Completing E2B(R3) Compliance in Total Safety 7

@ris global Let s Innovate for Life 2016 Completing E2B(R3) Compliance in Total Safety 7 Author: Christian Schmitz-Moormann, Senior Director, Leading Practices Mark Loudon Senior Director, Risk Management Products & Compliance

EUROPE USA E2B COMPLIANCE JAPAN Introduction In nearly all industries and markets, companies are subject to increasing regulation concerning transactions, transparency, and privacy and have to bear the costs associated with ensuring compliance to these regulations. In the life sciences industry, this cost is further compounded by the need to monitor potential safety risks related to the use of their products. Regardless of geographic location or organization size, all manufacturers of devices or pharmaceuticals have the regulatory and ethical requirement of collecting, investigating, and monitoring suspected adverse reactions and all associated product use and complaint information. Exchange of such information between stakeholders in electronic format is becoming the standard. The ICH E2B(R2) standard has been implemented and widely used since it was first adopted in 2001. The ICH E2B EWG revised the guideline, joined forces with other international standards organizations (such as HL7 and ISO), and the E2B(R3) guideline was finalized in July 2013. The shift from E2B(R2) to E2B(R3) is one of the most important regulatory and procedural shifts in the industry, touching the way drug safety and regulatory departments, clinical and licensing partners do business, and requiring significant technological changes. While this is perceived as an evolution rather than a revolution, the challenges in complying with E2B(R3) requirements successfully should not be underestimated. However, due to our industry-leading experience in safety, ArisGlobal has evolved our software products in Safety and other areas to enable companies to implement E2B(R3) on time and on budget and in ways that match real-world, rather than theoretical use. Because of the iterative approach of ICH, and the fact that agencies are even now evolving their final guidances, this paper provides information which was not available when we released our white paper Preparing for E2B(R3): Understanding the Challenges, Options and Opportunities and provides information on how to operationalize and how to go live with E2B(R3). 2

Current Status What is available in the current system? The current version of ArisGlobal's Total Safety suite (TS7.2) supports both export and import capabilities of R3 cases through ESM as per the ICH E2B(R3) Implementation Guide released on 12 April 2013 (ICH Step 4 Document) along withpmda local regulations released in Sep 2013. Further local regulations will be implemented as they become available during Step 5. Documents While the global requirements were made official in 2013 reaching ICH Step 4 in July, there was a minor revision in November 2014 and a Q&A document was released in November of 2014. Regional and local implementation guidelines already exist, or are in the process of being made available. These regional and local implementation guidelines extend the regulatory framework and business rules to be implemented. Frequently, the different regional guides implement divergent rules. The nature of the underlying technical standard for E2B(R3) facilitates this divergence a good thing from the perspective of flexibility, but a bad thing from the perspective of solidifying and aligning regional requirements with each other. It has been made clear that information in the ICH Q&A document supersedes information in the ICH implementation guideline and that the regional/local implementation guidelines again supersede the information in the Q&A document. All current implementations of E2B(R3) are technically independent of IDMP however, some regions (such as Europe) have linked their implementation timetables for these two standards either in whole or in part. The regions have provided guidance as follows: Japan issued a first set of local regulations in September 2013, a second set in October 2014, and a third set in February 2015. The EU provided an ICSR Implementation Guide in Dec 2014. The US provided a FDA Regional Technical Specifications for ICH E2B(R3) Implementation document which is limited to the Post market submission of Individual Case Safety Reports (ICSRs) for vaccines. This document is still in draft stage (0.3) and dates from May 2015. As of this writing, no other regional content is available from the US which goes beyond what is stated in the ICH documents. Other countries have not made official any plans for supporting E2B(R3). However, this does not mean that there are no such plans. Both Canada and Switzerland, for example, are known to work on alignment of their regulatory frameworks with the US and the EU, respectively. 1 In ICH, Step 4 represents the final global document and formally, the standard is therefore finalized from the ICH perspective. However, during the ICH Step 5 (implementation), each agency issues local guidance that can significantly alter how implementation needs to be done for each jurisdiction. 3

April 2016 Japan accepts electronic submission in R3 April 2019 R3 submissions mandatory in Japan 2015 2016 July 2016 Readiness to accept electronic submission in R3 in EU 2019 2017 August 2015 R3 submissions mandatory in US for vaccines (postmarketing) Mid 2017 EU accepts electronic submissions in R3 Japan will start accepting electronic submissions in R3 format on 01-Apr-2016; electronic submission in R3 format will be mandatory in Japan on 01-Apr-2019. The PMDA has stated that the authority will not send cases in R3 format before the mandatory date. While for the EU the official date for E2B(R3) readiness is still 01-Jul-2016, this is now interpreted as be able to test with EMA. Production use of E2B(R3) is currently communicated as being planned for mid-2017 ( 6 months post announcement of successful EudraVigilance Audit by the NCAs ). By this date the EMA also plans to send cases out in R3 format. No date has been given yet when electronic submission in E2B(R3) will be mandatory in the EU. The current statement is Post ISO IDMP Implementation which in turn will only start after EU has started accepting R3 format messages. In the US electronic reporting is now mandatory, with the special aspect that for post-marketing information regarding vaccines, E2B(R3) format is required for submission to the authority. If the electronic submitter tool provided by CBER is not used, waivers can be obtained, if a plan for implementation of E2B(R3) reporting for post-marketing cases for vaccines is provided. Beyond this, there are currently no clear rules as to when E2B(R3) reporting will be possible or mandatory in the US. Plan 1 Plan 2 Plan 3 The TS service pack is planned for 31-Aug-2016 release is planned for 31-Jul 2016 ArisGlobal will continue to support changing regulations in accordance with our release policy for the duration of d evelopment s u p p o r t. I n practice, this means that, while support may first be available in upcoming main releases, for regulations that existed when a release was published, and which are modified subsequently, continued compliance will be provided through our service packs 4

