisation marketing authorisation applications, which applications and by contributing to scientifi c contain all data collected and evaluated during advices. Furthermore, scientists from the Paul- medicinal product development, are conducted Ehrlich-Institut are experts frequently consulted by experts from the Paul-Ehrlich-Institut and other by and active in international organisations such EU member state regulatory authorities. The as the World Health Organisation or the Interna- proposal for authorising marketing tional Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Due to its experience in the area of blood products and in vitro diagnostic tests for pathogens, the Paul-Ehrlich-Institut has been designated “WHO Collaborating Centre for Quality Assurance of Blood Products and in vitro Diagnostic Devices” in 2005. Within this function, the Paul-Ehrlich-Institut supports the WHO in the organisation of training courses and meetings, and also organises and performs laboratory studies and standardisation exercises in order to establish internationally accepted test standards. This ensures a harmonized global view on the The buildings of the safety and effi cacy of medicines and their optimal Paul-Ehrlich-Institut regulation. in Langen near Frankfurt/Main. International Competence for Vaccines and Biomedicines

Regulatory Activities of the Paul-Ehrlich-Institut Scientifi c Advice supporting rapid and effi cient biomedicines development National Level European Level As the complexity of biomedicines differs con- Scientifi c Advice siderably from chemical drugs, the conventional test methods used for the fi nal chemical drug Clinical Trial Authorisation product are often not appropriate for biomedi- Marketing Authorisation cines and they also vary depending on the nature of the given biomedicine. Therefore, the regula- Pharmacovigilance tory requirements for biomedicines need to be Inspections / Contribution to Inspections more fl exible and different testing strategies may be applied. However, this fl exibility may create Batch Control uncertainty in whether a chosen development Contribution to Working Parties and testing strategy will be appropriate. To address this uncertainty, the Paul-Ehrlich-Institut provides guidance and scientifi c advice to pharmaceutical or biotechnological companies 12 and academic research groups to their medicinal product development. Scientifi c advice at the of a new medicinal product is made by the Com- Paul-Ehrlich-Institut is provided during an open mittee for Medicinal Products for Human Use and informal discussion meeting where product (CHMP) at the EMEA followed by provision of the experts from the Paul-Ehrlich-Institut meet face to marketing authorisation by the European Com- face with applicants to discuss all scientifi c and mission. An expert from the Paul-Ehrlich- medical topics relevant for biomedicine develop- Institut is a co-opted member of the CHMP. A sin- ment, clinical testing and marketing authorisation. gle marketing authorisation application to EMEA One of the experts of the Paul-Ehrlich-Institut is allows marketing of a new medicinal product in also a member in the Scientifi c Advice Working, all EU member states and thus standard use in which coordinates the scientifi c advice provided medical care. by EMEA. The EMEA scientifi c advice focuses on Experts from the Paul-Ehrlich-Institut are also technical requirements and development strate- members in most of the currently 12 Working gies presented by the pharmaceutical company Parties that support the CHMP. The Paul-Ehrlich- with a view to a future centralised marketing Institut is involved in up to 50 % of all procedures authorisation. Furthermore, for ATMPs of small or coordinated by the EMEA concerning these medium-sized enterprises, the newly established biomedicines. Furthermore, the co-opted CHMP CAT will also certify the data collected on the member from the Paul-Ehrlich-Institut is also a quality and non-clinical pharmacology-toxicology member of the newly formed Committee for of a new product. Certifi cates are intended to Advanced Therapies (CAT). The CAT will play a allow these companies to get additional support, central role in the assessment of innovative medi- also fi nancially, for their product development. cines such as gene therapy, somatic cell therapy and tissue engineered medicinal products, which Clinical trial authorisation are termed advanced therapy medicinal products As a pre-requisite to marketing authorisation, (ATMPs). biomedicines, just like all medicinal products, are tested in controlled clinical trials. Initiation of clinical trials of biomedicines in Germany requires Research Activities of the Paul-Ehrlich-Institut a positive appraisal by the local ethics committee and authorisation by the Paul-Ehrlich-Institut. The Research Groups Research areas applicant has to provide data on quality and non- Medical Biotechnology clinical studies that support safety and provide a Experimental Vaccines, Experimental proof of concept for the medicinal product, which Virology Therapies and Diagnostics has to be in accordance with the current state of Microbiology scientifi c knowledge. To facilitate successful clini- Host interaction with pathogens and cal trial applications, the Paul-Ehrlich-Institut has Veterinary Medicine retroelements issued a guidance document termed Third Noti- Immunology fi cation on the Clinical Trial of Medicinal Products Immune activation and evasion for Human Use, jointly published with the BfArM. Allergology Here, the requirements of the German Medicinal Product Act and references to the relevant EMEA Hematology & Transfusional Safety, Effi cacy and Quality of Medicine Biomedicinesedicine International Competence for Vaccines and Biomedicines

guidelines are laid down to refl ect the current transfer and cell therapy medicinal products. state of scientifi c knowledge. “Host interactions with pathogens and retroele- Authors ments” are important because understanding the Pharmacovigilance mechanisms by which different pathogens cause Dr. Jens Reinhardt The Paul-Ehrlich-Institut is also responsible for the diseases may lead to novel treatment and preven- Dr. Evelyne Kretzschmar pharmacovigilance of biomedicines. The adverse tion strategies. Studying “immune activation and Prof. Dr. Klaus Cichutek effects of medicinal products, observed by and evasion” fosters a better understanding on how Biotechnology collected from healthcare providers, pharma- the immune system is activated to respond to pa- Paul-Ehrlich-Institut (PEI) ceutical industry and patients, are continuously thogens. This knowledge may also contribute to Paul-Ehrlich-Straße 51-59 monitored and evaluated to identify unexpected vaccine development against novel targets such 63225 Langen | GERMANY adverse reactions associated with medicines in as certain viruses or tumours. Another area of the order to prevent harm from patients. research in the Paul-Ehrlich-Institut focuses on Phone +49 6103 77-0 Necessary actions are taken by the Paul-Ehrlich- “safety, effi cacy, and quality of biomedicines” by Fax +49 6103 77-1234 Institut or coordinated in conjunction with other developing and validating novel test methods for [email protected] authorities. Thus, by continuously monitoring the appropriate examinations of biomedicines. www.pei.de risk-benefi t, the Paul-Ehrlich-Institut ensures the This is particularly important for innovative medi- safety and effi cacy of medicinal products, thereby cinal products, and for new emerging diseases. contributing to patient safety and public health. An illustrative example for research performed at Offi cial biomedicines control by experimental the Paul-Ehrlich-Institute is the development of testing of medicinal products new lentiviral vectors for gene transfer. The idea of gene transfer is to treat inherited diseases by Vaccines and some other biomedicines require replacing the defect gene with a functional copy that each new production batch has to be tested of this gene. Lentiviral vectors are frequently used or assessed and offi cially released by the Paul- for these genetic modifi cations since they can Ehrlich-Institut before it may be marketed. The enter cells of the haematopoietic system. Current Paul-Ehrlich-Institut also carries out experimental safety and effi cacy limitations of these viral gene testing of some centrally authorised medicinal vectors are for example due to the broad range products. Experimental testing of biomedicines of cells that can be infected. Paul-Ehrlich-Institut by a governmental authority parallels in-process researchers are engineering lentiviral vectors control and release testing by the manufacturer to restrict the gene transfer to a targeted cell to ensure the quality and effi cacy of each indivi- Dr. Jens Reinhardt population of interest. This work not only helps to dual product dose. For vaccines, for example, this facilitate gene transfer, but also contributes to the provides a high level of confi dence for patients understanding of the possibilities and challenges and public health because vaccines with low effi - with which the manufacturers of gene therapy cacy would not protect individual recipients from products are confronted. The Paul-Ehrlich-Institut infectious disease, nor would they inhibit spread also develops tools to assure the safety of biolo- of infectious diseases in a population. Unsafe gical and biotechnological medicinal products. vaccines would possibly harm healthy individuals As already described, the Paul-Ehrlich-Institut and children receiving vaccines to protect their performs offi cial experimental batch testing health. for biomedicines such as immunoglobulins or vaccines, independent of the manufacturer, thus Research at the Paul-Ehrlich-Institut providing an essential contribution to the safety Dr. Evelyne Kretzschmar Right from the beginning the Paul-Ehrlich-Institut of the biological medicinal product. has focused its research on applied and basic to- The experimental research conducted at the Paul- pics related to biomedicines. This goes back to its Ehrlich-Institut is an indispensable basis for the founder, Paul Ehrlich, whose fame is based on his fulfi lment of its duties, ensuring excellent know- success with experimental testing of diphtheria ledge and expertise of the scientifi c staff, to base toxin as a biomedicine and on his visionary con- their assessment of the dossiers of biomedicines tributions to immunology. Currently, the different on fi rst-hand research experience. It also allows research groups at the Paul-Ehrlich-Institut are the Paul-Ehrlich-Institut to provide health policy working in four main areas in the fi eld of “expe- decision-makers with competent expert advice rimental vaccines, therapies and diagnostics”, on biomedicine-relevant issues. scientists study, e.g., the mechanisms of gene Prof. Dr. Klaus Cichutek Regulatory Compliance

Regulatory Compliance How can external regulatory experts help ensure regulatory compliance? as a Prerequisite for At the latest when the proof-of-concept has been established for a new drug, the following Lean Drug Development steps including preclinical and clinical studies will need careful planning. Very often a fi rst-in- Dr. Julia Wellsow human Phase I study is seen as a fi rst milestone to be reached. In most cases a Scientifi c Ad- vice at a competent authority is useful at some stage(s) during the development process. The When developing a drug product, every com- • most suitable approach ensuring a lean develop- pany aims for a lean development process, which ment process varies from drug product to drug is focused on the target to obtain an international product, and identifying essential development marketing authorisation within the shortest pos- steps requires substantial experience with regard sible time. One important measure speeding up to regulatory needs. Experienced regulatory the development and authorisation process is consultants can help with the coordination of the 14 ensuring regulatory compliance as early as pos- development and ensure that regulatory needs sible during drug development. are suitably considered. What is regulatory compliance? At various stages during a drug products’s life cycle the need will arise to submit certain documen- Regulatory compliance means the adherence tations to the competent authorities. This is not to all regulatory requirements relevant for the only the actual submission of the application for respective drug product throughout the comple- marketing authorisation in CTD structure (Module te life cycle of the drug product. This includes not 1 - 5), but also during the development process only legal and marketing authorisation aspects, submissions will have to be made, e.g. before a classically referred to as regulatory affairs, but Scientifi c Advice and before starting clinical stud- does in fact comprise the complete package ies in form of an Investigational Medicinal Product of pharmaceutical, toxicological, medical, and Dossier (IMPD) and an Investigator’s Brochure regulatory affairs. A vast variety of regulations, (IB). Once the drug product is authorised, phar- directives and guidelines exist with regard to the macovigilance observations will need to be docu- Author drug development and authorisation process in mented and reported. These documentations Europe. need to comply with very specifi c requirements, Dr. Julia Wellsow To ensure drug product approval within the short- which raises the need that data are recorded and YES Pharmaceutical est possible time and thus an early market entry, processed in compliance with these requirements Development Services GmbH substantial understanding of regulatory require- as early as possible during drug development. While a large drug company might have suitable Bahnstraße 42 - 46 ments for development and for the drug authori- documentation systems available, this will be 61381 Friedrichsdorf | GEMANY sation processes is most important. While larger drug companies can usually afford bundling this more diffi cult for smaller drug companies which Phone +49 61 72 7 64 64 - 29 knowledge within various departments of their may want to outsource data organisation for Fax +49 61 72 77 74 57 enterprise, smaller companies such as biotech or regulatory purposes. [email protected] advanced therapy start-ups may not have the re- www.yes-services.eu In the following specifi c aspects of regulatory sources to set up a modern “all-in-one” regulatory compliance with regard to pharmaceutical qual- affairs department and therefore would most of- ity, preclinical studies, clinical studies, and data ten need to rely on external consulting by special- documentation are discussed. ised experts and contract organisations. Since the necessity to comply with regulatory requirements Why consider pharmaceutical quality begins early on in the drug development process, it is generally advisable to integrate regulatory early in the development? competence as early as possible. Concerns regarding pharmaceutical quality run Biotechnological and other innovative drug like a thread through the complete development products, such as e.g. advanced therapy medici- process and the life cycle of a drug product. nal products, present a special challenge in this According to our long experience, these are un- respect, since the products are much more com- fortunately often missed in the beginning of the plex than small molecule products, and so are the development process, which can have substantial respective regulatory requirements. impact on later stages of the development, particularly in the case of complex biotechnological Dr. Julia Wellsow and other innovative drug products. Regulatory Compliance

