The European Clinical Trials Framework Update on the Draft Clinical Trials Regulation Dr. Ilona Reischl BASG/AGES Austrian Agency for Health and Food Safety GmbH
Content - References "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 http://ec.europa.eu/health/human-use/clinical-trials/index_en.htm#rlctd OPINION on the 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 European Parliament; ITRE Committee - Opinions Guidance on posting and publication of result-related information on clinical trials in relation to the implementation of Article 57(2) of Regulation (EC) No 726/2004 and Article 41(2) of Regulation (EC) No 1901/2006 (October 2012) EudraLex Vol. 10 2
Statistics # of CT applications (e.g. 1 entry for CT in AT, DE, UK) 2007 2008 2009 2010 2011 2012 Total 5037 4635 4627 4415 3783 3986 # of CT applications (e.g. 3 entries for CT in AT, DE, UK) 2007 2008 2009 2010 2011 2012 Total 9964 10092 9879 9786 8569 9275 3
Draft Clinical Trial Regulation The Concepts Harmonised authorisation dossier (EudraLex, Vol. 10) Free, single portal for submission managed by the EC Flexible and swift assessment largely controlled by MS Involvement of all intended Member States Clear timelines - tacit approval Coordination/advisory forum managed and chaired by the Commission Distinction between cooperative and intrinsic ethical or national/local aspects `Qualified opt-out for a MS 4
The Concepts Organisational setup and internal competences MS responsibility Swift procedure to extend a CT to additional MSs Modification subject to authorisation only if it has substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the CT Crucial element: clear distinction between aspects where MSs shall cooperate and those where MSs conduct assessment individually: Aspects which are of an intrinsically national (for example, liability), ethical (for example, informed consent), or local (for example suitability of the clinical trial site) nature 5
Clinical Study.. any investigation in relation to humans intended a) to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products; b) to identify any adverse reactions to one or more medicinal products; or c) to study the absorption, distribution, metabolism and excretion of one or more medicinal products; with the objective of ascertaining their safety or efficacy 6
Clinical Trial a clinical study which fulfils any of the following a) the IMPs are not authorised b) IMPs are not used in accordance with the terms of the MA of the Member State concerned c) Therapeutic strategy assignment of the subject is decided in advance and does not fall within normal clinical practice of the Member State concerned d) decision to prescribe the IMP is taken together with the decision to include the subject in the clinical study e) diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects 7
Low-interventional Clinical Trial.. a clinical trial which fulfils all of the following: a) the IMPs are authorised b) according to the protocol of the clinical trial, the IMPs are used in accordance with the terms of the MA or their use is a standard treatment in any of the Member States concerned 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 8
Open Question Routine Clinical Practice How should Routine Clinical Practice be documented/supported? When does clinical use become normal clinical practice? The procedure/documentation needs to be harmonized, since it needs to be accepted from any member state How can this be verified in general and in particular during validation? Evidence based medicine Is standard treatment (in any member state) supported by the same level of evidence as a MA? 9
Single Authorization The National authorisation of CT should incorporate all aspects One single administrative decision per Member State Decision on appropriate body or bodies is Member State responsibility (NCA, EC), but involvement of lay persons, patients and necessary expertise need to be insured Assessment should be done jointly by a reasonable number of independent persons who collectively have the necessary qualifications and experience The purported elimination of ethics assessment through the CT regulation is an incorrect interpretation of the text However, coming to a single decision within the proposed timelines would require a standing ethics committee Independence? 10
Single Portal A single portal to submit an application for conducting a clinical trial linked to an EU database. This portal is managed by the European Commission and is free of charge for sponsors All information is transferred through the portal All communication is transferred through the portal Vital role of a functioning portal otherwise complete standstill! No text on consequences of system failure in the draft regulation No details on how and where information is meant to be archived Implications for IT Systems of Agencies and Industry 11
CT Lifecycle In order to allow patients to assess possibilities to participate in a CT, and to allow for effective supervision of a CT by the Member State concerned, the start of the CT the end of recruitment for the CT and the (national) end of the CT should be notified The results of the CT should be reported to the competent authorities within 1 year of the end of the clinical trial Transparency policy 12
Assessment Report Part I (i) Anticipated therapeutic and public health benefits (ii) Risks and inconveniences for the subject (iii) Compliance with the requirements concerning the manufacturing and importation of IMPs and auxiliary medicinal products (iv) Compliance with the labelling requirements (v) The completeness and adequateness of the IB 13
Assessment Report Part II requirements for informed consent rewards or compensations for investigators and subjects arrangements for recruitment of subjects compliance Dir/95/46/EC (data protection) compliance Art 46 (suitability of personnel) compliance Art 47 (suitability of trial site) compliance Art 72 (damage compensation) compliance with the applicable rules for the collection, storage and future use of biological samples of the subject 14
