The ASEAN CTD (ACTD)

Not only has the (e)CTD taken hold in Europe, North America, Japan, and Australia, but it even has given rise to some pseudo-CTD standards. Many of us have heard about the NeeS standard being used in Europe by some agencies to accept eSubmissions in cases where either the sponsor or regulator can't (or won't) yet accept eCTDs.

The ASEAN (Association of Southeastern Asian Nations) have observed this and are now drafting the ASEAN CTD, a standard derived from the CTD.

So, what does it look like? Well, it's similar to the CTD, but a little off. In place of the 5 modules, the ACTD organized the submission into 4 parts. This is done because ASEAN members usually only receive reference applications -- applications to put a drug on the local market that has already been approved elsewhere. As a result, the need for detailed documentation is lessened -- most study reports are not required to be submitted.

Module 1 in the CTD (the regional and registration information) is still present as Part I in the ACTD. ICH M2 is dropped and the summaries are absorbed into the subsequence parts. Quality information (ICH M3) is Part II of the ACTD, Nonclinical (ICH M4) is Part III, and Clinical (ICH M5) is Part IV. The comparison pyramids below should give a rough idea of the differences.


Further reading is available on other online sources -- a good starting point is searching "ACTD" at the Singapore HSA website...especially for English speakers. :)

So, why should drug companies consider the ACTD as a part of their global regulatory operations? Well, as this presentation by Hunton & Williams alludes to, the economic benefits of free trade between ASEAN nations and Europe (and presumably North America as well) could be huge (Powerpoint presentation here).

A Tribute to the CTD Pyramid

I would like to confess my undying love, and total respect for the CTD pyramid.

Oh sure, at first I thought it was an overused bit of clipart, sort of like the thinking man with question mark above his head or perhaps a rotating globe. I however, was mistaken.

True, the CTD pyramid has to some become something that does not explain a whole lot...but it has grown on me for the following reasons:

• It roughly explains the typical Regulatory Authority review process. In all this talk of study tagging files, node extensions, xlink hrefs, etc. etc. it brings you back to what a truly beautiful idea the CTD format is -- a roughly consistent approach to submitting eCTD applications that you can count in many of the biggest markets for life sciences: the US, European Union (and many non-EU European nations such as Switzerland and Norway), Canada, South Africa, Australia, Japan, and to a lesser extent ASEAN nations, Russia and some Latin American countries. Historically this is such a huge step in the right direction and a big effort saver for life sciences orgs. Now, you roughly have an idea not only on how to format these submissions, but additionally how they will use the section to navigate: starting at the regional M1 to get legal and regional requirements, etc. answered, moving on the M2, for the high level executive summary in the 2.2 Introduction, moving onto the high level overviews in 2.3, 2.4, and 2.5 and more detailed summaries in 2.6 and 2.7. and then branching out (usually via paper based cross-references or PDF hyperlinks) into the details of M3, M4, and M5. It's not accident that the subsection of these summaries in M2 (2.3, 2.4 and 2.5) correspond the Module number (M3, M4, M5) of the details the refer to. Oftentimes people complain about the regional differences (or non-harmonies) but the benefit of a roughly defined review process is worth the price of entry by itself.
• When you stroll late into a session at a DIA, RAPS, or other regulatory conference and see this beauty on a PowerPoint slide, you know you're in the right place. I can't be the only person who has done this. C'mon conferences are supposed to be half networking opportunities anyway!
• It invokes the mystical powers of the pyramids. Seriously, this thing looks like a triangle to me but everyone still calls it a "Pyramid". I think there's something more to this.
  

Wikipedia eCTD Entry: Room for Improvement

The Wikipedia entry for eCTD has a lot of room for improvement. Although it contains some useful information for the eCTD novice, it offers little of significant benefit to the initiated eCTD user.

Kudos to Wikipedia user Flowanda who recently cleaned up and organized the list of eCTD vendors at the bottom of the page. The list was quickly becoming a case study in viral marketing practices on the Web.

So, the questions is, where do we go from here? There has been some significant information released lately with regards to eCTD deadlines in the US and Europe that are oddly missing. Maybe if I have some time I can make the change sooner rather than later.

Aside from that, what else could be used to improve this page?

Just in case, here's how to edit a Wikipedia page.

The Laszlo Letter: Top 12 Issues for eCTD Success

This is a great post on another blog, the always-worthwhile Laszlo Letter, that details the top 12 issues for eCTD success as presented by a member of the FDA.

Reading the comments of that post details a similar listing of challenges from an EMEA presentation.

Although both are bit dated (the original post is from February 2007), they are still very much relevant.

The Laszlo Letter: Top 12 Issues for eCTD Success

Japanese eCTD Differences: Backbone Basics

If you thought the differences between US and EU eCTDs were significant, you probably don't want to hear about the differences in the Japanese eCTD. :)

Because the Japanese review agencies rely less on review software, the XML backbone itself acts more as a significant reference for their review. This is a bit of a double-edged sword.

It does allow the sponsor to more accurately predict what the agency sees, although some could argue that this is pretty well known for all eCTD reviewers, anyway.

Because of this, the XML backbone of each sequence is cumulative, not isolated. If you have ever opened up an XML backbone from a US\EU submission and viewed the output, you would see something like this.

---

Sequence 0000 eCTD DTD version 3.2

• m1-administrative-information-and-prescribing-information
• us-regional [new]

• m2-common-technical-document-summaries
• m2-2-introduction
• New A Sequence 0000 [new]
• New B Sequence 0000 [new]
• New C Sequence 0000 [new]

Sequence 0001 eCTD DTD version 3.2

• m1-administrative-information-and-prescribing-information
• us-regional [new]

• m2-common-technical-document-summaries
• m2-2-introduction
• Delete C Sequence 0001 [delete]
• Append B Sequence 0001 [append]
• Replace A Sequence 0001 [replace]
• New D Sequence 0001 [new]

---

In Japan however, each sequence automatically points to the documents submitted in previously related sequence. Therefore, instead of each sequence's XML backbone being isolated, it automatically includes previously submitted example. Here's the scenario above, as viewed from a sequence 0001 backbone with the default stylesheet.

---

Sequence 0001 DTD version 3.2

• m1-administrative-information-and-prescribing-information
• 1. 申請書等行政情報及び添付文書に関する情報 [replace]

• m2-common-technical-document-summaries
• m2-2-introduction
• Replace A Sequence 0001 [replace]
• New B Sequence 0000 [new]
• Append B Sequence 0001 [append]
• Delete C Sequence 0001 [delete]
• New D Sequence 0001 [new]

---

As this example hopefully illustrates, the Japanese XML will point to all current documents, across sequences.

There are certainly more eCTD differences in Japan, technical, cultural, and lingual. Interested? Leave some comments and I'll share some more if there are enough Japanese eCTD followers out there.