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The CDER Small Business Assistance Program recently posted a web-based training course on electronic submission in eCTD format. The primary goal and purpose of CDER’s training is to encourage sponsors to submit in eCTD format. The training explains the FDA’s policies and practices regarding electronic submissions and provides sponsors with the fundamental information needed to submit new and transition old applications to the eCTD format. The training also includes information for sponsors that are currently submitting in paper format and would like to transition existing paper applications to eCTD.
The web-based training course takes about an hour to complete and can be accessed here.
Recently a client asked me if the FDA would accept a PDF/A document. The short answer is yes, but I would not build your system based on the PDF/A standard. I will explain why below.
PDF/A is an ISO-standardized version of the Portable Document Format (PDF) specialized for the digital preservation of electronic documents. PDF/A differs from PDF by omitting features ill-suited to long-term archiving, such as font linking (as opposed to font embedding). PDF/A-1 is based on the PDF Reference Version 1.4 from Adobe Systems Inc. (implemented in Adobe Acrobat 5 and latest versions) and is defined by ISO 19005-1:2005, an ISO Standard that was published on October 1, 2005:
Below is a snippet from the FDA’s PDF Specifications
(http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM163565.pdf)
PDF versions 1.4 through 1.7 are acceptable. Submitted PDF files should be readable by Adobe Acrobat 8.0, should not require additional software or plug-ins to be read and navigated, and should be text searchable. If plug-ins are used during the creation of a PDF document, prior to submitting the document, ensure that a plug-in is not needed for review or archive.
The specifications for PDFs are backward inclusive. The PDF 1.7 specification includes all of the functionality previously documented in the Adobe PDF Specifications for versions 1.0 through 1.6. Therefore any agency that accepts PDF 1.7 (or PDF 1.4) will accept PDF 1.0.
This is also true for PDF/A. Since all PDF/A files are PDF 1.4 files.
The problem with PDF/A is that many believe that PDF/A does not support links external to the document are valid. The following article refutes that claim (http://www.ebriefpro.com/pdfs/pdfa.pdf).
Regardless, if PDF/A actually allows links external to the document, some rendering tools will strip out external links when complying to PDF/A.
In conclusion, yes the FDA will accept PDF/A since there is no way to distinguish a PDF/A from PDF 1.4; however, your rendering tool might remove your important cross-document links. Thus, I would not recommend building your systems around the PDF/A standard.
Publishing Best Practices: 1 File is Applicable to 2 Locations in the CTD Structure Within or Across Applications
In some cases, a document in an eCTD application may be applicable in more than one content location in the CTD structure. For example, a single nonclinical pharmacokinetic (PK) study may have evaluated both absorption and distribution of the drug. In the CTD structure, the study report could belong in either Module 4 Section 4.2.2.2 Absorption, or Module 4 Section 4.2.2.3 Distribution. The best practice recommendation is for the sponsor to submit one copy of the report in the application, and provide a reference to the report from the second location to direct the reviewer where to find to the content. For example, the nonclinical PK study report would be provided once in Module 4, Section 4.2.2.2, and a single page “Note to Reviewer” would be provided in Module 4, Section 4.2.2.3. The “Note to Reviewer” should state a brief explanation that the study evaluated both absorption and distribution of the drug and the report is provided in Section 4.2.2.2. Study tagging files should be created in both 4.2.2.2 and 4.2.2.3 for the study, and the “Note to Reviewer” should be tagged as study-report-body. This method of cross-referencing content applicable to more than one location in the CTD structure will clearly point the reviewer to the relevant information in the eCTD application.
This same technique may be used to cross-reference information between two applications. For example, a clinical study may be relevant to more than one eCTD application. Rather than submitting the study documents to each eCTD application, the information may be submitted once, and then referenced in the second application utilizing the “Note to Reviewer” practice. The sponsor should include Module 1.4.4 Cross Reference to Other Applications in the eCTD application. Prior to implementing this practice, it is recommended that the sponsor receive confirmation from the review division. We do not recommend sponsors create hyperlinks from one eCTD application to another. In order for cross-application hyperlinking to work, the applications must reside on the same physical server and the application folder names cannot change. Although cross-application hyperlinks may work at the time of submission, there is no guarantee that the information will continue to reside on the same physical server and retain the same folder naming structure throughout the months and years ahead. To avoid broken links, the “Note to Reviewer” method may be employed to gain the benefits of cross-referencing information from one application to another, while maintaining the technical integrity of the eCTD application over time.