Current VHP Procedure Rapporteur Member states (P-NCAs) Rapporteur NCA Submission Dossier dar Comments AR Assessment Report; GNAs EC Submission Gene technology Act Co-Rapporteur 15
Assessment Part I Same procedure for subst. amendments 16
Article 14: 2 nd wave Arbitrary example 2 nd wave EU-portal RMS Part II Part II Part II Part I Part II Approval Part II Applicant cms Part II Part II Part II May choose rapporteur Flags from http://en.wikipedia.org/wiki/flags_of_europe 17
Article 11 Limitation to part I Arbitrary example 2 nd wave (Part I)? Followed by 2 nd wave (Part II) Part II Part II EU-portal RMS Part II Part I Part II Applicant Approval Part II Part II Implicit acceptance of Part I assessment Part II Part II Flags from http://en.wikipedia.org/wiki/flags_of_europe 18
Involvement of all intended Member States? The current text does not foresee a draft assessment report Unrealistic timelines Second wave Comments on part I only under very limited conditions and only to the initial rapporteur who decides on relevance? No incentive for multinational trials it seems much easier to go for mononational approval and then a second wave, which, in effect, eliminates the involvement of member states where the trial will be conducted Revisions, restrictions and clarifications needed 19
Assessment report AR to be sent to cms, the EC and the applicant previously only deficiencies were sent out Change of policy Higher requirements in preparation time single opinion Publication Benefit? equally for mono-national trials - potential extension to multinational ARs required for substantial modifications Assessment time for multinational CTs is de facto shorter than for mono-national CTs (coordination efforts) 20
The same as in the USA? The need for adaptation to the US System is frequently voiced The modus operandi of FDA during the IND stage: Within 30 days the hold/non-hold decision is taken If the study is placed on hold, the (hold-)deficiencies need to be sent out within these 30 days If the study is not placed on hold, a list of (minor) deficiencies may be sent out, but this is not compulsory NO assessment report is sent out According to the EU draft regulation, the entire assessment report needs to be finalized and sent within the timeframe. 21
Safety Reporting (Chapter 7) Principles of the applicable international guidance documents streamlined, simplified and modernised: The option to exclude reporting by the investigator to the sponsor of adverse events, if this is provided for in the protocol Direct reporting of SUSARs by the sponsor to EudraVigilance Simplified submission of ASRs by the sponsor for unauthorized IMPs No ASR for authorised IMPs used within their authorised indication 22
Withdrawals Withdrawal of the CT by the applicant is possible at multiple stages Art. 12: The sponsor may withdraw the application at any time until the assessment date. In such a case, the application may only be withdrawn with respect to all MS concerned Art. 13:. possibility for the sponsor to submit, following the refusal to grant an authorisation or the withdrawal of an application, an application for authorisation to any intended MS concerned. That application shall be considered as a new application for authorisation of another CT No withdrawal in a single MS possible? 23
Withdrawals - Rejections Withdrawal of the CT by the applicant is possible at multiple stages ( Art. 12; Art. 13) but no withdrawal in a single MS foreseen Prediction that significant GNAs cannot be addressed by applicants within the timeframes (10/20d) (preparation of response, internal sign-off) increase in withdrawals/rejections Consequences of rejection and a withdrawal are the same: New EudraCT New Fee 24
Summary Based on the initial draft.. Administrative obligations are shifted from applicant to competent authority (coordination of opinions) Same procedure for mono-national and multinational trials EU portal as an essential element of the process Need to establish IT Systems compatible with the portal Timelines are maintained or shortened for agencies in spite of a significant increase in administrative load Double impact on the time available for scientific assessment: Shortened timelines and additional coordinative tasks reflection of the value placed on agency review? 25
Comments by the EU Parliament http://www.europarl.europa.eu/sides/getdoc.do?pubref=-//ep//nonsgml%2bcomparl%2bpe- 504.236%2B01%2BDOC%2BPDF%2BV0//EN 26
Proposed Amendments EU Parliament Explicit mention of evaluation by independent ethics committees Off-label use Focus on transparency Focus on participant s benefit Possible sanctions for non-compliance 27
Proposed Amendments EU Parliament In order to allow for independent control as to whether these principles are adhered to, a CTs should be subject to prior authorisation and prior approval by an ethics committee EUP: Currently, the ethics review procedure varies greatly between MS, often with various bodies at national, regional and local levels, and multiple procedures leading to divergent assessments. This is a source of delays and fragmentation. In the interests of European patients and public health, the procedures and principles of ethical review should be better harmonised through the sharing of best practices between ethics committees. To this end the Commission should facilitate the cooperation of ethics committees. Single opinion proposed is not accepted? Duty to get Agency and EC approval falls back to sponsor? Intended procedure unclear 28
Off-Label Use Art.2 2 2b: according to the protocol of the clinical study, the investigational medicinal products are not used in accordance with the terms of the marketing authorisation of the Member State concerned and their use does not fall within normal clinical practice; EUP: As many standard treatment protocols use medicines outside their MA, it has to be clarified that studies collecting data on the standard off-label use of a medicinal product are not considered as clinical trials. Impact on evidence based medicine? Data will not be usable for a MAA; impact on paediatric off-label use? 29
