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Archive for the ‘Regulated Product Submissions (RPS)’ Category

PDUFA V and the Impact on You

posted by Jason Rock @ 3:08 PM
Tuesday, March 20, 2012

In September, the FDA issued its Proposed PDUFA V Reauthorization Performance Goals and Procedures for Fiscal Years 2013 through 2017.

There are many proposed improvements related to the FDA review procedures, including a mandate of the eCTD. This mandate will start 24-months after publication of the corresponding final guidance for marketing applications and 36-months after publication of the final guidance for commercial INDs and amendments.

The final guidance will be released no later than 12 months from the close of a public consultation period on the draft guidance. The corresponding draft guidance will be issued by December 31, 2012 at the very latest. The initial guidance will reference eCTD version 3.2.2; however, the final guidance might refer to a different standard, namely RPS, if the FDA determines the new standard is more efficient and effective. The FDA also mentions that they “shall also accept submissions using the previous version for no less than twenty-four (24) months.”

Although many of the goals for priority and standard NDA and BLA review (including Class 1 and Class 2 resubmissions, efficacy supplements, and manufacturing supplements) remain the same as under PDUFA IV, the proposed PDUFA V agreement establishes a new review model that will apply to all New Molecular Entity (“NME”) NDAs and original BLAs received from October 1, 2012 through September 30, 2017, including applications that are resubmitted following a refuse-to-file action.

The new program includes a pre-submission meeting, a mid-cycle communication, and a late-cycle meeting at which the FDA review team and the applicant will discuss the status of the review of the application. At the pre-submission meeting, the FDA and the applicant will agree on the content of a complete application for the proposed indication(s), and the applicant may also reach agreement on submission of a limited number of application components.

Another important change is the treatment of “major amendments” to pending applications.

Under PDUFA IV (and FDA’s regulations at 21 C.F.R. § 314.60), “[a] major amendment to an original application, efficacy supplement, or resubmission of any of these applications, submitted within three months of a goal date, may extend the goal date by three months. A major amendment to a manufacturing supplement submitted within two months of the goal date extends the goal date by two months” (emphasis added). Under the proposed PDUFA V agreement, however, “[a] major amendment to an original application, efficacy supplement, or resubmission of any of these applications, submitted at any time during the review cycle, may extend the goal date by three months”, and “[a] major amendment to a manufacturing supplement submitted at any time during the review cycle may extend the goal date by two months.”

The Latest on Regulated Product Submission (RPS)

posted by Jason Rock @ 2:26 PM
Monday, June 6, 2011

It has been a while since I have updated you on the RPS project. Back in September, I had expressed cautious optimism on being able to bring RPS to vote (ballot) in May 2011. We did not make the May 2011 ballot, thus the ballot is now delayed until September 2011.

We did not make the ballot, in my opinion, since we are still working on refining all of the requirements. We have two requirements left to be finalized; namely, being able to reuse studies and all of the components in two applications and support for the new European variation legislation.

Being able to reuse studies and all of the components in two applications will allow sponsors to create a study, define all of the components (e.g. protocol, study report body, synopsis, etc) in one application (e.g. investigational application) and refer to the study in your marketing application. This benefits sponsors since it allows them to synchronize content for a study in more than one application.

The new European variation allows a sponsor to create one sequence (e.g. a manufacturing change) and apply that sequence to many products. This will benefit sponsors since they will no longer have to track multiple products for one manufacturing change.

To create the publication before the ballot opens, HL7 headquarters needs content over a month in advance. The ballot period is one month: see the following sample HL7 publishing schedule.

  • 5 weeks before publication: Initial Content Due – Submissions should be as complete as possible, particularly for a first-time ballot. In all cases, the submission should indicate the topics and artifacts that will be included in the forthcoming ballot. If possible, complete preview material should be submitted so that it can be made available on the Ballot Preview site by the end of this week.
  • 4 weeks before publication: Ballot Preview – All content to be included in the preview site is due. The Ballot Preview site (based on the previous ballot) will go live.
  • 3 weeks before publication: Reconciliation, Complete & Supporting Content Deadlines – All previous ballot reconciliations for normative ballots must be completed and appropriately captured on the ballot website.
  • 2 weeks before publication: Final Content Due – All final corrective changes to existing content are required.
  • 1 week before publication: Provisional Ballot Opening – This is the earliest date that the ballot site can open and be announced to the membership. In any event, the ballot must open before the end of this week. 

I feel confident that we will make the September 2011 ballot. Stay tuned for more information.

