fda and pmda study data submission distinctions

FDA and PMDA Study Data Submission Distinctions

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Contents

1.0. Overview: Purpose of this Document . . . . . . . . . . . . . . . . . . . . . . . 1 1.1. Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2. Problem Statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.3. Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.4. Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2.0. Comparison of FDA and PMDA Study Data Distinctions Chart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

3.0. FDA and PMDA Study Data Distinctions Categories . . . . . . . 3 3.1. Mandates across FDA and PMDA Agencies . . . . . . . . . . . . 3 3.2. Comparison of Similarities and Differences in Study

Data Submissions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.3. Analysis Results Metadata (ARM) . . . . . . . . . . . . . . . . . . . . . 7 3.4. Dataset and Variable Requirement Differences . . . . . . . . 7 3.5. eCTD Folder Usage Differences [2] [14] . . . . . . . . . . . . . . . 8 3.6. Validation Rules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3.7. Reviewer’s Guide (cSDRG/ADRG/BIMO) Differences . . 9 3.8. Formal Meetings during Drug Development Lifecycle . .10 3.8.1. Timelines of Initial/Final Delivery and

Communication across Agencies . . . . . . . . . . . . . . . . . . . . . .10 3.9. Dictionary Comparisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.10. Controlled Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.11. Use of System International (SI) Units Versus

Conventional Units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

4.0. Industry Experiences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 4.1. Case Study: FDA and PMDA Submission Experience

from a Sponsor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 4.2. Questions to Consider when Planning for FDA and

PMDA Submissions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

5.0. Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

6.0. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

7.0. Project Contact Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

8.0. Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

9.0. Disclaimer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

10.0. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14


Version Date Summary

1.0 2020-Dec-15 Initial Version

1.1 2021-Feb-12 Updates in section 3.6

Revision History



1.0. Overview: Purpose of this Document

The requirement to adhere to electronic submission guidance from the United States Food and Drug Administration (FDA) and the Japan Pharmaceuticals and Medical Devices Agency (PMDA) to submit data in a standardised Clinical Data Interchange Standards Consortium (CDISC) format is becoming critically important. The FDA mandate, to submit data using the Study Data Tabulation Model (SDTM) and the Analysis Data Model (ADaM) formats, became effective as of 16 December 2016 for all study starts* after this date. (*Study start is the date of the earliest subject informed consent form.) The mandate for submitting standardised data to the PMDA became effective as of 1 April 2020, regardless of when the study commenced.

In the end-to-end process of drug development, it is essential to be aware of the regulatory requirements to plan, develop and submit the study data submission deliverables.

The focus of this document is to highlight the similarities and differences between the FDA and PMDA recommendations and requirements when submitting standardised CDISC data. Additionally, a case study of a sponsor’s experiences, along with questions to consider when preparing for dual agency submissions, will be shared.

This paper will be updated, as necessary, based on new requirements from regulatory agencies.

1.1. Scope

This paper covers clinical data submitted in CDISC SDTM and ADaM formats to the FDA and PMDA. This paper does not cover CDISC Standard for Exchange of Nonclinical Data (SEND) and other regulatory agencies such as medical devices. We acknowledge requirements coming out of the NMPA (National Medical Products Administration), the China regulatory agency, which will be assessed in a future version of this white paper.

1.4. Acronyms

1.2. Problem Statement

Although both health agencies require electronic study data for submission in CDISC SDTM and ADaM formats, there are underlying differences in the data standards requirements that are to be addressed prior to submission. At present, it would be very difficult to submit the identical electronic submission data package to both agencies.

1.3. Objective

This paper addresses the recommendations and requirements of study data submission between the FDA and the PMDA covering mandates, data standards catalogs, data packages, dictionaries, validation rules, regulatory meetings and timelines. Additionally, a case study and questions to help sponsors plan for submitting to both agencies based on industry experiences are included.

Doc ID: WP-047 Version: 1.1 Working Group: Optimizing the Use of Data Standards Date: 12-Feb-2021

