Secrets of eCTD Related Sequences

February 12, 2010

Applied Clinical Trials

During my consulting work and product training sessions, clients often ask me to explain the concept of “related sequences.” It’s not surprising that this question comes up so often when one considers that related sequences are not part of the ICH standard and that regional authorities have not provided much written guidance on how to relate eCTD sequences.

The need to relate eCTD sequences arises from a “missing link” in the two major organizational constructs: applications and submissions. Applications manage the entire regulatory lifecycle of a marketed product. Submissions, or sequences, allow a sponsor to submit a set of information in support of a claim. But in fact, neither applications nor sequences are approved by any authority. Instead, authorities approve a “regulatory activity” or RA.

In the United States, this is generally an original application or a supplement. In Europe, it might be an initial Marketing Authorization Application (MAA), variation, line extension, etc. In Canada, it would be a New Drug Submission (NDS), Supplemental New Drug Submission (SNDS), Abbreviated New Drug Submission (ANDS), etc. Although the details are different, each authority needs to understand which sequence represents the start of a new RA, and which sequences represent additional information in support of an existing RA.

The metadata the sponsor provides in the regional backbone allows the sponsor to state the relationships between sequences. The result is a cohesive collection of information that the authority can review and approve.

U.S. Use of Related Sequences

As stated in the Specifications for eCTD Validation Criteria, the FDA recognizes two types of submissions:

  • High-level submission types that represent regulatory activities and include original applications, annual reports, all types of supplements, and “other”. These submission types should never have a related sequence.

  • Second-level submission types are provided in support of high-level submissions and include amendments and resubmissions. They should always have a related sequence (generally only one, although occasionally an amendment can be in support of multiple supplements).

There are software tools out there that enforce these rules and generate errors to alert you to missing or extraneous related sequence metadata. Once alerted, you can correct the errors or find the missing or extraneous related sequence data.

Figure 1 shows how the use of the Submission Type view in one software solution allows both the sponsor and the health authority to see the submissions assigned to each Regulatory Activity. The figure also shows a typical error seen by the FDA – sequence 0002 -- which is an amendment for which the related sequence number was not specified. In this case, because a related sequence number was not specified, neither the software nor the FDA will be able to identify what RA the amendment applies to without reading the cover letter or application form.

Figure 1 Submission Type View

Figure 2 shows a feature that FDA reviewers find very useful – the combination of the Current view with a submission type filter. This allows reviewers to see the current files in a supplement such as the Efficacy Supplement being viewed in the screen snapshot. As many sequences are added to an application throughout its lifecycle, the ability to narrow the view to just those sequences related to a specific supplement becomes more and more important.

Figure 2 Current View Combined with Submission Type Filter

Looking at the screen snapshot, you’ll also see the presence of an RA labeled, "Unspecified”. This is what the Health Authority sees for any sequence that should have a related sequence but does not. In this case, it is caused by an amendment with no related sequence – so there’s no way for the FDA to know what Regulatory Activity it relates to without digging into the contents, and no way to see a complete current or lifecycle view of the RA that it should be supporting. It goes without saying that this makes the reviewer’s job more difficult.

Finally, there is the case of INDs. Although little has been said on how to organize them, they are in reality fairly straightforward, with high level submission types of Original Application and Annual Report only. Over time, the Original Application will have a very large number of related sequences (amendments) as shown in Figure 3.

Figure 3 Regulatory Activities for INDs

EU Use of Related Sequences

In Europe, the EU M1 Guidance gives examples of the use of related sequences, but does not actually provide rules or define which types of sequences are Regulatory Activities. Claire Holmes, Project manager at the European Medicines Agency, was kind enough to clarify this for us: "For us, actually every item on the list is classed as a regulatory activity since it will change the approved information, with the exception of 'supplemental-info' (as this can be applied to an eCTD submission within the context of any regulatory activity), and 'reformat'."

Recently, Tim Buxton of European Medicines Agency confirmed a change to this rule: “Corrigendum” should never be used as a regulatory activity, but should be used as a related activity under specific circumstances.

To summarize, for EU submissions, the only types of submission that should have a related sequence are Supplemental Info and Corrigendum. (Reformat is not an RA as it does not actually get approved, but neither is it related to an RA).

Health Canada’s Use of Related Sequences

In “

”, 2006/01/20, Health Canada defines the rules for related sequences:

For life cycle management at the submission layer, the related-sequence-number sub-element should be treated as described:

  • For all drug submissions types (NDS, SNDS, ANDS, SANDS, and NC) in eCTD format, the related-sequence-number sub-element should not be used.

  • For additional information, the related-sequence-number sub-element should be the sequence number of the submission to which the additional information applies. The related-sequence-number sub-element should only be one sequence number. If the related-sequence-number sub-element is empty or not included, the submission will fail the verification process.

Health Canada has no submission type representing amendments or supporting information like the US or Europe, and their guidance is not explicit on what submission types should relate to which others. However, I’ve learned from talking with Health Canada that in fact a second level submission should always be of the same type as its related high-level submission. For example, when you provide additional information to sequence 0000, an original NDS, such as a Clarifax, the new sequence should have the same submission type (NDS) and record 0000 as its related sequence. Health Canada only allows one related sequence.

In addition, although HC mentions that lack of a related sequence for additional information will result in a verification failure, there is no error related to this condition in its published

.

Swissmedic’s Use of Related Sequences

Swissmedic is accepting eCTDs as of January 1, 2010. In their newly issued “Guidance for Industry on Providing Regulatory Information in eCTD Format” , they provide guidance on the use of the related sequence: “The related eCTD Sequence attribute should always be left blank for new applications or new regulatory activities (for example variations, PSURs). When submitting lifecycle eCTD Sequences within an existing activity, the related eCTD Sequence attribute should be populated with the eCTD Sequence number of the first eCTD Sequence in the activity, regardless of how many eCTD Sequences make up the activity.”

Although they don’t provide further rules, their example clearly shows that second-level submissions have the same sequence type as high-level submissions. For example, after a Variation requiring authorisation including scientific review (var-authorisation-scientific) is submitted, any additional information related to that variation is also of the submission type var-authorisation-scientific. Swissmedic’s related document “Guidance for Industry on Providing Regulatory Information in eCTD Format” makes it clear that these rules are mandatory. It also states that only a single related sequence number should be used.

Australia’s Use of Related Sequences

TGA provides examples of related sequence usage in its Draft guidance document “Guidance for Industry on Providing Regulatory Submissions for Prescription Medicines in Electronic Format (eCTD) in Australia”. However, they have not yet provided detailed rules or metadata descriptions, or a Module 1 DTD.

 

Kathleen Clark is Director, Professional Services at GlobalSubmit and the developer and main contributor to The eCTD Summit, a widely read industry specific blog. You can reach her at kathleen.clark@globalsubmit.com.