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About
BIMO
PHUSE BIMO FAQ Forum Project
How to effectively utilize PHUSE BIMO FAQ Forum Project
Acronyms used in PHUSE BIMO FAQ Forum Project
BIMO Submission Helpful Resources
FDA portal
Q-Is there Reference of latest PHUSE BDRG in latest FDA CDER BIMO TCG?
A-Yes,
As per latest FDA CDER BIMO TCG V3.0 (11th August , 2022), Page 2, there is a footnote 4 that references and provides a link for the latest version of PHUSE BDRG (Hint: Within the link click on "Bio-research Monitoring Data Reviewers Guide (BDRG) Package" that should open latest version of PHUSE BDRG. We believe this footer link would be available in the future FDA CDER BIMO TCG release as well).
Please reference the below snapshot from the latest FDA CDER BIMO TCG V3.0 (11th August , 2022), Page 2, footnote 4
PHUSE portal
White paper [Useful and applicable]
BIMO Submission Standards / Guidance
Standardized Format for Electronic Submission of BIMO
BIMO Technical Conformance Guide (TCG)
Q-Where to refer for Geopolitical Entities, Names and Codes (GENC) code list mentioned in the FDA CDER BIMO Technical Conformance Guide (TCG) v3.0?
A-You can refer to FDA (GENC) code list provided at the location https://evs.nci.nih.gov/ftp1/GENC/ [Refer the latest (GENC) code list file from this hyperlink].
We believe in the future FDA CDER BIMO TCG release the above link would be mentioned with some additional instructions for Sponsor/Applicant.
Q-In the BIMO TCG V3.0 Section IV. Submitting BIMO Clinical Data in the eCTD format, the file name of the BIMO Data Reviewer's Guide is listed as "bimo-rev-guide.pdf" whereas the PHUSE BDRG names the document as "bdrg.pdf" (consistency with other study data and analysis reviewer's guides). Can we submit using naming conventions for the BDRG that are different than the BIMO TCG as long as we identify them in the BDRG 'Section 9. eCTD Folder Structure Skeleton for BIMO Items in MODULE 5'? Will "bimo-rev-guide.pdf" file name be modified in a future BIMO TCG version to be "bdrg.pdf"?
A-FDA CDER BIMO TCG V3.0 has referenced BIMO Reviewer’s Guide as BIMO Data Reviewer’s Guide (For Example: As per latest FDA CDER BIMO TCG V3.0 (11th August , 2022), Page 2, there is a footnote 4 that references and provides a link for the latest version of PHUSE BDRG (Hint: Within this link click on "Bio-research Monitoring Data Reviewers Guide (BDRG) Package" that should open latest version of PHUSE BDRG. We believe this footer link would be available in the future FDA CDER BIMO TCG release as well).
PHUSE BIMO team acronyms BIMO Data Reviewer’s Guide as BDRG and also recommends BIMO Data Reviewer's Guide deliverable file name as "bdrg.pdf" as defined in the PHUSE BDRG Package documentation instead of filename "bimo-rev-guide.pdf" that is recommended in FDA CDER BIMO TCG V3.0. Yes, we can identify this deliverable as "bdrg.pdf" in the BDRG 'Section 9. eCTD Folder Structure Skeleton for BIMO Items in MODULE 5'.
Future BIMO TCG release is expected to reference BIMO Data Reviewer's Guide with standard acronym as BDRG and also update BIMO Data Reviewer's Guide deliverable file name to "bdrg.pdf".
Q-Whenever FDA CDER TCG new version is released what should be the ideal time frame for Sponsor OR Applicant to implement them in their BIMO submission Packages to FDA.
A-FDA has not published formal policy regarding the time allotted for implementation of changes when a new version of a TCG is published. An updated BIMO TCG would become effective immediately upon publication. However, recognizing that some BIMO TCG updates may require changes in SOPs and/or processes, we suggest implementing revised BIMO TCG on all BIMO submission packages within 6-12 months of its release depending on the complexity of the updates in the release. Below you can refer to a hypothetical scenario of BIMO TCG release (with complexity) on Sponsor/Applicant BIMO submission Packages that are READY/ONGOING/Planning for BIMO submission to FDA CDER.