Term Description

acrf Annotated Case Report Form

ADaM Analysis Data Model

ADRG/adrg ADaM Data Reviewer’s Guide

ANDA Abbreviated New Drug Application

ARM Analysis Results Metadata

ASCII American Standard Code for Information Interchange

BE Bioequivalence

BIMO Bioresearch Monitoring

BLA Biologics License Application

BMV Bioanalytical Method Validation

CDISC Clinical Data Interchange Standards Consortium

CBER Center for Biologics Evaluation and Research

CDER Center for Drug Evaluation and Research

CFSAN Center for Food Safety and Applied Nutrition

CRF Case Report Form

cSDRG/csdrg Clinical Study Data Reviewer’s Guide

CSR Clinical Study Report

CSV Comma-separated Values file

CT Controlled Terminology

DUNS Data Universal Numbering System

eCRF Electronic Case Record Form

eCTD Electronic Common Technical Document

eData Electronic Data

ELD Evaluation and Licensing Division

EOP End of Phase

e-study Electronic study

eSub Electronic Submission

FAQ Frequently Asked Questions

FDA Food and Drug Administration

GB Gigabytes

HIV Human Immunodeficiency Virus

ICH International Council for Harmonization

IG Implementation Guide

IND Investigational New Drug

ISE Integrated Summary of Efficacy

ISS Integrated Summary of Safety

LAB or LB Laboratory

LOINC Logical Observation Identifiers Names and Codes

MedDRA Medical Dictionary for Regulatory Activities

MED-RT Medication Reference Terminology

NDA New Drug Application

NDF-RT National Drug File Reference Terminology

NMPA National Medical Products Administration

OSI Office of Scientific Investigations

P1 Phase I

P2 Phase II

P21E Pinnacle 21 Enterprise

pdf Portable Document Format

PDUFA Prescription Drug User Fee Act

.phxproj Phoenix Project file format

PMDA Pharmaceuticals and Medical Devices Agency

PMSB Pharmaceutical and Medical Safety Bureau

.pwo WinNonlin Workbook Object



Term Description

Q&A Questions and Answers

SAS Statistical Analysis Software

sBLA Supplemental Biologic License Application

SDSP Study Data Standardization Plan

SDTM Study Data Tabulation Model

SDTMIG Study Data Tabulation Model Implementation Guide

SEND Standard for the Exchange of Nonclinical Data

SI Standardized International

SNOMED CT Systematized Nomenclature of Medicine Clinical Terms

sNDA Supplemental New Drug Application

TAUG Therapeutic Area User Guide

TCG Technical Conformance Guide

txt text

UNII Unique Ingredient Identifiers

V version

WHO World Health Organization

WHODrug WHO Drug Dictionary

XLS Excel Spreadsheet

XLSX Excel Spreadsheet (a newer file format referred to as Open XML)

XML Extensible Markup Language

XPT SAS Transport 5 File Format

XSL Extensible Stylesheet Language

2.0. Comparison of FDA and PMDA Study Data Distinctions Chart

The diagram below shows the comparison of documents, standards and tools between both agencies.

** See the References section for respective agencies’ recommendations and requirements.

FDA** PMDA**

MandatesFDA Data Standard Catalog

SDSP, Waiver, TAUGs, CRF, BIMO(CDER) TCG

CDISC SDTM, ADaM and TAUGS

acrf, xpt, Define-XML, csdrg

xpt, Define-XML, adrg, programs, ARM (optional)

listings, clinsite.xpt, define.xml

P21 E v4.1.1

FDA Validation and Business Rules

MedDRA, WHODrug Global,LOINC, UNII, SNOMED, MED-RT, CDISC CT

Type A, B and C

PMDA Data Standard Catalog

Form A (Attachment 8) & B (Attachment 8-2), CRF

CDISC SDTM and ADaM, TAUGS (optional)

acrf, xpt, Define-XML, sdrg

xpt, Define-XML, adrg, programs ARM (strongly recommended)

Not Applicable

P21 E v4.0.2

PMDA Study Data Validation Rules

MedDRA, WHODrug Global,CDISC CT

Clinical Trial and eData Consultation

Analysis

Planning

BIMO (CDER)

Study Data Standards

P21

Dictionaries/CT

Tabulation

Validation Rules

Meetings



3.0. FDA and PMDA Study Data Distinctions Categories

The distinctions are classified into the following categories for ease of comparing standards, data packages, dictionaries, rules and requirements between the FDA and PMDA.

• Mandates across FDA and PMDA Agencies• Comparison of Similarities and Differences in Study Data

Submissions• Analysis Results Metadata (ARM)• Dataset and Variable Requirement Differences • Electronic Common Technical Document (eCTD) Folder Usage

Differences• Validation Rules• Reviewer’s Guide (cSDRG/ADRG/BIMO) Differences • Formal Meetings during Drug Development Lifecycle • Dictionaries Comparison• Controlled Terminology (CT)• Use of System International (SI) Units versus Conventional

Units

3.1. Mandates across FDA and PMDA Agencies

FDA PMDA

Mandates across Agencies

References: [3] [12] References: [13] [19]

• New Drug Application (NDA) Abbreviated New Drug Application (ANDA) Biologics License Application (BLA)

• Investigational New Drug (IND) Application

17-December-2016

17-December-2017

NDA 01-April-2020

• Studies starting on or after 17-December-2016 are to adhere to CDISC format for NDAs, ANDAs and certain BLAs and subsequent submissions to these types of applications.

• Studies starting on or after 17-December-2017 are to adhere to CDISC format for certain INDs.

• All electronic submissions are to be compliant to FDA ‘Data Standard Catalog’ requirements.

• Waivers are possible for studies that started before 17-December-2016.

• Irrespective of study start date, study data is to adhere to the CDISC format as of 01-April-2020. Refer to the PMDA Data Standard Catalog for the supported CDISC Standards and Terminology Standards.

• Waivers/Exemptions are allowed under certain conditions based on the PMDA guidance updated on 18-Mar-2020. Waivers/Exemptions include:

A. Studies in orphan drug designation that started before 01-April-2020. (See Ref 19–Q10.)

B. Anti-HIV drugs which are eligible for prior assessment based on the Pharmaceutical and Medical Safety Bureau (PMSB)/Evaluation and Licensing Division (ELD) Notification No. 1015 (dated 12-November-1998), and the data in legacy format. (See Ref 19–Q11.)

C. Studies in “public knowledge-based applications”. (See Ref 19–Q2.)

D. Old studies that are considered extremely difficult to convert to CDISC format (e.g. studies which have no electronic legacy data). (See Ref 19–Q2.)

• Waiver/Exemption means that the PMDA allows sponsors based on a condition:

1) Not to submit electronic e-study data itself; 2) To submit e-study data in legacy format.

• Sponsors need to consult with the PMDA for requesting a waiver/exemption.



Data Standards Catalog

References: [3] References: [15]

• The FDA Data Standards Catalog is scheduled for six-month interval updates.

• The PMDA Data Standards Catalog last update was on 01-November-2019.

• The ‘Date Requirement Begins’ and ‘Date Requirements Ends’ do not exist for both Exchange and Terminology Standards.

• Does not have information regarding Logical Observation Identifiers Names and Codes (LOINC), Unique Ingredient Identifiers (UNII) and SNOMED CT.

• Basically, the PMDA does not accept the version which is not listed in the Data Standards Catalog. In case the sponsor considers there is no essential difference between the version sponsor used and the version listed in the Data Standards Catalog, the sponsor can consult the PMDA in a ‘Consultation on preparation’ meeting for using the version not listed.

