ICH E2B(R3) Guideline of China

ICH E2B(R3) Guideline of China

Stella Xu

05Sep2019

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Disclaimer

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Agenda

• Background, Implementation Plans, Standards

• Electronic Submission of IND Safety Reporting

• Electronic Submission of Post-Marketing Safety Report

• E2B (R3) Challenges in China

Background, Implementation Plans, Standards

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Background

National Medical Products

Administration (NMPA)

Center for Drug Evaluation (CDE)

Center for Drug Re-evaluation (CDR)

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China has joined the International Council for Harmonization (ICH) as its eighth regulatory member in Jun2017Accelerate it’s pace in regulatory reform to follow ICH guidelines:• ICH M4• ICH E2A• ICH E2B• ICH M1• ICH E2D• …

Background

China E2B (R2) Specification has been released in Jul-2018.

ICH E2B (R3) XML formatting could be accepted by CDE currently.

The draft China E2B (R3) Specification has been released, and is currently under reviewing by the industry as well as the Health Authority.

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IND Safety Report

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Original Process Process Starting from 01May2018

Paper NMPA SAE report fax to health authority• Lack of universal tracking system• Inefficiency for review

ICH E2B XML files to CDE• Allows both gateway submission & sponsor’s

portal upload to CDE• Allows for use of data visualization and analytic

tools for review and tracking

• 01May2018-30Apr2019, E2B XML R2 is acceptable

• 01May2019, E2B XML R3 should be submitted to CDE

• To fullfil the E2A expedited reporting, English can be submitted within 7/15 days, and Chinese version should be submitted in additional 15 days.

IND Safety Report

Type of IND Safety Report Reporting Format

Single Cases of Serious, Unexpected ADRs related to sponsor study drug, including from other studies*(Break blind is required before reporting)

Report to CDE via E2B XML

Other observations: an "expected," serious ADR, an increase in the rate of occurrence which is judged to be clinically important. A significant hazard to the patient population, such as lack of efficacy with a medicinal product used in treating life-threatening disease. A major safety finding from a newly completed animal study (such as carcinogenicity).

Report to CDE via Email

Single Cases of Serious, Unexpected ADRs related to active comparator from other MAH

Report to other MAH; Or the medical institution can report to CDR directly

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Safety Reporting for Post-Marketing Products

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Original Process Future Process

Online reporting in ADR Monitoring System Drug Adverse Event Reporting System (DAERS) is being up-versioning to accept E2B XML (R3) reportsFeedback reports received in the system

Drug Adverse Event Reporting System(DAERS)

Preparation Period Phase I Phase II Phase III

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Regulation: Order 81Function: ICSR (old)Cluster reportsForeign reportsPSUR (old)Feedback report (delayed, monthly)

Regulation: Order 81, MAH direct reportFunction:ICSR (new)Cluster reportsPSUR (old)Feedback report (delayed)MAH Product information management

Regulation: Order 81, MAH direct reportFunction:ICSR (E2B)Cluster reportsPSUR (new)MAH annual reportFeedback report (delayed)MAH Product information management

Regulation: MAH direct reportFunction:ICSR (E2B)Cluster reportsPSUR (new)MAH annual reportFeedback report MAH Product information managementRisk management & Decision making SupportMAH PV Assessment

New Function:ICSR (new)Feedback report (new rules)MAH product information collection

New Function:ICSR (E2B)PSUR (new)MAH Annual Report

New Function:Risk ManagementDecision Making SupportMAH PV Assessment

01Jul2022, post-marketing safety reports must be submitted via E2B (R3)

Use

New Function

Jul2018 Dec2019 Dec2020 Jul2022

Electronic Submission of IND Safety Reporting

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Technical Specifications

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Data Element Title Element Values Notes

E.i.9 Identification of the Country Where the Reaction / Event Occurred

Optional fieldThis data element captures the country where the reaction occurred.

Required by CDE in actual case.All cases submitted to CDE via E2B XML R3 should have this field entered.



G.k.3.1 Authorisation / Application Number

If MPID (G.k.2.1.1) is unavailable, This data element captures the Authorisation or Application number of the medicinal product for the country where it was obtained when the case report is sent to that country. Pharmaceutical companies should provide this information at least for their own suspect drug(s).