Difference between FDA CDER Vs FDA CBER BIMO submission
Pre-Submission FDA Meeting Planning/Discussion
Q-For BIMO Submission to FDA, During pre-submission meeting/discussion how effectively sponsor/applicant can plan/discuss BIMO requirement for smooth review of BIMO submission packages to FDA.
A-'For BIMO, Sponsor/Applicant can effectively plan for pre-submission meeting/discussion by bringing critical topics for discussion/suggestion/acceptance at least on below areas:
- Clarify/Identify major (pivotal) studies that should be part of BIMO submission to FDA
- For identified major (pivotal) studies, Clarify/Identify input data of agreed major (pivotal) studies data to be used for BIMO submission to FDA
- Any data not available/not compatible for alignment with latest BIMO TCG release.
- FDA CDER BIMO TCG version to be followed (Highly recommended and expectation is for latest BIMO TCG released by FDA), also do check for your in-house BIMO processes align with the FDA CDER BIMO TCG version that is followed and if any challenges raise it/plan for the discussion.
- Review of Latest FDA CDER TCG V3.0 AND Latest PHUSE BDRG V3.0, to have fair idea of information that will be required to be followed/part of BIMO submission deliverables to FDA, and if any challenges documenting in BDRG then raise it/plan for the discussion.
- Any Learnings/Experience from other BIMO submission FDA IRs that needs to be clarified from FDA perspective.
So, overall If any items related to BIMO deliverables are unclear based on your review of the most current BIMO TCG posted, then questions related to BIMO deliverables may be included with your pre-submission meeting packet. In cases when BIMO deliverable questions will be submitted, we suggest that applicant/sponsor request input on these questions from CDER/OC/OSI/GCPAB staff, along with other members of the pending application FDA review team.
BIMO Clinical Data consistency with SDTM/ADAM
Q- For PART III : SUMMARY-LEVEL CLINICAL SITE DATASET, FDA CDER BIMO TCG V3.0 requires COUNTRY variable to use FDA GENC Code List instead of ISO 3166-1-alpha-3.
Should SDTM/ADaM datasets from FDA CSR Submission also use FDA GENC Code List?
A- No,
If your BIMO submission package is based on FDA CDER BIMO TCG V3.0, Within PART III : SUMMARY-LEVEL CLINICAL SITE DATASET, Country (Including State) variable is highly recommended to be based on FDA GENC code List.
If your BIMO submission package is based on BIMO TCG (V1.0 / V2.0), Within clinsite data set Country variable is highly recommended to be based on ISO 3166-1 Alpha-3 code list ONLY.
For your Data Package submission as per the CDISC SDTM/ADAM Implementation guidelines, Country variable should be based on the ISO 3166-1 Alpha-3 code list ONLY. Moreover, this does not seem a question for PHUSE BIMO FAQs team, we suggest send query on preparation of SDTM/ADAM to edata@fda.hhs.gov
Q-As per BIMO TCG V3.0, For the Clinsite data set variable ARM has variable label "Description of Planned Treatment Arm", whereas in SDTM.DM variable ARM has variable label "Description of Planned Arm"
Is it acceptable to use the label from DM.ARM in clinsite.arm ?
A-For Sponsors/Applicant that are using BIMO TCG V3.0 (Or any future BIMO TCG) for their BIMO submission, it is highly recommended that they are aligned with that BIMO TCG that is used by them for their BIMO submission. From clinsite data set perspective aligning with Data set name, data set label, variable name, variable label, variable derivation criteria...etc....as this will help FDA reviewer to review BIMO submission deliverables smoothly from the BIMO TCG and inspection perspective.
BDRG consistency with cSDRG/ADRG
Consistency among BIMO Submission to FDA
Q-1. Background about Financial Disclosure Form/Statement collected for Current Principal Clinical Investigator and all Sub-Investigators per SITE and how it is applicable BIMO CDER submission and under which eCTD submission module.
