Download European Perspective - Society of Nuclear Medicine

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
© Nuclear Medicine
Version 26.Jan.2010
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
© Nuclear Medicine
Version 26.Jan.2010
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
© Nuclear Medicine
Version 26.Jan.2010
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 predefined criteria for acceptance are feasible for all.
© Nuclear Medicine
Version 26.Jan.2010
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
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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
© Nuclear Medicine
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European Council
Wikipedia
Council of Europe members
Non-members invited to sign conventions
© Nuclear Medicine
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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.
© Nuclear Medicine
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European Union
Wikipedia
© Nuclear Medicine
Version 26.Jan.2010
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.
© Nuclear Medicine
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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.
© Nuclear Medicine
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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.
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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…
© Nuclear Medicine
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Cross-References
© Nuclear Medicine
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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]
© Nuclear Medicine
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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
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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
© Nuclear Medicine
Version 26.Jan.2010
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
© Nuclear Medicine
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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)
© Nuclear Medicine
Version 26.Jan.2010
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.
...”
© Nuclear Medicine
Version 26.Jan.2010
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
© Nuclear Medicine
Version 26.Jan.2010
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.
© Nuclear Medicine
Version 26.Jan.2010
Distribution
• Distribution within Europe and across EU and nonEU borders needs special attention
• Distribution distances and customs procedures are
vital for the success and feasibility of a clinical multicenter trial.
• Production site needs to submit it‘s monograph also
to Health Authorities of receiving Institutes. Additional
quality control might be needed on site.
© Nuclear Medicine
Version 26.Jan.2010
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
© Nuclear Medicine
Version 26.Jan.2010
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
© Nuclear Medicine
Version 26.Jan.2010