This is meant to be a narrative rather than a critical summary I have a lot of questions about the proposal but I will look into these separately.

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1 REVISION OF THE CLINICAL TRIALS DIRECTIVE Proposal for a Regulation of the European Parliament and of the Council on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC. 2012/0192 (COD) Introduction This is a summary, prepared by Jim Murray, of some of the main features of the proposed regulation to revise the Clinical Trials Directive. I hope it is correct but I make no promises on that point. If any reader thinks I ve got it wrong anywhere please let me know that way I can try to improve this current version. This is meant to be a narrative rather than a critical summary I have a lot of questions about the proposal but I will look into these separately. This note is published subject to a Creative Commons licence. If you pass it on, it would be nice of you to mention me. Background Most clinical trials are single country trials but multi country trials tend to be bigger and account for some 67% of patients in all trials in the EU (European Commission). The main purpose of the proposed regulation is to address the following criticisms by industry, academics and others: 1. The current application procedure for multi-country trials is too slow, complex and expensive in ways that do not add to the safety or efficacy of such trials. 2. The requirements for insurance or indemnification cover impose very high expenses and acts as a deterrent to clinical trials, especially but not only for academic researchers. 3. The current regime is does not distinguish between the different levels of risk for different clinical trials; low risk ( low intervention ) trials are subject to the same rules as others with higher levels of risk, and are therefore more expensive and cumbersome than they need to be.

2 Application for Authorisation of a Clinical Trial Under the regulation, there will be only one way to apply for authorisation for a clinical trial through a portal run by the European Commission. The Commission will not assess the application but all communication between the applicant and the member states where the trials will take place will pass back and forward through the portal one single application in one single dossier, shared by all the member states concerned. (Article 5 et al). On my reading of the proposal it also applies to single country trials, in other words to all clinical trials in the EEA without exception (Article 1). Assessment Part I One member state, probably the one suggested by the applicant, will take on the role of reporting member to prepare an assessment report on the scientific, therapeutic and safety aspects of the proposed trial. The other member states may submit opinions or queries to the reporting member state before the assessment is complete, but not after. When the assessment report is published, other member states may disagree with it but only on the specific grounds, set out in Article 8.2, and then only with a detailed justification in writing to be sent to the Commission, the other member states concerned and to the sponsor of the trial. (Article 6) Assessment Part II All member states where the trials will be conducted may carry out their own individual assessments on aspects of the trial that are governed by national laws, including informed consent, treatment of minors, liability for damages, recruitment of subjects and payment of investigators. (Article 7) Time Limits All stages of the process are subject to strict time limits. Reporting member states have ten days to say if an application is complete or not otherwise it is presumed to be complete. The reporting member state must complete the assessment report within ten days (for low intervention trials), 25 days (for ordinary trials) and 30 days (for advanced therapy trials). They may stop the clock to seek more

3 information but for no more than ten or twenty days depending on the type of trial. They may set deadlines for sponsors to reply to their questions and the application will be considered to be withdrawn if the sponsors do not reply on time. (Article 6) Member states must complete their (Part II) assessment within ten days. (Article 7.2) Modifications Clinical trials are sometimes changed while in progress. Under the regulation a new application will be necessary in such cases only where there is substantial modification a modification likely to have a substantial impact on the safety or rights of the subjects or on the reliability or robustness of the data generated in the clinical trial.(articles 16-24) Low Intervention Trials The regulation proposes a lighter regime for low intervention trials. These would be trials of medicines already authorised for use, used in the way for which they are authorised and with no more than minimal additional safety risks or burdens to patients in the monitoring and diagnostic process such as taking blood samples, for example. (Article 2.3) The time limits for approving low intervention trials are shorter than for other trials. Furthermore, the proposal does not require investigators and sponsors to have insurance or compensation schemes in place for low intervention trials on the grounds that standard professional liability insurance will provide sufficient coverage for such trials. (Article 72) Compensation Mechanisms For trials other than low intervention trials, member states are required to have in place national compensation mechanisms to ensure compensation under the national laws on legal liability if things go wrong. Coverage under these schemes should be free of charge for clinical trials that will not be used to obtain a marketing authorisation. In other cases, fees may be charged but on a not-for-profit basis. (Article 72-73)

4 Data The proposal contains a number of provisions on data. Clinical data submitted in support of an application should be based only on clinical trials recorded in a publicly accessible database. (Recital 20 et al) This provision would apply from the date the Regulation takes effect. Data from unregistered trials before that date could be included many relevant trials might have been carried out before registration was in place. Results of clinical trials should be reported to the competent authorities within one year of the completion of the trial unless a longer period was foreseen and approved at time of application. (Article 34.3) The Commission will set up a database that will include all the information passing through the portal. It will be publicly accessible, with exceptions for personal data, commercial confidentiality and law enforcement (i.e. data for the effective supervision of clinical trials by member states). (Articles 77-78) A summary of the results of each clinical trial should be placed on the EU database within one year of the completion of the trial. (Article 34.3) Sponsors must retain the Clinical Trial Master File, containing all details of the trial for five years. (Article 55) Administration Each member state must appoint a single contact point for the purposes of the regulation, to communicate through the portal with the reporting member state and the trial sponsor. A new EU advisory committee will be formed, made up of the members from the national contact points. (Articles 79-81) Member states are free to make their own arrangements for assessing applications, but the assessors must in each case be independent, without conflicts of interest and shall include a patient and someone whose primary interests are non-scientific. (Article 9) (Given the tight time scales, member states will have to have procedures in place to act quickly; otherwise they may just have to accept that a trial is authorised in their

5 country. Member states with complex authorisation procedures, perhaps involving different bodies, will have to adapt to the proposed regulation.) Safety Reporting Investigators shall report adverse events to the sponsor according to the terms of the particular protocol for a given trial.(article 37) Investigators must record all serious adverse effects during the trial and report them to the sponsor, unless the protocol says otherwise. (Article 37) Serious unexpected adverse effects must be reported immediately to a database set up by the European Medicines Agency. (Article 38) Unexpected events which affect the benefit-risk balance of the trial must be reported, without undue delay to all the relevant member states, through the portal. (In such cases urgent new safety measures may have to be taken and reported immediately.) (Article 50-51) Sponsors must report, within seven days, again through the portal, any serious breach of the regulation or the trial protocol. (Article 49) The sponsor must send to the EMA once a year a report on the safety of the medicines in the trial (apart from placebos and authorised medicines used according to their authorisation). (Article 39) For authorised medicines used according to their authorisation, any suspected serious adverse reactions should be reported once a year to the holder of the authorisation for that medicine (e.g. when a company is using a competitor s product in the trial). (Article 41) NB More specific requirements for safety reporting are set out in Annex III. Other Points There are many other provisions in the proposal that I have not covered here, including provisions on informed consent, contents of application dossiers, labelling, and (very important) trials outside the EU.

6 I think I have covered the main points, such as they are, relating to access to data and data disclosure. If you find anything I have overlooked on this point, please let me know. If you think there are other parts of the proposal that I should try to summarise, I m open to suggestions. Jim Murray 4 th October 2102.