2. For Part III – Summary-level Clinical Site Dataset : How do we assign a particular Financial Disclosure Amount category per SITE when there are various combinations of Financial Disclosure Amount category among Current Principal Clinical Investigator and all Sub-Investigators per SITE.
A- 1) Background about Financial Disclosure Form/Statement:
Whenever a sponsor selects a new Investigator [.i.e. Current Principal Clinical Investigator OR Sub-Investigators] to participate in a clinical investigation, Sponsor/Applicant receives completed and signed Form FDA 1572 as per regulations (21 CFR 54) from each new investigator and also completed and signed financial disclosure form or the drug company-specific Financial disclosure form/statement [Prior/After completion of Study at SITE, For BIMO it would be 'After completion of Study at SITE' that would be relevant] from each new investigator.
The completed and signed financial disclosure form or the drug company-specific Financial disclosure form/statement received by Sponsor/applicant from new investigator are ideally captured in FORM FDA 3455 including an attachment with detailed information about those financial interests and arrangements (This will have questionnaire on Financial Disclosure Amount categorical value of >=$25000 to be answered as YES/NO/Left unanswered, So YES means >=$25000, NO would mean <$25000 or Left unanswered could lead to sponsor/applicant for couple of attempt of due-diligence to confirm if the new investigator should finally be classified as >=$25000 OR <$25000 OR “unknown” (i.e., unable to obtain information from investigator at site) OR “masked” if information on this item is available but it has not been provided by the sender due to security, privacy, or other reasons.
2) As per latest FDA CDER BIMO TCG V3.0 (11th August , 2022):
For Part III – Summary-level Clinical Site Dataset, variable FINLDISC (Financial Disclosure Amount), a particular Financial Disclosure Amount category per SITE needs to be assigned
Where Total financial disclosure amount (US$) by site calculated as the sum of disclosures for the Current Principal Clinical Investigator and all Sub-Investigators, to include all required parities under the applicable regulations (21 CFR 54, 312, 314, 320, 330, 601, 807, 812, 814, and 860). Enter “>=$25,000,” “< $25,000,”unknown” if a proper value is applicable but is not known (i.e., unable to obtain information from investigator at site), or “masked” if information on this item is available but it has not been provided by the sender due to security, privacy, or other reasons.
Note:-
- Sponsor/Applicant collects, maintains and finalized financial interests and arrangements information as Financial Disclosure tracker for use in the BIMO Module 1 Administrative information (.i.e. 1.3.4 Financial certification and disclosure - Financial Disclosure tracker) AND BIMO Module 5 (.i.e. 5.3.5.4 Other Study reports and related information - Part III – Summary-level Clinical Site Dataset) eCTD deliverables.
Important Note: Between BIMO Module 1 Administrative information (.i.e. 1.3.4 Financial certification and disclosure - Financial Disclosure tracker) AND BIMO Module 5 (.i.e. 5.3.5.4 Other Study reports and related information - Part III – Summary-level Clinical Site Dataset) , finalized financial interests and arrangements information should be consistent where applicable.
- Use for Financial Disclosure tracker in BIMO Module 5 (.i.e. 5.3.5.4 Other Study reports and related information - Part III – Summary-level Clinical Site Dataset) eCTD deliverable has below challenges:-
As SITE may have Current Principal Clinical Investigator AND multiple Sub-Investigators with Financial Disclosure Amount categorical value of "<$25000",">=$25000",“unknown” OR “masked”, it would be challenging for Sponsor/Applicant [Regulatory/Programming/ClinOps/eSubmission Functional team] to assign one Total Financial Disclosure Amount categorical value for a SITE when there is various Financial Disclosure Amount categorical values for a SITE. So to overcome this challenge below algorithm can be used to assign one Financial Disclosure Amount categorical value for a SITE:-
- If a SITE has Current Principal Clinical Investigator AND multiple Sub-Investigators with at least one Total Financial Disclosure Amount categorical value of ">=$25000" then assign
FINLDISC=">=$25000" for that SITE.
