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The Medical Devices Regulations 2002 (SI No 618), as amended by the Medical Devices (Amendment) Regulations 2008, came into force on 13 June 2002 and implement the provisions of the Medical Devices Directive 93/42/EEC (as amended by Directive 2007/47/EC), the Active Implantable Medical Devices Directive 90/385/EEC (as amended by Directive 2007/47/EC) and the In Vitro Diagnostic Medical Devices Directive 98/79/EEC. These Regulations establish systems under which a manufacturer must submit to the UK Competent Authority, information about clinical investigations of medical devices to be carried out in the UK.

These Notes outline the legal requirements relating to the conduct and performance of a clinical investigation as set out in these Regulations. They also provide background and guidance to manufacturers on how to apply for pre-clinical assessment of a proposed clinical investigation in human subjects, involving a device falling within the scope of the Regulations.

Manufacturers wishing to make an application for pre-clinical assessment of a proposed clinical investigation of an active implantable medical device or a medical device to be carried out in part or in whole in the UK should apply to the Medicines & Healthcare products Regulatory Agency of the Department of Health (referred to in this document as the UK Competent Authority), in accordance with these Guidance Notes.

This guidance is intended as a general explanation of the legislation and should not be regarded as an authoritative statement of the law nor as having any legal consequence. It follows that manufacturers and others should not rely solely on this guidance but should consult the legislation referred to and make their own decisions on matters affecting them in conjunction with their lawyers and other professional advisers. The MHRA does not accept liability for any errors, omissions or other statements in the
guidance whether negligent or otherwise. An authoritative statement could be given only by the courts. Information and assistance in individual cases may be sought from the UK Competent Authority whose address and telephone number are given on pages 12 – 13 of this document.

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

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In its Communication of 10 December 2008 to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions on “Safe, Innovative and Accessible Medicines: a Renewed Vision for the Pharmaceutical Sector”, the Commission announced that an assessment would be made of the
application of Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use (“Clinical Trials
Directive”).

This assessment would consider, in particular, various options for further improving the functioning of the Clinical Trials Directive with a view to remedy shortcomings and unintended negative consequences while taking the global dimension of clinical trials into account.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

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The impact of the clinical trials directive on clinical drug development has been evaluated by ICREL (Impact of Clinical Research of European Legislation) who have just published their report (HEALTH-F1-2007-201002).  When the clinical trials directive was brought in in 2001, its main objectives were:

• Protection of human subjects in clinical research
• Implementation of the Good Clinical Practice (GCP) standard in all clinical trials with medicinal products
• Harmonised procedures for clinical trials authorisation from competent authorities and ethics committees
• Central collection of information on clinical trials activities and safety results

Implementation of the directive into national legislation of all 27 EU member states was completed in 2006. Principles like Clinical Trial Authorisation by the competent authority and favourable opinion of a single ethics committee within defined maximum time-lines led to significant harmonisation of the clinical trial approval process. However, differences in interpretation of the modalities for this and other processes harmonised by the CTD, led to even higher complexity levels – especially in the performance of multi-national clinical trials. Today, a sponsor of a clinical trial needs to have very detailed knowledge about every country’s national requirements for clinical trial authorisations from competent authorities and ethics committees and has to integrate the different requirements to the protocol and IMPD resulting from parallel submission in multi-national trials.

This FP7-funded ICREL project aimed at objectively measuring the impact of the clinical trials legislation on the key stakeholder groups “commercial and non-commercial
sponsors”, “competent authorities” and “ethics committees” in the European Union by providing:

• objective information on positive and negative impact factors on clinical trials with medicinal products and on other types of clinical research
• reliable figures on the impact of the legislation on the clinical research activity of big Pharma Industry -, SME- and academia-sponsored trials
• evaluation of the resource, cost and effectiveness implication of the EU CTD implementation for all stakeholders
• comparison of the success of national CTD implementation
• consolidated conclusions on the findings amongst the stakeholders
• dissemination of the conclusions to the public at large

The Results

The Results of the Clinical Trials Directive research was broken down by stake holder:

Competent Authorities

• The vast majority (25 out of 28) of EU CAs participated in the survey. Two non-EU CAs from countries integrated within the EU regulatory system accepted to participate and provided responses.
• Content and quality of the responses varied greatly and were obviously dependent on the time, resources and systems the CAs had available to compile the information
• An impact on clinical research activity in the EU derived from the CTD implementation was apparent, though could not be readily confirmed from the available data
• No negative impact of the CTD on commercial sponsors could be detected. The number of CTAs submitted by commercial sponsors increased slightly (+11%) between 2003 and 2007
• Overall, a slight potential negative impact of the CTD on non-commercial sponsors was detected represented by a relative change of -25% of CTAs between 2003 and 2007, however, while some countries faced strong or even dramatic decreases other countries experienced an increase of non-commercial CTAs.
• The number of substantial amendments and SUSAR reports increased strongly after CTD implementation
• Average CTA timelines decreased after CTD implementation and were, in 2007, with 49 days clearly below the 60-day limit
• The indisputably increased administrative burden imposed by the CTD on the evaluation process and supervision of CTAs was reflected by an increase in workforces and related costs which was paralleled by a raise in fees