FDA PMDA

Study Data Planning

References: [2] [9] [25] References: [14] [18] [21] [22]

Study Data Standardization Plan (SDSP) • Form A (Attachment 8): ‘Consultation on Data Format of Submission of Electronic Study Data’ and ‘Consultation on Preparation of Submission of Electronic Study Data’

• Form B (Attachment 8-2): ‘Consultation on Exemption of Submission of Electronic Study Data’

• The latest version is in Japanese, released in March 2020. Expecting the English version later in 2020.

The SDSP is a living document expected to be updated and submitted throughout development. It is recommended to initiate and submit at pre-IND but no later than the end of Phase 2. For CBER submission, include the CBER appendix within the SDSP.

Form A and/or B is a living document expected to be submitted prior to the eData Consultation meetings as a preliminary meeting document. The finalised document is required for the ‘Pre-NDA meeting’. This meeting is planned 1–3 months prior to the submitted application.

Therapeutic Area User Guides (TAUGs)


TAUGs are expected to be followed if they are listed in the FDA TCG (Technical Conformance Guide – section 5.2 Supported Therapeutic Areas). TA standards that have been approved by the FDA are considered part of the CDISC foundational standards. Refer to ‘Technical Guides’ – ‘Therapeutic Area Information and Specifications’ for additional information on the study data submissions to CDER and CBER (e.g. Next Generations Sequencing, QT Studies, BMV, HIV, Vaccines and Comparative Clinical Endpoint BE Studies).

All Therapeutic Area standards that have been published by CDISC may be used for submission and must be referenced in the Define-XML and the data guide.

Individual CRFs

Individual eCRFs of subjects for four standard AE categories of interest are required for a submission (death, discontinuation from AE, discontinuation due to any other reason and serious AE). Additional AE categories may exist depending on protocol specific details (i.e. AEs of Interest).

Not Applicable

Individual eCRFs are not part of a dataset folder but part of m5 eCTD CSR.

Not Applicable

TabulationsReferences: [2] References: [14]

SDTM Annotated blank CRF (acrf.pdf) Identical Requirement

Tabulations SAS transport files (.xpt) version 5.0 Identical Requirement

Clinical Study Data Reviewer’s Guide with Legacy Data Conversion Plan, if applicable (csdrg.pdf)

Study Data Reviewer’s Guide is acceptable as study-data-reviewers-guide.pdf or csdrg.pdf. See section 3.7 for further info.

• Define-XML v1.0 and define.pdf prior to 15- March-2018• Define-XML v2.0 on or after 15 March 2018 • define.pdf is not required with v2.0 but recommend checking with

the reviewer if define.pdf is needed.

Both Define-XML v1.0 and v2.0 are permissible. The define.pdf is not necessary.

Supplement Data Definition (optional) is provided for describing the complex computation algorithm. It is not recommended to describe the complex and lengthy derivation in the Define-XML due to the style limitation of Define-XML (e.g. carriage return in Define-XML does not render making text longer than 5 lines difficult to read).

Identical Requirement

3.2. Comparison of Similarities and Differences in Study Data Submissions



Analysis


ADaM datasets are to use transport format (.xpt) version 5.0 and prefix ‘ad’ for the dataset name (example: adxxxx.xpt).


The Analysis Data Reviewer’s Guide is to be saved as adrg.pdf. The Analysis Data Reviewer’s Guide is acceptable as analysis-data-reviewers-guide.pdf or adrg.pdf. See section 3.7.

• Use Define-XML v1.0 and define.pdf prior to 15 March 2018.• Use Define-XML v2.0 on or after 15 March 2018. • define.pdf is not required with v2.0 but recommend checking with

the reviewer if define.pdf is needed.

Both Define-XML v1.0 and v2.0 are permissible. The define.pdf is not necessary.

ADaM datasets should be submitted for efficacy and safety analysis. ADaM datasets should be submitted for analyses performed to obtain important results on efficacy and safety and clinical study results that provide the rationales for setting of the dosage and administration, such as

• primary/secondary efficacy analysis• primary safety analysis• basic analyses of adverse events• analyses to investigate the effect of major factors on efficacy and

safety

Provide the software programs and macros used to create all ADaM datasets, tables and figures associated with primary and secondary efficacy analyses.

• Submit programs in ASCII text format.

For the label: If applicable, submit data and programs for any additional analysis to support the Prescribing Information.

Provide the software programs used to create ADaM datasets and programs used for analyses shown in the above row.

• The file name should include the extension of the analysis software used (i.e. .sas). If the file name does not contain an extension, an explanation about the file format should be included in the ADRG.

• If submission of the macro program is difficult or submission of the program itself is difficult, then the submission of specifications that show the analysis algorithm would be sufficient.

• Based on sponsors’ experience, programs in txt format has been allowed with consultation of the PMDA beforehand.

Analysis-Results-Metadata (optional – refer to section 3.3) Analysis-Results-Metadata is strongly recommended (as part of Define-XML v2.0 or as a separate PDF file). See details in section 3.3.

Integrated Summary Safety (ISS)/Integrated Summary Efficacy (ISE)

References: [2] [3] References: [18] [20] [21]

Use Define-XML v2.0; define.pdf is not required with v2.0 but recommend checking with the reviewer if define.pdf is needed.

Either version of the Define-XML (v1.0 or v2.0) are acceptable. The define.pdf is not necessary.

Submit additional ADaM datasets needed to support the Integrated Analysis. Use transport format (.xpt) version 5.0 and prefix ‘ad’ for the dataset name (example: adxxxx.xpt).

Submit additional ADaM datasets needed to support the Integrated Analysis. Use transport format (.xpt) version 5.0 and prefix ‘ad’ for the dataset name (example: adxxxx.xpt).