ELSE - If a SITE has Current Principal Clinical Investigator AND multiple Sub-Investigators with Financial Disclosure Amount categorical value of ">=$25000" ONLY then assign
FINLDISC=">=$25000" for that SITE.
ELSE - If a SITE has Current Principal Clinical Investigator AND multiple Sub-Investigators with Financial Disclosure Amount categorical value of "<$25000" ONLY then assign
FINLDISC="<$25000" for that SITE.
ELSE - If a SITE has Current Principal Clinical Investigator AND multiple Sub-Investigators with Financial Disclosure Amount categorical value of “unknown” ONLY then assign
FINLDISC=“unknown” for that SITE.
ELSE - If a SITE has Current Principal Clinical Investigator AND multiple Sub-Investigators with Financial Disclosure Amount categorical value of “masked” ONLY then assign
FINLDISC=“masked” for that SITE.
ELSE - If a SITE has Current Principal Clinical Investigator AND multiple Sub-Investigators with Financial Disclosure Amount categorical value of “unknown” AND "masked" ONLY then assign FINLDISC=“unknown” for that SITE.
ELSE - If a SITE has Current Principal Clinical Investigator AND multiple Sub-Investigators with NO Financial Disclosure Amount categorical value of ">=$25000" AND [at least one Financial Disclosure Amount categorical value of “unknown” OR "masked"] then assign FINLDISC=“unknown” for that SITE.
BIMO Submission Deliverables
Part I (Item A) - List of All Clinical Sites
Q-Among Investigator (Current Principal Clinical Investigator AND/or multiple Sub-Investigators) for a SITE, which of investigator information should be reported in Part I (Item A) – List of All Clinical Sites as well as in Part III – Summary-level Clinical Site Dataset?
A- As per FDA CDER BIMO TCG :-
For BIMO Part I (Item A) – List of All Clinical Sites PDF deliverable for each of the major (i.e. pivotal) studies for each SITE that participated in the study (i.e. SITE that have screened one subject with a signed informed consent) there is Current Principal Clinical Investigator information .i.e. LAST NAME, FIRST NAME,Middle INITIAL,PHONE, FAX and EMAIL (along with Prior Principal Clinical Investigator(s) information<if applicable> .i.e. LAST NAME, FIRST NAME,Middle INITIAL,PHONE, FAX and EMAIL) information needs to be provided as recommended in the 2nd and 4th column as per format "APPENDIX 1: CLINICAL STUDY-LEVEL INFORMATION, Table A: Format for Clinical Site Lists" mentioned in the latest FDA CDER BIMO TCG version 3.0.
For Part III – Summary-level Clinical Site Dataset deliverable for each of the major (i.e. pivotal) studies for each SITE that participated in the study (i.e. SITE that have screened one subject with a signed informed consent) there is ONLY Current Principal Clinical Investigator Information .i.e. LAST NAME, FIRST NAME,Middle INITIAL,PHONE,FAX and EMAIL information needs to be provided as separate variables in the clinsite data set (But, NO Prior Principal Clinical Investigator(s) information AND NO multiple Sub-Investigators NAME information is needed).
Part I (Item B) - Entities Contact Information and Trial-related Files
Part I (Item C1) - Protocol and Amendments
Part I (Item C2) - Annotated Case Report Form (aCRF)
Part II - Subject-level Data Line Listings by Clinical Site
Q-For FDA CDER BIMO Part II - deliverable should we use source as SDTM/ADAM data sets and should it match to FDA study data submission for CSR OR equivalent other FDA study data submission?
A-For FDA CDER BIMO Part II - Subject-level Data Line Listings by Clinical Site deliverable, there is information that is displayed, reported or summarized based on the inputs from SDTM, ADAM AND other external transfer data sets (eDT) which are based on FDA CSR submission OR equivalent FDA submission data.
Since ADAM contains SDTM as well as additional analysis reporting requirements, therefore between SDTM/ADAM, we highly recommend to use ADAM as an input data along with other external transfer data sets (eDT) for FDA CDER BIMO Part II - Subject-level Data Line Listings by Clinical Site deliverable.