Educational Webinar Recap: Preparing for the eCTD mandate
The FDA is planning to mandate electronic submissions in 2014. Since most large pharmaceutical and biotech companies already submit electronically, the greatest impact will be to the smaller companies that do not have substantial IT infrastructure in place and lack the resources of their larger peers.
Jason Rock, Chief Technical Officer at GlobalSubmit, offered greater insight into this topic during a free educational webinar, “Preparing for the eCTD Mandate”, on Wednesday, February 27th at 12:00 p.m. EST.
During this discussion, Jason discussed the implications that PDUFA V will have on regulatory submissions, in particular the mandate to convert all regulatory submissions to eCTD.
We received some great questions during the webinar, and have provided these questions and answers below.
Q: Is it mandatory to put all strength in the same 32P, or can we make one 32P for each? But files are common for all strengths?
A: No. Attributes like drug product are not stored in any system for analysis purposes (e.g. show me all documents for this drug product). Attributes are only used for organization. You should look at your submission, and determine the best organization. It is not a good idea to repeat content where it does not need to be repeated.
Q: How can I manage broken links during the lifecycle?
A: You can always replace a document if you have broken hyperlinks. I would consider that a reviewer will re-review a document if you submit it again. If the document only has one broken hyperlink, then I would not resubmit that content.
Q: Can you tell us about PDF 1.7 and below, or PDF 1.4 & 1.7?
A: The agencies are asking for PDF 1.4 to 1.7. Since the PDF standard is always additive, PDF 1.1 is fully compliant to PDF 1.7 (or PDF 1.2 and above).
Q: For replace and delete operations, when the leaf IDs don’t match, will the FDA still be able to accept and review?
A: Yes. You should think about resubmitting the leaf if the history is really important.
Q: What is the typical cost of software?
A: Every vendor charges a different amount for different parts of the product. The number of submissions and users you have will also impact pricing. If you are interested in learning more about GlobalSubmit, please contact sales@globalsubmit.com.
Q: Should PDF be text-based meaning “OCR”?
A: Yes, wherever possible.
Q: What is the main difference between eCTD and RPS?
A: eCTD is version 3.0 and RPS is version 4.0, so it’s essentially just a new version. The big difference is that RPS is an open standard, while eCTD is closed.
Q: If a sequence number exceeds 9999, what will be the next step?
A:The next version of eCTD will have 6 digits. Right now, no submission is close to going over 9999.
Q: What are STFs? Can you provide a snapshot of one?
A: STFs are study tagging files. STFs extend the eCTD to add extra sections like protocol, study body, etc.
Q:What aspects of the eCTD process can a typical vendor usually handle?
A: Vendors can pull your documents together, reformat them, and create an eCTD XML file for you. For more information on GlobalSubmit, contact us at sales@globalsubmit.com.
Q: The way I understand STFs is that a tag is needed for the protocol, and a tag for the report. Are separate tags needed for each component of the low level granularity report?
A: Correct.
Q: What about DMF submissions? Is there also a plan to have eCTD mandatory? If yes, when?
A: DMF submissions will eventually be mandatory. The guidance for these submissions is currently being worked out.
Q: Will promotional submissions to OPDP most likely be required in eCTD by the end of 2014 Q1?
A: No.
Q: Will we be able to change incorrect metadata with future versions of eCTD?
A: Yes, you should be able to change metadata in future versions (i.e. eCTD version 4).
Q: Is it cheaper to outsource publishing then have it in-house?
A: It depends. There are a lot of factors that go into the pricing of software and services. If you are interested in learning more about GlobalSubmit, please contact us at sales@globalsubmit.com.
Q: Can publishers submit to the FDA gateway if I am located in India?
A: Yes, you can submit to the gateway from anywhere in the world.
Q: What is meant by publishing? Please clarify since this is not publishing to paper.
A: Publishing means eCTD assembling.
Q: As a follow-up, what is the most effective way of training employees to enable us to bring eCTD publishing in-house?
A: I recommend a training program, get a trainer, go to classes. The RAPs classes are a good place to start. Then for first submission, you should also get a contractor to help you through the process. There are a lot of unknowns that you will want to have an expert to help guide you through them.
Q: What criteria should a company consider in choosing an eCTD publishing software?
A: It is important to consider the vendor’s experience, the number of submissions completed, the relationships that vendor has with regulatory agencies. Other key criteria are the quality checking processes.
Q: Is eCTD required for academic institutions that have sponsor-investigator INDs? IDEs?