If additional SDTM datasets are used to support the Integrated Analysis, those SDTM datasets can be acceptable instead of ADaM datasets.

Provide the software programs and macros used to create any additional ADaM datasets, tables and figures to support the ISS/ISE programs in ASCII text format.

Provide the software programs used to create ADaM datasets and analysis outputs.

• The file name should include the extension of the analysis software used (i.e. .sas). If the file name does not contain an extension, an explanation about the file format should be included in the ADRG.

• Based on sponsors’ experience, programs in txt format has been allowed.

Create an Analysis Data Reviewer’s Guide to support the ISS/ISE (adrg.pdf).

Create an Analysis Data Reviewer’s Guide to support the ISS/ISE (‘analysis-data-reviewers-guide.pdf’ or adrg.pdf).

Analysis-Results-Metadata (optional, refer to section 3.3) Analysis-Results-Metadata (as part of Define-XML v2.0 or as a separate PDF file if needed). For details, see section 3.3.

An e-submission of ISS/ISE information will be requested when integrated analyses of multiple clinical studies were performed for the assessment of specific efficacy or safety, and for clinical results that provide additional rationale for setting the dosage and administration of the product. The assessment of what should be included in the eSub must occur at the ‘clinical trial consultation’ meeting, not at the ‘consultation on data format of submission of electronic study data’. The ISS/ISE may still be needed, even if there is no Japanese population included.



Office of Scientific Investigations (OSI)/BIMO

References: [6] [7] [27]

Only for CDER Submission (NDA/BLA/sNDA/sBLA, as regulated by CDER)

Not Applicable

Table listing of Clinical Study-level Information Not Applicable

Subject-level Line Listings by clinical site. If the size of the PDF file exceeds 500 megabytes, it should be split into smaller components.

Not Applicable

Dataset: clinsite.xpt and Define-XML Not Applicable

Reviewer’s Guide: bimo-rev-guide.pdf Not Applicable

ICH Listings

The FDA does not specifically mention ICH listings. Some sponsors do include the ICH listings in the eSub package.


Software Programs


File names should only contain letters, numbers or hyphens, and no underscores or spaces.

File names should only contain letters, numbers, hyphens or underscores, and no spaces.

All file names should be in lower case. Identical Requirement

Does not require any specific software for statistical analyses. Sponsor should consult with regulatory agencies to confirm the choice of software and document this in the Analysis Data Reviewer’s Guide.

Does not require any specific software for statistical analyses. Sponsor to document what was used in both Form A and the Analysis Data Reviewer’s Guide.

Does not expect sponsor to submit executable programs, unless specifically requested by the agency.

Does not expect sponsor to submit executable programs.

No specific requirements for submitting standard company macros. Helpful in submitting analysis macros.

Prefers that macros be submitted when macros are used in programs submitted.

If it is difficult to submit macros, specifications that describe algorithms can be documented.

File Types Accepted


CSV, XLS, XLSX for non-patient data CSV, XLS, XLSX acceptable (no specific rule defined in regulatory documents)

PDF Identical Requirement

XPT Identical Requirement

XML, XSL Identical Requirement

Programs in txt (ASCII) Programs in .sas or software extension• The following files can be submitted in the ‘cp’ folder, which stores

clinical pharmacology data in formats other than the CDISC standard, in the eCTD backbone structure.

• ASCII Format Data Files• Phoenix Projects (*.phxproj)• WinNonlin Files (*.pmo, *.pwo)

Regulatory Documents

Study Data Standards Resources [28] New Drug Review with Electronic Data [29]

Providing Regulatory SubmissionsIn Electronic Format — Standardized Study Data [1]

Basic Principles on Electronic Submission of Study Data for New Drug Applications [13]

Study Data Technical Conformance Guide [2] Technical Conformance Guide on Electronic Study Data Submissions [14]

FDA Data Standards Catalog [3] PMDA Data Standards Catalog [15]

Business Rules [4] No Business Rules

Validator Rules [4] Study Data Validation Rules [16]

FDA Technical Rejection Criteria for Study Data [5] Study Data Validation Rules [16]

Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions [6]

Not Applicable

Bioresearch Monitoring Technical Conformance Guide [7] Not Applicable

Not Applicable Notification on Practical Operations of Electronic Study Data Submissions [18]

Not Applicable Question and Answer Guide Regarding “Basic Principles on Electronic Submission of Study Data for New Drug Applications” [19]

Not Applicable Question and Answer Guide Regarding “Notification on Practical Operations of Electronic Study Data Submissions” [20]

Not Applicable FAQs on Electronic Study Data Submission (Excerpt) [21]

Portable Document Format (PDF) Spécifications [11] Electronic Common Technical Document Specification [26]



3.3. Analysis Results Metadata (ARM)

Analysis Results Metadata is an optional ADaM metadata component according to the ADaM version 2.1 document. [23]

The FDA does not specifically mention the ARM requirement in the regulatory documents listed above. However, some reviewers find it useful for identifying the critical analyses, providing links between results, datasets, and documenting the analyses performed. The same guidance of the PMDA ARM recommendations can be adopted for developing ARM for an FDA submission.

The PMDA Technical Conformance Guide [14] clearly states the recommendation of ARM. At industry conferences, PMDA representatives have strongly recommended submitting ARM.

According to guidance, corresponding analyses covered by ARM will be:

• primary and secondary efficacy analysis • primary safety analyses and basic analysis for adverse events • analyses to investigate the effect of major factors on efficacy

and safety.