Off-Label Use Art.2 2 3b: according to the protocol of the CT, the IMPs are used in accordance with the terms of the MA in any of the MS concerned or, where the use of a medicinal product is outside the terms of the MA, their use is supported by sufficient published evidence and/or standard treatment guidelines EUP:. In order to avoid fundamental differences between MS in applying the definition of a low-interventional trial including off-label use, the acceptable level of evidence should be stated; and if the trial treatment is only to compare standard practice treatment approaches, then, regardless of whether the drugs are being used off-label, the trial should be categorised within the lowinterventional trial category. Considers only risk of therapeutic but not diagnostic intervention 30
Study Report Art. 2, 2 30 a (new) Clinical study report : a report containing the full protocol and any subsequent modifications and dates thereof, a statistical analysis plan, summarised efficacy and safety data on all outcomes, and individual anonymised patient data in the form of tabulations or listings, in accordance with the guidelines provided by the ICH E3. Same requirements for all CTs Art. 3 2: EUP: CTs should be conducted only if the results are relevant for improving the prevention and treatment of diseases. The relevance of the trial is one of the assessment criteria pursuant to Art. 6, and should therefore be included in the general principles of CTs. 31
Population to be treated Art. 6 1 a) i ) 2 the relevance of the CT, ensuring that the groups of subjects participating in the trials represent the population to be treated, and taking account of the current state of scientific knowledge, and of whether the CT has been recommended or imposed by regulatory authorities in charge of the assessment and authorisation of the placing on the market of medicinal products Art. 31 a (f) some direct benefit for the group of patients (e.g. improved quality of life) is obtained from the CT. Annex I, 13, 6 if the trial subjects do not reflect a balanced distribution in age and/or justification for these exclusion criteria; gender, this must be justified and explained; Impact? 32
Data robustness Art. 6, 1 a) i) 3: the reliability and robustness of the data generated in the clinical trial, taking account of statistical approaches, design of the trial and methodology (including sample size allowing for a stratified analysis by age and gender and randomisation, comparator and endpoints EUP: The data generated in CTs can be considered as reliable and robust only if they adequately reflect the population groups (e.g. women, the elderly) that are likely to use the product under investigation. Impact on the number of subjects needed for the trials? Early trials? 33
Information Art. 29, 4 The subject shall be provided with information on the results of the CT that he or she has participated in, once it has come to an end. Extra information needed? Report will be in the public database Art 34 3: Within one year from the end of a CT, the sponsor shall submit to the EU database the clinical study report, including a lay summary of the CT 34
Compliance 2a. In the event of sponsor noncompliance with the obligation referred to in paragraph 3, financial penalties shall be imposed by the Member States concerned. EUP: To ensure compliance with the provision to submit the summary of the results and the CT report within 12 months, the MS should be entitled to enforce a penalty. Art 55: The sponsor and the investigator shall archive the content of the clinical trial master file for an indefinite period of time after concluding the clinical trial. 35
Impact Art 78 1. 2. The EU database..to enable the co-operation between the competent authorities of the MSs..and to search for specific CTs. It shall also enable sponsors to refer to previous submissions of an application for authorisation of a CT or a substantial modification. It shall also enable the public and independent researchers to analyse the results of CTs. Annex I 13 2 Application..a discussion of the relevance of the clinical trial and its design to allow assessment in accordance with Article 6, referencing all existing evidence, including systematic reviews and meta-analysis; 16a. The protocol shall contain information regarding funding, sponsors, institutional affiliations, and any other potential conflicts of interest Consequence on size of the dossiers and assessment? 36
Transparency Initiative 2 Levels: EMA: Publication of clinical trial (raw) data once a marketing authorization approval has been given for a specific product Applies only to products after licensure www.ema.europa.eu/docs/en_gb/document_library/report/2012/12/wc500135841.pdf Clinical Trials: Public access to final reports of clinical trials Applies to ALL clinical trials 37
EudraLex Volume 10 Guidance on posting and publication of result-related information on clinical trials in relation to the implementation of Article 57(2) of Regulation (EC) No 726/2004 and Article 41(2) of Regulation (EC) No 1901/2006 (October 2012) Applicability as soon as IT programming finalized Result-related information should be posted for all clinical trials, including those prematurely ended Reporting by the sponsor of the trial, the addressee of a PIP decision or the MA holder (Art 45/46 REG/1901/2006/EC) Upload via secure account, publication after techn. validation No review by National Agencies prior to publication Publication via the EU Clinical Trials Register 38
EudraLex Volume 10 Automatic upload of required protocol-related information from EudraCT, to be included with result-related information Upload required within 6 months (paediatric trials) or 1 year Member States should verify upload for CTs authorized by them Non-compliance publicly flagged within 9/15 months Applies retrospectively: ο ο Trials that ended less than 1 year prior to IT availability - 1 year for upload Trials that ended 1 year or more prior to availability - 24 months based on full data, with exception of trials according to Art. 45 REG/1901/2006/EC IT structure published 22.1.2013 http://ec.europa.eu/health/files/eudralex/vol-10/2013_01_22_tg_en.pdf Considerable impact on sponsors 39
Public Initiatives www.alltrials.net/ 40
Thank you for your attention! 41