Configure the Clinical Trial Application (CTA) number in this field for the sponsor’s suspect drug. For Cross-reporting, if there are many CTAs for the same compound under CDE, enter all the CTA numbers here, rank the CTA associated with the SUSAR first.

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H.1 Case Narrative Including Clinical Course, Therapeutic Measures, Outcome and Additional Relevant Information

Required This data element captures a focused, factual and clear description of the case, including the words or short phrases used by the reporter. Each ICSR must include a narrative. This data element should not be confused with Reporter’s or Sender’s comments.

Language: Chinese is required

In order to fulfills the expedited reporting as per E2A, English XML can be submitted in 7/15 days to CDE, and an Chinese version should be submitted in additional 15 days.

Electronic Submission of Post-Marketing Safety Report

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Current Status

• The MAH should follow both ICH E2B R3 Specification (v5.02) and the China ICH

E2B (R3) Specification – 1st Draft for comment published on 29May2019

• 35 data elements with local technical specification

• 11 new data elements by regional requirements

• 2nd Draft for comment published on 23Aug2019

• No data elements with local technical specification required further

• 19 new elements required by regional requirements

• The E2B R3 Specification fit for both IND and post-marketing safety report submission

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C.1.1 Sender’s (case) Safety Report Unique Identifier

country code-company or regulator name-report number

For domestic cases, this should be Country code-Social Credit Code-case number

C.1.8.1 Worldwide Unique Case Identification Number

C.1.10.r Identification Number of the Report Linked to This Report

This data element captures an identifier of another report or case that warrants being evaluated together with this ICSR.

When C.1.CN.1 = regulatory authorityThis field should be filled with CDR-feedback number

C.2.r.1.2 Reporter’s Given Name MSK、ASKU、NASK There is no middle name for Chinese people, the name should be filled here

C.3.3.3C.3.4.1, C.3.4.2,C.3.4.3,C.3.4.6

Sender’s Given NameSender’s Street Address, City, State or Province, Telephone

Required Depending on the local legal requirements regarding confidentiality, it might be necessary to omit some of the elements used to identify the person responsible for sending the report in the transmitted message.

Not required in 2nd Draft comment


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Data Element

Title Element Values Notes

D.2.1 Date of Birth RequirednullFlavor: MSK

Most of the fields are optional in ICH E2B

D.5 Sex RequirednullFlavor: MSK, UNK, ASKU, NASK

E.i.4 Date of Start of Reaction / Event

Required

E.i.6b Duration of Reaction / Event (duration unit)

Required

E.i.7 Outcome of Reaction / Event at the Time of Last Observation

Required

E.i.9 Identification of the Country Where the Reaction / Event Occurred

Required



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Data Element

Title Element Values Notes

G.k.1 Characterisation of Drug Role

Each ICSR must contain at least one ‘Suspect’ 1- Suspect 2-Concomitant

ICH allows 3-interacting 4-drug not administeredFor medication error, capture both suspect products, including the one not administered.

G.k.2.2 Medicinal Product Name as Reported by the Primary Source

Required General name reported by the reporter should be entered here

G.k.3.1 Authorisation / Application Number

Required, nullFlavor = ASKUNDA number for the suspect drug of the MAH should be entered here

Optional by ICH E2B

G.k.3.3 Name of Holder / Applicant

RequiredName of the license holdernullFlavor = unk

Optional by ICH E2B

G.k.4.r.4G.k.4.5.5

Date and Time of Start of Drug/Last Administration

Required when G.k.1=Suspect If specified date of drug stop date is unknow, or not sure if the patient has stopped the medication, the date can be entered as ADR onset date



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G.k.4.r.9.1 Pharmaceutical Dose Form (free text)

RequiredLocal dictionary to be followed

Optional by ICH E2B

G.k.4.r.10.1 Route of Administration (free text)

OptionalLocal dictionary to be followed

G.k.7.r.2aG.k.7.r.2b

MedDRA Version for IndicationIndication (MedDRA code)

RequiredFor unreported indication, find appropriate MedDRA term for coding

Optional by ICH E2B

G.k.9.i.2.r.1 Source of Assessment Required1- primary reporter 2- MAH

Optional by ICH E2B

G.k.9.i.2.r.3 Result of Assessment Required1- certain 2-probable 3-possible 4-unlikely 5-unassessable 6-Conditional/Unclassified

Optional by ICH E2BFree text allowed

G.k.9.i.4 Did Reaction Recur on Re-administration?