The pharmaceutical quality of the drug product drug product. In addition, particularly with pro- used for preclinical studies should be compa- teins administered in low doses, the observation rable to the pharmaceutical quality of the drug that the drug substance is adsorbed to the plastic product used for clinical studies and for the mar- packaging material is not uncommon, and can ket once the drug product is authorised. Compa- result in loss of effi cacy. The stability of drug sub- rability in terms of pharmaceutical quality needs stance and drug product in the chosen packaging to be documented. This means that consideration material needs to be addressed before clinical has to be given to the pharmaceutical quality of studies can be started. the drug substance and the drug product before Manufacture in a GMP regulated environment the start of preclinical studies and any modifi ca- is mandatory for drug products used in clinical tion during development must be continuously studies. In order to ensure comparability it is assessed with regard to their scientifi c and regu- always advisable to start production in a (c)GMP latory impact. regulated environment as early as possible. One needs to be aware of the fact that the phar- The pharmaceutical quality of the drug substance maceutical quality of the drug product and the and the drug product needs to be documented drug substance can have substantial infl uence on within the IMPD before a clinical study can be 15 the outcome and interpretation of preclinical and started. The complexity of the documentation for clinical studies. The rationale behind it is that, for pharmaceutical quality depends on the type of instance, the impurity profi le of a drug substance the investigational medicinal product and also on or drug product may infl uence the toxicity and the clinical study phase. The IMPD needs to be even the effi cacy of a drug product. This is par- compiled in accordance with relevant regulations ticularly the case for biotechnological products and guidelines, which regulate the structure of where the drug substance is rarely a pure protein, presentation and the level of detail needed at a but often a mixture of various protein variants. certain stage. The immunogenicity of a protein product may also be strongly infl uenced by its impurity profi le. When suitably planned, the IMPD can later be used as a basis for the more comprehensive For biotechnological products, the composition pharmaceutical quality documentation of drug of the drug substance in terms of protein variants substance and drug product required for market- and the impurity profi le strongly depends on the ing authorisation in CTD format. synthesis and purifi cation process. During early development of a biotechnological drug product the synthesis and purifi cation process and the What needs to be considered during analysis of the drug substance may not have preclinical development? been ultimately optimised and will be subject to Particularly for biotechnological and other in- change at a later stage. Most often an upscale of novative drug products the general concepts the synthesis process has not yet taken place. of designing preclinical studies as applicable The above considerations not only apply to for small molecules cannot be followed without biotechnological products, but also to the broad being critically surveyed, and most often preclini- variety of advanced therapy medicinal products. cal study programmes specifi c for the particular drug product have to be designed. This includes, With regard to the required comparability of drug for instance, choosing a relevant animal species product(s) used during the development stages, and considering specifi c risks associated with the reference samples of the drug substance and particular drug product. Close cooperation with drug product(s) used during all studies should be toxicological experts is advisable. In order to plan retained in order to be able to re-analyse these the preclinical study design, the target disease, samples, e.g. in case more sensitive analytical the route of administration, and the intended methods have been developed. In case the appli- dosage regimen should ideally be known for the cant is not able to show comparability, it cannot drug product. be excluded that the authorities request that e.g. certain preclinical studies are repeated before the Since very often no specifi c guidelines exist for clinical studies can be started, and even clinical innovative biotechnological drug products with studies may require repetition. regard to toxicological studies, a Scientifi c Advice at a competent authority may be advisable. This Moreover, the chosen packaging for the drug ensures that the chosen preclinical study pro- substance and the drug product needs careful gramme will be acceptable when submitting consideration. In case plastic packaging materi- the IMPD for clinical studies. A Scientifi c Advice als are chosen, the drug product may need to be meeting at a competent authority needs careful investigated with regard to leachables from the preparation. The authorities expect that the appli- plastic that may have effects on the safety of the cant only discusses those questions that are not Regulatory Compliance

covered by regulatory guidelines. Early involve- and also for submission to national authorities ment of an experienced regulatory specialist is (e.g. within a decentralised procedure (DCP) or a strongly recommended in order to maximise the mutual recognition procedure (MRP)) electronic company’s benefi t from such meetings. submission is increasingly required. This poses additional and complex demands on document What is important with regard to preparation. clinical studies? It makes sense to put all data in a central reposi- tory already at an early stage during drug devel- Protection of the people enrolled in a clinical opment. All data will then need to be processed study should be of highest priority. Toxicological in accordance with ICH eCTD requirements. results from preclinical studies should therefore This means, for instance, the use of a certain fi le be the basis for dose fi nding and implementing structure and certain fi le names, the creation of safety measures. This is particularly important for searchable pdf fi les, bookmarking and tagging, highly effective drug products, and special guide- and the use of defi ned hyperlinks and cross-refer- lines exist for these kinds of products, all of them ences. Use of that database can already be made focussing on enhancing drug safety, i.e. assess- for the IMPD and later for preparation of the fi les 16 ing potential risks and implementing measures for marketing authorisation. for a safe use. Since very often a case-by-case approach is necessary, experienced regulatory What post-approval activities are specialists can help enhancing interpretation of required? these guidance documents. The risk management plan that must be submit- The study design of clinical studies is no trivial ted with the application for marketing authorisa- task and requires a certain amount of experience. tion describes the risk management system cho- The relevant patient population, suitable study sen for the specifi c drug product. This includes endpoints, and the location for the study need to post-authorisation studies (Phase IV studies) be chosen. Clinical studies with conceptual weak- with much larger patient populations in order to nesses should be avoided as these may fail to further evaluate the risk-benefi t ratio of the new demonstrate the effi cacy of the drug product. A drug product as well as all pharmacovigilance ac- Scientifi c Advice with a competent authority may tivities planned. Risk management is a continuous prove useful to ensure acceptance of the study process throughout the life cycle of a medicinal during drug product authorisation. product and requires timely planning, involving Quality management during conduct of the regulatory expertise. clinical study is most important and should be Complex and continuous safety data man- surveyed by experienced experts. This includes agement according to legal stipulations and e.g. monitoring of the study and process audits. regulatory standards is necessary within the Study results have to be adequately processed pharmacovigilance activities including e.g. safety and study reports have to be compiled follow- signalling, database searches, CIOMS and E2B ing the relevant regulatory requirements. Since reporting. This requires access to relevant data many clinical studies are conducted within bases and certain technological equipment which classical research environments, the awareness may not be profi table for smaller companies. towards regulatory requirements with regard to Therefore various possibilities exist to outsource data documentation and reporting should be certain or all pharmacovigilance activities. suffi ciently supported. Current studies not being conducted and reported according to GCP/ICH requirements will not be accepted as pivotal data Conclusion and may not even be considered as supportive To speed up the entire drug product authorisa- data. tion process, regulatory compliance should be Moreover, one should be aware of the fact that ensured as early as possible and at all relevant when developing a new drug product the poten- steps of the drug product’s life cycle. This in- tial use in children needs special consideration, cludes the areas pharmaceutical quality, pre- which requires approaching early the paediatric clinical and clinical studies, data documentation committee and, usually at the end of Phase I, and post-authorisation activities within the risk submitting a Paediatric Investigation Plan (PIP). management system. Integration of a regulatory full-service provider What are the requirements regarding proved to be one factor of success for small and data documentation? medium sized enterprises (SMEs) and should be sought as early as possible during the develop- Complete electronic submission in eCTD struc- ment in order to ensure a lean development ture is required for EMEA submissions within the process and an early market entry. centralised procedure from July 2009 onwards, Formation of Winning Teams

• sterna biologicals is a young entrepreneurial company dedicated to the development of third Biotech Start-ups and Contract generation anti-sense therapy for the causative treatment of chronic inﬂ ammatory diseases, in research Organizations particular bronchial asthma, atopic dermatitis and rheumatoid arthritis. Forming winning teams

Based on more than a decade of biological and medical research sterna was founded as a spin- A Case Study off of the Department of Clinical Chemistry and PD. Dr. Holger Garn, Dr. Joachim Bille Molecular Diagnostics at the Philipps University of Marburg and the TransMIT GmbH - Center for Because of the newness of both, class of sterna´s Immunomodulation (an institution promoting therapeutic molecule and therapeutic approach, Authors the transfer of academic research results into there was few experience regarding preclini- economic applications). cal study outlines as well on the side of service PD. Dr. Holger Garn sterna biologicals has established a novel class providers (e.g. for toxicological studies) as on the Dr. Joachim Bille of therapeutic compounds for the key indications side of the authorities. So we early decided to get sterna biologicals GmbH & bronchial asthma, atopic dermatitis, and rheu- the help of an experinced and well established Co. KG BMFZ matoid arthritis representing a highly attractive CRO (from Hessen) to achieve our aim: to get as Hans-Meerwein-Str. 2 pharmaceutical market. quick and as cost effective as possible into a First- 35043 Marburg | GERMANY The rationale of sterna biologicals’ approach for in-Man study. The experts helped us to structure identifying desirable therapeutic compounds is to steps and milestones. Together we prepared [email protected] interfere with the most relevant key events in the for and obtained an invaluable Scientifi c Advice www.sterna-biologicals.com disease causing cascade that are responsible for from the BfArM regarding toxicological studies the development of the infl ammatory response. and currently are preparing another regarding This has been achieved by sterna biologicals’ pharmaceutical quality. The CRO-team taught us patented third generation anti-sense molecules, to plan preclinics from the sight of the needs of so-called DNAzymes. The novel approach - as the later clinical studies (application route, estimation name already indicates - is that these compounds of dosing in man, favoured inhalation device etc.). are enzymatically active DNA structures with all They helped us avoiding short-term AND long- the inherent advantages of this type of com- term costs by concentration on the minimum pound which contrasts well with other anti-sense requirements for an early approval of the First- therapies. in-Man study, but not disregarding necessary preclinical work which may be essential for later PD. Dr. Holger Garn This principle has already been successfully prov- clinical phases (e.g. repeated dose toxicology). en for the GATA 3 mRNA-specifi c DNAzyme with Summing up, our urgent advice to biotech start regard to effi cacy, side effects, off-target effects ups in the fi eld of therapeutics is to get expert including escalating dose response in a variety monitoring by an experienced (in the fi eld of of validated animal disease models for acute and clinical AND preclinical studies) contract research chronic bronchial asthma. organization. The key success factors of sterna biologicals are Figure: related to the unique mode of action allowing Potential points of therapeutic interference within intervention at a point of the natural course of and outside the cell to block the generation of the infl ammatory diseases resulting in a causative proteins involved in the infl ammatory cascade. treatment effect without stimulation or suppres- Dr. Joachim Bille Whereas interference at the DNA level is a more sion of other immunological mechanisms. The hypothetical possibility due to its irreversibility causative effect stems from catalytic elimination/ the direct interference with the mRNA is the earli- destruction of mRNAs that encode early key est point of action to inhibit the generation of a molecules in the signaling cascade that cause specifi c protein. and maintain each specifi c infl ammatory process. Thus, the cascade is interrupted at the earliest possible point at the origin of the disease. gene knockout antisense technologies antagonists antagonists gene therapy • DNAzymes • small inhibitors • mAb The corporate goal is to develop therapeutic • siRNA • decoys • peptides DNAzymes from animal models to Clinical Phase • antisense DNA • aptamers • ligands II trials. But especially for a small start-up com- aptamers pany it´s a long and winding road to get there. First (and big) step is to manage preclinics and fi le a suffi cient and promising submission of the study to the ethics commissions and the regulatory authorities. DNA RNA Investigator Initiated Trials

