CSDG Annex VI of CTR Latest developments Personal view of Tony Moult. Any facts or opinions expressed in this presentation may not represent the company view. These have been formed as the leader of the Work Group formed by Efpia TDOC and CTWG to respond to the Annex VI aspects on labels causing Industry concern

The sequence of events July 2012: draft CTR text published by the Commission for stakeholder comment April; 2014: Approved in the EU Parliament (EP) in ‘first reading’ and in Council. Published in the Official Journal: 27 May 2014 EFPIA input was mainly via the CTWG (Clinical Trial Working Group) Prior to the EP vote in April 2014, some changes in Annex VI were included at the insistence of a small number of MS. They were not at the suggestion of the European Commission (EC). These changes were documented in the official notes (Mid 2013) but visibility was not high Industry and the CTWG became aware of the changes after the April parliament vote. The CTWG requested technical support and expert help from the Technical Development Operational Committee (TDOC). Tony Moult as a member of that committee was requested to form a joint TDOC/CTWG expert working group.

High level concerns New in Annex VI: expiry dating on inner as well as outer pack. Efficacy and Quality of product Temperature and other special atmospheric conditions may be an issue for date extensions Risk of error / tamper evidence on date extension Error risk in depots is increased Error risk in Clinic is significantly increased Breaking of tamper evidence is needed and the consequent risk

High level concerns New in Annex VI: expiry dating on inner as well as outer pack (continued). Legibility Additional information makes space a problem . Particularly with no small container exemption. Waste Small packs etc. may not be able to have date extension labeling. Continuity of supply. Increased and more difficult process to extend date

High level concerns New in Annex VI: prohibiting use of electronic systems (IRT/IWRS/IVRS/etc.*) to justify omission of Expiry Date and other label elements. Expiry date is the current main concern. IRT control can be safer Backward step compared with other regions (e.g. US) Cost Prevents future innovation *IRT: Interactive Response Technology, IWRS: Interactive Web Response System, IVRS: Interactive Voice Response Sytem

Timelines for implementation 27 May 2014 CTR published. 28 May 2016* Effective if IT systems are in place. IT portal for submission and control is a prerequisite of CTR going live. Challenging to achieve within stated timelines Timelines will move back if there is any delay Prior to commitment a independent audit of system is needed We will have 6 months notice in the EC Journal of actual effective date One year to implement from the effective date Studies from 28 May 2016* may use either process up to 28 May 2017* All studies compliant by 28 May 2019* Long terms studies may need supply strategy now to meet this or have mid study change. * All dates move back if IT Portal is not completed, audited and this confirmed in the Journal 6 months before effective date.

Impact of current Annex VI - Conclusion Will create great difficulty for IMPs Will reduce patient safety Will increase cost Will reduce innovation Will reduce EU competitiveness.

The sequence of events continued An initial letter of concern was drafted and sent to the EC by the Director General of EFPIA (Richard Bergström) the day before the CTR was published. 27th May 2014 Publishing of the Official Journal L158. Volume 57 included Regulation (EU) No 536/2104. http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=OJ:L:2014:158:FULL&from=EN This repeals Directive 2001/20/EC – The so call Clinical Trial Directive. The EC stated that it would be difficult to propose amendments to the Annexes before application. The EFPIA TDOC/CTWG work group produced and had ratified a more detailed position paper (4 August 2014).

The sequence of events continued The position paper is the basis of communication between EFPIA and the national trade associations/ EC. A number of trade associations have responded about contact with their authorities over the concerns expressed. Some member states agree with EFPIA. There is reluctance to push change on this from some even if they agree. A copy of the position paper is provided (4 August 2014)

Current Situation Meeting with Fabio D’Atri of EC. 20th August 2014 EFPIA could see no quality or safety benefit and asked what the reasoning was for the changes. The response was : It was at the insistence of some member states insisting on the changes. From best personal recollection the justification of the Member States was. “Essential information to the Patient or in an Emergency situation” “Expiry Date labelling is linked to the Patient Number on the Label shortly before dispensing and it would not be a problem” The EFPIA position was reinforced by physical demonstration. Discussions took place on how the situation could be remedied ISPE presentation – Including two MS GCP inspectorates Video produced and made public http://www.efpia.eu/mediaroom//44/Rete205st-or-Expiry-Date-Labelling-in-Clinical-Trials Potential article in Script Meeting requested by ABPI with MHRA

Potential for Change from the current Annex VI Change has to be driven by Member States. Optimal solution; for the member state that insisted on the current text to request the change to the commission. On request to the commission some checks would be made if there were other member states that objected to the changes. Assuming consensus that the changes are needed they could be introduced before the CRT became effective. This would be via a delegated act.

Best case EFPIA / National Trade Associations / Individual Companies to make aware to the Member State Authority contacts the need for change based on innovation and patient safety needs. Change requested by Member States to the commission ASAP. The best opportunity would be the Adhoc group meeting of Member States meeting 27 November 2014 Consensus building may result in an indication a change is likely by the end of 2014. Change via a Delegated act may be possible by May 2015.

Video then Q and A?