The Analysis Results Metadata of each analysis should include the following items:

• Figure or table numbers and titles showing the analysis results displayed in the clinical study report

• Purpose and reasons for performing the analysis • Parameter name and code used• Variables subject to analysis• Dataset to be used • Selection criteria for the records subject to analysis • Corresponding description in the statistical analysis plan,

analysis program name, and summary of the analytical methods • Extract of the analysis program corresponding to the analysis

method

Although the ARM is generally included as a part of Define-XML version 2.0 for ADaM, the FDA and PMDA allow sponsors to submit ARM in PDF format.

3.4. Dataset and Variable Requirement Differences

FDA PMDA


Datasets must be submitted using the SAS Transport Files v5 format. Identical Requirement

Dataset names (maximum 8 characters) should only contain lowercase letters, numbers and must start with a letter.


No other symbols or special characters should be included in variable and dataset names.

Special characters can only use low line ‘_’

For legacy studies on/before 17 December 2016 it is permissible to use the underscore character ‘_’ in variable names and dataset names.

Special characters can only use low line ‘_’

Variable names (maximum 8 characters) should only contain uppercase letters, numbers and must start with a letter.


Variable names require use of ASCII text codes Variable names require use of ASCII alphanumeric text codes

The allotted length for each variable containing text in SDTM datasets is to be set to the maximum length needed by that variable.

The allotted length for each variable containing text in SDTM datasets is to be set to the maximum length needed by that variable due to the PMDA validation rule.



Variable length (maximum 200 characters), variable labels (maximum 40 characters) and dataset labels (maximum 40 characters) can include ASCII text codes and punctuation characters but avoid:

• unbalanced apostrophe• unbalanced single and double quotation marks • unbalanced parentheses, braces or brackets ‘(‘ ‘{‘ and ‘[‘ • ‘<’ less than sign and ‘>’ greater than sign.

• Identical Requirement

Dataset > 5GB must be split and both the split and the non-split versions of the datasets must be submitted. Non-split dataset remains in the main dataset folder and split dataset goes to the sub folder (/split) within the main folder.

Consult the PMDA beforehand if the size of a dataset file is greater or equal to 5GB.

Not Applicable If variables were collected in Japanese text, then refer to PMDA TCG section 4.1.5 ‘Handling of data written in Japanese text’ for the guidance.

Technical Conformance Guides

Screen failures, when provided, should be included as a record in DM with the ARM, ARMCD, ACTARM and ACTARMCD fields left blank. This convention is inconsistent with the SDTMIG v3.2 and earlier versions.

No such specific requirements for PMDA. However, PMDA validation rules have a note for this inconsistent (violation): Violation of SD0002 (required variables cannot be NULL for any records) will be considered part of Rejection Criteria, except for the following variables in DM domain that will be considered Errors. -ARMCD, ARM, ACTARMCD, and ACTARM.

For subjects who are randomised in a treatment group but not treated, the planned arm variables (ARM and ARMCD) should be populated, but actual treatment arm variables (ACTARM and ACTARMCD) should be left blank per TCG v4.2. This convention is inconsistent with the SDTM IG.

No such specific recommendation. Refer to the above information from the PMDA validation rules.

3.5. eCTD Folder Usage Differences [2] [14]

Refer to the FDA Study Data TCG and PMDA TCG for eCTD backbone structure and descriptions.

Summary of the differences between the FDA and the PMDA eCTD folder structures are the following:

• The FDA contains ‘split’ subfolders under each folder containing datasets to store cut datasets for files >5 GB.

• The FDA contains a ‘profile’ sub-folder to store patient profiles. • The PMDA eCTD backbone contains ‘sdtm_j’ and ‘adam_j’ sub-

folders to store Japanese language datasets. • The PMDA contains a ‘cp’ subfolder to store clinical

pharmacology files in formats other than the CDISC standard.

3.6. Validation Rules

FDA PMDA

References: [4] [5] References: [16] [17]

Four rejection rules based on FDA Technical Rejection Criteria. (Refer to section 2.6.1 FDA Technical Rejection Criteria.)

Based on PMDA new validation rules v2.0:

• 9 SDTM Rejects • 13 ADaM Rejects • 14 Define-XML Rejects

P21Tool

The FDA accepts P21 latest version with latest validation engine. Current validation engine is 1907.2.

• The PMDA uses P21 Enterprise v4.0.2, which has two validation engines: 1511.6 for validation rules v1.0 and 1810.3 for validation rules v2.0. Validation rules v1.0 support ends on 31-March-2021.

• Validation rules v2.0 support begins 01-April-2020 and will be required after 01-April-2021.

• The PMDA accepts P21 community version with the validation engines: 1511.6 for validation rules v1.0 and 1810.3 for validation rules v2.0.

P21 validator checks against CDISC standards (validation rules), which also covers FDA Business rules. However, some of these rules are based on conditional factors. (Refer to SDTM IG Conformance Rules document and associated Excel file columns ‘M’ and ‘N’.) [24]

P21 validator checks against CDISC standards (validation rules), which also covers PMDA validation rules.



• Two validations should be performed: Define-XML alone and datasets with Define-XML.

• When validating ADaM packages, SDTM datasets DM, AE and EX are to be included in the validation as there are some ADaM validation checks verifying SDTM vs ADaM contents, e.g. an USUBJID in ADSL should also be present in SDTM.DM. This is supporting traceability between SDTM and ADaM.


REJECT

• Rejects are reported as Errors in the P21 tool.• The technical rejection criteria should be met before submission

(not yet turned on).

• Rejects will cause the review to be suspended until corrections have been made.

• All rejects must be resolved before submission.

ERROR

• Errors that CAN be fixed SHOULD be fixed.• Errors that cannot be fixed should be documented and explained in

the Data Reviewer’s Guide with a clear rationale.

• Errors that CAN be fixed SHOULD be fixed.• Errors that cannot be fixed should be documented and explained in

both the Data Reviewer’s Guide and Form A with a clear rationale. In addition, it is required to explain them at the ‘Consultation on Data Format’ meeting before the NDA.