scientifi cally compelling and innovative clinical Investigator-initiated trials research within various fi elds of interest. Dr. Torsten Arndt, Dr. Silke Busch However, beside IITs of pure non-commercial interest, some IITs are entirely funded by industry. As the pharma industry continues to struggle to • Academia has been and still is the pool for launch new drugs, it has to rely on life-cycle man- innovative therapies and clinical trials, which are agement of existing products to meet economic crucial for medical progress and the develop- aims. In this respect, IITs became a tangible asset ment of novel therapeutic concepts. Investigator- and are rather regarded as part of a sophisticated initiated trials (IITs) have a long tradition at Univer- product development strategy by the pharma- sity hospitals and represent an important aspect ceutical industry, than a non-profi table, science- of medical research, translating discoveries made focused merit. IIT fi ndings not only provide in basic science into novel therapies, new drugs clinical data to expand scientifi c knowledge of or devices. IITs are clinical studies set off by physi- marketed drugs, but also further the extension of cians at academic medical centers. The goal of on- and off-label use in new indications to reach IITs is to advance and improve existing therapeu- larger patient groups. Furthermore, IITs gener- 18 tic concepts by supporting investigator-initiated ate data for scientifi c publications and establish research that will enhance the understanding fruitful relationships with academic key opinion of disease entities and provide clinicians with leaders. Hence, IITs proposing unique applica- the most reliable evidence for careful decision- tions, possibly leading to new indications for the making at the bedside. A major advantage of aca- drug, are willingly funded by the pharmaceutical demic translational research, particularly in a hos- industry. pital setting, is direct access to patients for clinical A main drawback of translational studies and studies. By contrast, research at pharmaceutical related personalized medicine approaches in companies is focused on gaining knowledge of a industry is the mandatory economical interest, new compound and bringing out new products, whereas IITs unravel all sophistications of drug however, IITs are patient-oriented and designed profi ling narrowing medical applications. Obvi- to optimize an already known therapy. ously, both interests aren’t necessarily mutually To further address the benefi t for patients, es- compatible. pecially in indications with so far unmet medical However, commercial and academic research need, it is crucial to come up with novel innova- should not be considered as opponents, because tive therapeutic concepts. These include studies both are interdependent and complementary such as diagnostic and therapy optimizing trials, and close ties between both partners should be applying modern genotyping and phenotyping encouraged. methods of important polymorphisms (SNPs), Recently the regulatory environment for IITs has personalized medicine and adaptive study de- been reformed substantially. The 12th amend- signs, investigating the combination of existing ment of the German Drug Law (Arzneimittelges- drugs and the development of orphan drugs. etz, AMG) was implemented to comply with the Patients will benefi t due to early access to novel, requirements of the European Union’s Clinical innovative therapies that is provided by these dy- Trials Directive 2001/20/EC for all clinical studies namic clinical research efforts. Most signifi cantly, on medicinal products. It defi nes comprehensive IITs represent the clinical translational efforts of administrative legal requirements with regard to academic centers and underline researchers´ academic clinical research with the intention to commitment to innovation for patients. stipulate and harmonize regulations for clinical re- Many times IITs address issues with only marginal search in respect of Good Clinical Practice (GCP). prospect of revenue, but commonly investigate Undeniably, compliance with GCP-guidelines so far inadequately solved clinical questions and ensures a valid design of the study, reliable data enhance knowledge of particular disease mecha- management and monitoring, as well as quali- nisms. IITs enable uncommitted clinical research fi ed analysis of study results, therefore enhancing and provide an environment for unbiased clinical the value and signifi cance of the collected data. trials. Of particular note in this respect is the need More likely, these trials generate reliable data of adequate public funding. Obtaining funding to improve disease understanding and increase for research is the greatest impediment. Gener- confi dence in new therapeutic treatments. There- ally, funding for IITs is provided by public institu- fore, investigators appreciate the importance of tions like the Federal Ministry for Education and methodological rigour. Research (BMBF), German Research Foundation (DFG) or foundations to support non-commercial, But the increased regulatory burden confronts investigators with almost unsolvable tasks and is regarded to substantially hamper independent Investigator Initiated Trials

clinical research. Due to the stringent regulations, open to all regional hospitals and physicians in a basic prerequisite for IITs is adequate assist- private practice and therefore provides a large ance of the investigator in fulfi lling the regula- patient pool crucial for considerably faster execu- tory requirements, guidelines and procedures. tion of clinical studies. Notably, the in-house Planning and implementation of an IIT demands Phase I unit provides capacities customized for specialized knowledge of regulatory issues, drug most Phase I trial designs, continuous safety safety and quality management. In this respect, monitoring and is backed up by the cooperating performing an IIT according to the new legal hospital emergency care unit, to assure a high environment requires a service for clinicians and degree of individual medical care for all trial academic researchers to tackle the increased subjects. Within this setting there is the option regulatory obligations. It requires professional or- to conduct fi rst-in-man trials, bioavailability/ ganisational structures, a highly trained staff and bioequivalence and PK/PD studies, to rapidly close cooperation with specialised experts, such translate therapeutic concepts from the labora- as project managers, statisticians, data managers, tory to the clinic. The KSRM guarantees a close pharmacists and monitors. Based on the emerg- contact to opinion leaders in the respective fi eld ing recognition of the value of non-industry and substantially contributes to the competitive originating studies, the structures and resources position of the Frankfurt region in the fi eld of 19 for investigator driven trials in academia are clinical research. The KSRM aims to represent a increasingly provided, especially through transla- balanced portfolio of both innovative publicly tional medicine centers like the Center for Drug funded IITs and clinical trials on behalf of spon- Research, Development and Safety (Zentrum für sors from the pharmaceutical industry, the latter Arzneimittelforschung, -Entwicklung und –Sicher- to continuously benchmark quality measures heit, ZAFES), leading to the implementation of against industry standards. centralized service institutions. Coordination Centers for Clinical Trial Center Rhine-Main Clinical Trials (Koordinierungszentren (Klinisches Studienzentrum für Klinische Studien, KKS) Rhein-Main, KSRM) In addition to the KSRM in Frankfurt the Coordi- The KSRM, as an integral part of ZAFES, provides nation Center for Clinical Trials (KKS) in Marburg a competent staff, the expertise and effi cient complements the highly competitive environment management structure regarding the conception, for compelling science-initiated trials in Hessen. implementation and monitoring of clinical studies The KKS Marburg belongs to the KKS network of to support independent patient-oriented clinical 12 sites throughout the country, funded by the research by physicians. The KSRM was supported BMBF, as a platform for transparent, patient-ori- by a triennial grant of the Hessen Ministry of ented development of new drugs and therapeu- Economics, Transportation and Regional Devel- tic principles in Germany. Furthermore, within opment (Hessischen Ministerium für Wirtschaft, the KKS network paediatric trials are supported Verkehr und Landesentwicklung, HMWVL) in in special modules to enable the conduct of ethi- order to implement a sustainable infrastructure for clinical research in the Rhine-Main region. The network build up by the KSRM integrates mainly university teaching hospitals, but is in principle Investigator Initiated Trials

cally sound and qualiﬁ ed drug trials with children, evaluate a scientiﬁ c rational in a clinical research to counteract the common practice to translate setting seamlessly, thus supporting a bench to results from studies with adults to children, often bedside approach. Furthermore, ZAFES trains inadequately taking into account the unique the next generation of clinical and translational pharmacology of children. In addition to that, researchers and creates an environment in which the KKS network is engaged in the organisation investigators have a clearer career path in the of training and further education in the areas of highly rewarding discipline of translational re- clinical pharmacology, investigator courses, study search. ZAFES is a partner for the pharmaceutical nurses, documentation, quality management, industry und biotech companies for joint-projects regulatory guidelines, monitoring, data manage- at all stages of the value chain of drug discovery ment and biometrics. and drug development and provides essential academic core technology facilities.

ZAFES In conclusion, there is a continuous need for Excellent academic networks are the key for inno- conducting IITs to assess novel and complex Authors vative drug discovery and development projects. therapeutic concepts to enable evidence based Academic medical centers can actively promote decision-making in medical care, whether in Dr. Torsten Arndt the discovery and development of novel drugs a completely independent manner funded by Dr. Silke Busch by combining their expertise in basic and clinical public grants or sponsored by the pharmaceutical Zentrum für Arzneimittel- science with the know-how of pharmaceutical industry. As compared to international standards forschung, -Entwicklung und and biotechnology companies. To effectively clinical research in Germany is only mediocre -Sicherheit (ZAFES) manage this interface, ZAFES was launched at the regarding number of scientifi c publications, quantity and impact of clinical studies across the Theodor-Stern-Kai 7 Goethe University of Frankfurt integrating hospi- board. There is a distinct awareness to substan- 60590 Frankfurt am Main | tals and academic centers to develop, manage, tially further expertise in clinical research and GERMANY and implement corporate alliances, design the optimal structure for cooperations, negotiate ac- effectively counteract the increasing allocation Phone +49 69 6301-87159 tual partnership agreements and provide project of clinical trials abroad. Therefore it is of strate- Fax +49 69 6301-7636 management for collaborative projects. ZAFES gic interest to address the establishment of the [email protected] implemented a structure to collect, integrate, and required infrastructure for clinical research and www.zafes.com disseminate the intellectual, organizational, and continuous education and training of physicians resource infrastructure needed to promote and in the fi eld of study concept development, coor- support multidisciplinary research collaborations, dination and regulatory processes. Of particular being considered to be a key factor for success- note in this respect is Hessens special position, ful translational research. The ZAFES platform because the large number of resident pharma- promotes university research ideas and inven- ceutical companies, biotech fi rms and CROs tions, expands and manages industry-academic along with a vital academic research environment collaborations and accelerates the translation of represent a unique cluster for compelling bio- biomedical research into therapeutic applica- medical research and constitute the driving force tions to rapidly deliver new drugs to the patients. for novel, innovative medical therapies. In addition the KSRM enables researches to

