New from 2013… to 2017 Declaration of Helsinki 2013 Updated definition of Critical Audit Finding from HRA April 2014 European Regulation 2014 Care Act 2014

THE DECLARATION OF HELSINKI 2013

Declaration of Helsinki th meeting of the World Medical Association (WMA) in Fortaleza, Brazil in October 2013, a new version of the Declaration of Helsinki was agreed and published - content has been reordered and the section titles changed. In some sections the word “should” has been replaced by the word “must”, informed consent “must” be sought by an appropriately qualified individual negative or inconclusive results “must” be published or otherwise made publicly available.

Declaration of Helsinki 2013 Researchers must also have ethics training as well as appropriate scientific education, training and qualifications Compensation and treatment is now required for subjects who are harmed as a result of participating in research. Continuous risk assessment and risk mitigation is now required

Declaration of Helsinki 2013 Additional requirement for the ethics committee to be transparent in its functioning and researchers must now submit a final report to the committee after the study. Subjects must be informed about post-study provisions as part of the consent process and should also be given the option of being informed about the outcome and results.

Declaration of Helsinki 2013 The two key controversial issues, placebo control and access to treatment post-trial, remain largely unchanged. The FDA have removed reference to the declaration from CFR 21 NOTE: The new EU Regulation still references 2008 version as the 2013 version had not been issued when the legislation was drafted…

UPDATE FROM MHRA APRIL 2014 NEW CRITICAL FINDING DEFINITION ‘where provision of the Trial Master File (TMF) does not comply with Regulation 31A 1-3, as the TMF is not readily available or accessible, or the TMF is incomplete to such an extent that it cannot form the basis of inspection and therefore impedes or obstructs inspectors carrying out their duties in verifying compliance with the regulations.’

NEW EU REGULATION NO 536/2014

Challenges with EU Directive The number of applications for clinical trials fell by 25% from 2007 to 2011 in the EU The cost and administrative requirements of conducting clinical trials have significantly increased For non-commercial sponsors, the administrative costs increased by 98% The average delay for launching a clinical trial increased by 90 per cent to 152 days.

Challenges with EU Directive National implementation Multiple applications if more than one country involved Divergent decisions Uncertain timelines Ethics Committee decisions vary One protocol but questions can result in country changes requiring subsequent amendments in other countries

EU regulation No 536/2014 A modern regulatory framework for submission, assessment and regulatory follow up. Regulatory requirements adapted to practical considerations, constraints and needs without compromising participant safety, rights and well being or data robustness. Address the global dimension of clinical trials when ensuring compliance with GCP.

EU regulation No 536/2014 It is a Regulation i.e. law within EU New simplified application/approval procedure Risk based approach Introduction of rules for emergency clinical trials, co-sponsorship and serious breaches. Increased transparency (registry, trial activity, results) New roles for Commission Details 3 rd Country [i.e. Non EU] expectations

EU regulation No 536/2014 A trial must be conducted in accordance with both the protocol and the principles of GCP. Adequately monitored – extent and nature determined by risk assessment IMP managed ‘as appropriate and proportionate’ Provisions for reporting of serious breaches Urgent Safety Measures – 7 days Investigator’s brochure: obligation for this to contain all clinical an non- clinical data in the IMP has been removed - relevant to trial only Clinical Trials Master File must be readily available and directly accessible upon request. Clinical Trials Master File must be archived for 25 years

What is in the Regulation New simplified approval procedure – Single EU portal – Single dossier and single submission – Coordinated assessment for multi-state clinical trials – Sponsor nominated Reporting MS – Clear timelines, concept of tacit approval Risk based approach to the monitoring of trials. Introduction of rules for emergency clinical trials, co-sponsorship and serious breaches. Increased transparency (registry, trial activity, results) National indemnification mechanism Commission inspection powers 3 rd Country Requirements

Low-intervention Clinical Trial A clinical trial that fulfils all of the following conditions a)The investigational medicinal products, excluding placebos are authorised: b)According to the protocol of the clinical trial, i.The investigational medicinal products are used in accordance with the terms of the marketing authorisation; or ii.The use of the investigational medicinal products is evidence-based and supported by pulished scientific evidence on the safety and efficacy of those investigational medicinal products in any of the Member States concerned; and c)The additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of the subjects compared to normal clinical practice in any member state concerned

Tacit Authorisation/Approval Concept Already exists for Competent Authorities in 2001/20/EC “The sponsor may not start a clinical trial until the Ethics Committee has issued a favourable opinion and inasmuch as the competent authority of the Member State concerned has not informed the sponsor of any grounds for non-acceptance. “ Regulation 536/2014 extends the concept to ALL assessors [within the concerned Member States]

New legislation EU No 536/2014… CONSENT Most discussed chapter Possibility of broad consent: use of data outside of protocol if subject agrees although this consent can be withdrawn at any time by the subject Interview can be conducted by a member of the investigating team who is appropriately qualified according to national legislation Trials on incapacitated subjects and minors can take place not only when there is direct benefit to the subject involved but also when there is some expected benefit to the population represented Provisions for clinical trials on pregnant and breast feeding women Possibility for MS rules on military personnel, prisoners and people in residential care institutions Trials in emergency situations can only take place where potential for direct benefit for the subject Simplified consent process for cluster trials in single member state

What's next? The legislative proposal is now going through the European Parliament and in the Council. It is expected to come into effect in mid 2016 The new system will run in parallel along side the old system for a period of 3 years with the Directive stopping completely in 2019