A number of good articles related to eSubmissions have been posted online recently.  Below, a recap based on posts from my twitter account,  

In Standards news:

Finally, a few upcoming conferences have been announced:


Recently, I was providing some training to a GlobalSubmit client and one of the participants asked me about an xml document that was present in a folder along with the sample eCTD that we use for training.  The document was called “porp.xml”.  I explained that GlobalSubmit’s VALIDATE product can transform eCTD into RPS and when it does, it produces the XML backbone used for RPS, which is called porp.xml.  This is a single xml document that replaces eCTD’s index.xml, regional xml, and study tagging files.

The next question was “Why in the world is it called porp?”  I couldn’t answer that one.  But recently, I attended several training classes held by the font of all RPS knowledge, GlobalSubmit’s CTO Jason Rock.  I took advantage of that opportunity to gain insight into what is different about RPS xml when compared to eCTD xml.  [For the record, it’s called porp.xml because it had to be different than eCTD – and porp is a combination of po, the business domain within HL7, and rp for regulated product.]

But on to bigger topics.  I, along with most other remotely technical people who have dabbled in eCTD for years, am pretty comfortable with eCTD xml.  I can create the xml for a sequence by hand, and I can look at a sponsor’s xml and figure out what it represents and what is wrong with it.  But when I look at the xml for RPS, all bets are off.  Jason walked us through the xml in our training class and here are some of the observations that I made:

  • With RPS, any pretense of representing the xml as “human readable” is over.  New code systems and levels of indirection make this almost impossible.
  • The table of contents is not readily apparent.  It’s created by combining a content code and keywords to determine placement within the TOC or tree.  For example, the location of a drug substance specification would be determined by a code representing its document type and then several keywords representing substance name and possibly manufacturer – not by nesting the document within a TOC section.
  • Everything is referenced by ID.  For example, a Context of Use (sort of the replacement for a leaf) contains references to the ID of a content file, as well as any keywords necessary, such as a code representing a specific route of administration or species.  Instead of just looking at something like a study ID, you see a code representing the study ID which you must then locate.
  • IDs themselves are more complex.  With RPS, IDs must be either an OID or a GUID.  An OID is formed by taking a unique numeric string (e.g. and adding additional digits in a unique fashion (e.g.,,, etc.).   A GUID is a 32 character hexadecimal character string, such as {21EC2020-3AEA-1069-A2DD-08002B30309D}.  Either way, they are much less easy to identify visually that the simpler IDs used by most of today’s eCTD publishing tools.
  • Many new concepts are introduces such as “Sets” (the equivalent of version trees in a document management system), explicit ordering of elements (a concept not present in eCTD, although many people assume it is), and status (active vs. obsolete, applies to keywords as well as documents).

The bottom line is that RPS XML is only for the brave.  Most of those intrepid souls creating XML by hand for eCTD will have to give up that practice, and everyone will need to ensure that they have a publishing vendor who is highly knowledgeable concerning the standard and who is able to produce very high quality software.

For those of you who would like to see what RPS xml looks like, check out Example RPS Code:  BLA Multiple Sequence along with other Informational Documents (i.e. Plans, Rosters, RPS Technical Walkthrough, Implementation Guide, etc. on the RPS wiki.  

Advanced eCTD and the Educated Sponsor

posted by mr.erhabi511 @ 6:31 PM
Monday, May 10, 2010

This week’s blog posting is from Rahul Mistry, CEO of GlobalSubmit, who recently was a featured speaker at the RAPS workshop entitled “Advance eCTD Submissions”.  Rahul’s presentation focused on eCTD quality, a topic that obviously interested the audience based on the significant number of questions that he received.    

Two weeks ago I had the pleasure at presenting at an Advanced eCTD Workshop hosted by RAPS in Rockville, MD. During the course of three days, I had the pleasure of speaking and listening with a number of people from different companies. Here is what I learned:

  • While the workshop provided for an international perspective on eCTD, most attendees wanted to focus on the US. It became apparent that the primary strategy of many companies is to produce all US submissions in electronic format, and handle other regions as a secondary goal, if at all.
  • There continues to be confusion on regulatory activities, and, specifically how to correctly use the related sequence tag in the regional XML file. Please see the article “Secrets of eCTD Related Sequences” for details.
  • The FDAs infrastructure and current practices are of particular interest. During my presentation I was able to address a number of questions including the FDAs severity levels, and what the consequences are of errors in a sponsor’s submission.
  • Most people are not aware of the advantages of using fillable forms for the FDA which is the ability to automate the integration of a submission with other systems that exist at the FDA, such as submission tracking.
  • There was great interest on RPS and how it will impact the day-to-day lives of a publisher. The reality is that there will be very little that changes for sponsors – the big changes are for the vendors who need to update their software, and even of then, the change is minimal. A fair analogy would be saving a Microsoft Word document as Word Perfect or PDF file. The author using Microsoft Word need not know how Word Perfect saves its files; rather it is Microsoft’s responsibility that they save the document correctly.
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