Dr. Torsten Arndt

Dr. Silke Busch Ethics Committees in Hessen

• The protection of patients during a clinical The Work of the Ethics trial is one of the most important issues in human research; this has been addressed by the Committees in Hessen Declaration of Helsinki, the European Conven- tion of Bioethics and also in many statutes of Prof. Dr. med. Sebastian Harder medical science. In accordance with European guidelines, the latest amendment of the Ger- man Drug Law (AMG § 40) requires the explicit tion facilities, the experience of the investigator approval of an ethics committee (EC) for a clinical in the fi eld of clinical trials, the number of parallel study with drugs. The trial has to be submitted by studies performed in this center (to ensure fair al- the sponsor of the trial and the submission has location of eligible patients) and the certifi cation to be addressed to the EC responsible for the of the trial staff. principal investigator of a single center study or the principal coordinating investigator of a multi- In the federal state of Hessen, there is an eth- center trial. Such ethics committees are present ics committee at each of the 3 medical faculties at almost every medical faculty (according to the (Frankfurt, Gießen, Marburg) and one ethics com- university laws of each province state) and for mittee at the physicians’ chamber of Hessen lo- 21 non-university researchers at each chamber of cated in Frankfurt (application and addresses see physicians of a province state. Further details on below). The two ethics committees in Frankfurt the work and coordination of these ethics com- share some members, but work independently. mittees are outlined in a guideline supplementary However, the principal rules for the format and to the German drug law (GCP-V). These proce- wording of study documents, e.g. the informed dures ensure a standardized process for the trial consent are the same, and there is close coopera- (i.e. all study documents such as patient information between these two ECs, as many clinical trials tion and consent forms will be similar nationwide) are performed at the medical department, but in a timely fashion (usually, 30 days for single involve co-investigators from adjacent teach- center trials and 60 days for multi-center trials). ing hospitals. There is also close cooperation Further EC-activities are the review of substantial with the other ECs which is coordinated by the protocol amendments and the appraisal of the Ministry of Social Affairs (which is responsible for suitability of a study site and the qualifi cation of the Health Sector). Recently, all ECs in Hessen the investigator. Since adoption of the new guide- adopted a common format for the submission lines in 2004, the submission procedure and and the submission fees. All ECs are accredited requirements for the study documents between by the competent authorities (i.e. BfArM or PEI) the different committees throughout Germany and working in compliance with FDA regulations. have now been widely harmonized, facilitated Thus, in Hessen, a high degree of cooperation by the activities of the so called “Arbeitskreis within the ECs and the applicants is ensured. Medizinischer Ethik-Kommissionen in Deutsch- Application procedure for studies, according land”. to the German Drug Law (AMG): Each EC has a The EC review of a study protocol and related detailed web-site which gives clear instructions documents is done by competent experts in on how to submit a study and the format of the the corresponding clinical fi eld of the research application (see below). EC meetings are usually project. The (honorary) members are nominated in monthly intervals. Furthermore, EC staffs will by the governing bodies of the medical faculties advise applicants (sponsors and investigators) or the Physicians Chamber. The composition of an EC follows the requirements of the AMG and ICH-GCP. At least one member is independent from the institution, at least one has a primary area of interest in a nonscientifi c area, one is a pediatrician and one is an expert in methodology (e.g. biometrician or pharmacologist). The review focuses on the validity of study rationale, the adequacy of the study design and sample size for reaching the study goals, the risk-benefi t ratio and the documents used for the informed consent. Several reference guides have been published which describe the principles of the review process (see Reference List). The appraisal of the study site and its investigators base on the review of its technical equipment incl. resuscita- Ethics Committees in Hessen

who are not familiar with the German or EU regu- and the time frame for notifi cation of approval or lations e.g. the EudraCT registry, the application rejection is expanded until the applicant has sup- to the competent authorities (see above) and plemented the documents or otherwise respond- registration with the local administration authori- ed. The submission to the competent authorities ties (RP). has to be made simultaneously, and, after getting If the coordinating or principal investigator is approval of the study, the study has to be reg- affi liated with the university hospital of Frank- istered with the local administration authorities furt (Klinikum der J.W.Goethe-Universität), the (i.e. Regierungspräsidium RP). The application responsible EC is that of the medical department procedure for studies according the German Law (http://ethik-kommission.klinik.uni-frankfurt. for Medicinal Products (MPG) follows a similar de). If the coordinating or principal investiga- pathway, with some variations (see websites for tor is affi liated with the university hospital of detailed guidelines). Gießen (Klinikum der Justus-Liebig-Universität) Since the substantial changes of the AMG in or one of the offi cial teaching hospitals of this 2004, time and experience with the new regula- medical faculty, the responsible EC is that of the tions has elapsed. Although the EU-wide har- medical department of Gießen (http://www.med. monization has been welcomed by most phar- uni-giessen.de/infoweb/intranet/ethik). If the 22 maceutical companies, smaller companies and coordinating or principal investigator is affi liated particularly independent researchers of so called with the university hospital of Marburg (Klinikum “Investigator Initiated Trials” (IIT) have criticized der Philipps Universität Marburg) or one of the the burden caused by e.g. the requirements of teaching hospitals affi liated with this medical SUSAR-reporting, the need for extensive labe- faculty, the responsible EC is that of the medi- ling of the study medication or the EC appraisal cal department of Marburg (http://www.med. of each single investigator. The Commission uni-marburg.de/stpg/zentr/ethikkomm/webneu/ Directive 2005/28/EG and a draft guidance on index.html). The EC of the Physicians’ Chamber ‘specifi c modalities’ for non-commercial clinical (http://www.laekh.de/Aerzte/Aerzte-Rund-ums- trials (Title: draft guidance on ‘specifi c modalities’ Recht/Aerzte-Rund-ums-Recht-Ethik-Kommission/ for non-commercial clinical trials referred to in Rund_ums_Recht,cat367.html) is the responsible Commission Directive 2005/28/EC laying down EC for all other study sites (hospitals or ambula- the principles and detailed guidelines for good tory care) in Hessen. After confi rmation of receipt clinical practice; disseminated in June 2006 but of a valid submission (i.e. all documents required not adopted yet) have taken these concerns into according to § 7 of the national GCP-directive), consideration, but several problems regarding Authors applicants will get their approval or rejection harmonization of procedures remain unsolved. within 30 days for single center and 60 days for Prof. Dr. Sebastian Harder multi-center studies, unless the submitted docu- Klinikum der ments are subjects of concern or not complete Goethe-Universität enough to fulfi ll GCP-requirements. However, Institut für Klinische Pharma- any objections by the EC can only be made once, kologie Theodor Stern Kai 7 60590 Frankfurt | GERMANY Phone. +49 69 6301 6423 Fax +49 69 63017636 [email protected]

Prof. Dr. Sebastian Harder The Monitoring Authority

• The Regional Board Darmstadt, the largest of the three Hessian Regional Boards, has more than COMPETENCE 5,000 functions in the areas of health, integration, aliens law, regional planning, building and AND COMMUNICATION construction trades, economy, transport, labor and environmental safety, agriculture, forestry, Mission Statement of nature conservation and consumer protection.

The employees provide contact points for 3.8 the Monitoring Authority million citizens, for cities and municipalities, the economy, industry, service industry, associations, as well as other organizations in the region Rhine-Main / Southern Hesse. Some functions are carried out for the entire state of Hesse. These include pharmacovigilance. The Regional Board Darmstadt has currently approx. 1,600 employees with a wide range The following activities of the two pharmaceutical of experts in the ﬁ elds of legal, administrative, departments of the Regional Board Darmstadt economical, natural and engineering sciences, are a priority: 23 human medicine, veterinary medicine and ¬ supervision of the trafﬁ c of drugs and active pharmacy. agents at manufacturers, pharmaceutical Principal services of the Regional Board entrepreneurs, wholesalers and retailers as Darmstadt are: well as in pharmacies

¬ active participation in and shaping of regional ¬ execution of permission, approval and certiﬁ ca- development tion procedures required according the Arznei- mittel- und Apothekengesetz (the German Drug ¬ safeguarding of the business location, as well and Pharmacy Law) for the production and as the international competitiveness of Hessian distribution of drugs on the national, European companies and international market

¬ preventive risk minimization, also in complex ¬ supervision of clinical trials of drugs on humans approval procedures for approx. 1,500 clinical trial physicians, approx. 50 commission research institutes and ¬ supervision in the interest of security and Authors quality of life approx. 40 sponsors

The exercise of functions of the Regional Board Susanne Huber Darmstadt is carried out: Team leader clinical trials Regierungspräsidium ¬ in accordance with the rule of law Darmstadt ¬ cooperatively Luisenplatz 2 64283 Darmstadt | GERMANY ¬ in a citizen-oriented manner Phone +49 6151 12 4025 ¬ securing a balance of interests Fax +49 6151 12 5789 [email protected] www.rp-darmstadt.hessen.de Dr. Jochen Daab Phone +49 06151 12 5697 [email protected]

Susanne Huber The Monitoring Authority

Regional Board Darmstadt - drug monitoring authority for Hessen

evaluation data notiﬁ cation* commission higher federal clinical trial research authority application* order order physicians institutes

production supply pharmaceutical special-order wholesalers companies order manufacturers

supply supply 24

* approval of a clinical trial or accredition of a drug pharmacies other retailers

RPDA supervision II23.1 permission and supervision

Within the framework of supervision of clinical ¬ competence, qualifi cation and independence trials of drugs on humans, the Regional Board of inspectors Darmstadt mediates between the interests of public welfare and the interests of institutions ¬ modern data techniques and people involved and works towards a fair ¬ orientation of the extent of supervision on the balance of interests, although the protection degree of autonomy and readiness to of patients and test persons has the highest cooperate priority. ¬ solution-oriented and constructive confl ict During the supervision of clinical trials of resolution drugs on humans, the Regional Board Darmstadt focuses particularly on: ¬ active and continuous dialogue through the organization of specialist conferences in order ¬ an optimum of patient protection through to discuss the regulatory rules a systematic and risk-based supervision approach ¬ quality assurance through defi ned standards and target agreements ¬ effective and committed communication with clinical trial physicians, commission ¬ stable presence in the federalwide professional research institutes, sponsors, collegiate group of experts authorities and higher federal authorities

¬ quality and transparence during inspections in order to ensure compliance with national and international normative provisions Company Proﬁ les

Company Proﬁ les

A.CRO Clinical Research Services Accovion GmbH Alcedis GmbH Amantec GmbH Averion Europe

Chiltern International 25 clinicalworks GmbH C.R.O.Cont(r)acts DR. RIETHMÜLLER M/R/S ECRON ACUNOVA ERGOMED GBG Forschungs-GmbH ICON Clinical Research GmbH Koordinierungszentrum für klinische Studien Klinisches Studienzentrum Rhein-Main (KSMR) Medical Consulting – Klaus Goldschmidt NeuroCode AG Omega Mediation GmbH Omnicare Clinical Research GmbH PAREXEL International GmbH PAZ Arzneimittelentwicklungsgesellschaft mbH PharmaPart GmbH PharmaProjekthaus GmbH & Co. KG Praxis Klinische Arzneiforschung Premier Research Germany Quintiles GmbH SciNuTec GmbH SCRATCH Pharmacovigilance Services SKM Oncology Research GmbH Trilogy Writing & Consulting GmbH YES Pharmaceutical Development Service GmbH Zentrallaboratorium Deutscher Apotheker e. V. GmbH Company Proﬁ les

A.CRO Clinical Research Services GmbH Accovion GmbH

Brunnenstr. 35 Helfmann-Park 10 65191 Wiesbaden | GERMANY 65760 Eschborn | GERMANY Contact Partner: Dr. Werner Kusche Contact Partner: Sonja Riedel Phone +49 611 564 08 80 Phone +49 6196 7709 339 Fax +49 611 564 08 82 [email protected] [email protected] www.accovion.com www.a-cro.com