Required Optional by ICH E2B



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G.k.11 Additional Information on Drug (free text)

Medical device information should be entered here

As defined by ICH1=Counterfeit, 2=Overdose, 3=Drug taken by the father, 4=Drug taken beyond expiry date 5=Batch and lot tested and found within specifications, 6=Batch and lot tested and found not within specifications, 7=Medication error, 8=Misuse, 9=Abuse 10=Occupational exposure, 11=Off label use

H.5.r Case Summary and Reporter’s Comments in Native Language (repeat as necessary)

Case comment in native language is also required besides English

H.5.r.1aH.5.r.1b

Case Summary and Reporter’s Comments Text/Language


New Elements by Regional Requirements

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C.1.CN.1 Report Source Required

1N

1=Regulatory authority, 2=Patient/friends3=Medical institution, 4=Business License5=Literature (Full literature needed)6=Study (ADR originated from authorization studies)7=Program (ADR originated from marketing programs), 8=Others

C.1.CN.2 Report Type Required 2N

11-Domestic Pre-market report12-Domestic post-market report21-Foreign pre-market report22-Foreign post-market report

C.1.CN.3 MAH Identifier OptionalRequired when C.1.CN.2=12 or 22

C.2.CN.1 Email Address Optional

D.CN.1 National Required at least for national or ethnic

Required and applicable for domestic case

D.CN.2 Ethnic Applicable for foreign case


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D.CN.3 Name of the Medical Institution/Business License Organization

Optional

D.CN.4 Nationality Optional2A

Nationality of the patientUse the country code

D.CN.5 Phone call Optional Phone call of the patient

D.CN.6 Description of Pregnancy details

OptionalFree text

Used in ChineseDescribe past pregnancy details as well as current pregnancy details and outcomeOnly for mother case


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G.k.CN.1 Generic Name Optional Used in ChineseNot required for foreign cases, if the product has not been marketed in China

G.k.CN.2 Relevant medical device

Optional Used in ChineseDescribe the medical device which is possibly related to the adverse reaction

G.k.CN.3 Whether the product is MAH’s suspect product

Required True = yesFalse = no

G.k.CN.4 CTA/NDA number OptionalRequired when C.1.CN.2=11, 12 or 21

For Pre-market report, enter CTA numberFor post-market report, enter NDA number


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G.k.9.i.CN.1 Event Listedness Optional1NRequired for the MAH’s suspect product

1= Listed2= UnlistedShould assess the event listednessbased on approved label in China or CCDS

G.k.9.i.CN.2 De-challenge results

Required1N

This data element indicates both if the patient was rechallenged with the drug and the known outcome. 1-yes2-no3-unk4-N/A

G.k.4.r.CN.1 Expiration Date Optional If the MAH knows the LOT number, this field should be filled with the expiration date


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G.k.9.i.2.r.1.CN.1 Primary report/MAH Source of Assessment

Optional1NRequired for domestic post-market report

1= Primary report2= MAH

G.k.9.i.2.r.1.CN.2 Result of Assessment

Required when G.k.9.i.2.r.1.CN.1 is provided1N

1- certain 2-probable 3-possible 4-unlikely 5-unassessable 6-Conditional/Unclassified

Language Requirement

• For the relevant data fields (free text) which can not be interpreted by standard code, such as medical institution/business organization name, drug brand name, generic name, formulation, route, Marketing Authorisation Holder/Manufacturer Name, medical devices, narrative of the adverse reaction, autopsy results, pregnancy details and case comments, Chinese is required.

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E2B (R3) Challenges in China

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Challenges in China

The changes of E2B (R3) impact the way MAHs capture and report information in Drug Safety databases, meaning MAHs now have to generate/upgrade their processes and technology or use the BFC tool.

For large companies or MNCs with disparate teams working on EV and case processing, cross functional working groups need to be formed to ensure that decisions are made centrally, and efforts aren’t duplicate.

For small companies or local MAHs in China, who don’t have an E2B R3 compliant system, need to start planning for this. It can take between six months to a year for the MAH to move to an R3 compliant system. Or, qualified CROs maybe connected to meet the compliance.

Language is a big challenge for case reporting.

Traditional Chinese Medicine to meet the requirement of IDMP.

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Documents

ICH E2B(R3) Guideline of China