European Perspective: Multicenter Clinical Trials Production

1. European Perspective: Multicenter Clinical Trials Production Valerie Treyer, PhD1,2 Gustav K. von Schulthess, MD, PhD, Dr. med. h.c.1,2 1Nuclear Medicine, University Hospital, and 2Timaq medical imaging Inc, Zurich, Switzerland

2. Overview • Multicenter Clinical Trials and PET/CT • Standardized Production • Some words about Europe • Legal situation in EU – EMEA • Submission to Health Authorities • Production Guidelines for Europe • Distribution in Europe • Conclusion - Summary

3. Multicenter Clinical Trials • Nuclear Medicine modalities can reveal changes earlier than pure anatomical imaging • But there is no image without tracer • FDG is a partially approved tracer in PET, showing good correlation with survival in some disease areas. Conventional NM also offers approved tracers for diagnostic purposes. • But the true power of Molecular Imaging goes beyond approved imaging agents

4. Standardized Production Beyond standardizing scanning equipment it is also important to standardize production and quality control especially of new non-approved radiopharmaceuticals • Impact of different production techniques - difficult to assess • Standardized production is appreciated - but not always possible across all centres, due to different technologies available. • But standardized quality control of product and pre-defined criteria for acceptance are feasible for all.

5. Europe • Europe is the world's second-smallest continent by surface area • Europe is the third most populous continent after Asia and Africa, with a population of about 11% of the world's population © Google maps

6. European Council • In his famous speech at the University of Zurich on 19 September 1946, Sir Winston Churchill called for a United States of Europe and the creation of a Council of Europe (founded 1949). • It has a particular emphasis on legal standards, human rights, democratic development, the rule of law and cultural co-operation. It has 47 member states. • European Court of Human Rights • European Pharmacopoeia Commission

7. European Council Wikipedia Council of Europe members      Non-members invited to sign conventions

8. European Union • The Treaty of Rome in 1957 established the European Economic Community between 6 Western European states. • In 1967 the EEC, European Coal and Steel Community and Euratom formed the European Community, which in 1993 became the European Union. • The EU established a parliament, court and central bank and introduced the euro as a unified currency. • Currently 27 European nations are members of EU, • The European Free Trade Association (EFTA) is a free trade organization between four European (non-EU) countries.

9. European Union Wikipedia

10. EMEA Legal role • The European Medicines Agency is the EU body responsible for coordinating the existing scientific resources put at its disposal by Member States for the evaluation, supervision and pharmacovigilance of medicinal products. • The Agency provides the Member States and the institutions of the EU the best-possible scientific advice on any question relating to the evaluation of the quality, safety and efficacy of medicinal products for human or veterinary use referred to it in accordance with the provisions of EU legislation relating to medicinal products.

11. EMEA • Existing medicines are authorized nationally • Genuinely novel medicines are authorized through the EMEA • The scientific assessment is decentralized and EMEA draws on resources of National Competent Authorities (NCAs) of EU Member states. • The CHMP (Committee for Medicinal Products for Human Use) is obliged by the Regulation to reach decisions within 210 days, but the clock is stopped if clarification/more information is needed.

12. Clinical Trials in EU • Within the EU EMEA as agency and EudraLex as collection of rules and regulations offer a vague framework for use of radiopharmaceutical products in clinical trials. • The NCAs & ethics committees, are responsible, in each Member State, for the oversight of clinical trials and their conduct. • They authorize manufacturing sites in their territories.

13. Submission within EU • GCP: The EU Directive 2001/20/EC & 2005/28/EC • GMP: EudraLex Volume 4, Annex 3: Manufacture of Radiopharmaceuticals (since 01 March 2009) • Guideline on clinical evaluation of Diagnostic Agents CPMP/EWP/1119/98/Rev. 1 (1 February 2010) • Guideline on radiopharmaceuticals EMEA/CHMP/QWP/306970/2007 (draft only) • … but…

14. Cross-References

15. Clinical Trials • Licensed products used within authorised indications – only GRP • Licensed products used ouside authorised indications – in some countries simpler submission • Product with established clinical use and discribed in a monograph – if authorised by competent authority may qualify simplified submission • New products – full IMP Dossier [exc. UK Biomarker]

16. Requirements • Active pharmaceutical ingredient starting material [In a radionuclide generator, both mother and daughter radionuclides are to be considered as active ingredients!] • Finished drug [short half-life – not all QC tests needed prior to application] • Minimal range of tocoxological data [depends if within limits of microdosing or not -> SA] • Dosimetry data Guideline to regulations for radiopharmaceuticals in early phase clinical trials in the EU, EJNM 2008 Nov;35(11):2144-51

17. Active Pharmaceutical Ingredient • API starting matierial produced by GMP certified lab – in the current country of user – mutual recognition possible • Else: • audit lab to verify GMP • Analyse according monograph of or validated methods according national regulations

18. Health Authorities Each country within Europe has its own: • ethics commitee structure and different guidelines • Medicines Agency with different guidelines • Pharmacopoeia (any starting material, i.e. precurser, 68Ga) • Federal Offices for Radiation Protection

19. Radiation Dose Each country has different : • Radiation dose limits including different critical values, also differing for patients and healthy controls • Regulations in allowing healthy young women to participate • Calculations of doses for multimodality imaging (adding PET and CT doses or approve separately)

20. Production Guidelines EANM / IAEA „Strategies for Clinical Implementation and Quality Management of PET Tracers” International Atomic Energy Agency Vienna, 2009 “…encourage further cooperation among various countries worldwide in the development of a set of harmonized acceptance test criteria for PET systems and sensible QA standards for all PET drug products. ...”

21. Production Guidelines EANM / IAEA EANM: Draft Guidelines for Radiopharmacy[Eur J Nucl Med Mol Imag (2003) 30:BP63–BP72]: The Committee has adopted the strategy of starting to develop “Draft guidelines for radiopharmacy” for nuclear medicine laboratories and to adapt the “Preliminary draft regulations on current good manufacturing practices for PET drugs” of the U.S. Food and Drug Administration

22. Harmonization • Production guidelines are now harmonized • Separate submission for each country still needed • Monograph for each tracer and production site needed • Alliances are needed and are being formed between production sites for conjoint monographs/ submissions of non-FDG tracers.

23. Distribution • Distribution within Europe and across EU and non-EU borders needs special attention • Distribution distances and customs procedures are vital for the success and feasibility of a clinical multi-center trial. • Production site needs to submit it‘s monograph also to Health Authorities of receiving Institutes. Additional quality control might be needed on site.

24. European Infrastructure Despite these difficulties a multi-center clinical trial within Europe or selected European countries is an option to be considered. • A dense population (731 million) • usually excellent health care infrastructure in this highly developed region. • According latest EANM survey in 35 countries: • 463 PET/CT systems • 142 cyclotrons

25. Summary • High diversity of government agencies and regulatory processes • Increased duration of submission processes, and in many cases local adaptation of the protocols • Calls for a common guideline across all countries to ensure standard production and quality control processes • and not to forget: Authorization of production site and starting material is vital