Data Submissions

At one point there was a joint CDISC/FDA team working on defining locations in SDTM/ADaM for BIMO components so that the CLINSITE information could be pulled from the submitted data instead of a separate dataset. This joint effort has currently been put on hold. However, at this point, the team recommends to continue to reference the current BIORESEARCH MONITORING TECHNICAL CONFORMANCE GUIDE

(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bioresearch-monitoring-technical-conformance-guide https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bioresearch-monitoring-technical-conformance-guide)

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

(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/standardized-format-electronic-submission-nda-and-bla-content-planning-bioresearch-monitoring-bimo) for details

PHUSE Team Response: 13th August 2020

The team has provided their response to the question on "Requirements for Clinical Site Data and Subject Level Data Listings for FDA CDER's Inspection Process (also called BIMO submission or OSI Pre-NDA request)." in the past. 

BIMO

PHUSE Team Response: 12th April 2018

According to the FDA Study Data Technical Conformance Guide (version 4.0), Section 7, which describes the Electronic Submission Format, the misc folder should “contain datasets that do not qualify as analysis, profile, or tabulation datasets in this subfolder.” These datasets should be in SAS Transport Format (.xpt). Since these datasets do not qualify as analysis, profile, or tabulation they do not need to be included in the define.xml however information about use of these datasets should be included in the reviewer’s guide.

If you have other documents/files that support the creation of your datasets, be they analysis or tabulation, or your TLGs, such as a spreadsheet for CTC Toxicity Grade or SMQ assignment, you can convert it to an acceptable format (e.g. PDF, TXT, or XPT) and place these in the “misc” folder. The file name must be in all lowercase letters or numbers with no spaces or special characters, only a hyphen is allowed in the name. Conventions on the files names can be found in the 

Technical Requirements for Registration of Pharmaceuticals for Human Use 

Name, page 11-12. Information about these additional files and their use in creating the datasets should be included in the reviewer’s guides

Additional References:

Electronic Common Technical Document Specification

Technical Conformance Guide 2018

PHUSE Team Response: 7th June 2017

FDA:

The study submitted electronically must be in CDISC format if the study start date is after Dec 17th, 2016

If ALL studies included in the NDA started after the mandate date and data are collected in legacy format, then yes, the conversion from legacy to SDTM is required

If ALL studies included in the NDA started prior and do not meet the CDISC mandate date of Dec 17th 2016, then it is still acceptable to submit the data in legacy (non-CDISC) format

In addition to the CDISC mandate above, if there is no consistent data format across ALL studies, e.g. the pivotal studies are in SDTM format, but the rest supporting studies in legacy format. The data contents and formats are proposed in the briefing package (BP) before the meeting with FDA, the reviewers either agree with your proposal or request different contents and formats

The Study Data Standardization Plan, which can be shared as early as the pre-IND and is recommended prior to the EOP2, is a way to communicate with FDA proposed study standards for nonclinical and clinical studies within an IND/indication. This is the opportunity to agree upon study standards early in the development of a compound

The SDSP:

Is used to establish and document a plan for describing the data standardization approach for planned studies within a specific submission in the development program

Contains information about the intended and/or current state of data standards that are being used for studies within a compound

Is used as a communication tool with the FDA or other Health Authorities to ensure that the reviewers understand the data standards that the sponsor is using for each study

Is recommended to be included as part of a regulatory submission to Health Authorities

PMDA:

Since October 2016, PMDA accepts submissions in CDISC format. Until March 2020, there is a transition period during which PMDA accepts the legacy submission and partial data submission (hybrid submissions). Sponsors need to have the special consultation meeting (consultation on data format of submission of electronic study data) with PMDA when decided to submit the electronic datasets (approximately one year before the submission - it will be the timing of the decision of the submission package) in order to agree about the electronic datasets format for NDA submission

From April 2020, all required study data need to be submitted in CDISC format, whatever when the study started. Studies in legacy format will need to be converted; No waivers are allowed on this point. Closed or completed studies will require data conversion if study meets eStudy data submission criteria as described in the Basic Principles on Electronic Submission of Study Data for NDA's (binding document):

• Target studies (phase I and CP studies, phase 2-3 studies) will be those classified as evaluation study in submission package
• If phase I or CP study used as evaluation study and is one of the following types, then electronic data always required
• Phase I studies of oncology drugs
• Phase I studies conducted on both Japanese and non-Japanese subjects (e.g.; global clinical trials and bridging studies)
• QT/QTc studies based on ICH E14 guideline

For other phase I and CP studies that don’t meet above criteria, electronic data required when PMDA needs them for their review. The study types will be those where standard PK analysis conducted, Population PK, and PBPK

Additional References:

FDA Binding Documents:

Providing Regulatory Submissions in Electronic Format

• Section 745A(a) of the Federal Food, Drug, and Cosmetic Act, Guidance for Industry
• Standardized Study Data, Guidance for Industry

FDA Non-binding documents and other resources can also be found in the FDA webpage for Study Data Standard Resources

PMDA Binding Documents:

• Basic Principles on Electronic Submission of Study Data for New Drug Applications
• Q&A Guide "Basic Principles on Electronic Submission of Study Data for NDA's"

PMDA Non-Binding documents and other resources can also be found on the PMDA website for 

Advanced Review with Electronic Data Promotion Group

PHUSE Team Response: 7th June 2017

FDA provides a dedicated website page on how to Submit an eCTD or Standardized Data Sample to the FDA – see reference below.
The pages provides recommendations and steps to submit a sample submission

