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Regulators Answer YOUR Questions At DIA ERI!

June 18, 2015 | BJ Witkin, Senior Manager | Regulatory Operations

A few weeks back I attended the DIA eRegulatory and Intelligence Conference, which gathers publishers, reg ops managers, and regulatory intelligence staff from all over the country to discuss trends and issues in regulatory operations.

In addition to learning about the new Module 1, another great thing about the conference for me was the “Ask the Regulators” session at the end. During this session, all the attendees had a chance to ask representatives from the FDA burning questions we’ve always wondered about.

FDA Panelists

The panelists were three people closely involved with eCTD and the ESG (Electronic Submissions Gateway):

  • Virginia “Ginny” Hussong, Acting Director of the Division of Data Management Services & Solutions and a member of the new ESG governing board (more about that at the end of this post);
  • Jared Lantzy, Operations Research Analyst in the Office of Business Informatics, he’s FDA’s point person for eCTD and PDF specifications;
  • Norman Schmuff, Associate Director of Science and FDA’s go-to guy for questions about module 3 of eCTD.
As you’d expect, there were a lot of questions—22 not including follow-up discussions! Many of them were about the new module 1 but quite a few were on publishing topics. I’ve gathered some of the best ones here. Also, look for my comments in red italics.Questions & Answers:

Q: Should the Delete operator be used when a protocol is withdrawn from an IND, or should the cover letter say it’s being withdrawn but leave the protocol?

A: Use the Delete operator on the protocol. The protocol will still be available via Cumulative view.

Q: Are we linking too much, too little, or enough?

Image courtesy of Ambro at

A: The FDA regulator who answered this said he asked one reviewer (small sample!) and he said more links are better.

Q: Should a new 32p (Drug Product) be created for each new dosage formulation?

A: Let’s say there are two oral forms. A new 32p is not recommended here. But if the dosage form is totally different—oral vs. IV, etc.—then a new 32p is probably helpful.

Q: Are placing the attributes (name, manufacturer, etc.) in 32p and 32s document headings required? (I thought this was a great question since at least one template set we use puts this info in each heading)

A: Definitely not required, and it’s not helpful to have it in the header or the headings.

Q: Do we have to submit a notification that we plan to switch to eCTD?

A: No. Just switch over. (This is a change from what Kathy Elks and I had been told by FDA at previous conferences.)

Q: If you have two submissions ready, do you have to wait for the first acknowledgment before sending the second?

A: No.

Q: Are there any plans to increase the submission size limit through the ESG?

A: Current limit is ~100GB. They are looking to increase the limit, but in the meantime send a hard drive for submissions over 100GB.

Q: How often should revised investigator information be submitted to the IND?

A: Typically, batch and send them every 30 days.

Q: Follow-up question to the previous question: Do sponsors have to submit both 1572s and CVs?

A: The Regulators said the guidance states that “investigator information” is required, so yes. (However, I’ve since spoken to other publishers who say their sponsors haven’t submitted CVs for years. I think we can stop sending CVs, but convincing Regulatory Affairs folks of this could take years unless FDA specifically states they’re not required.)

Q: Does FDA want literature references to be provided for initial INDs? Is “available upon request” OK?

A: Depends. Ask your division before you submit.

Q: Is submission size required in the cover letter?

A: Yes. FDA finds it helpful. (Personally, I don’t see the point in this. Between md5 checksum and FDA validating every submission, it should be immediately obvious if there’s a problem with the size of a submission on their end.)

Q: With respect to Reviewer Guides:

Should the Overall Reviewer Guide go in m1? Yes.

Should the Dataset Reviewer Guide go in m1 or m5? It should be placed in m5.

Q: For CROs, why are we required to obtain a separate ESG account per sponsor?

A: Ginny Hussong answered this one and said it doesn’t make sense to her either (I actually yelled YAY!). The board will review this requirement and look to change it.

Q: The new FDA PDF specification says that inter-document links must be set to “Open in New Window” (the default is “Set by User Preference”). Was this intentional? I asked this question because EMA doesn’t require this setting, which means having to rework all your submissions if you submit to both agencies.

A: Jared Lantzy said he will check on that, as he hadn’t even realized it was stated in the specification. However, the reason for it is that reviewers want to click a link and have documents open in different windows. (I pointed out that they can do this either by changing their viewer settings or by holding down Ctrl while clicking.) Jared agreed with me but explained that unfortunately they have to find a lowest common denominator since they have a large user community with differing levels of IT skills.

Q: Are nongranular m3s allowed? I submitted this one too.

A: According to Norman Schmuff, there’s actually no specification! He said it seems to be reviewer preference, but many reviewers prefer a single large document. He went on to say that industry seems to like a hybrid, where parts of m3 are granular (parts that are more likely to change) and other parts aren’t.

Q: When lifecycling the documents in a study, which operator should be used on the STF? Should it be New, Replace, or Append?

A: It doesn’t matter, as their viewer will accept any, but the specification says it should be Append.

Q: Are there any plans to increase the 100MB file size limit?

A: The file size limit was recently increased to 400MB! (This came as news to me.)

Q: With the new m1 spec, should we put a technical contact in every submission or just with the initial submission?

A: With each one.

I asked a followup question: Now that a technical contact will be provided in each submission, does that mean we’ll hear from FDA if there are problems?

A: No. We’ll still only hear if there’s a major problem or if something jumps out at them.

Q: Are regulators allowed to request paper briefing books? Any chance to make electronic books the standard?

A: The new guidance allows for reviewers to request them, but it’s up to each review team.

Other Important News

There was some other big news from the discussion: management of the ESG has been given to a Board of Directors. They have plans to make improvements to speed and capacity over the next two years.

Even better, the Board is going to review a lot of current requirements to see if they’re really necessary (CROs having a separate ESG account for each sponsor is a good example).

I learned so much having this chance to ask these questions in person and I’m really happy I get to share the information with you. I hope it makes you more efficient and lets you advise your colleagues better.

If you have any questions or want to hear more about this session, please don’t hesitate to contact us or email me at

Image courtesy of Stuart Miles at

Category: Regulatory Operations
Keywords: DIAeRI, Ask the Regulators, specification questions, eCTD publishing questions

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