• Errors without any prior explanation will cause the review to be suspended until corrections or explanations have been made.

WARNING

• Warnings that CAN be fixed SHOULD be fixed.• Warnings that cannot be fixed should be documented and explained

in the Data Reviewer’s Guide with a clear rationale..

• Warnings that CAN be fixed SHOULD be fixed.• Warnings that cannot be fixed should be documented and explained

in both the Data Reviewer’s Guide and Form A with a clear rationale.

Refer to FDA Technical Rejection Criteria [5] and PMDA validation rules [16] for corresponding agency rejection details.

3.7. Reviewer’s Guide (cSDRG/ADRG/BIMO) Differences

The name of the reviewer’s guide, study-data-reviewers-guide.pdf or csdrg.pdf and analysis-data-reviewers-guide.pdf for adrg.pdf, is not mandatory per PMDA guidance. These file names are acceptable, and the PMDA recommends that the sponsor should give a file name that clearly defines the contents of the file, as per their technical conformance guide.

A summary of conformance issues has to be described differently because of differences in validation levels between the PMDA and the FDA. Even though both agencies’ checks are implemented by Pinnacle 21 or other validation check software, the severity of issues are different. The PMDA categorises validation severity as Reject, Error and Warning to SDTM, ADaM and Define-XML, whereas the FDA defines only Error and Warning categories. Refer to the section of Validation Rules for severity comparison.

PMDA FAQ 4–8 [21] states that the use of standard international (SI) units is required for all variables and parameters of test results to be stored in the Findings class domain of the SDTM dataset, as long as SI units are applicable. The PMDA requested a SI unit conversion table to be added to the cSDRG Appendix or dataset definition document. For details regarding the handling of SI units, see PMDA FAQ 4–8 starting on page 12.

Per FDA CDER BIMO industry guidance and technical conformance guide, additional information supporting study-level information, subject-level line listings and clinsite dataset can be provided in the BIMO Reviewer’s Guide. BIMO is not applicable to PMDA submission.



FDA PMDA


There are four different types of formal meetings: Type A, Type B, Type B (end of phase (EOP)), and Type C.

There are 2 different types of formal meetings:

• Clinical trial consultation (e.g. Pre‐P1, Pre-P2, End of Phase 2)• eData consultation meetings (i.e. Consultation on preparation,

Consultation on data format and Consultation on exemption)

• Technical questions as part of Type C meeting.• Could also be part of Type B and Type B (EOP) meetings

(e.g. Pre‐IND, End of Phase 2, Pre‐NDA/Pre‐BLA meeting).

Clinical trial consultation:

Sponsor needs to consult which study data/analysis will be submitted as part of the clinical trial consultation meeting. (Sponsors cannot consult this at eData consultation meetings.)

Three types of eData consultation meetings:• Consultation on exemption of submission of electronic study data• Consultation on preparation of submission of electronic study data

for methods of storing data and/or submission• Consultation on data format of submission of electronic study data

for validation results

Data consultation meetings can be requested multiple times at any time during the drug development.

Pre-NDA meeting: • Consultation on final confirmation of the contents of materials

attached to approval application and scheduled submission date by the PMDA. Form A (Attachment 8) should be submitted prior to the Pre-NDA meeting.

• Please refer to the FAQ 1–5 for the details on consultation meetings at “FAQs on Electronic Study Data Submission (Apr 2019)” document.

3.8. Formal Meetings during Drug Development Lifecycle

3.8.1. Timelines of Initial/Final Delivery and Communication across Agencies

As part of the filing activities (pre- and post-submissions), there are many meeting types with the FDA. [10] From a data delivery perspective, you can submit your dataset packages to the FDA at the time of the planned submission date together with the rest of the filing dossier. The format of the dataset package (i.e. legacy or CDISC format) is based on when the study commenced (first informed consent date) compared to the CDISC mandate (17-December-2016). CDISC submissions to the FDA require all documentation of CDISC SDTM and ADaM standards and related validation issues (errors and rejects) to the respective reviewer’s guides (cSDRG & ADRG). There are no requirements to submit data to the FDA prior to the planned filing date.

The requirement is different when submitting to the PMDA with CDISC packages. The timelines for the delivery of electronic data to the PMDA is earlier than for the rest of the dossier. Before data is delivered, there is a requirement to have a consultation meeting regarding the eData submission. This consultation meeting has to be requested via a Form A. The consultation meeting will take place approximately two months prior to the planned filing date. The objective of the consultation meeting is for the sponsor to go through the submission format of the data and explain any non-conformant SDTM or ADaM data standards errors. All validation rules that showed an ‘Error’ will need to be explained. There should not be any ‘Reject’ findings based on the validation rules. If there are ‘Reject’ findings, the PMDA will NOT accept the data. This is not negotiable. After a successful consultation meeting, the sponsor

can continue to proceed as planned with the submission of the eData, as per the agreed filing timelines.

Important aspects include the following:

• Implement SDTM and ADaM standards early and ensure conformance checking is performed early and on an ongoing basis.

• Plan a test submission if appropriate. • Resolve issues and ensure there are no Reject validation

outcomes.• ‘Reject’ validation rule outcomes MUST be fixed.• Any legacy study that is used for the filing will need to be

converted into CDISC standards, unless a waiver has been granted. Plan for sufficient time to do the conversion.

• Have a completed CDISC eSub dataset package ready at least two months prior to the planned filing date.

• Plan early!



Dictionary FDA PMDA Comments

References: [3] References: [15] [21]

MedDRA

Medical Dictionary for Regulatory Activities

Must use current version of MedDRA for SDTM AE and MH domains for study starts by 15-March-2019 and for certain INDs by 15-March-2020, otherwise version 8.0 or earlier is acceptable.

