Bio-IT World Report on eCTD 6 Months in

I just caught up to a really interesting article on Bio-IT World's website, titled "The eCTD - a Six-Month Checkup".

The article talks about the challenges the industry has faced due to changes the eCTD has introduced, but also of the response and the dramatic results in the number of eCTDs submitted. The biggest problem? Quality:

“As of June 30, we have received 3,169 applications comprised of 31,386 submissions, as compared to 846 applications comprised of 10,560 submissions one year earlier. But the quality of those submissions is not what we would have expected,” Ventura says. She says that submissions sometimes lack the basics of the eCTD such as a comprehensive table of contents and navigation links to individual files.

The solution? If you don't know what you're doing, consider outsourcing. eCTDs can definitely be built competently inhouse, but they require know-how, and either time and man power or an elegant inhouse system. See fellow blogger Zack Pabst's last post regarding the typical systems that come together to form a strong basis for inhouse eCTD building.

These system also take time and effort to implement (and implement well), especially considering that they are often times subject to 21 CFR 11 audit criteria. Although they will pay for themselves over time, the small life sciences organization could benefit from outsourcing:

Sponsors will be wrestling with eCTD preparation as more regulatory agencies start requiring this format. According to Perez of ISI, agencies worldwide are at dramatically different places in terms of accepting or requiring eCTD submissions, but they are moving in that direction. “Some, such as Argentina, don’t have the technical infrastructure in place, but others, such as Canada, European Medicines Agency (EMEA), and Australia are farther along,” she explains.

I thought it was an interesting article -- although it could have done more to talk about the benefits of eCTD it also paints a realistic picture of where the industry is with this (rapidly) emerging standard. Read the entire article here.

eCTD All Star

Here I sit watching the commercial break after the bottom of the 14^th inning of this year’s Major League Baseball All Star game. Some fans have left the yard, many TV viewers are probably asleep right now, and the last thing anyone wants is for the players to tire themselves out (or get injured) playing a semi-meaningless exhibition game. Wait, what does this have to do with eCTD?

Nothing really, but I think that there is a lesson that we can apply to eCTD-related IT projects. Have you had the experience of an IT project taking much longer to complete than planned? I know I have. Now think about all of the IT systems that a company can consider when making the switch to eCTD. A global life sciences company might need:

• A comprehensive eCTD template package.
• An SPL (Structured Product Label) and/or PIM (Product Information Management) building tool.
• A document management system.
• Enterprise implementations of Adobe Acrobat.
• Enterprise implementations of MS Office.
• A paper/report publishing tool.
• An eCTD publishing tool.
• An eCTD viewing tool.
• A variety of plugins and other "small" applications.
  

Medium and small-sized companies will need at least a subset of these tools.

When implementing complex IT systems, companies considering the switch to eCTD should always be sure to set realistic expectations. How many IT resources will I have available during the implementation process? What is the target date for my first eCTD? Should I build in some wiggle room to let my regulatory team get used to new eCTD-specific business processes? Does the system’s vendor think that my implementation timeline is tight based on their previous experiences?

The answers to these questions (and thousands more) can vary depending on both the nature of the system being implemented and the nature of my organization. Setting realistic expectations for future IT projects will save me the tension of having to sit through unanticipated delays.

Regulation vs. Guidance

Above image borrowed from this presentation by Steve Wilson of FDA (where it was originally credited to S. Woolen)

Looking online, one can find a lot of information regarding regulatory submissions standard strewn about. Whether from the ICH, FDA, EMEA and its member authorities, or beyond, there is tons of information out there. In general, we can group information from the authorities into two tiers: Regulations, and Guidance.

These two terms themselves carry some connotation as what the differences are, but a problem I have observed is newcomers to submissions (and eCTD specifically with all of it's new technical components) often get the two confused, and will go to great lengths to comply exactly with Guidance. Regulations on the other hand, must be complied with in order to allow the agency to review your submission. In some cases they are technical (i.e. to ensure that your eCTD XML file can be properly read and reviewed), in other cases reviewers have submission processes in house that are powered by prerequisites established in regulations. Failure to comply with regulations can (in the best case) result in approval delays or (in the worst case) a Refusal to File.

As the above picture illustrates, in most cases guidance points to best practices that will make life easier when it comes to submission prep for the sponsor, or reviewing procedures for the reviewer. I have heard inquiries indicating that a sponsor is going to to great pain for what might not be a requirement in the eyes of the reviewer.

In one extreme case, a company had inherited (through an acquisition) a selection of legacy study reports that would be submitted as part of a marketing application. Seeing a guidance document that mentioned that non-scanned, ICH E3-formatted reports are prefered, they were prepared to generate OCR copies, paste the OCR text into Word, QA and spellcheck the OCR results, redefine headings and section breaks, redistill to PDF and re-bookmark and hyperlink. Although this might ultimately produce nicer copies, the potential for errors and time-crunch would have far-outweighed the benefits from an effort and resource perspective.

So, how do you know which side to err on in an individual case? There are a number of options. First, most agencies will hold pre-submissions meetings. Doing a gap analysis based on current guidelines and the state of your submittable documents will help you know what the issues are, clearly illustrate them to the reviewers, and get their opinion. If issues come up later and you have missed this opportunity, leveraging a capable eCTD submissions partner who can ask these questions anonymously on your behalf or leverage their experience and opinion across multiple sponsors might be worth its weight in gold.

Learn XML?

I'm a new contributor! I'll update my profile soon to include a little background information about myself.

I heard something that shocked me last week. With a wide-eyed look of horror slash fear slash dismay, an employee from a medium-sized biotech told me "Zach, I heard that if we are going to start submitting electronically, we need to learn XML." I actually haven't heard anyone say this since the dawn of eCTD adoption (years ago).