26 Type and range of services provided Type and range of services provided ¬ General consultation in the area of clinical research ¬ General consultation in the area of clinical research ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the CRF (Case Report Files) ¬ Trial plan: design of the CRF (Case Report Files) ¬ Training and further education (e.g. training in GPC etc ¬ Training and further education (e.g. training in GPC etc ¬ Audit- and compliance services ¬ Audit- und Compliancedienste ¬ Monitoring ¬ Monitoring ¬ Selection and acquisition of trial centers and physicians ¬ Selection and acquisition of trial centers and physicians ¬ Acquisition of patients ¬ Acquisition of patients ¬ Data management / databases / biostatistics etc. ¬ Data management / databases / biostatistics etc. ¬ Supervision of procedures for authorization of the study: ¬ eCTD (Electronic Common Technical Document) Submission to the Senior Federal Authority ¬ Supervision of procedures for authorization of the study: ¬ Supervision of procedures for notification of the Regional Submission to the Senior Federal Authority Supervising Authority ¬ Supervision of procedures for notification of the Regional Supervising Authority Customer Groups ¬ Approval of Drugs / Medical devices ¬ Start-up ¬ Producers of Generics Clinical Phases covered ¬ Mid-sized pharmaceutical companies ¬ Preclinical I, II, III, IV ¬ Big Pharma ¬ Other CROs Customer Groups ¬ Start-up ¬ Mid-sized Pharmaceutical Companies ¬ Big Pharma Company Proﬁ les

Alcedis GmbH Amantec GmbH

Winchester Str. 2 Industriepark Höchst Gebäude C820 35392 Gießen | GERMANY 65926 Frankfurt am Main | GERMANY Contact: Dr. Elke Heidrich-Lorsbach Contact Partner: Sven Engel Phone +49 641 944 360 Phone +49 69 305 288 77 Fax +49 641 944 36 70 Fax +49 69 305 246 00 [email protected] [email protected] www.alcedis.de www.amantec.com

Type and range of services provided Type and range of services provided 27 ¬ General consultation in the area of clinical research ¬ General consultation in the area of clinical research ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the CRF (Case Report Files) ¬ Trial plan: design of the CRF (Case Report Files) ¬ Training and further education (e.g. training in GPC etc ¬ Training and further education (e.g. training in GPC etc ¬ Audit- and compliance services ¬ Audit- and compliance services ¬ Monitoring ¬ Monitoring ¬ Selection and acquisition of trial centers and physicians ¬ Selection and acquisition of trial centers and physicians ¬ Acquisition of patients ¬ Acquisition of patients ¬ Data management / databases / biostatistics etc. ¬ Data management / databases / biostatistics etc. ¬ eCTD (Electronic Common Technical Document) ¬ Supervision of procedures for authorization of the study: ¬ Supervision of procedures for authorization of the study: Submission to the Senior Federal Authority Submission to the Senior Federal Authority ¬ Supervision of procedures for notification of the Regional ¬ Supervision of procedures for notification of the Regional Supervising Authority Supervising Authority ¬ Approval of Drugs / Medical devices ¬ Approval of Drugs / Medical devices ¬ (Quality) management of distribution of clinical trial supplies ¬ Other Services: web-based tumor documentation system ¬ (Quality) management of storage of clinical trial supplies for online conference systems , web-based study ¬ (Quality) management of import of clinical trial supplies documentation, web-based registrary ¬ Security supervision and coverage

Clinical Phases covered Customer Groups ¬ I, II, III, IV ¬ Start-up ¬ Producers of generics Indication areas ¬ Mid-sized pharmaceutical companies ¬ Oncologie ¬ Big Pharma ¬ Other CROs Customer Groups ¬ Other: Medicinal Products ¬ Start-up ¬ Big Pharma ¬ Other: Universities Company Proﬁ les

Averion Europe GmbH Chiltern International GmbH

Siemensstr. 9, Eingang B Norsk-Data-Str.1 63263 Neu-Isenburg | GERMANY 61352 Bad Homburg | GERMANY Contact Partner: Nur Sidki Gomez Contact Partner: Ruth Sakowski Phone +49 6102 599 8430 Phone +49 6172 9443-0 Fax +49 6102 599 8410 Fax +49 6172 9443-300 [email protected] [email protected] www.averionintl.com www.chiltern.com

28 Type and range of services provided Type and range of services provided ¬ General consultation in the area of clinical research ¬ General consultation in the area of clinical research ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the CRF (Case Report Files) ¬ Trial plan: design of the CRF (Case Report Files) ¬ Training and further education (e.g. training in GPC etc.) ¬ Training and further education (e.g. training in GPC etc.) ¬ Audit- and compliance services ¬ Audit- and compliance services ¬ Monitoring ¬ Monitoring ¬ Selection and acquisition of trial centers and physicians ¬ Selection and acquisition of trial centers and physicians ¬ Acquisition of patients ¬ Data management / databases / biostatistics etc. ¬ Data management / databases / biostatistics etc. ¬ Supervision of procedures for authorization of the study: ¬ eCTD (Electronic Common Technical Document) Submission to the Senior Federal Authority ¬ Supervision of procedures for authorization of the study: ¬ Supervision of procedures for notification of the Regional Submission to the Senior Federal Authority Supervising Authority ¬ Supervision of procedures for notification of the Regional ¬ Approval of Drugs / Medical devices Supervising Authority ¬ Security supervision and coverage ¬ Approval of Drugs / Medical devices ¬ Other ¬ (Quality) management of production of clinical trial supplies ¬ EDC Support ¬ (Quality) management of distribution of clinical trial supplies ¬ (Quality) management of storage of clinical trial supplies Clinical Phases covered ¬ (Quality) management of import of clinical trial supplies ¬ I, II, III, IV ¬ Security supervision and coverage ¬ Electronic Reporting (e-Pharmacovigilance and E2B) Indication areas ¬ Other: EDC; IVRS (Interactive Voice Response System); ¬ Oncology, Central Nervous System, Infectious diseases, Pharmacovigilance; Endpoint Adjudication Committees; Pediatrics, Women’s health Medical Writing; Training Customer Groups Clinical Phases covered ¬ Start-up ¬ Preclinical I, II, III, IV ¬ Mid-sized pharmaceutical companies ¬ Big Pharma Indication Areas ¬ Cardiology, Oncology, Medical Devices, Vaccines, Neurology, Dermatology

Groups of agents / substances ¬ Biopharmaceuticals, Small Drugs, Dietary Supplements, Functional Food, Medical Devices, Diagnostics

Customer Groups ¬ Start-up ¬ Mid-sized Pharmaceutical Companies ¬ BigPharma ¬ Other: Medical Devices; Other medical centers (for investigator initiated trials) Company Proﬁ les

clinicalworks GmbH C.R.O.Cont(r)acts

Bernsfelder Str. 9 Luisenstr. 13 35325 Mücke | GERMANY 65773 Kelkheim | GERMANY Contact Partner: Hans-Heinrich Otter Contact Partner: Dr. Wolfgang Schaub Phone +49 6400 95976-12 Phone +49 6195 976210 Fax +49 6400 95976-29 Fax +49 6195 976212 [email protected] [email protected] www.clinical-works.com www.cro-contracts.com

Type and range of services provided Type and range of services provided 29 ¬ General consultation in the area of clinical research ¬ General consultation in the area of clinical research ¬ Trial plan: design of the trial protocol ¬ Electronic Reporting (e-Pharmacovigilance and E2B) ¬ Trial plan: design of the CRF (Case Report Files) ¬ Laboratory services ¬ Monitoring ¬ Selection and acquisition of trial centers and physicians Clinical Phases covered ¬ Acquisition of patients ¬ I, II, III, IV ¬ Data management / databases / biostatistics etc. ¬ Supervision of procedures for authorization of the study: Customer Groups Submission to the Senior Federal Authority ¬ Start-up ¬ Supervision of procedures for notification of the Regional ¬ Producers of Generics Supervising Authority ¬ Mid-sized Pharmaceutical Companies ¬ Approval of Drugs / Medical devices ¬ Big Pharma ¬ Security supervision and coverage ¬ Other CROs

Clinical Phases covered ¬ Preclinical, II, III, IV

Customer Groups ¬ Start-up ¬ Mid-sized Pharmaceutical Companies ¬ Big Pharma ¬ Other CRO ¬ Other: Universities, Medical-Centers for IITs, Producer of Medical Devices Company Proﬁ les

DR. RIETHMÜLLER M/R/S GmbH ECRON ACUNOVA GmbH

Mittelweg 27 Hahnstr 70 60318 Frankfurt am Main | GERMANY 60528 Frankfurt am Main | GERMANY Contact Partner: Dr. Hilde Riethmüller-Winzen Contact Partner: Harald von Eick Phone +49 69 1302560 Phone +49 69 6680300 Fax +49 69 13025629 [email protected] [email protected] www.ecronacunova.com www.drmrs.com

30 Type and range of services provided Type and range of services provided ¬ General consultation in the area of clinical research ¬ General consultation in the area of clinical research ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the CRF (Case Report Files) ¬ Trial plan: design of the CRF (Case Report Files) ¬ Training and further education (e.g. training in GPC etc.) ¬ Training and further education (e.g. training in GPC etc.) ¬ Audit- and compliance services ¬ Audit- and compliance services ¬ Selection and acquisition of trial centers and physicians ¬ Monitoring ¬ eCTD (Electronic Common Technical Document) ¬ Selection and acquisition of trial centers and physicians ¬ Supervision of procedures for authorization of the study: ¬ Data management / databases / biostatistics etc. Submission to the Senior Federal Authority ¬ Supervision of procedures for authorization of the study: ¬ Approval of Drugs / Medical devices Submission to the Senior Federal Authority ¬ Supervision of procedures for notification of the Regional Clinical Phases covered Supervising Authority ¬ I, II, III, IV ¬ Other: Submission to ethics committees, project management, medical writing, pharmacovigilance, peri-approval Customer Groups studies, rescue studies ¬ Start-up ¬ Producers of generics Clinical Phases covered ¬ Mid-sized pharmaceutical companies ¬ I, II, III, IV ¬ Big Pharma ¬ Other CROs Indication areas ¬ Other: Universities ¬ Allergology, cardiovascular diseases, clinical immunology/ infectiology, dermatology, diagnostic imaging, endocrinology, ENT, gastroenterology, gynaecology, metabolic disorders, nephrology, neurology, nutrition, oncology, ophthalmology, peripheral arterial diseases, psychiatry, pulmonology, rheumatology, urology, surgery, women’s health

Groups of agents / substances ¬ Pharmaceuticals, biopharmaceuticals, herbal medicines, small drugs, serological products, medical devices, generics, dietary supplements, nutracuticals

Customer Groups ¬ Start-up ¬ Producers of Generics ¬ Mid-sized Pharmaceutical ¬ Big Pharma ¬ Other: Medical device companies, Food Industry Company Proﬁ les

ERGOMED GmbH GBG Forschungs-GmbH

Otto-Volgerstr. 96 Schleussnerstr. 42 65843 Sulzbach | GERMANY 63263 Neu-Isenburg | GERMANY Contact Partner: Klemens Schütte Contact Partner: Prof. Dr. med. Gunter von Minckwitz Phone +49 6196 907540 Phone +49 6102 7480-420 Fax +49 6196 9075489 Fax +49 6102 7480-440 [email protected] [email protected] www.ergomed-cro.com www.germanbreastgroup.de

