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2016

Completing E2B(R3) Compliance

in Total Safety 7

Author:

Christian Schmitz-Moormann, Senior Director, Leading Practices

Mark LoudonSenior Director, Risk Management Products & Compliance

2ArisGlobal White Paper

IntroductionIn 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).

E2B COMPLIANCEUSA

EUROPE

JAPAN


Current StatusWhat is available in thecurrent 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) a long withPMDA local regulations released in Sep 2013. Further local regulations will be implemented as they become available during Step 5.

Documents

It has been made clear that information in the ICH Q&A document supersedes information in the ICH implementation guidel ine 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.

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.

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.


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

ArisGlobal will continue to support changing regulations in accordance with our release policy for the duration of d eve l o p m e nt 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

7.3 release is planned for 31-Jul 2016

The TS 7.2.5 service pack is planned for 31-Aug-2016

20162015

April 2016

July 2016

Japan accepts electronic

submission in R3

Readiness to accept

electronic submission in R3

in EU

2017

2019

EU accepts electronic

submissions in R3

Mid 2017

R3 submissions mandatory

in Japan

April 2019

R3 submissions mandatory

in US for vaccines (post-

marketing)

August 2015


Currently, the 7.3 release is planned for 31-Jul 2016.

Currently, the TS 7.2.5 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.

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 7.2.5.

PMDA Submission in R3 Format as per ICH Guideline

Here is a tentative overview with regard to E2B(R3) support in the 7.2 and higher releases of the Total Safety Suite:

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

7.3

7.3

7.2.2

7.3

7.3

7.3

7.3

7.3

7.3

7.3

7.3

7.3

7.3

7.3

7.2.5

7.2.5

7.2.5

7.2.5

7.2.5

7.2.5

7.2.5

7.2.5

7.2.5

7.2.5

7.2.5

7.2.5

7.2.5

Feature Release in Backport to


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.

Pre 7 Releases – Backward Forward Compatibility IntegrationAutomated 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:

Test Well-formedness of XML

independent of format

Arrival in Receiver

Environment

Identify XMLWell-Formed XML

R3?agConvert R3 to R2

Depends on available DTDs

and XSDs (Configuration)

Archive

NO

YES YES

Import

NOConverted Data

MDN Returned?

Nack Returned?

NO

NO

Import

Attach R2 XML in DMO



END

Proposal for integration of BFC Converter for TS 6.5.x

The plan is to provide this integration in a TS 6.5 convergence release (6.5.4) initially by end of Q3 2016.


§ 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.

Conclusion

For questions about the approach that is right for your company,please contact you client partner


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