Here is a tentative overview with regard to E2B(R3) support in the 7.2 and higher releases of the Total Safety Suite: Feature Release in Backport to PMDA business rules evaers Local data entry for R3 (Narrative) 2014 and 2105 local regulations regarding R3 reporting to PMDA R3 submissions through OST Regional R3 Submission validations - FDA Regional R3 regulations and field changes - FDA Regional R3 submission validations - EMA Regional R3 regulations and field changes - EMA Regional R3 submission validations - Japan PMDA report form changes R3 elements in IRT forms emdr3 import emdr3 export 7.2.2 Currently, the release is planned for 31-Jul 2016. Currently, the TS service pack is planned for 31-Aug-2016. Accommodation of additional changes to regulations regarding E2B(R3) will be planned as new information becomes available. PMDA Submission in R3 Format as per ICH Guideline ArisGlobal has been successfully participating in Japan's PMDA Pilot Tests -- in the PMDA Pilot Test of Q2-Q3 2014, ARISj-generated R3 XML files were verified as being compliant with ICH E2B(R3) guideline and the Japanese local regulation of Sep 2013. The PMDA Pilot Test of Q2-Q3 2015, which verifies functionality of importing and exporting R3 XML files from ARISj in accordance with ICH E2B(R3) guideline and Japanese local regulation of Feb 2015 is currently ongoing. Items that show up during this test process and require a correction will be addressed in the upcoming TS 7.2 service packs, and at the very latest in TS. 5

Pre 7 Releases Backward Forward Compatibility Integration For customers on releases which do not natively support E2B(R3) (releases prior to TS 7), two options will be made available. ArisGlobal will provide access to a hosted environment to which E2B(R3) files can be sent for conversion to R2. The system will also provide acknowledgments to be returned upon successful import of the converted data into the database system. An alternative is to integrate with the ICH or EMA BFC tool, which provides capabilities to convert E2B (R3) to E2B(R2) and vice versa, including acknowledgment messages. Automated integration with the ArisGlobal hosted conversion solution will require some changes to the existing 6.5.x Total Safety systems. Integration with the ICH or EMA BFC tool would require additional steps before and after import. An integration project would have to be agreed. Integration for the ArisGlobal hosted conversion solution is planned as follows: Proposal for integration of BFC Converter for TS 6.5.x Arrival in Receiver Environment Test Wellformedness of XML independent of format Well-Formed XML YES Identify XML R3? YES agconvert R3 to R2 NO NO Converted Data Depends on available DTDs and XSDs (Configuration) Archive Import MDN Returned? NO Attach R2 XML in DMO Attach R3 XML in DMO Nack Returned? NO Import The plan is to provide this integration in a TS 6.5 convergence release (6.5.4) initially by end of Q3 2016. Attach R2 XML in DMO END 6

Conclusion ArisGlobal solutions are fundamentally ready for ICH E2B(R3), and will keep pace with regulatory changes during and after the implementation period. Total Safety 7.2 onwards are inherently ICH E2B(R3) compliant. For versions prior to Total Safety 7, ArisGlobal offers approaches to provide the ability to receive incoming ICH E2B(R3) files, in compliance with the first round of regulatory requirements in Europe. For full two-way exchange of ICH E2B(R3) files, customers will need to upgrade to a then current version of Total Safety 7. For questions about the approach that is right for your company, please contact you client partner 7

CORPORATE HEADQUARTERS ArisGlobal, 401 East Las Olas, Suite 1400 Fort Lauderdale, Florida 33301 Tel: +1 609 360-4042 Fax: +1 203 356 1673 Email: info@arisglobal.com REGIONAL OFFICES AMERICA East Coast Office: ArisGlobal LLC 600 College Road East Suite 3100 Princeton, New Jersey 08540 Tel: +1 609 360-4042 MidWest Office ArisGlobal LLC 377 Butterfield road Suite 260, Lombard IL Tel: +1 609 360-4042 Germany ArisGlobal GmbH Inselkammerstrasse 11 82008 Unterhaching, Germany Tel: +49 89 666 0840 Italy ArisGlobal GmbH Via Castelfidardo, 8 00185 Roma, Italy Tel: +39 (06) 4745932 EUROPE Ireland ArisGlobal Ltd. 16a Lincoln Place, Dublin 2 Ireland Tel: +353 1 9052430 Belgium ArisGlobal BVBA Groote Steenweg 323 B-2600 Berchem Belgium Tel: +32.3.500.9678 United Kingdom ArisGlobal UK Limited 5-6 Shenley Pavilions Chalkdell Drive Shenley Wood Milton Keynes MK5 6LB England Tel: +44 (0) 1908 506075 ASIA PACIFIC Japan ArisGlobal KK TK Shin-Toshin Bldg., 6F 1-23-1, Nishi-Shinjuku, Shinjuku-ku Tokyo, 160-0023 Japan Tel: +81 3 6304 5462 India ArisGlobal Software Pvt. Ltd. SKR Towers, # 19/2, 15th Cross JP Nagar 4th Phase, Dollars Colony Bangalore 560078, India Tel: + 91 80 6621 2747 ArisGlobal Mysore Center Belagola Industrial area, K.R.S. Road, Metagalli Mysore 570016, India Tel: + 91 821 6641000 8