Type and range of services provided Type and range of services provided 31 ¬ General consultation in the area of clinical research ¬ General consultation in the area of clinical research ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the CRF (Case Report Files) ¬ Trial plan: design of the CRF (Case Report Files) ¬ Training and further education (e.g. training in GPC etc.) ¬ Training and further education (e.g. training in GPC etc.) ¬ Audit- and compliance services ¬ Monitoring ¬ Monitoring ¬ Selection and acquisition of trial centers and physicians ¬ Selection and acquisition of trial centers and physicians ¬ Acquisition of patients ¬ Acquisition of patients ¬ Data management / databases / biostatistics etc. ¬ Data management / databases / biostatistics etc. ¬ Supervision of procedures for authorization of the study: ¬ eCTD (Electronic Common Technical Document) Submission to the Senior Federal Authority ¬ Supervision of procedures for authorization of the study: ¬ Supervision of procedures for notification of the Regional Submission to the Senior Federal Authority Supervising Authority ¬ Supervision of procedures for notification of the Regional ¬ (Quality) management of distribution of clinical trial Supervising Authority supplies ¬ Approval of Drugs / Medical devices ¬ Other ¬ (Quality) management of import of clinical trial supplies ¬ Academic Research Organization for Investigator initiated ¬ Security supervision and coverage and sponsored trials ¬ Electronic Reporting (e-Pharmacovigilance and E2B) ¬ Other Clinical Phases covered ¬ Pharmacovigilance-Management ¬ I, II, III, IV

Clinical Phases covered Indication areas ¬ I, II, III, IV ¬ Breast cancer

Indication areas Groups of agents / substances ¬ Oncolgy, Neurology, Immunology / Allergy ¬ Chemotherapy, Hormonal therapy, Immunotherapy

Customer Groups Customer Groups ¬ Start-up ¬ Big Pharma ¬ Producers of Generics ¬ Mid-sized Pharmaceutical Companies ¬ Big Pharma ¬ Other CROs Company Proﬁ les

ICON Clinical Research GmbH KKS Marburg

Heinrich-Hertz-Str. 26 Robert-Koch-Str. 5 63225 Langen | GERMANY 35037 Marburg | GERMANY Contact Partner: Claudia Asmus Contact Partner: Carmen Schade-Brittinger Phone +49 6103 904 1204 Phone +49 6421 2866458 Fax +49 6103 904 100 Fax +49 6421 2866517 [email protected] [email protected] www.iconclinical.com www.kks-mr.de

32 Type and range of services provided Type and range of services provided ¬ General consultation in the area of clinical research ¬ General consultation in the area of clinical research ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the CRF (Case Report Files) ¬ Trial plan: design of the CRF (Case Report Files) ¬ Training and further education (e.g. training in GPC etc.) ¬ Training and further education (e.g. training in GPC etc.) ¬ Audit- and compliance services ¬ Monitoring ¬ Monitoring ¬ Selection and acquisition of trial centers and physicians ¬ Selection and acquisition of trial centers and physicians ¬ Data management / databases / biostatistics etc. ¬ Data management / databases / biostatistics etc.. ¬ Supervision of procedures for authorization of the study: ¬ Supervision of procedures for authorization of the study: Submission to the Senior Federal Authority Submission to the Senior Federal Authority ¬ Supervision of procedures for notification of the Regional ¬ Approval of Drugs / Medical devices Supervising Authority ¬ (Quality) management of storage of clinical trial supplies ¬ Approval of Drugs / Medical devices ¬ (Quality) management of import of clinical trial supplies ¬ Security supervision and coverage Clinical Phases covered ¬ I, II, III, IV Clinical Phases covered ¬ I, II, III, IV Customer Groups ¬ Start-up Stoff-/Substanzgruppen ¬ Mid-sized Pharmaceutical Companies ¬ Biopharmaceuticals, natural products, small drugs, ¬ Big Pharma serological products, medicinal devices ¬ Other CROs ¬ Other: Customer Groups Universities and University Research Hospitals ¬ Start-up ¬ Mid-sized pharmaceutical companies ¬ Big Pharma Company Proﬁ les

Klinisches Studienzentrum Rhein-Main Medical Consulting – Klaus Goldschmidt (KSMR)

Schleusenweg 22 Rohrwiesenstr 22 60528 Frankfurt am Main | GERMANY 63654 Büdingen | GERMANY Contact Partner: Dr. med. Jochen Graff Contact Partner: Klaus Goldschmidt Phone +49 69 63015836 Phone +49 6041 5700 Fax +49 69 63015825 [email protected] [email protected]

Type and range of services provided Type and range of services provided 33 ¬ General consultation in the area of clinical research ¬ General consultation in the area of clinical research ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the CRF (Case Report Files) ¬ Trial plan: design of the CRF (Case Report Files) ¬ Monitoring ¬ Audit- and compliance services ¬ Selection and acquisition of trial centers and physicians ¬ Monitoring ¬ Data management / databases / biostatistics etc. ¬ Selection and acquisition of trial centers and physicians ¬ Supervision of procedures for authorization of the study: ¬ Acquisition of patients Submission to the Senior Federal Authority ¬ Supervision of procedures for authorization of the study: ¬ Supervision of procedures for notification of the Regional Submission to the Senior Federal Authority Supervising Authority ¬ Supervision of procedures for notification of the Regional ¬ Approval of Drugs / Medical devices Supervising Authority ¬ (Quality) management of distribution of clinical trial Indication areas supplies ¬ Cardio-Vascular System ¬ (Quality) management of storage of clinical trial supplies Groups of agents / substances Clinical Phases covered ¬ Medical devices ¬ I, II, III, IV Customer Groups Customer Groups ¬ Start-up ¬ Start-up ¬ Producers of Generics ¬ Mid-sized Pharmaceutical Companies ¬ Big Pharma ¬ Other CROs Company Proﬁ les

NeuroCode Omega Mediation GmbH

Sportparkstr. 9 Herrnstr. 57 35578 Wetzlar | GERMANY 63065 Offenbach | GERMANY Contact Partner: Prof. Dr. Wilfried Dimpfel Contact Partner: Volker Hofmann Phone +49 6441 002030 Phone +49 69/850933872 Fax +49 6441 2002039 Fax +49 6573953542 [email protected] [email protected] www.neurocode-ag.com www.omega-mediation.com

34 Type and range of services provided Type and range of services provided ¬ General consultation in the area of clinical research ¬ General consultation in the area of clinical research ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the CRF (Case Report Files) ¬ Trial plan: design of the CRF (Case Report Files) ¬ Selection and acquisition of trial centers and physicians ¬ Training and further education (e.g. training in GPC etc.) ¬ Acquisition of patients ¬ Audit- and compliance services ¬ Data management / databases / biostatistics etc.. ¬ Monitoring ¬ Supervision of procedures for authorization of the study: ¬ Selection and acquisition of trial centers and physicians Submission to the Senior Federal Authority ¬ Acquisition of patients ¬ Supervision of procedures for notification of the Regional ¬ Data management / databases / biostatistics etc. Supervising Authority ¬ eCTD (Electronic Common Technical Document) ¬ Approval of Drugs / Medical devices ¬ Supervision of procedures for authorization of the study: ¬ Laboratory services: - EEG, Psychophysiology Submission to the Senior Federal Authority ¬ Sleep laboratory ¬ Supervision of procedures for notification of the Regional ¬ Tele-stereo EEG Supervising Authority ¬ Hippocampal slice ¬ Electronic Reporting (e-Pharmacovigilance and E2B)

Clinical Phases covered Clinical Phases covered ¬ Preclinical, I, II, III, IV ¬ Preclinical, I, II, III, IV

Indication areas Indication areas ¬ Psychiatry, Central Nervous System, Sleep disturbances, ¬ Neurology, Oncology, Diabetes Migraine Customer Groups Groups of agents / substances ¬ Start-up ¬ Biopharmaceuticals, Natural products, Small drugs, Dietary ¬ Producers of Generics supplements, Functional food etc. ¬ Mid-sized Pharmaceutical Companies ¬ Big Pharma Customer Groups ¬ Other CROs ¬ Mid-sized pharmaceutical companies ¬ Big Pharma ¬ Other CROs Company Proﬁ les

Omnicare Clinical Research GmbH PAREXEL International GmbH

Königsteiner Str.10 Paul Ehrlich Str. 7 65812 Bad Soden | GERMANY 63225 Langen | GERMANY Contact Partner: Benoit Martin Contact Partner: Hans-Georg Kauer Phone +49 6196 52280 Phone +49 6103 5976-0 [email protected] Fax +49 6103 5976-22 [email protected] www.parexel.com

Type and range of services provided Type and range of services provided 35 ¬ General consultation in the area of clinical research ¬ General consultation in the area of clinical research ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the CRF (Case Report Files) ¬ Trial plan: design of the CRF (Case Report Files) ¬ Training and further education (e.g. training in GPC etc.) ¬ Training and further education (e.g. training in GPC etc.) ¬ Audit- and compliance services ¬ Audit- and compliance services ¬ Monitoring ¬ Monitoring ¬ Selection and acquisition of trial centers and physicians ¬ Selection and acquisition of trial centers and physicians ¬ Data management / databases / biostatistics etc. ¬ Data management / databases / biostatistics etc. ¬ eCTD (Electronic Common Technical Document) ¬ Supervision of procedures for authorization of the study: ¬ Supervision of procedures for authorization of the study: Submission to the Senior Federal Authority Submission to the Senior Federal Authority ¬ Supervision of procedures for notification of the Regional ¬ Supervision of procedures for notification of the Regional Supervising Authority Supervising Authority ¬ Approval of Drugs / Medical devices ¬ Approval of Drugs / Medical devices ¬ (Quality) management of import of clinical trial supplies ¬ (Quality) management of distribution of clinical trial supplies Clinical Phases covered ¬ (Quality) management of storage of clinical trial supplies ¬ I, II, III, IV ¬ (Quality) management of import of clinical trial supplies ¬ Security supervision and coverage Customer Groups ¬ Electronic Reporting (e-Pharmacovigilance and E2B) ¬ Start-up ¬ Producers of Generics Clinical Phases covered ¬ Mid-sized Pharmaceutical Companies ¬ I, II, III, IV ¬ Big Pharma ¬ Other CROs Customer Groups ¬ Start-up ¬ Producers of Generics ¬ Mid-sized Pharmaceutical Companies ¬ Big Pharma ¬ Other CROs ¬ Other: University Research Hospitals, Medical Device Companies Company Proﬁ les

PAZ Arzneimittelentwicklungs- PharmaPart GmbH gesellschaft mbH

In der Schildwacht 13 Rheingaustr. 190–196 65933 Frankfurt am Main | GERMANY 65203 Wiesbaden | GERMANY Contact Partner: Dr. Otto Schuster Contact Partner: Dr. Birgit Hoffmann Phone +49 69 38035020 Phone +49 611 9627305 [email protected] Fax +49 611 9629091 www.paz.de [email protected] www.pharmapart.com