A: Most academic institutions will be exempt, depending on the size of the submission. Single investigator studies will be exempt.
Q: You mentioned the available set of validation criteria. However, how do you find those high/low errors?
A: In my presentation, I provide a link to the FDA website. For more details visit: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm153574.htm
Q: What is the purpose of the us-regional.xml file?
A: This is essentially just another XML file. This is where the application, sequence number, and sequence type goes. This file is not harmonized, so each region has their own standard. This will also go away with RPS.
Q: What about legacy CSRs?
A: You should not need to reconvert legacy documents; a scanned version of the document should be fine.
Click here for a copy of the presentation slides.
Free Educational Webinar: Preparing for the eCTD mandate
Presentation Details:
The FDA is planning to mandate electronic submissions in 2014. Since most large pharmaceutical and biotech companies already submit electronically, the greatest impact will be to the smaller companies that do not have substantial IT infrastructure in place and lack the resources of their larger peers.
Jason Rock, Chief Technical Officer at GlobalSubmit, will provide greater insight into this topic during a free educational webinar entitled, Preparing for the eCTD Mandate, on Wednesday, February 27th at 12:00 p.m. EST.
During this discussion, Jason will discuss the implications that PDUFA V will have on regulatory submissions, in particular the mandate to convert all regulatory submissions to eCTD. By the end of this interactive session, you will have the information necessary to effectively prepare your organization for the impending mandate.
Top 3 Learning Objectives:
1. Understand PDUFA V’s repercussions on regulatory submissions
2. Learn the steps needed to move from paper to electronic submissions (eCTD)
3. Realize the advantages of direct communication with the FDA during the approval process
Presenting Expert:
Jason Rock, CTO at GlobalSubmit
Click here to Register
Drug Development Costs Continue to Rise
The cost of bringing a new drug to market is often cited as $1.3B according to a Tufts University study from several years ago. In this study, the $1.3B estimate is an increase of 60% from the previous estimate of $800M. Much of the cost associated with drug development is attributed to resources invested in drugs that never make it to market. Only one out of 10 drugs that are used as part of a clinical trial will become a marketed product. Therefore, the research and development investments and budgets include the 90% of drugs that fail to reach market, and thus never provide return on investment. The other 10% of drugs must cover the cost of the failure rate, as well as all other costs, such as administration, sales, marketing, etc.
A recent article in Forbes estimates that the current cost of drug development is closer to $4 billion. While the average cost may be $4 billion per drug, some companies may see costs as high as $12 billion. The cost of drug development was analyzed in several ways, and included data over the past 15 years. In the end, the different analyses yielded similar and alarming high numbers. For example, one simple analysis divided the number of approvals for each company, and divided it by the total research and development budget. Since the biggest culprit in the cost of drug development are the failed drugs, companies who have fewer drugs that make it to market per dollar spent in research and development tend to have higher drug development costs.
Naturally, the price of drug therapies has also risen and is part of the much larger debate on how to reform healthcare. While there are no easy answers, the only thing that is certain is that the current trends cannot continue forever.
Transitioning an Existing Application to eCTD
The transition from paper-based or non-eCTD to eCTD application can be done at any time the sponsor is ready to implement eCTD. It is important to note that once an eCTD submission has been made to an application all subsequent submissions to that application must also be in eCTD format. Typically, the first submission sent to the application as an eCTD will contain the appropriate form (1571 or 356h) and cover letter indicating that all future submissions to the application will be done in eCTD format. After the first eCTD sequence is sent, sponsors should submit new information only to the IND. It is not necessary to resubmit information that has been previously submitted to the application in paper or non-eCTD format.
When a sponsor company references information that was previously submitted in non-eCTD format, the sponsor should provide enough information so that the reviewer can locate the referenced information. A common practice for cross referencing previously submitted material includes providing the application or master file number, serial number, date of submission (e.g. cover letter date), the document name, and volume/page number within the referenced document that contains the supportive or relevant information referenced in the new document. A document detailing previously submitted information that is referenced by the current application can be submitted in Module 1, Section 1.4.4 Cross Reference to Other Applications of the eCTD.
Regulatory Publishing is unfortunately not an exact science. Many different factors from different facets of an organization come into play as you prepare your applications for submission. Coordination is a must in organizing and managing the process from start to finish. Using templates to ensure content is written in the proper format, rendering into acceptable PDF documents, compiling them into the appropriate table of contents, and creating the corresponding XML required are just some of the many tasks made easier by software solutions currently available. But what about those “gray” areas, such as the quality assurance of your bookmarks and hyperlinks, or managing the complexity of converting an IND into an NDA? Perhaps your regulatory workload has expanded and resources are unavailable. The workflows needed for successful and timely submissions can be enhanced by incorporating a solution mix which includes both software and servicing options.
