question fda response cdisc response · pdf fileepoch. is fda asking companies to submit these...

Questions and Answers from CDISC Standards in the Regulatory Submission Process Webinar 26 January 2012

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Question FDA Response CDISC Response

1. With the addition of the RFICDTC is it acceptable to not duplicate this in the DS domain as a Protocol Milestone?

The applicant should submit a question to the FDA review division because it might depend on the reviewer needs.

2. I noticed the PT term was not included in the SDTM mappings - is this an oversight? Only the PT code was collected versus all others with the term and code.

PT belongs in the --DECOD variable which already exists in SDTM. The slides only showed the variables that are new in Amendment 1.

3. There is a statement about ELEMENT, ELEMENT CODE, EPOCH. Is FDA asking companies to submit these for all domains except for DM and Trial design datasets?

This differs from Center to Center; for CDER, please refer to the Common Issues document posted to the CDER Data Standards Program website. [http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm249979.htm] For CBER there is currently no requirement.

4. If sponsors submit these variables now, are they to be submitted in the DM and AE domain datasets or are they to be submitted in the supplemental DM and supplemental AE datasets?

We assume that this question is a follow up question to ELEMENT, ELEMENT CODE and EPOCH. Please refer to the Common Issues document posted to the CDER Data Standards Program website for clarification for submitting to CDER, and the CDER-edata mailbox: [email protected]. For CBER, submit to CBER email address [email protected].

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm249979.htm




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5. When is the SDTM amendment 1 expected (from FDA) to be part of submissions from sponsors'

CDISC is upversioning all the changes to date into SDTM version 1.3.3. Our understanding is that this will occur over the next several months, but please see CDISC for further information. After that time, FDA will publish a notice to the data standards website announcing its ability to accept submissions in this version.

6. When (will) a new version (with a new amendment) of sdtmv1_2_sdtmigv3_1_2_2009_03_27_final.xls becomes available?

CDISC should address this

7. Will the new SDTM standard be provided in excel or access or some format that can be read with SAS? If so, where can we get that?

CDISC plans to continue to create Excel metadata files for SDTM with each new SDTM and SDTMIG final version that is published. These are available in the member’s only area of the CDISC website.

8. Any amendments expected for ADaM IG?

The ADaM IG will be updated on a regular basis to reflect new content beginning in 2013. However, individual ADaM documents and models will continue to be posted for comment and use in between formal IG version releases.

9. Question about first presentation: Should the new MedDRA variables (high level

This has been addressed in Amendment 1.


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term, etc) be placed in the AE or SUPPAE sdtm dataset? 10. Is the FAQ database available publicly (or will it be)?

FDA cannot make this public because of policy issues. Q&A from these webinars will be posted.

11. We follow a rule to define character variable lengths to be the shortest that can hold the longest actual value in the data. Is this compliant?

Defining any variable lengths to be the shortest that can hold the longest actual value in the data is the intended expectation for all CDISC formatted submissions. Be sure that all instances of a field within a submission have the same length (especially required fields) to avoid any potential truncations as new datasets are made. Please find more about this at (insert URL). Add Doug’s answer here.

12. I understand that the FDA expects that sponsors use amendments as soon as they become final for all submissions moving forward. I would assume that sponsors can submit eCTD updated data packages if any new amendment is considered relevant for the reviewers

FDA will publish a notice on its DS website when it can accept a new version, as versions are made final.

13. Could you please expand on your expectations?

Unfortunately we don’t have enough information to answer this question. If you still have a


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question, submit the question to [email protected]

14. Are there any plans on defining the requirements for a domain or a data set structure where the population pharmacokinetics data are to be presented: so-called Nonmem dataset.

The FDA has no immediate plans to pursue development of an SDTM equivalent of NONMEM. For more information, contact CDISC.

15. Is there a target date for the release of a specification for ADaM metadata? We are currently utilizing CRT-DDS, but that is not ideal as its intended purpose is for CRT data sets, not ADS.

FDA defers to CDISC for this question. The define.xml v2.0 specification, which includes support for ADaM metadata, is expected to be released for public comment this summer.

16. a. Are there plans still to move away from SAS v5 XPT files and move toward XML? b. If so, any idea as to the timing?

a. The Agency envisions a future where v5 transport files will be replaced, b. It is unknown at this time what the replacement standard will be and therefore what the implementation time frame will be.

17. Does FDA still utilize WebSDM, or just OpenCDISC?

WebSDM is no longer supported for validation.

