This page provides information about the possibility of using Extensible Markup Language (XML) for an IND Cumulative Table of Contents (CTOC). This was discussed at a public meeting held on January 26, 2001, where demonstration software was presented for authoring, validating and using a prototype XML CTOC.
Udated Software (May 14, 2001):
The working model that was presented at the meeting is available at: CTOC Working Model
Numerous requests for the software used in the meeting have been received. The working demonstration model is provided in a single zip file and an information file in PDF at the following links:
CTOC Model Download (You should place this zip file in an empty folder and extract the contents using appropriate Winzip software)
Information File (Information for installation of the CTOC Model Download in PDF format)
Since the January meeting, there are revisions in the model and the Document Type Definitions (DTDs) to simplify the folder structure and the hyperlinking software. Specifically, the "section" attribute is no longer used and no subfolder structure is specified for the PDF files containing review information.
Meeting Results:
The public meeting was a success because valuable feedback was received by the Agency about a potential new development in electronic submissions.
The public meeting Federal Register Announcement included a request for public comment on a series of questions. About a dozen complete responses were received. The list of questions and a summary of the comments is provided below:
1. Would a cumulative table of contents offer you advantages?
All responses to this question were yes. The participants indicated that functions provided by the model Cumulative Table of Contents (CTOC) offer benefits to the sponsors of Investigational New Drug Applications (INDs).
The ability to relate changes to previously submitted information without providing copies of obsolete documents is valuable. The ability to identify changes when reading an old document is also valuable. The vendors present at the meeting indicated that they would be able make and support tools that work as well as the FDA demonstration model as long as everyone aggrees on the standards upon which CTOC is built. The standards for CTOC type information are being developed at the International Conference on Harmonization (ICH) within the M2 group.
The CTOC model stores information about each file submitted to the IND. The more that the IND is separated into individual PDF files the more powerful CTOC becomes. This creates a more "granular" IND submission. Participants indicated that using smaller PDF files, each containing one report, procedure or item, has the potential to simplify the IND publishing process.
2. How difficult is it for you to create and maintain the XML files needed for the cumulative table of contents?
Using tools similar to the FDA demonstration CTOC Author tool present little challenge to the participants. It was felt that the FDA demonstration tool should be made available, even though it will not be fully supported for the long term. This will allow easy participation in any potential pilot and provide a starting point for software vendors to develop their own products. More information about this is in the piloting question (4.) below.
Vendors present at the meeting indicated that because XML is a well-supported standard across a number of industries and applications, there is an expectation of inexpensive off-the-shelf software availability.
3. How difficult will it be for you to incorporate the preparation of an XML document in your submission preparation process?
Some participants felt that they did not have enough experience to provide comment on this question. Among those willing to answer it was generally felt that as long as there was no requirement for a expert knowledge of XML there should be little difficulty. Tools similar to the FDA demonstration tools may be acceptable starting points.
The largest change that may affect IND publication is not related to XML. It is the concept of using smaller and more numerous PDF files. This has the potential to simplify the publishing process after an initial learning experience.
5. Do you have suggestions for improvements on the cumulative table of contents?
The following suggestions were received:
a. Incorporate a system of DTD change control.
b. Assure that the Acrobat indexing and search catalog are fully functional within CTOC.
c. Improve Keyword entry.
d. Allow for inactivation and reactivation of an entire IND.
4. Are you interested in piloting the cumulative table of contents in electronic IND's with the agency?
There is enough interest to justify planning a limited demonstration of the CTOC using models provided by sponsors. Approxomately 6 participants are interested in active participation in a demonstration program. Many others requested to be placed on the mailing list for such a program for information purposes.
These participants are providing the Agency with demonstration IND submissions that will help us develop our electronic IND review infrastructure while the submission standards are under development within the ICH M2 process. Instructions for assembling and validating the demonstration are provided.
If you want to participate in this demonstration, please contact Jon Clark at CLARKJO@CDER.FDA.GOV .
5. Are you interested in working with us to develop tools to be used with the cumulative table of contents?
Most of the interest here was from software vendors. The best way to incorporate this feedback is for them to participate in the limited demonstration described above.
6. Comments
The comments were incorporated into responses for the other questions
INFORMATION FROM THE ORIGINAL PAGE BELOW HERE
What is a Cumulative Table of Contents?
The Cumulative Table of Contents (CTOC) is a document that would list all the files submitted to an electronic IND, along with information about the type, location, and status of the file and any previously submitted information it references.
Why use XML?
Using XML-based Cumulative Table of Contents files (CTOC files) would allow the Agency to provide multiple views of the TOC for an electronic IND. This would bypass the expense of developing a proprietary database to index and access these documents or of developing multiple hypertext-linked TOCs in PDF format. The IND reviewer would use the CTOC files to access, sort, and search the electronic IND submission's content according to multiple criteria (e.g., amended, replaced, or current documents; submission dates; related documents; etc.).
Validation of the information contained in the CTOC files is automated and the information can be uploaded to or downloaded from databases. This is because of the structure provided by the Document Type Definition (DTD) containing the rules for formating CTOC files.
What XML files do the IND sponsors provide?
The sponsor would be responsible for providing the transport file formats being developed within ICH M2. These would be transformed into the CTOC files that keep track of all the submissions to an electronic IND. The specifications for the CTOC files is provided at the hyperlink below:
Technical Information:
XML describes the structure of a document in a machine-readable format called a Document Type Definition (DTD). These DTDs would be used across electronic IND submissions and would not need to be developed by anyone again or submitted with any IND submission. The CTOC files provided by the sponsor will obey the rules for sturcture defined in the DTD. There are two DTDs that control the structure of each of the two CTOC file types that are submitted:
DTD for Admin.xml File (updated in February 2001)
DTD Module TOC File (updated in February 2001)
XML can provide lists of valid information about the documents. There are two lists referenced by the TOC DTD File. One lists the headings for arranging the documents in the CTOC called "categories". The second lists the types of documents referenced in the CTOC files called "subcategories". The DTD files are:
DTD for Valid Heading Categories (updated in February 2001)
DTD for Valid Document Subcategories (updated in February 2001)
How would the Agency use the XML CTOC documentation?
By using stylesheets and programming scripts, the reviewer can search and sort the XML CTOC document. A model application illustrates this is available at the link on the top of this page and at "IND CTOC Model" .
Model Requirements:
Microsoft Internet Explorer® 5.0 (IE 5.5 preferred)
Please report problems using these materials to Jon E. Clark.
Feel free to report positive comments too.