Additional References:

Submit an eCTD or Standardized Data Sample to the FDA

PHUSE Team Response: 12th September 2017

The data standards requirements may differ from country to country and each regulatory body will have their set of requirements. Below you will find basic available information from the US (FDA), Japan (PMDA), and other countries that may or may not require dataset submission at this point

US (FDA): CDER and CBER strongly encourage IND sponsors and NDA applicants to consider the implementation and use of study data standards as early as possible in the product development life cycle so that data standards are accounted for in the design, conduct, and analysis of studies

• Sponsors whose studies start after Dec. 17, 2016, must submit data in the data formats supported by FDA and listed in the FDA Data Standards Catalog. This applies to NDAs, BLAs, ANDAs, and subsequent submissions to the types of applications

• For INDs, the requirement applies for studies that start after Dec. 17, 2017

• Beginning after the dates specified above, FDA may refuse to file for NDAs and BLAs or refuse to receive for ANDAs any electronic submission whose study data do not conform to the required standards specified in the FDA Data Standards Catalog.
  • See the Technical Rejection Criteria for Study Data (PDF - 87 KB)

FDA Submission Type & Timing

NDA, ANDA, and certain BLA submissions - Studies which start after 2016-12-17 (December 17th, 2016)

Commercial INDs and amendments, except for submissions described in section 561 of the Federal Food, Drug, and Cosmetic Act - Studies which start after 2017-12-17 (December 17th, 2017

For the definition of "study start date," see the 

Providing Regulatory Submissions in Electronic Format - Standardized Study Data (PDF - 131 KB)

Source for FDA:
-US FDA Website on Study Data for Submission to CDER and CBER
-US FDA Website on Study Data Standards Resource

Additional reference documents/webinar for FDA:

Study Data Standards in eCTD: What You Need to Know About the New Technical Rejection Criteria, October 12, 2016: 

eCTD Study Data Standards Webinar

Japan (PMDA): Electronic data submission starts from 01-Oct-2016 with the transition period as noted below

PMDA Submission Type & Timing

NDAs (eStudy Data submission criteria*) - Transition Period - Submission on or after 2016-10-01 (October 1st 2016) until 2020-03-31 (March 31st, 2020)

All NDAs (eStudy Data submission criteria*) - Submission on or after 2020-04-01 (April 1st, 2020)

During the transition period, PMDA accepts the legacy submission and partial data submission (hybrid submissions)

• Sponsor need to have the special consultation meeting (consultation on data format of submission of electronic study data) with PMDA one year before the submission (it will be the timing of the decision of the submission package)

• During that meeting, Sponsor needs to have an agreement with PMDA about the electronic datasets for NDA submission

All required study data need to be submitted in CDISC format after April 1st, 2020

• No waivers are allowed after this date. All the clinical studies data meeting eStudy submission criteria* must be compliant to CDISC standard format for submissions on or after April 1st, 2020. Therefore closed or completed studies in legacy format need to be converted

*eStudy Data submission criteria: electronic data in CDISC format needed for studies meeting the following criteria

• Target studies (Phase I and Clinical Pharmacology studies, Phase 2-3 studies) will be those classified as evaluation study in submission package
• If Phase I or Clinical Pharmacology study used as evaluation study and is one of the following types, then electronic data always required
• Phase I studies of oncology drugs
• Phase I studies conducted on both Japanese and non-Japanese subjects (e.g: global clinical trials and bridging studies)
• QT/QTc studies based on ICH E14 guideline
• For other phase I and Clinical Pharmacology studies that don't meet above criteria, electronic data required when PMDA needs them for their review. The study types will be those where standard PK analysis conducted, Population PK, and PBPK

Supported standard and versions data standard catalog and validation rules including rejection criteria are available together with applicable guidance on the PMDA Advance Review with Electronic Data promotion group website

Source for PMDA:
-PMDA Techical Notification for Electronic Data Submissions
-PMDA Website for Advanced Review with Electronic Data promotion group

The below response for other regulatory agencies was put together on 28-Jun-2017, the regulation may have updated since then. We strongly suggest checking each regulatory website for most current information

-Other countries like Europe, China recommend the use of CDISC data standards and define.xml following the FDA requirements but they do not mandate it yet

As far as the European Medicines Agency (EMA) goes, the Clinical Trial Advisory Group on clinical trial data formats (CTAG2) is working on advising the EMA on clinical data formats, where it is leaning toward CDISC standards (although if it accepts, it would likely follow a similar progression as the FDA, with a 2-3 years pilot. CTAG2 provided the EMA with recommendations to use CDISC (SDTM/ADaM) and define.xml similarly to FDA requirements. 

Advice to European Medicines on Clinical trial data formats. (30APR2013)

Source from EMA:

• EMA Website page on Documents from advisory groups on clinical-trial-data

China Food and Drug Administration (CDFA) has endorsed CDISC standards in their Clinical Trial Data Management Technology Guide* (July 2016): they mention "CDISC standards have seen more and more recognised and widely used in the industry, has become an international clinical trial data "common language"

Although, not yet mandatory in every country, CDISC data standards has operational use, such as transfer between organisations, sponsor warehousing, etc., such that it is a good idea to produced CDSIC complaint datasets, even if not technically required for submission. This also allow to create one unique package with ver few or minor updates for submission in different countries

*English translation of the Clinical Trial Data Management Technology Guide is not available on the CFDA website. CDISC website has its own translation of the Document in English

Source for CFDA:
CFDA Website (Chinese)
CFDA Website (English)