Pharmaceutical and biotech sponsor organisations are making the switch from paper to electronic format for their marketing applications to the FDA. The decision to adopt the electronic common technical document (eCTD) submission format is a strategic one, offering the sponsor the following benefits:
- a greatly enhanced ability to efficiently organise, prepare and manage submission content
- the opportunity for streamlined interactions with agency reviewers
- a potentially more efficient and thorough agency review.
Barriers to adoption typically include:
- costs (initial capital of $200,000-300,000 and $100,000-200,000 annually) of building, validating and operating an electronic publishing system
- effort and time to learn and understand the regulatory requirements, and to develop the organisational competency to efficiently produce compliant eCTD submissions.
eCTD trends, facts and considerations
Since the FDA established the capability to receive and process submissions in eCTD format, there has been huge growth in the total number of eCTD submissions sent. According to the Office of Business Process Support of the Center for Drug Evaluation and Research (CDER) at the FDA, during 2005-08, eCTD submission volume grew at a compound annual growth rate of approximately 300%. In the years 2009 through 2012, volume has grown at rates of 40 to 50% a year.
Beyond the total number of electronic submissions to the FDA, it is important to understand the growth of eCTD as a fraction of total submissions. In 2007, eCTDs represented 10% of total submissions to the CDER. By March 2012, eCTDs were 59% of the total received. It is not unreasonable to expect that by the end of 2017, eCTD submissions may represent 80 or 90% of total submissions to CDER.
The growth in popularity of eCTD is remarkable considering that it has occurred without a mandatory requirement from the FDA. Effective from 1 January 2008, electronic submissions must be in eCTD format. Paper submissions are still acceptable and no date has yet been announced for an electronic-only requirement for original applications.
FDA representatives are increasingly speaking in favour of the eCTD. For example, at the Drug Industry Association (DIA) conferences on eCTD and electronic document management in 2008 and 2009, eCTD was described as the "agency’s preferred format". In pre-investigational new drug (IND) and pre-new drug application (NDA) meetings, it is not uncommon for review personnel to indicate their preference for eCTD or to request that submissions be made in the eCTD format.
The Regulated Product Submission (RPS) standard, developed by Health Level Seven, is a key element in the FDA bioinformatics vision for a "fully automated and interoperable infrastructure for managing the exchange of regulatory product information". The RPS will enable two-way electronic flows of information, providing an efficient conduit for review comments and questions to move from the regulatory agency to the sponsor.
Sponsors can use experience gained with eCTD submissions to prepare for FDA adoption of the RPS standard. As RPS is implemented, those who have adopted eCTD will likely be at a strong advantage.
The decision to adopt eCTD
For some organisations, the strong industry adoption trends and the agency’s clear preference for eCTD are reason enough to adopt. Others believe the navigation, ease of review and data transparency improves the quality of the submission, and the efficiency and thoroughness of the review. Others may have made their choice following a direct request from agency personnel to a specific application.
Use of the eCTD may also enable an organisation to achieve important internal benefits, such as:
- reducing the use and costs associated with producing and storing paper dossiers
- increasing the use and value from electronic document management system deployments
- streamlining the workflows in development, regulatory and marketing departments
- facilitating collaboration between teams of document authors, reviewers, publishers and external partners
- efficient re-use of documents and submission components for projects involving applications to global regulatory agencies
- enabling a more effective ability to respond to agency questions
- supporting efficient and effective submission lifecycle management
- providing a convenient mechanism for information sharing during licensing, marketing and other business partnership transactions.
Together, these benefits may represent substantial cost savings and efficiency gains over the pre and post-approval lifetime of a project. Sponsor companies who are hesitant to adopt eCTD may wish to consider the potential risks of the traditional paper approach. As the eCTD format becomes even more widespread, there is increased likelihood of an eventual mandate from the FDA.
The recently implemented requirements for electronic submission of drug establishment registrations and drug listings provide a strong demonstration of the FDA’s ability to impose electronic requirements.