Who is still spreading this terrible rumor? You certainly don't need to go out and sign up for the next XML class at the local community college to prepare for your next submission. XML is the computer standard that is used to describe your submission to the reviewers. If you’re in the business of getting drugs approved, all you really need to learn about XML are some ideas specific to the eCTD XML standard, not the general rules of XML. The eCTD XML standard can be learned by attending eCTD conference sessions, training sessions, or by utilizing online resources like zenosis.com.

Acrobat 9 and Life Sciences

Greetings blog readers. Recently, I had a chance to get a (slightly) early look at Adobe Acrobat 9.0. Here are my thoughts on some of the significant differences for Life Sciences Professionals:

• Inclusion of Acrobat Connect: Although perhaps not significant for large organizations which already have access to WebEx, NetMeeting, etc. for smaller organizations some lightweight teleconferencing
  
• Basic Form Tools in Standard: Creating forms in Adobe Acrobat 9 has gotten dramatically easier thanks to a really intuitive forms wizard. As a result, this has become the premium form feature in Acrobat Pro 9, and Acrobat Standard 9 regains the standard Forms tools which have been absent from the entry-level version of Acrobat since the 5.0. This is significant since some EDC systems and Publishing systems make use of the Forms tool. The new wizard is very nice, particularly for converting paper forms to PDF forms.
  
• Split Capability: Previously you couldn't easily split PDFs from one PDF into multiple documents, but instead had to delete page ranges manually and save multiple times. Acrobat 9 introduces a split capability, but I am not sure how it compares to more established third party options such as ISIToolBox.
• OCR Improvements: The out of the box OCR engine continues to improve in Acrobat, and it has made steady and significant imrovements since Acrobat 6. Language support beyond English is also getting better. Another nice compliment is the fact that ISIToolBox 6.0 adds the ability to spellcheck OCR results. This is particularly nice in Europe (see NeeS eGuidance, Annex 1, page 12) where the agencies will ask for hidden text, unlike the FDA who generally OCRs on demmand.
• Flash Support: A cool feature is the ability to embed Flash directly into PDF files. While it is unclear how this could be used for submisisons specifically, this could provide an easy way to embed multimedia marketing material into a PDF file for eCTD submissions.
• PDF Portfolios: Another feature that might not be readily usable for submissions but could very well be used internally for efficient content distribution are PDF packages, which bundle related content together (like a ZIP file). The upside is that you don't need any additional software or knowhow to use the ZIP file -- you open it directly in Acrobat. For reviews of groups of documents (think CMC, Study Reports, etc) this could become very useful.

There are certainly a number of other features out there. Get more information directly from the Adobe website. One other item which is not a new feature per se, but something I think has been overlooked for some time are these instructions on how to get Acrobat 8 (and I assume 9) working with SAFE signatures.

eCTD Professionals Group on LinkedIn.com

Are you connected on LinkedIn.com? Are you interested in connecting with other professionals that work with eCTD and want to create a group of interested peers? Then you, my friend, are just the type of person that might benefit from joining the eCTD Professionals Discussion Group on LinkedIn!

If you join, you'll not only join a growing group of professionals, but you'll be able to proudly display these designer badges on your LinkedIn page.

If these don't say, "Yes, I know eCTD", I don't know what does.

Click HERE to Join!

FDA: 30,000 eCTDs and Counting!

One of the more interesting tidbits listed from the DIA Annual -- a rough breakdown of how many eCTDs the FDA is processing. I'm really impressed by these numbers. FDA has definitely been the strongest advocate of eCTD (for a variety of reasons) and these numbers drive that point home:

Application	No. of Applications	No. of Sequences
IND	912	15,827
NDA	939	8,365
ANDA	993	3,142
BLA	76	2,940
MF	182	307
FDA Internal	220	419
Total	3,327	30,999

So, where are the areas of expansion for eCTD? Europe is promising to enable eCTD as a viable submissions option across the EU in 2009, although individual nations may have legislation that makes complete abandon of an eCTD difficult. The EMEA is leading by example, requiring that all Centralised Procedures be submitted as eCTDs. Canada is still in a slow adoption mode, and Japan, while a growth area for drug submissions, have made their standard deviate enough from the other areas that there seems to be a lag in eCTD adoption there. Australia is rumored to be working on their Module 1 guidance. Expansion beyond ICH regions would be a nice precedent towards global adoption.

SharePoint Integration: A Commodity?

So, if you're in most parts of Life Sciences, you have probably heard a little bit of the buzz that Microsoft SharePoint has generated. SharePoint is being touted as a viable competitor to EMC Documentum, and although that transition is still to be proven, it is being looked at strongly by small and medium business who have not yet selected a document management system. SharePoint enters a competitive market, and our friends at the Laszlo letter have some thoughts on this issue.

With that in mind, many companies are examining their eCTD creation and related processes and trying to asses the cost and effort related in integrating these processes with SharePoint.

Well, good news! Much has been made of the integration between SharePoint and MS Office (which allows saving and check-in of office documents without navigating back to the DMS), but not enough has been made of the fact that SharePoint is by default exposed as a UNC file share. This is in most respects identical to the fileshares (and mapped network drives) that exist at almost all Life Sciences companies. This means that you should be able to use most software and processes that are compatible with a network share with SharePoint with little to no additional effort and cost. For a more detailed explaination, check out this information at MSDN.

Now, having said that, there are additional opportunities for more elegant integrations. SharePoint has an API available for development which could open up additional opportunities io integrate with SharePoints versioning model, properties, etc.