18. Annotations (crf) for SDTM. Usually we get the

1. FDA prefers to have the CRF annotated with the variables from the tabulation


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annotated CRF (from data management) for Raw data. 19. a. Should we re-annotate the CRF for SDTM variables? b. What is the process to define the traceability for the CRF?

datasets in the regulatory submission. It is however, acceptable to have both naming conventions on the CRF.

2. We are uncertain what this question is specifically asking. Please feel free to resubmit this question with more detail to the eDATA Team for CDER or CBER Review Management, [email protected]

20. What is the turn around time we can expect from responses from review team when sent an email?

This is variable and depends upon the question being asked. Please be sure to copy [email protected] or [email protected] on all questions for fastest service.

21. Where would you recommend getting an example of a "Review's Guide"?

We assume the question is referring to a Study Data Guide to clarify study-specific content. FDA is currently collaborating with PhUSE to develop the contents of a Study Data Guide to be housed in the eCTD M5 folder.

22. Where should a reviewer's guide for data issues be placed in the eCTD and what should its filename be?

See above answer

23. Dr. Cooper, can you update us on efforts to disseminate standards information to the review

We recently completed a re-design of the training resulting in 3 Modules that provide an Overview, and cover SDTM and ADaM. This effort has been extremely successful and is getting very high

mailto:[email protected]




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divisions and train them on CDISC?

ratings. CDER has identified data standards leads within each Division who are responsible to keep their Division up to date and communicate issues. CDER has also developed an Internal website to track resources and share resources and information to Reviewers.

24. Since AE treatment emergent flag is analysis variable, will it be acceptable to FDA reviewer for sponsor to submit the AE treatment emergent flag in analysis dataset(s), and the analysis dataset(s) will include all AE records incl. non-TE AEs.

A sponsor should always consult the review division about the content of any analysis file that needs to be submitted.

25. Is it possible to add a new variable to one of our SDTM findings domain?

A sponsor should always consult the review division and cc the eData team about any of the content of any analysis file that needs to be submitted. At minimum, if it is agreed that a new variable should be added, the submission should include that a new variable has been added

26. I.e., there is a LLOQ (lower level of quantitation) SDTM variable but there no ULOQ (upper level OQ) and it is used in Biomarker results. Is SUPP the only option?

We will work with CDISC to have the variable added to the findings variables on the next release.


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27. Reviewers Guide: Please address the expectation of including this in submissions, and whether there is a template

Please refer to the draft eStudy Guidance on the FDA website. We have no additional guidance at this time. The draft guidance is available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292334.pdf

28. We are confused with the Traceability material and the need to have Analysis Datasets created from SDTM and with respect to Legacy Studies that all ready have Analysis datasets created from the Raw data. FDA has previous stated when performing Legacy Data -Conversion of SDTM datasets, the sponsor does not need to recreate all of the Analysis Datasets from the SDTM datasets. Please clarify how sponsors should proceed...

The requirement that ADaM datasets be built from SDTM is a CDISC requirement that FDA advocates. There are potential alternative options that could allow the Sponsor to document the traceability in the Clinical Study Report while not recreating the analysis datasets. It is not possible to give a single answer to how industry should proceed; any specific question about a submission can be submitted to the CBER or CDER Data Standards Questions Team.: [email protected]

29. Our RAW data from eDC systems is not SAS v5 compliant. How to submit RAW data that is in SAS v9 format?

FDA does not support SAS v. 9 format. SAS v 5 refers to the transport version, not the data version. FDA requires submissions of SAS datasets in version 5 transport format (XPT)

30. Where will the Both the slide deck and the Q&A will be

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292334.pdf





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presentation material be posted?

published on the CDISC website.

31. Within a submission, is it ok for studies to use different versions of the CDISC standards, i.e. some studies used SDTM v3.1.1, v3.1.2, v3.1.2 amend 1?

CDER recommends asking the Review Division - in some cases it might cause a problem, and in other cases it might not. For now CBER is allowing it. A major issue is identifying which studies are in which version so that they can be properly validated. FDA is currently exploring ways to sunset v. 3.1.1.

32. Is it correctly understood that SEND will be required very soon? Will that also apply to SDTM?

Refer back to the timeline slide for SEND. This is a preferred, supported standard right now. When and if it is approved, those expectations will also apply to SDTM.

33. Can you clarify whether population flags should be included in the SDTM, or can only be put in ADaM?

FDA defers to CDISC on this question.

This one’s a catch 22. The SDTMIG does not define what content should be included in tabulations. Such content questions should be discussed with the FDA review division. Appendix C5 of the SDTMIG describes QNAM values for certain population flags that may be included in tabulations.

34. Will the OpenCDISC-issues portion of the presentation be posted on the website? I would like to show it to members of my team.