36 Type and range of services provided Type and range of services provided ¬ General consultation in the area of clinical research ¬ General consultation in the area of clinical research ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the CRF (Case Report Files) ¬ Trial plan: design of the CRF (Case Report Files) ¬ Data management / databases / biostatistics etc. ¬ Training and further education (e.g. training in GPC etc.) ¬ Supervision of procedures for authorization of the study: ¬ Audit- and compliance services Submission to the Senior Federal Authority ¬ Monitoring ¬ Supervision of procedures for notification of the Regional ¬ Selection and acquisition of trial centers and physicians Supervising Authority ¬ Acquisition of patients ¬ Approval of Drugs / Medical devices ¬ Data management / databases / biostatistics etc. ¬ (Quality) management of production of clinical trial supplies ¬ eCTD (Electronic Common Technical Document) ¬ (Quality) management of distribution of clinical trial ¬ Supervision of procedures for authorization of the study: supplies Submission to the Senior Federal Authority ¬ (Quality) management of storage of clinical trial supplies ¬ Supervision of procedures for notification of the Regional ¬ Security supervision and coverage Supervising Authority ¬ Laboratory services: - EEG, Psychophysiology ¬ Approval of Drugs / Medical devices ¬ Bioanalytics (Analytics of substances in body fluids) ¬ (Quality) management of production of clinical trial supplies ¬ Pharmaceutical analytics ¬ (Quality) management of distribution of clinical trial supplies ¬ (Quality) management of storage of clinical trial supplies Clinical Phases covered ¬ (Quality) management of import of clinical trial supplies ¬ I, II, III, IV ¬ Security supervision and coverage ¬ Electronic Reporting (e-Pharmacovigilance and E2B) Indication areas ¬ Pain and inflammation Clinical Phases covered ¬ II, III, IV Groups of agents / substances ¬ Enantiomerically pure active agents Indication areas ¬ Oncology, Cardiology, Neurology, Diabetology, Vaccines, Customer Groups Dermatology, Gastrointestinal Disorders, Infectiology, ¬ Start-up Pneumology, Rheumatology ¬ Producers of Generics ¬ Mid-sized Pharmaceutical Companies Groups of agents / substances ¬ Big Pharma ¬ Biopharmaceuticals, natural compounds, chemical drugs, ¬ Other CROs medicinal products ¬ Other: Public authorities Customer Groups ¬ Start-up ¬ Producers of Generics ¬ Mid-sized Pharmaceutical Companies ¬ Big Pharma Company Proﬁ les

PharmaProjekthaus GmbH & Co. KG Praxis Klinische Arzneiforschung

Altenhöferallee 3 Langgasse 8 60438 Frankfurt am Main | GERMANY 35415 Pohlheim | GERMANY Contact Partner: Johanna Schenk Contact Partner: Dr. Dr. Ewald Schrader Phone +49 69 5870035-10 Phone +49 6403 68834 Fax +49 69 5870035-29 [email protected] [email protected] www.pharmaprojekthaus.com

Type and range of services provided Type and range of services provided 37 ¬ General consultation in the area of clinical research ¬ Data management / databases / biostatistics etc. ¬ Trial plan: design of the trial protocol ¬ Training and further education (e.g. training in GPC etc.) Groups of agents / substances ¬ Selection and acquisition of trial centers and physicians ¬ natural compounds ¬ Supervision of procedures for authorization of the study: Submission to the Senior Federal Authority Customer Groups ¬ Supervision of procedures for notification of the Regional ¬ Start-up Supervising Authority ¬ Producers of Generics ¬ Mid-sized Pharmaceutical Companies Clinical Phases covered ¬ I, II, III, IV

Indication areas ¬ Cardiology, Dermatology, Endocrinology, Gastrointestinal Disorders, Infectious Diseases including HIV and other viral infections, Oncology, Pediatrics - Vaccines and Therapeutics Psychiatry and Neurology, Respiratory Disorders, Urology

Customer Groups ¬ Start-up ¬ Mid-sized Pharmaceutical Companies ¬ Big Pharma Company Proﬁ les

Premier Research Germany Quintiles GmbH

Birkenweg 14 Hugenottenallee 167 64295 Darmstadt | GERMANY 63263 Neu-Isenburg | GERMANY Contact Partner: Dr. Jürgen Schmidt Contact Partner: Dr. Ludger Beckmann Phone +49 6151 8280601 Phone +49 61022960 Fax +49 6151 828010 Fax +49 6102296296 [email protected] [email protected] www.premier-research.com www.quintiles.com

38 Type and range of services provided Type and range of services provided ¬ General consultation in the area of clinical research ¬ General consultation in the area of clinical research ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the CRF (Case Report Files) ¬ Trial plan: design of the CRF (Case Report Files) ¬ Training and further education (e.g. training in GPC etc) ¬ Training and further education (e.g. training in GPC etc.) ¬ Audit- and compliance services Monitoring ¬ Monitoring ¬ Selection and acquisition of trial centers and physicians ¬ Selection and acquisition of trial centers and physicians ¬ Acquisition of patients ¬ Acquisition of patients ¬ Data management / databases / biostatistics etc.. ¬ Data management / databases / biostatistics etc. ¬ eCTD (Electronic Common Technical Document) ¬ eCTD (Electronic Common Technical Document) ¬ Supervision of procedures for authorization of the study: ¬ Supervision of procedures for authorization of the study: Submission to the Senior Federal Authority Submission to the Senior Federal Authority ¬ Supervision of procedures for notification of the Regional ¬ Supervision of procedures for notification of the Regional Supervising Authority Supervising Authority ¬ Approval of Drugs / Medical devices ¬ Approval of Drugs / Medical devices ¬ Security supervision and coverage Clinical Phases covered ¬ Electronic Reporting (e-Pharmacovigilance and E2B) ¬ I, II, III, IV

Clinical Phases covered Customer Groups ¬ I, II, III, IV ¬ Start-up ¬ Producers of Generics Indication areas ¬ Mid-sized Pharmaceutical Companies ¬ Pain (general), Oncology, Neurology, Dermatology ¬ Big Pharma

Groups of agents / substances ¬ Drugs and Medical devices, Medicinal products

Customer Groups ¬ Start-up ¬ Producers of Generics ¬ Mid-sized Pharmaceutical Companies ¬ Big Pharma Company Proﬁ les

SciNuTec GmbH SCRATCH Pharmacovigilance Services GbR

Ricarda-Huch-Str. 13 Marktplatz 10 – 11 35516 Münzenberg | GERMANY 35510 Butzbach | GERMANY Contact Partner: Dr. Günther Sawatzki Contact Partner: Dr. Susanne Kienzle-Horn Phone +49 6033 73020 Phone +49 6033 974777 Fax +49 6033 73024 Fax +49 6033 974778 [email protected] [email protected] www.scratch-services.de

Type and range of services provided Type and range of services provided 39 ¬ General consultation in the area of clinical research ¬ General consultation in the area of clinical research ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the CRF (Case Report Files) ¬ Trial plan: design of the CRF (Case Report Files) ¬ Monitoring ¬ Training and further education (e.g. training in GPC etc.) ¬ Selection and acquisition of trial centers and physicians ¬ Supervision of procedures for authorization of the study: ¬ Acquisition of patients Submission to the Senior Federal Authority ¬ Supervision of procedures for notification of the Regional Clinical Phases covered Supervising Authority ¬ Preclinical, I, II, III, IV ¬ Security supervision and coverage

Indication areas Indication areas ¬ Clinical Studies on functional; new ingredients in ¬ All aspects of pharmacovigilance for both clinical as well as "infant formulas". post-marketing

Groups of agents / substances Customer Groups ¬ functional food, prebiotics, n-3 fatty acids, functional ¬ Start-up carbohydrates, protein hydrolysates, metabolics ¬ Mid-sized Pharmaceutical Companies ¬ Other CROs Customer Groups ¬ Other: Manufacturers of phytomedicines ¬ Start-up ¬ Big Pharma ¬ Other: dietetic food industry Company Proﬁ les

SKM Oncology Research GmbH Trilogy Writing & Consulting GmbH

Wilhelmstr. 64 Sudetenstr. 18 65183 Wiesbaden | GERMANY 36110 Schlitz | GERMANY Contact Partner: Renate Walter-Kirst Contact Partner: Christiane Hintermann Phone +49 611 533166-10 Phone +49 69 1382 5280 Fax +49 611 533166-66 Fax +49 69 2553 9499 [email protected] [email protected] www.skm-cro.com www.trilogywriting.com

40 Type and range of services provided Type and range of services provided ¬ General consultation in the area of clinical research ¬ General consultation in the area of clinical research ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the trial protocol ¬ Trial plan: design of the CRF (Case Report Files) ¬ Training and further education (e.g. training in GPC etc.) ¬ Training and further education (e.g. training in GPC etc.) ¬ eCTD (Electronic Common Technical Document) ¬ Audit- and compliance services ¬ Other: Study Documentation: clinical study reports (CSR), ¬ Monitoring clinical study protocols (CSP), common technical ¬ Selection and acquisition of trial centers and physicians documents ¬ Data management / databases / biostatistics etc. ¬ Supervision of procedures for authorization of the study: Customer Groups Submission to the Senior Federal Authority ¬ Start-up ¬ Supervision of procedures for notification of the Regional ¬ Mid-sized Pharmaceutical Companies Supervising Authority ¬ Big Pharma ¬ Approval of Drugs / Medical devices ¬ (Quality) management of distribution of clinical trial supplies ¬ (Quality) management of storage of clinical trial supplies

Clinical Phases covered ¬ I, II, III, IV

Indication Areas ¬ Oncology

Groups of agents / substances ¬ All oncological substances

Customer Groups ¬ Start-up ¬ Producers of Generics ¬ Mid-sized Pharmaceutical Companies ¬ Big Pharma ¬ CRO Company Proﬁ les

YES Pharmaceutical Development Zentrallaboratorium Services GmbH Deutscher Apotheker e.V. GmbH

Bahnstr. 42-46 Carl-Mannich-Str. 20 61381 Friedrichsdorf | GERMANY 65760 Eschborn | GERMANY Contact Partner: Dr. Rainer Canenbley Contact Partner: Dr. Mona Tawab Phone +49 6172 7 64 64 11 Phone +49 6196 937-955 Fax +49 6172 777 457 Fax +49 6196 937-810 [email protected] [email protected] www.yes-services.eu www.zlgmbh.com

Type and range of services provided Type and range of services provided 41 ¬ Audit- and compliance services ¬ General consultation in the area of clinical research ¬ eCTD (Electronic Common Technical Document) ¬ Trial plan: design of the trial protocol ¬ Supervision of procedures for authorization of the study: ¬ Trial plan: design of the CRF (Case Report Files) Submission to the Senior Federal Authority ¬ Training and further education (e.g. training in GPC etc.) ¬ Supervision of procedures for notification of the Regional ¬ Audit- and compliance services Supervising Authority ¬ Monitoring ¬ Approval of Drugs / Medical devices ¬ Selection and acquisition of trial centers and physicians ¬ Security supervision and coverage ¬ Acquisition of patients ¬ Electronic Reporting (e-Pharmacovigilance and E2B) ¬ eCTD (Electronic Common Technical Document) ¬ Other Services: ¬ Supervision of procedures for notification of the Regional Coordination of development with main emphasis on Supervising Authority regulatory compliance ¬ Approval of Drugs / Medical devices ¬ identification of essential development steps ¬ (Quality) management of production of clinical trial supplies ¬ advice on regulatory needs ¬ (Quality) management of distribution of clinical trial suplies ¬ gap analyses, milestone definition ¬ (Quality) management of storage of clinical trial supplies ¬ tracking ¬ Laboratory Services: ¬ scientific ad - Development and validation of analytical methods for the determination of substances in biological samples Customer Groups - Quality control of active ingredients and finished products ¬ Start-up ¬ Mid-sized Pharmaceutical Companies - Stability studies ¬ Big Pharma - Bioavailability and Bioäquivalence Studies ¬ Other: Biosimilar companies, SMEs - Permeability studies

Clinical Phases covered ¬ Preclinical, I, II, III, IV

Groups of agents / substances ¬ Biopharmaceuticals, natural compounds, small Drugs, medicinal products, Peptides/Oligonukleotide