Ethics Committees

• Despite multiple contacts, the number of responding ECs was quite low
• The overall number of positive opinions increased by 23% between 2003 and 2007, with especially strong increases in CTs with medical devices and radiotherapy as well as non interventional/observational studies
• A huge increase in workload for ECs was observed since the implementation of the CTD, evidenced by not only the increase of opinions but also higher numbers of substantial amendments and SUSAR reports to ECs
• The number of negative opinions issued by lead or central ECs increased between 2003 and 2007 in line with the overall increase of reviews. More than 25% of responding ECs did not have an appeal system in place in 2007, but in countries where an appeal system was in place, it was significantly more frequently used than in 2003
• An increase in FTEs per EC was reported, however, the absolute numbers of employees per EC were still very low and often no clear differentiation was made between unpaid EC members and employees
• More than half of the ECs did not involve external reviewers in assessing applications despite the increasing complexity of the CTAs
• No differences could be detected in number of EC meetings and duration of review time per protocol between 2003 and 2007. However, the duration of the meetings increased slightly, but significantly
• Fees charged by lead or central ECs to commercial sponsors, SMEs and orphan drug trial sponsors for review of protocol and substantial amendments increased significantly from 2003 to 2007, but the fee level was different for these categories. The fee for academic trials was much lower and increased only slightly. Non-lead ECs did not charge significantly lower fees than lead or central ECs
• The annual budget of ECs increased by 50% between 2003 and 2007
• In 2007 ECs received final report summaries for less than 20% of the reviewed protocols
• 60% of responding ECs had no patient representative in their membership
• Especially non-lead/central ECs considered the procedure to generate a single opinion to be difficult

Commercial Sponsors

• The overall number of commercially-sponsored clinical trials increased by about 30%, driven by increases seen in large and medium-sized companies
• SMEs did not experience an increase but faced higher staff needs and related costs due to an increase in trial complexity
• Areas of relatively stronger increases were clinical trials with biotechnology products and with orphan indications
• Clinical trials were increasingly organized in more countries and more sites than before implementation of the CTD, however, the number of recruited patients increased only slightly
• There was no shift detectable in the responding companies in the type of trial phases performed in 2003 and 2007. However, generic companies did not participate in the survey because they reportedly do not perform their bioequivalence trials in Europe anymore
• Time lines for the overall protocol and substantial amendment approval process were extended by approximately 30%.
• Need for staff increase for preparation and management of clinical trials as well as for pharmacovigilance tasks, need for investment required to adapt IT systems to the new safety reporting requirements, and an increase of subject indemnity insurance fees added to an overall increase in resources required for the performance of clinical trials in the new regulatory environment without a demonstrable impact on improving patient safety
• In the opinion of commercial sponsors, the CTD has created a certain level of harmonisation of the clinical trials infrastructure in the EU, but as this harmonisation has not been sufficiently far-reaching, the complexity of clinical trials has increased

Non-Commercial Sponsors

• According to this survey’s data, the major impact of the CTD on the NCS activities was reflected in a significant increase of the workload and timelines, i.e., an increase in the time period before the entry of the 1st patient. The CA data did not show significant changes in the overall number of clinical trials conducted by NCSs. Overall, the CTD was perceived as having introduced a partial harmonisation of procedures, but this positive effect was heavily counterbalanced by the general lack of harmonisation, the increase of the administrative burden and related costs. NCSs called for simplified and harmonised requirements and sound
  risk based-approach
• A great heterogeneity was observed in the responses rates, the number of missing values, and the trends arising from the data collected from NCSs. These reflected the great heterogeneity of the NCS organisations, reaching from large research organisations and well-organised structures to small structures with a lower level of cooperative and dedicated resources. The capacity of NCSs to log critical information needs to be improved
• This survey was not designed for qualitative assessment of the impact of the CTD on the performance of future studies. The following questions need to be addressed: has the CTD improved patient protection and safety? What is the impact of the CTD on the quality of science: do we guarantee progress for patients in a timely manner? Can the nature of investigator-driven trials be preserved when independence from industry is threatened by the increasing burden of conducting such kinds of activities?
• A re-evaluation of the situation with respect to the implementation of the CTD and its impact would need to be performed over a 3-year time frame in order to take advantage of a more complete EudraCT database. The systematic comparison with the situation in non-EU territories, e.g. US, Canada and Japan, should also be included.

Overall Conclusion and Recommendation

ICREL provided strong arguments supporting some of the recommendations proposed by various stakeholders in scientific journals, at the EC-EMEA conference on the Directive (2007) and in the ESF “Forward Looks on investigator-driven clinical trials” (2009).

• A risk-based approach to regulation would result in a substantial reduction in workload and cost, particularly for academic institutions that run a number of low-risk studies using marketed drugs
• Simplification of the Clinical Trial Authorisation process by the competent authorities through a single CTA for multi-national trials would reduce duplication of efforts and also save time, costs, and expertise
• Harmonised practice in ethics committee requirements would facilitate and reduce the administrative burden of dossier submission, and changes in expedited SUSAR reporting to the ethics committees would alleviate their workload
• Insurance coverage for clinical trials should be reconsidered at the EU level and adequate funding should be provided to institutions performing clinical trials to ensure capacity and expertise for all trial-related activities

The above coments are form the Executive Summary and I woudl advice anybody with an interest in teh area to read the full report which is available from the ICREL site.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

Grow your Expertise for Free

As you know this website is a great resource for keeping up to date with developments and regulations, why not get our FREE monthly regulatory and market round up. You can un-subscribe at any time and we do not share your details with anybody.