Software can quickly make your internal operations automated and run smoothly, but many times, industry expertise is required to complete a task. Having access to a reliable subject matter expert (SME) who can assist with operations can vastly improve both the productivity and quality of your submission by taking advantage of their direct experience. Their out-of-the-box thinking and suggestions can provide insight to your regulatory team that can significantly impact your future approach. Leveraging their knowledge and incorporating best practices gained can help you discover new, more efficient ways to solve problems. This powerful software/service mix can be the boost your organization needs to redirect your internal resources to focus on new and innovative endeavors.
Simultaneous Submission to Multiple Regions
Traditionally, a pharmaceutical company would seek to have a drug approved in one region, and then move to other regions around the world to seek approval. Typically, companies would seek approval in their country of origin, then pursue the biggest markets, and finally focus on the rest of the world.
The advent of CTD provided a common organizational structure to create submissions around the world. The ability to reuse large parts of submissions created for one region to submit to another provided the opportunity to submit to more than one region at the same time. Furthermore, with electronic submissions, the ability to reuse and manage submissions was greatly streamlined, while also introducing some new challenges. Namely, with the realistic opportunity to simultaneously submit to multiple regions, there is an increasing pressure to provide new applications to major markets at the same time.
So the question becomes: Is it advisable to submit to multiple regions at once?
From experience we know that simultaneous submission to multiple regions is possible; however, planning this approach is directly related to its success. Oftentimes when new filings are created by the regulatory operations group, it is an all-hands on deck experience with everyone working to 110% of capacity. Once the submission is out the door and the adrenaline has worn off, fatigue sets in. Naturally, your team is exhausted, the personal and vacation days that were put off are taken, and your staff is no longer capable of producing at heroic levels. Fortunately, the number of follow-ups and responses after the initial submission is manageable to a single agency with reduced resources. Nevertheless, if your team chooses to submit to two or three or (gulp!) more agencies at the same time, the number of commitments for follow-ups and responses to the agencies after the initial filings will overlap from a timing perspective. That said, the information requests will diverge. This leaves you vulnerable to having too much work and too few resources.
The key to success is planning and communication. Planning far ahead of the actual submission and setting achievable milestones and expectations with the entire team is essential for success. Communication among the many contributors is important because the decisions and delays upstream have tremendous impact on other team members. The earlier you can finalize sections of the application, the easier it will be to handle the last minute changes which are inevitable. For example, Module 4 can realistically be locked down, finalized, and published six months in advance of the actual submission date. By finalizing sections of your submission in advance and allotting enough time for multiple reviews, you ensure that a high quality submission is being built throughout the process.
Lastly, during the planning process you need to map out the post-filing commitments for each region that you are submitting to, and ensure you have the resources in place to manage that process. You may find that delaying one submission in a region by two weeks will provide a less stressful and more realistic project plan for your team.
eCTD Spurs Communication Amongst Regulators
When the ICH first met in 1990, the group of men and women could only dream of the ways in which their work would influence the future of regulatory authorities. One of the greatest accomplishments of the ICH is the Common Technical Document (CTD) which provides a common organization and structure for the information that drug companies submit. As the CTD evolved into its electronic counterpart, the eCTD, the ways in which drug regulatory authorities reviewed applications continued to progress. Today, regulators have acquired enough experience to develop best practices, and have dramatically increased the efficiency of the drug review process.
One lesser known aspect of this efficiency gain is that drug authorities often discuss applications and their review practices. For a number of years, the US FDA and EMA have shared confidential information about drug application reviews. These discussions often involve specific applications that are seeking approval in both regions. Because a common format is shared, sponsors are able to provide the information to multiple agencies simultaneously. Furthermore, since the applications are formatted in the same way, the regulators are able communicate their common concerns very effectively as the submissions are evaluated.
The ability of submissions to be received in eCTD format has allowed for greater efficiencies. Besides the obvious fact that electronic submissions can be delivered faster and more information can be stored in a smaller area, the eCTD format has led to repeatable best practices. The development of reviewer templates and tools for each discipline is made easier by having a common electronic format. Many of these tools and practices can be and are shared with other regulatory authorities resulting in harmonized good practices. The end result is the creation of a consistent approach to evaluating drug submissions and reaching conclusions in a systematic way.