The aims of the Clinical Trials Directive are noble – to harmonise legal acts for the set-up, conduct and reporting of clinical trials, implement GCP-principles Europe-wide and enforce patient safety. Yet there are concerns that its mandatory implementation will be to the detriment of future non-commercial trials as requirements, obligations and clinical costs associated with the new legislation continue to increase. In order to investigate differences, obstacles and pitfalls for the conduct of future multicentre trials in member states, a comparative European analysis was undertaken.
Evidence from this examination of 8 member states whose legislation has been adapted in line with the new requirements highlights major differences in the scope of the revised legislations, as well as differences in sponsorship and liability issues. The findings described at ECCO reveal that only a few member states have expressively added provisions for non-commercial trials into their legislation – for example, by specifying the use of commercially available products or allowing for exemption from IRB/dossier approval fees. Furthermore, no common definitions exist throughout the EU for 'Phase IV' studies, nor the term 'investigator-initiated' or 'non-interventional studies.'
The conclusion is that the new legal framework for clinical trials renders the realisation of future pan-European multi-centre studies much more difficult. There has been a failure to simplify the conduct of academic clinical trials in the European trial space. In addition, radiotherapy studies, trials investigating surgical techniques and some multimodal trial concepts remain out of the scope of the revised legislative texts in some cases. In certain member states, non-interventional trials allow limited research in the form of observational studies outside of the new legal framework – although these are heavily restricted to small Phase I/II case series within or in close proximity to the approved prescription window given by drug labeling.
In contrast, the new European pharmaceutical legislation due to come into force on the 20 November 2005 received a more positive introduction and review at ECCO 13. Regulation (EC) No 726/2004 will entail that all oncology drugs seeking approval in the EU will be evaluated via the European Medicines Agency (EMEA) leading to an EU-wide approval.
The legislation will contain new tools and procedures allowing early access to new drugs, including anticancer drugs. One of these measures is the 150 days accelerated procedure (instead of 210 days) for drugs that are of major public health interest, particularly in terms of therapeutic innovation. Moreover, renewable conditional authorisations may be granted for certain products pending completion of further studies. Importantly, the new rules will retain the existing mechanism of approval under exceptional circumstances – when the rarity of the indication, the state of the scientific knowledge or the principles of medical ethic do not allow for the provision of comprehensive data on the efficacy and safety of such products. In addition, the EMEA may permit cohort compassionate use of certain products.
"Overall it appears that just one year after its implementation, the Clinical Trials Directive has resulted in a harsh drop-down in the number of new investigator-initiated clinical trials and instead is promoting primarily the conduct of nationwide research projects," noted Dr Markus Hartmann from the European Consulting & Contracting in Oncology, Germany. "In paediatric oncology and cancers of very low incidence, the expected drop-down of available clinical trials will constitute a major challenge for all stakeholders, including patients and physicians as well as drug manufacturers and policy-makers. On the other side of the coin, the new EU approval legislation scheduled for implementation in November, as well as the new GCP Directive which must be transposed until January 2006 into member state legislation, look set to be positive steps which might hasten patient access to important new cancer medicines. Anyway, both Directives promote trial participants' safety undoubtedly by setting uniform and unmistakable standards of patient protection across Europe, judged necessary especially in case of experimental therapy forms like innovative biological medicinal products or therapies with engineered cells."
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Abstract: 528 Abstract: 527
Regulation (EC) No 726/2004 introduces new tools and procedures allowing early access to new drugs, including anticancer drugs. One of theses measures is the 150 days accelerated procedure (instead of 210 days) for drugs that are of major public health interest, particularly in terms of therapeutic innovation. Moreover, renewable conditional authorisations may be granted for certain products pending completion of further studies (detailed implementing legislation is expected to be adopted by the time of reporting). The existing mechanism of approval under exceptional circumstances when the rarity of the indication, the state of the scientific knowledge or the principles of medical ethic do not allow to provide comprehensive data on the efficacy and safety of such products, is retained. In addition, opinions for cohort compassionate use of products eligible to the centralised procedure may be given by the EMEA to treat patients with chronically or seriously debilitating disease, considered life-threatening, when no other authorised alternative exists.
The new European pharmaceutical legislation contains a number of new tools to provide early access to medicinal products of public health interest. The new approval mechanisms and the impact on the authorisation of oncology drugs are reviewed based on EMEA guidance.
501 Clinical trials methodology and ethics
Conduct of international multi-centre Investigator-Initiated Trials (IIT) in Europe after the transposition of the Clinical Trials Directive in national Member States law
M. Hartmann1, F. Hartmann-Vareilles2
Background:
Due to the mandatory implementation of the Clinical Trials Directive, Member States (MS) of the European Union (EU) have adapted their existing legislation to the new requirements for the conduct of clinical trials into humans. The Directive is aimed to harmonise legal acts for the set-up, conduct and reporting of clinical trials, to implement GCP-principles European-wide and to enforce patient protection. For non-commercial trials, the Directive is seen to impede the realization of future trials, as requirements, obligations and costs for clinical research projects are considerably increasing.
Methods:
The comparative analysis carried out is aimed to investigate differences, obstacles and pitfalls for the conduct of future multi-centre trials in MS. The legislation of 8 MS has been revised, major differences and alleviations allowed for non-commercial trials are tabulated. 3 IIT case studies in oncology are presented; the feasibility to conduct each trial throughout the EU will be discussed.
Results:
Major differences are noticed regarding the scope of revised legislations in the MS. Differences also apply to sponsorship and liability issues. Until now, only a few MS have expressively added provisions for non-commercial trials into their legislation. These specify e.g. the use of commercially available products and address reimbursement issues, simplified or exempted submissions of an Investigational Medicinal Product Dossier to competent authorities, or allow for exemptions from fees for IRB/dossier approval. No common definitions are available throughout the EU neither for the so-called 'phase IV' studies, nor for the terms 'IIT' or 'non-interventional studies'.
Conclusion:
The new legal framework for clinical trials renders the realization especially of future pan-European multi-centre trials much more difficult. In having harmonised organisational requirements for trials throughout the EU, the Directive has failed to simplify the conduct of academic clinical trials in the European trial space. Radiotherapy studies, trials investigating surgical techniques and some multi-modal trial concepts remain in some, but not all MS out of the scope of the revised legislative texts. Apart from 'interventional' trials, non-interventional trials allow - although heavily restricted to small phase I/II case series within or in close proximity to the approved prescription window given by drug labelling - in some MS limited research in form of observational studies outside of the new legal framework. 12 months after implementation, the new EU legislation results in a harsh drop-down of the number of new clinical trials and promotes primarily the conduct of nation-wide research projects.
501 Clinical trials methodology and ethics
Impact of the new European regulation on the authorisation of new oncology drugs in the European Union (EU)
M. Chapelin, F. Pignatti, B. Aronsson, A. Saint-Raymond, P. Le Courtois
European Medicine Agency , Pre-Authorisation Evaluation of Medicines for Human Use, London, United Kingdom
On 20 November 2005, new European pharmaceutical legislation will enter into force. Thereafter, all oncology drugs seeking approval in the EU will be evaluated via the European Medicines Agency (EMEA) leading to an EU-wide approval. This review focuses on the main regulatory changes related to the centralized procedure and the new concepts for approval that may affect applications for oncology products.