Version 8.0 or later (multiple versions accepted). Support began 01-October-2016.

Event Problem Codes

(Used by the CDRH: the Center for Devices and Radiological Health)

The latest version is to be used. No requirement for Event Problem Codes.

WHODrug Global

World Health Organization Drug Dictionary

B3 format will be required for all studies that start on 15-March-2019, otherwise B2 format is acceptable.

Data support for WHO Drug Dictionary. Enhanced version 2008:4 (01-December-2008 or later) begins 01-October-2016. Use of WHO Drug Dictionary is required; if there is no WHO DD code available, then sponsor-defined codes are acceptable but must be documented in the Data Reviewer’s Guide.

There is no public documentation for PMDA endorsement of B3 format but is known to be acceptable. Discuss topic with the PMDA.

LOINC

Logical Observation Identifiers Names and Codes

The latest version is to be used for the SDTM Lab domain. Required by 15-March-2020 and 15-March-2021 for certain INDs.

No requirement for LOINC LB codes.

UNII

Unique Ingredient Identifiers

Must use latest version for study starts 17-December-2016 or 17-December 17-2017 for certain INDs.

For parameters using UNII, MED-RT, DUNS, or SNOMED CT, it is acceptable to store only code values available to the applicant.FDA Substance Registration System [Q4–6 in FAQs on ‘Electronic Study Data Submission’ document].

UNII is used in the SDTM.TS domain and SDTM.CM.CMDECOD. Used by CDER, CBER and CFSAN (Center for Food Safety and Applied Nutrition).

It is important to include the date of the dictionary in the SDTM TS domain.

MED-RT

Medication Reference Terminology

(Prior name of MED-RT was NDF-RT. Change became effective on 5-March-2018.)

Must use latest version for study starts 17-December-2016 and 17-December-2017 for certain INDs.

For parameters using UNII, MED-RT, DUNS, or SNOMED CT, it is acceptable to store only code values available to the applicant.

FDA Substance Registration System [Q4–6 in FAQs on ‘Electronic Study Data Submission’ document].

MED-RT is used in the SDTM TS domain and CM.CMDECOD. Used by CDER, CBER and CFSAN.


SNOMED CT

Systematized Nomenclature of Medicine – Clinical Terms

As applicable to study starts 17-December- 2016 or 17-December-2017 for certain INDs.

For parameters using UNII, MED-RT, DUNS, or SNOMED CT, it is acceptable to store only code values available to the applicant.FDA Substance Registration System [Q4-6 in FAQs on ‘Electronic Study Data Submission’ document].

SNOMED CT is used in the SDTM TS domain to report ‘Trial Indication’ (INDIC) and Diagnosis Group (TDIGRP). Used by CDER, CBER and CFSAN.


3.9. Dictionary Comparisons

FDA PMDA


All versions; requirement began 17-December-2016 (for NDAs, aNDAs) and 17-December-2017 (for certain INDs).

• Use versions 10-June-2011 or later. • Consult the PMDA (Consultation on preparation of submission of

electronic study data) if sponsor needs to use the versions between 17-February-2009 (inclusive) and 10-June-2011 (exclusive).

3.10. Controlled Terminology



FDA PMDA


Discuss the need for SI units with the Review Division as the FDA uses conventional units.

SI units are required for all standard unit variables and test results that are stored in the SDTM Findings domain (e.g. Lab and Vital Signs datasets). However, data using “mmHg” as a conventional unit (e.g. blood pressure) can be retained in SDTM without converting to SI units.

3.11. Use of System International (SI) Units Versus Conventional Units

4.0. Industry Experiences

This section contains two parts:

• A Case Study of FDA and PMDA Submission Experiences from a Sponsor

• Questions to Consider when Planning for FDA and PMDA Submissions

4.1. Case Study: FDA and PMDA Submission Experience from a Sponsor

Project Description: Sponsor prepared a submission that contained 2 studies. The sponsor submitted the same data submission package to the FDA and PMDA.

Sponsor Experience:

• The sponsor followed the conformance validation rules applied to all SDTM and ADaM. Conformance issues found were explained in the cSDRG. The packages for both studies were accepted by the FDA.

• The same submission package was delivered to the PMDA. One study that only contained “ERROR” issues was accepted, with the “ERROR” issues being properly explained in the cSDRG; however, the second study was rejected because it contained “REJECT” issues.

Lessons Learned:

Although both agencies have adopted CDISC standards, the regulatory validation rules, including severity categories, are different. What is acceptable to the FDA may not be acceptable to the PMDA. Therefore, it is essential to execute validation checks using both FDA and PMDA validation rules; resolve “REJECT” issues; and share the “ERROR” issues with the PMDA at the data consultation meeting ahead of the submission.

4.2. Questions to Consider when Planning for FDA and PMDA Submissions

Can we create a single study data package and submit it to both the FDA and PMDA?

This limits the sponsor’s ability to create a single study data package that satisfies both the FDA and PMDA. The differences include:

• Requirement to implement a version of standards from their respective Data Standards Catalog

• Severity of the validation rules • File naming conventions

5.0. Recommendations

• Plan early for planning, developing and submitting standardised study data.

• Implement SDTM and ADaM standards early. • Convert any legacy study that is used for the filing into CDISC

standards. • If a waiver is going to be requested, do this early. • Ensure checks are performed early and on an ongoing basis

against the CDISC and agencies’ conformance rules.• Resolve issues and ensure there are no Reject validation

outcomes early on and on an ongoing basis.• Complete the eSub data package earlier than the planned filing

date.