Preference for the eCTD among FDA review personnel may ultimately leave paper submissions at a disadvantage. While current PDUFA review period targets are not different between paper and electronic submissions, it is possible that future targets will be set according to submission format. It is also possible that the ease of review of eCTD will see a reduction in actual review times for eCTD format submissions.
Sponsors planning or considering submissions to more than one jurisdiction, directly or through marketing partners, may disadvantage their business strategy by pursuing paper submissions. It can take more time, effort and cost to produce additional paper submissions compared with the efficient re-purposing of content that the eCTD enables.
Sponsors submitting a paper IND or NDA may need to make an unplanned and potentially last-minute conversion to the eCTD format, due either to an FDA mandate or a request by FDA representatives that is communicated in a pre-IND or pre-NDA meeting. Such a conversion could divert critical focus from the submission content, and possibly delay the filing and subsequent approval.
Common eCTD adoption barriers
The upfront and ongoing costs to establish and maintain an electronic publishing platform represent a significant barrier to eCTD adoption. The principal upfront cost components are as follows:
- publishing software and hardware
- system and process validation
- training for system administrators and publishers.
Ongoing expense components are:
- publishing software maintenance and support fees
- system administration and operations
- publishing operations (staff).
A system of very modest capacity might represent a total capital commitment of $200,000-300,000 in the first year. The cost of the software alone is a small portion of this. With one or two dedicated resources for administration, maintenance and publishing operations, ongoing expenses might range from $100,000-200,000 annually. Capital and first-year expense together represent a potential requirement of $300,000-500,000.
A software-as-a-service option for the publishing system might allow this total to be reduced by $50,000-100,000, potentially yielding in the range of $200,000-250,000 for a system with limited capacity. Effort to establish and maintain a system can be substantial. To put a system in place, a small team of resources is typically required to accomplish the following:
- definition of requirements
- product research and evaluations
- system procurement
- system installation, configuration and testing
- validation documentation and execution
- FDA eCTD pilot execution
- FDA Electronic Submissions Gateway pilot execution.
While every implementation project is different, a typical time-frame to complete all of the above steps might be nine to 18 months, depending on the system size and configuration complexity.
Every electronic publishing system implementation carries with it the risk of failed submissions. To produce compliant eCTD submissions requires a deep knowledge of the regulatory requirements and specifications for eCTD, as well as an ability to configure and operate a publishing platform to correctly assign every document-level and submission-level attribute. To develop deep subject matter expertise in both domains requires talented people and an organisational commitment to train and support these individuals so they may acquire and maintain this expertise.
Overcome eCTD adoption barriers with outsourcing
Given the initial costs described earlier, it is clear that the implementation of an in-house system is difficult to justify for a sponsor with modest submission requirements on an annual basis. These sponsors and others may well find a solution in eCTD outsourcing, collaborating with a service provider or partner company experienced in eCTD publishing and equipped with a high-capacity platform.
Many original eCTD submissions may be published by a service provider for between $10,000 and $50,000, less than 20% of the first-year costs of an in-house system. For companies with a focus on early-stage development, with only IND applications and associated amendments to submit, the business case for an in-house platform is difficult if not highly improbable. Equally, a sponsor with one NDA or a small number of abbreviated NDAs to submit annually is likely to find the economics of outsourcing far more favourable.
Outsourcing may also save time and effort involved in maintaining an in-house publishing system, leading to immediate eCTD capability compared with a nine to 18-month delay. It can also offer substantially reduced risk of failed submissions. A professional service provider with an extensive eCTD track record likely has the expertise necessary to help a sponsor successfully navigate all of the complex regulatory and technical details of their electronic submission.
Finally, outsourcing may represent an attractive short-term option for sponsors to gain eCTD experience, even if their long-term plan is to implement an in-house system. Equipped with real eCTD experience, a sponsor will be better-equipped to assess their requirements, select the best solution, and understand the effort associated with implementing, operating and maintaining a publishing system.
This white paper was originally published on www.cardinalhealth.com