Yes Both the slide deck and the Q&A will be published on the CDISC website.

35. When removing trailing

The Agency prefers the sponsor to size the dataset column width according to the maximum


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spaces from variables in xpt datasets would you prefer that we ensure that common variables found across domains ( e.g. VISIT) have a common single length?

column width needed for the data in the dataset column. The sponsor does not need to “size” column width based on any other criteria.

36. a. For MedDRA data now in parent domain, can FDA speak to the impact of case (e.g., not all upper case) for SOC and PT, vs for all additional terms that have been moved up from SUPP--. Clients often have different case across the terms. b. Is it more critical for exact case to match for PT, or is it essential across all the added terms also?

The Agency prefers the sponsor use the dictionary-supplied variables verbatim; this ensures that the values in the dictionary can be matched with the Agency’s copy of the dictionary. Changes to standardized dictionary terminology, such as the MedDRA dictionary, can be problematic for the review process.

37. Is it recommended to create ADaM datasets in cases where there are no derivations needed, solely to have a dataset with core variables merged on?

Consult the review division to determine specific review needs for analysis files.

38. Is there any recommendation on adding ATC level Text 1 - 4 in main

In the current version of SDTMIG there are no variables available in the main CM domain to add more than one ATC level, although additional ATC levels may be added as


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CM domain at this time supplemental qualifiers. Additional information will be provided in a future (possibly 3.1.4) version of the SDTMIG.

39. We map only one ATC level text in CMCLAS, the rest are added in SUPPCM.

This is not a question

40. Will the slide deck include the Q&A?

Both the slide deck and the Q&A will be published on the CDISC website.

41. From Anne Russotto of Roche: Please elaborate on data that does not need to be submitted. The example given was patient initials. Are there other examples?

We are evaluating our ability to provide more guidance on this subject in the future.

42. Do we know how soon OpenCDISC will be releasing an update with Amendment one additions?

CDISC question Please refer to the OpenCDISC website for information about their version updates.

43. What is the approximate timeframe when ADaM datasets will be required in NDAs/BLAs?

Standardized electronic data is preferred at this time. As more information becomes available, it will be posted to the data standards website (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm249979.htm)

44. Do reviewers find the RELREC domain to be useful?

We have not done a systematic evaluation on RELREC.

45. Is the expectation that 'controlled terminology' should also be applied to data

Where possible, yes.





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in SUPPQUAL? 46. What can we expect at the PhUSE conference?

phusewiki.org for more info

Thank - you all, for very useful information!

47. You mentioned that ADaM has the variables that provide traceability to SDTM. If derived variable (eg, composite endpoint) comes from multiple domains including ADaM, the current SRC--- variables do not allow to identify multiple source in one row. what is your recommendation to handle this limitation?

Contact [email protected] with more details in your question so that we can address.

48. I completed agree with your workflow of ADaM datasets creation. Is there expectation from FDA to submit raw data as well?

Please submit your question with more details to [email protected]

49. If we are already implementing the Amendment 1 changes - how should we then handle the resulting errors in the opencdisc val reports?

The expectation is to document an explanation for all errors and warnings in the Validation and Data Interpretation Report.



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50. Elements and style sheet in current version of Define.xml does not support "Parameter Value Level Metadata" of ADaM version 2.1. Does CDER insist on ADaM datasets with Define.xml, or a Define.pdf is acceptable for ADaM datasets?

CBER allows for define.pdf with ADaM datasets until such time as an updated specification is provided by CDISC. CDER awaits a define.xml structure that could support parameter value level metadata. In the meantime, CDER strongly encourages the submission of a define.xml as currently defined and the inclusion of a define.pdf that includes the parameter value level metadata as well.

51. Regarding validation of the define.xml: are you also using OpenCDISC or another tool?

OpenCDISC

52. For SEND: are CDER and CBER both accepting SEND already?

CDER is accepting SEND-formatted datasets. It is CDER’s preferred, supported format for receiving general toxicology and carcinogenicity study data. A Federal Register request for SEND pilot for CBER has been published. We hope to be able to implement in 2013.

53. Please give an example on how you handle the length regarding >200 characters in the document.

Refer to SDTM IG

54. In common data issue document, FDA requests

The Common Issues document has been updated. Refer to the Common Issues document


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EPOCH, ETCD, and Element for some domains. However, ETCD and Element are not part of SDTM model for those domains. How do we implement that?

for more information: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM254113.pdf

55. Beside AE, if a sponsor uses MedDRA to code medical history or physical examination, is it still recommended to provide all of the MedDRA lower terms specified in the Amendment 1?

Yes

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM254113.pdf



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