• Analysis Results Metadata (ARM) (strongly recommended by the PMDA)

• Potential update to the cSDRG and ADRG due to the PMDA officer’s recommendations

• TS domain had to be adapted. According to the answer to Q4–6 [21] (page 10) it states: ‘For parameters using UNII, NDF-RT, DUNS, or SNOMED CT, it is acceptable to store only code values available to the applicant.’

What do you recommend if a study is submitted to both the FDA and PMDA?

• Adopt the latest CDISC model and IG of SDTM, ADaM, and controlled terminologies supported by both agencies, as per their respective Data Standards Catalog.

• Ensure checks are performed against the CDISC conformance rules and regulatory authorities’ business and validation rules.

• Resolve rejection issues and address (resolve or justify) remaining issues.

• Open a dialog with the authorities as early as possible. • Use the ARM to facilitate the review of key analyses.

What if I do not know if we are submitting to the PMDA?

The implications could be severe and could require significant re-work. Plan ahead and be prepared. Regardless of which regulatory authority you are dealing with, sponsors should run compliance checks against CDISC conformance rules and the agency’s validation rules to ensure there are no ‘REJECT’ issues.



6.0. Conclusion

Although agencies require CDISC standards and have similar guidelines, there are differences in the validation rules, other requirements and documentations, which limits the ability for a sponsor to create one package that satisfies both the FDA and PMDA requirements.

7.0. Project Contact Information

Kiran K. KundarapuMerck & Co., Inc. 351 N. Sumneytown PikeNorth Wales, PA [email protected]

Nancy BauerBoehringer Ingelheim Pharmaceuticals 900 Ridgebury RoadRidgefield, CT [email protected]

8.0. Acknowledgements

Yoshiko Kitagawa, Yasuhiro Iijima, Nhi Beasley, Akira Kurisu, CJUG ADaM sub-team for “Efficient preparation of eData submission to both the PMDA and FDA” and CJUG SDTM collaboration members (S. Hibino, K. Masubuchi, M. Tanaka), Bhupendra Mistry.

9.0. Disclaimer

The opinions expressed in this document are those of the authors and should not be construed to represent the opinions of PHUSE members, respective companies/organisations or regulators’ views or policies. The content in this document should not be interpreted as a data standard and/or information required by regulatory authorities.



10. References

FDA

[1] Providing Regulatory Submissions in Electronic Format - Standardized Study Data

[2] Study Data Technical Conformance Guide

[3] Data Standards Catalog

[4] Business Rules and Validator Rules

[5] Technical Rejection Criteria for Study Data

[6] Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions (Draft Guidance)

[7] Bioresearch Monitoring Technical Conformance Guide

[8] Position on Use of SI Units for Lab Tests

[9] Study Data Standardization Plan Checklist Recommendations

[10] Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products Guidance for Industry

[11] Portable Document Format (PDF) Specifications (Sep 2016)

[12] Guidelines for Requesting Waiver to Current Supported Study Data Standard Versions

PMDA

[13] Notification on Basic Principles (Mar 2020)

[14] Technical Conformance Guide on Electronic Study Data Submissions (Jan 2019)

[15] Data Standards Catalog (2019) or http://www.pmda.go.jp/english/review-services/reviews/0002.html

[16] PMDA Study Validation Rules v1.0 (2015-11-18) PMDA Study Validation Rules v2.0 (2019-09-27)

[17] PMDA announcement on Validation Rules v2.0 and P21 Enterprise upgrade (Japanese) Electronic Data Submission in Japan - Yuki Ando, PMDA

[18] Notification on Practical Operations (Jan 2019)

[19] Q&A Regarding Notification of Basic Principles (Mar 2020)

[20] Q&A Regarding Notification on Practical Operations (Mar 2020)

[21] FAQs on Electronic Study Data Submission (Apr 2019)

[22] Attachment 8 (Form A) (April 2019) Attachment 8-2 (Form B) (The latest updated version released in March 2020 is available in Japanese: https://www.pmda.go.jp/files/000234768.pdf)

CDISC

[23] Analysis Results Metadata Specification Version 1.0 for Define-XML Version 2

[24] CDISC SDTM IG Conformance Guide and Excel File

PHUSE

[25] PHUSE Regulatory Referenced Final Deliverables (Templates/Guidelines)

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-regulatory-submissions-electronic-format-standardized-study-data

https://www.fda.gov/media/136460/download


https://www.fda.gov/industry/fda-resources-data-standards/study-data-standards-resources






http://www.fda.gov/downloads/biologicsbloodvaccines/developmentapprovalprocess/ucm535589.docx

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM590547.pdf

https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM163565.pdf

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ucm303265.htm

https://www.pmda.go.jp/files/000234977.pdf


http://www.pmda.go.jp/files/000232074.zip

http://www.pmda.go.jp/english/review-services/reviews/0002.html



https://www.pmda.go.jp/review-services/drug-reviews/about-reviews/p-drugs/0028.html

https://www.phusewiki.org/docs/2019_SDE_Tokyo/Yuki Ando_.pdf




http://www.pmda.go.jp/files/000229469.pdf


http://www.pmda.go.jp/files/000229471.pdf


https://www.cdisc.org/standards/foundational/define-xml/analysis-results-metadata-arm-v10-define-xml-v20

https://www.cdisc.org/standards/foundational/sdtmig/sdtmig-v32-conformance-rules-v10

https://advance.phuse.global/display/WEL/Deliverables



ICH

[26] Electronic Common Technical Document Specification (July 2008)

[27] Q&A Regarding Notification on Practical Operations (Mar 2020)

Websites

[28] Study Data Standards Resources

[29] New Drug Review with Electronic Data


http://estri.ich.org/ssf/Specification_for_Submission_Formats_for_eCTD_v1_2.pdf

https://www.fda.gov/industry/fda-resources-data-standards/study-data-standards-resources

https://www.pmda.go.jp/english/review-services/reviews/0002.html