Customer Groups ¬ Start-up ¬ Prooducers of Generics ¬ Mid-sized pharmaceutical companies ¬ BigPharma Supplement

a test subject or study patient is voluntary. The Some basics on clinical trial is carried out in three phases, in which safety, dosage, effi cacy, as well as tolerance to clinical research other drugs and interactions with other diseases are examined. After successful completion of the so-called third phase of the clinical trial, the What is clinical research (KliFo – CliRe) collected data is submitted to the responsible • Clinical research deals with both further and authorities for obtaining market approval for the new developments of drugs and therapeutic drug. approaches for the improvement of treatment op- tions of patients and preventive measures. The approval process Clinical research does not mean ‘research in the After completion of all clinical studies, the data hospital’. Naturally, part of the research is carried collected for the approval must be correspond- out in hospitals or university clinics. However, ingly prepared and forwarded to the responsi- basic research, which forms the fundamentals ble authorities. In Germany, the BfArM (Federal of clinical research, is carried out in university Institute for Drugs and Medical Devices) in Berlin/ 42 laboratories or clinics or in special research estab- Bonn is responsible for the national approval of lishments, e.g. conducted by the pharmaceutical pharmaceuticals, and the Paul-Ehrlich-Institut in industry. Clinical studies which are carried out on Langen is responsible for the national approval voluntary test subjects and patients are a building of vaccines, sera and blood products. Since 1995, block of clinical research. The physical examina- applications for EU-wide approvals can be fi led tions during the clinical studies take place in by submitting to the central admission's offi ce so-called test centers. These can be research EMEA (European Medicines Evaluation Agency) establishments, hospitals, and doctor’s offi ces. in London. Thus, submission in Germany is no The organization, direction, supervision and longer necessary. Genetically engineered phar- evaluation of the clinical studies are carried out maceuticals must be submitted to the EMEA. by a pharmaceutical company and/or a contract Should the submitted data not clearly prove the research institute working together with physi- effi cacy and safety according to the discretion of cians, ethics commissions and authorities. Clinical the approval authorities, said authorities can then studies are based on knowledge acquisition and require further trials/studies. are strictly separated from marketing activities. After initial approval, medicaments are available

exclusively by prescription. What is a pharmaceutical? According to the Arzneimittelgesetz (AMG) After inital approval (German Drug Law), pharmaceuticals consist of The authorities continue to supervise medica- plant, animal or synthetic materials. These are ments after approval. The pharmaceutical indus- employed for diagnostics or, in suitable dosages, try and physicians are required to register side as therapeutics for infl uencing bodily states and effects with the authorities. If required, market ap- functions, as well as substitutes for substances proval can be withdrawn. Examinations concern- naturally generated by human or animal bodies ing the long-term relationship between risks and or bodily fl uids, and for the elimination or neu- benefi ts are carried out after market approval by tralization of pathogens, parasites or foreign sub- a Phase 4 clinical trial. Every 5 years, an extension stances in the body. [Roche Lexikon 3rd Edition] must be resubmitted for each medicament. Pro-

vided that a medicament is safe, the producer can The path to a new pharmaceutical request to remove the requirement for prescrip- After isolation / synthesis of a novel substance, tion by the ﬁ rst extension at the earliest. Medica- the path to a new pharmaceutical (medicament) ments available without prescription are referred leads, according to legal requirements, from a to as OTC (over the counter) drugs. preclinical trial to the clinical trial. These novel substances are examined with established mod- The effort els in the preclinical trial stage. The clinical phase Around 10 of approximately 10,000 substances of the development begins after critical evalua- reach the clinical trial after the preclinical trial. Of tion of the results obtained regarding pharmaco- these 10 substances, 8 to 9 are sorted out in the logical efﬁ cacy and safety. For that purpose, the clinical trial. Only around 1 or 2 of the original substance is tested on humans through so-called 10,000 substance are submitted for approval. De- clinical studies. These clinical studies must be velopment takes an average of 8 to 12 years. As a authorized beforehand by the responsible ethics rule, this time period is shorter for HIV or cancer. commissions and authorities; participation as Development expenses are accordingly high: Supplement

An overview of the phases of new pharmaceutical developments

Isolation Preclinical Clinical trial Clinical trials Phase I, II and III Approval Synthesis trials Phase IV

Isolation / Synthesis of Substances

Preclinical trial Trials with diverse models Safety examinations: 2 - 3 years ¬ isolated cells ¬ toxicology ¬ cell cultures ¬ pharmacology Research and Discovery ¬ tissue ¬ biochemistry ¬ organs ¬ mutagenicity ¬ animals ¬ carcinogenicity ¬ teratogenicity ¬ fertility 43 ¬ perinatal and postnatal toxicity ¬ pharmacokinetics: absorption, dispersal, metabolism, excretion

Clinical trial Trials on humans Phase I-III 3 - 5 years

Phase I approx. 50 healthy test subjects Examinations: ¬ pharmacokinetics ¬ tolerance ¬ effect on bodily functions: cardiovascular, neurological

Phase II approx. 500 chosen patients Examinations: homogeneous patient population; ¬ efﬁ cacy the latter is affected exclusively ¬ safety by the examined indication ¬ side effects

Phase III large number of patients Examinations: diverse patient populations with ¬ efﬁ cacy Divided into diverse diseases ¬ safety ¬ side effects Phase III a, relevant for approval: ¬ interactions with other medications Main focus on efﬁ cacy and safety aspects ¬ contraindications ¬ therapeutic advantages Phase III b, approval might already ¬ health economics be submitted: ¬ quality of life Main focus on health economics and quality of life

Approval process

Clinical trial ery large number of patients Completion of the data as described Phase IV the most diverse patient population above should the submitted data not 2 - 3 years with the most diverse diseases clearly be proven (safety, efﬁ cacy), then the approval will be withdrawn (negative example: teratogenicity of Contergan) Supplement

in 1999, approx. 23 billion US$ were invested Legal basis and guidelines for worldwide in research and development (R+D) carrying out clinical studies by pharmaceutical corporations. Clinical trials in Germany account for approx. 14 billion US$ of this. Other sources allude to costs of over Euro 0.5 billion for 1. German Drug Law (AMG, Law about the the development and marketing of each drug. commerce of pharmaceuticals) The costs accrued during the developmental 2. Chamber Law for Health Care Professions phase must be correspondingly covered after 3. Law for Medicinal Products (MPG, Law about market approval. An important aspect of this is medicinal products) the duration of the patent. When a substance which possesses a possible pharmacological 4. German Transfusion Law, Law about value has been newly discovered or synthesized, regulation of the nature of transfusions it is protected under a corresponding patent 5. German Transplantation Law, Law about the application. After the patent has expired, this donation, removal, and transfer of organs substance is allowed to be produced and mar- 6. Genetic Engineering Law (GenTG, Law about keted from other companies as well (generics). regulation of genetic engineering) 44 Therefore, each company is very concerned with 7. Embryo Protection Law (ESchG, Law for the having the shortest development time possible protection of embryos) for its products, in order to use the duration of the patent, namely the market monopoly, as long as 8. X-ray Ordinance (RöV, Ordinance on the pro- possible. tection from damage caused by X-rays) 9. German Radiation Protection Ordinance After approval, post-marketing (StrlSchV, Ordinance on the protection from surveillance studies can also da mage caused by ionizing radiation) be carried out. 10. Professional Code of Conduct for German Physicians Post-marketing surveillance studies - PMS 11. World Medical Association Declaration of Post-marketing surveillance studies (PMS) are Helsinki carried out exclusively on approved medicaments 12. Principles for the proper execution of the and are strictly separated from clinical studies. clinical trial of pharmaceuticals, edited by the PMS are an additional control instrument of the Minister for Youth, Family, Women and Health pharmaceutical industry, in order to collect fur- 13. EU guideline for "Good Clinical Practice" ther knowledge on the effi cacy and possible side (GCP, Guideline for Good Clinical Practice, effects through broad application in the popula- ICH Harmonised Tripartite Guideline) tion. Data from patients who have followed the stand- 14. List of requirements for a "Director of the ard instructions included in the package insert is Clinical Trial", Drug Commission of the collected anonymously for PMS and statistically German Medical Association evaluated. There is no study protocol and no 15. Procedure principles of the ethics additional examinations or other demands on the commission physician or patient. Documentation of the data 16. Data Protection Law is carried out (as in clinical studies) by a physician in a structured and anonymous form on special documentation forms. The burden of documentation for this is signifi cantly less than in clinical studies (approx. 2-5 pages). As a rule, pharmaceutical representatives are highly involved in the support of the physicians. PMS are often carried out retrospectively, i.e. the physician fi lls out the documentation form based on the patient fi le after treatment is completed. Informing the patient is not necessary during PMS, since the patient is receiving an approved medicament in an approved form of therapy and his personal details (patient fi le) are not disclosed to third parties (monitor, auditor). Supplement

Number of beds in hessian hospitals Physicians in private practice in Hessen according to specialities

Indication Number of beds Anesthesiology 229 cardiac surgery 274 Cardiac Surgery 3 child and adolescent Psychiatry / 438 Child and Adolescent Psychiatry 51 Psychotherapy Dermatology and Venereology 236 Dermatology and Venerology 324 General Medicine 2.915 Intenal Medicine 11.062 Human Genetics 7 Neonatology 156 Internal Medicine 1.398 Neurology 1.716 Laboratory Medicine 67 Neurosurgery 411 Microbiology and Virology 18 Nuclear Medicine 39 Neurology and Psychiatry 382 45 Obstetrics and Gynecology 2.723 Neuropathology 2 Ophthalmology 323 Neurosurgery 52 Oral and Maxillofacial Surgery 959 Nuclear Medicine 66 Orthopedics 1.731 Obstetrics and Gynecology 788 Other/Miscellaneous 1.085 Ophthalmology 373 Otorhinolaryngology 959 Oral and Maxillofacial Surgery 63 Pediatrics 1.097 Orthopedics 405 Pediatric Cardiology 37 Otorhinolaryngology 290 Pediatric Surgery 81 Pathology 79 Plastic Surgery 83 Pediatric Surgery 7 Psychotherapy and Psychiatry 3.714 Pediatrics and Adolescent Medicine 437 Surgery 5.706 Phoniatrics and Pediatric Audiology 13 Therapeutic Radiology 157 Physical and Rehabilitative Medicine 37 Urology 1.038 Plastic Surgery 14 Total 34.113 Psychiatry and Psychotherapy 90 Psychotherapeutic Medicine 239 Radiology and Diagnostic Radiology 259 Surgery 378 Therapeutic Radiology 22 Transfusion Medicine 8 Urology 205 Total approx. 9.100 Supplement

Examination of the study plan by the ethics commission responsible for the director of the clinical study

46 Submission to BfArM (Federal Institute for Modiﬁ cation/ Drugs and Medical Improvement Devices) of the protocol, patient information, or other study documents

Deﬁ ne goal Design study protocol Submission of Resubmission Organization of Determine general incl. e.g. the study to the the study material framework patient diaries ethics commission - Study documents Assemble team responsible Design patient forms - Clinical trial supplies for the director Find director for the for written informed - Laboraty & the clinical study clinical study consent Approval of the study Laboratory supplies - Equipment

Possible rejection of the study, thus cessation of the study plan

Design CRF, creation of guidelines for investigating physicians, Preparation of the trail centers / creation of guidelines for monitoring, training of the study monitors investigating physicians (see above)

Set up a database, design data input form, determine plausibility checks Supplement

Examination of the study plan by the ethics commissions responsible for the investigating physicians

47 Information of local authorities

Meeting Recruitment of the Initiation Patients of trial investigating of trial particpate Patients end Closure of Payment of centers physicians centers in the study the study trial centers trial centers

Undertake any necessary modiﬁ cations / improvements

Close trial Complete data Monitoring centers

Data entry in database Final data check Data check Draft ﬁ nal report, Submit ﬁ nal queries Submit queries pass the data on to statisticians Final data preparation Data preparation www.hessen-biotech.de

Executing organisation of Hessen-Biotech, a project of the Hessian Ministry of Economics, Transport, Urban and Regional Development