Sponsor/applicant can discuss during their pre-submission meetings with FDA for input data [Based on the Week # /Data-Cut applied...etc..] to be used for the approval/support labelling of their application and then establish agreement.
Part III - Summary-level Clinical Site Dataset
Q-Is there a tool to generate define.xml for Part III – Summary-level Clinical Site Dataset (clinsite.xpt)?
A-Yes, based on the finalized Part III – Summary-level Clinical Site Dataset (clinsite.xpt) and it's finalized metadata/specification, You can use the following either of the below application/tool/automated programs :
1) Pinnacle 21 (Enterprise version)
2) Pinnacle 21 (Community version)
3) Sponsor/Applicant Inhouse validated and tested SAS programs and/or SAS macros
4) Sponsor/Applicant Inhouse validated and tested R programs and/or R Functions and/or R applications and/or R Packages.
5) Sponsor/Applicant Inhouse validated and tested Python programs and/or Python Functions and/or Python applications and/or Python Packages.
etc....
Part IV - BIMO Data Reviewer’s Guide (BDRG)
General
eCTD Folder Structure for BIMO
About eCTD
How your BIMO preparation and submission is related to eCTD
Where and how to use eCTD within BIMO submission to FDA
Submitting BIMO Clinical Data in the eCTD Format
Q-For Part III – Summary-level Clinical Site Dataset (clinsite.xpt) , is define.xml mandatory?
A-Yes, when submitting the clinsite.xpt it should be accompanied by a define.xml file. As per latest FDA CDER BIMO TCG V3.0, which provides current FDA specifications, recommendations, and general considerations for preparing and submitting Clinical Study-Level Information, Subject-Level Data Line Listings by Clinical Site, and a Summary-Level Clinical Site Dataset that are used by the Center for Drug Evaluation and Research (CDER) for planning of Bioresearch Monitoring (BIMO) inspections in electronic format.
Moreover, as per latest FDA CDER BIMO TCG V3.0 (11th August , 2022) document :
- Under III. SUMMARY-LEVEL CLINICAL SITE DATASET -> Section B. Variables and Variable Names for Site-Specific Efficacy Results - It is mentioned that The summary-level clinical site dataset should be accompanied by a data definition file.
- Under IV. SUBMITTING BIMO CLINICAL DATA IN THE eCTD FORMAT -> Section A. Study Tagging File (Table 1: STF File Tags) mention data definition file i.e. define.xml as one of the requested item by FDA CDER for the submission, please refer the below snapshot.
- Under IV. SUBMITTING BIMO CLINICAL DATA IN THE eCTD FORMAT -> Section D. File Format - it is mentioned that the summary-level clinical site data set should be submitted in SAS transport file format (*.xpt). The define file for the summary-level clinical site data set should be submitted in Extensible Markup Language (define.xml) format. Here the requirement to submit a complete and informative define.xml file with complete metadata that describes the summary-level clinical site data set (clinsite.xpt).
BIMO Submission Conformance Rules
Is it mandatory (Yes or No)
Q-Are there any FDA conformance rules for Part III – Summary-level Clinical Site Dataset (clinsite.xpt and define.xml) ?
A-For Part III – Summary-level Clinical Site Dataset (clinsite.xpt and define.xml):
As of now, there are no FDA/CDISC conformance rules, But, If there are any validation checks created by this (validated industry tool) OR (Sponsor/Applicant In house validated Tool/Programming applications to align with the followed latest FDA CDER BIMO TCG release), then these tools/application and it's validation checks for now can be utilized on the Part III – Summary-level Clinical Site Dataset (clinsite.xpt and define.xml). Any valid anomalies/deviations that are flagged by the tool/validation checks should be fixed OR addressed in the latest BDRG [Under Section 5. Part III – Summary-level Clinical Site Dataset .i.e. Section 5.4 Conformance Inputs and 5.5 Conformance Issues Summary] which will be part of their BIMO submission deliverables.