1. Validation Gary Gensinger Deputy Director Office of Business Process Support Center for Drug Evaluation and Research

2. You see validation everyday

3. Why Validate?  Just good business practice  Enhance the accuracy and integrity of Agency records  An important component for achieving PDUFA IV commitments

4. Areas of Validation  Process Validation Do we have the information we need to automatically process your submission  Information Integrity How accurate is your submission  Conformance Validation How well do you conform to specifications  User Validation Content validation that can only be performed by reviewers

5. Process Validation  Have you submitted a machine readable form http://www.fda.gov/opacom/morechoices/fdaforms/cder.htm  Have you submitted a single identifiable form Not Helpful  20080417-taxol-356h-revised.pdf  20080417-gemzar-application-form.pdf Helpful  356h.pdf  1571.pdf If you need a continuation sheet  application_form_continuation.pdf  application_form_addendum.pdf

6. Process Validation …Continued  If using Electronic Submission Gateway Include only a single submission in Gateway transaction Be sure to use only valid characters in file and folder names http://www.fda.gov/esg/userguide/WebHelp_10_2007/WebHelp_10_2007.htm

7. Is this Valid?

8. Information Integrity  Did you send us what you said? Does number on form match the number in the eCTD backbone? Does the application type in the backbone match the form you submitted  NDA/BLA – 356h  IND - 1571

9. Why institute these checks?  Because computers are very judgmental, it is either right or wrong  Because these checks are at the heart of our ability to receive, process, and route your submissions in an automated fashion  Because FDA would like to sponsor a 12-Step program to end the FDA Error Correction Addiction

10. Conformance Validation  How well do you conform to the specifications and guidances eCTD SDTM  The implementation guides from SDO bodies are just a starting point Organization and/or regional differences impact how the specifications are applied

11. eCTD Validation  First published March 10, 2008 http://www.fda.gov/cder/regulatory/ersr/validation_1.0.pdf  Describes the various validation checks and identified the severity associated with each error High - Cannot be processed/received Medium – Can be processed but might not be reviewable Low – Can be processed and reviewed but minor error found Ignore – Specification error that have no impact

12. Putting it all together …From a PDUFA IV Perspective Automated Submission Receipt Agency Tracking Systems SponsorFDA ESGCDER Process Integrity Checks Information Integrity Conformance Validation YesNo Pass?

13. What’s next  Looking at sending validation reports back to submitters through Gateway  Looking at sending positive acknowledgement of processing to submitters through Gateway

14. Questions

15. Q Why isn’t the Medium severity considered a ‘technical error’? Also, please provide more clarity around ‘reviewability’ and ‘integrity’ in relation to the severity levels? A Medium errors are generally those that impact the reviewer’s ability to access information. They are sometimes technical in nature. Technical, as it’s used in describing Low errors, is meant to describe an error that violates the specification but has no impact on loading and viewing the submission, e.g., File name exceeds maximum length (64 characters) per eCTD specification.

16. Questions Q For Medium severity, this suggests that a sequence may need to be ‘backed-out’ of the tool and replaced by the Sponsor if the review staff finds the reviewability unacceptable. What will this process be? Resubmit that entire sequence or provide a subsequent sequence that corrects the issues? A It depends on the actual situation and, in part, what is the easiest way to fix the situation. For example, we’ve seen submissions missing large sections of a sequence. Easier to back out and reprocess. If missing one or two files, may be easier to simply submit a new sequence.

17. Questions Q For Medium severity, this suggests that a sequence may need to be ‘backed-out’ of the tool and replaced by the Sponsor if the review staff finds the reviewability unacceptable. What will this process be? Resubmit that entire sequence or provide a subsequent sequence that corrects the issues A It depends on the actual situation and, in part, what is the easiest way to fix the situation. For example, we’ve seen submissions missing large sections of a sequence. Easier to back out and reprocess. If missing one or two files, may be easier to simply submit a new sequence.

18. Questions Q Can the validation criteria be supplied by severity rather than just listed numerically? A Yes, we will look at adding that to a future update.

19. Questions Q There appears to be an inconsistency with regard to the severity level of errors that are considered XML parsing errors, e.g., launching index.xml within Internet Explorer produces an error? A FDA’s validation tool is capable of opening and evaluating these instances. I would suggest that sponsors open up their submissions in Internet Explorer before sending them in to identify any serious problems before sending to FDA.

20. Questions Q Clarification of what the FDA requires when they state that the submission should be resubmitted. Is this to resubmit the same sequence or to resubmit in a future sequence? A Where the document states to resubmit your submission it provides guidance on the sequence number as in: Resubmit your submission specifying a properly formatted application-number. You may resubmit using the original sequence number of the submission. In the case of a duplicate sequence number it should be implied that you need to submit using a different sequence number.

21. Questions Q Clarification of what the FDA requires when they state that the submission should be resubmitted. Is this to resubmit the same sequence or to resubmit in a future sequence? A Where the document states to resubmit your submission it provides guidance on the sequence number as in: Resubmit your submission specifying a properly formatted application-number. You may resubmit using the original sequence number of the submission. In the case of a duplicate sequence number it should be implied that you need to submit using a different sequence number.

22. Questions Q If the filename contains invalid characters, why is that considered a “low” severity level? If that same file with the invalid characters was to be submitted through the FDA ESG should that have a “high” severity level? A These are invalid characters per the eCTD specification and not invalid characters per the operating system, e.g., an underscore.

23. Questions Q Please provide a definition of “circular relationship” and what this actually means? A A circular relationship is where, using submission B is related to A and A is releated to B, e.g., an amendment is related to an original submission through. But an original is not relaetd to the amendment through

24. Questions Q There is no requirement for doc-content and leaf titles to match. The examples in the STF specification (FDA Implementation) show doc-content without titles. What is this check based on? A This is a quality related check and meant to inform sponsors what the reviewer will see when they use two different names. It is form informational purposes only and is rated Low

25. Next Steps  We will review the questions that we receive, update the document where we feel that we can improve the clarity and accuracy of the document, and republish as resources allow.