Planning is key
According to a 2008 survey by ISI, INDs were the most anticipated submission for 2009, with two-thirds of the companies surveyed
in Phase I development reporting that they planned to file an IND last year. A majority of the 216 survey respondents (63%)
were emerging companies with fewer than 250 employees.
Figure 1: Investigational new drug (IND) applications lead the way in planned submissions. BLA is biologic license application.
NDA is new drug application. Source: ISI.
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The US Food and Drug Administration advises sponsors to submit INDs in eCTD format to facilitate review and life-cycle management
throughout the product portfolio lifespan. Strategy is the key to getting the most out of IND eCTD submissions, and there
needs to be a good understanding of how the IND fits into product development and global marketing plans so that documents
can be harmonized to accommodate present needs and future uses. This important step should not be overlooked, as regulators
worldwide have cited a lack of eCTD experience and planning for a myriad of submission mistakes and delays. FDA and the European
Medicines Agency have suggested that those new to the eCTD process seek expert help for submissions (see Figure 1).
Moving from an IND to an NDA
There is no one-size-fits-all approach to IND building. Each application must consider long-term product uses and global marketing
goals, so that submission documents can be created that easily flow within the application or across applications of the same
drug product. Regional regulatory issues such as granularity and content requirements should be considered at the planning
stages to gain the maximum utility and flexibility because the IND eCTD becomes the foundation for future regulatory submissions
and applications. By leveraging the regulatory similarities and consistencies across target documents, sponsors can develop
a cohesive strategy that will save time and money in the submission-publishing phase by taking advantage of eCTD cross-application
referencing capabilities.
Cross-application linking is possible within the following eCTD submission combinations:
- IND to IND applications
- NDA to IND applications
- Abbreviated New Drug Applications (ANDA)
- Select Biologic License Applications (BLA) submitted to FDA's Center for Drug Evaluation and Research (CDER).
Cross-application functionality currently is outside the scope of EU eCTD specifications, however, and it is not yet available
for BLAs submitted to FDA's Center for Biological Evaluation and Research (CBER). FDA is encouraging sponsors to build submissions
that use the cross-reference linking capabilities of the eCTD format to reduce submission size, lessen redundancies, minimize
errors, and improve life-cycle management over the product's application lifespan.
IND documents that will typically be reused in an NDA application include:
- M5-Protocol
- Investigator CVs
- Form 1572s
- M4-Noclinical data
- M3-CMC or quality information.
However, Clinical Study Reports (CSRs), or components of CSRs, are far more granular in the IND than in the NDA (in this case,
for example, documents should not be cross-referenced). When making reference decisions, sponsors need to remember that one
of the key drivers in making the cross-application linking function work is determining whether or not the granularity will
change from the original IND submission to the NDA submission. If there are differences in the level of granularity, it will
not work. FDA encourages sponsors to incorporate communication with regulators (esub@fda.hhs.gov
) into the submission planning stage to gain additional information and to test sample cross-application links before submission
(1).
Using the right tools
As sponsors develop a proactive plan that will set up documents for reuse and life-cycle management chores throughout a product
application, they must also seek appropriate submission publishing tools to ensure proper integration of cross-application
linking and associated life-cycle changes into the submission process. Before taking advantage of the cross-application linking
benefits, sponsors need to have a capable eCTD tool or a vendor that does.
Whether compiling eCTDs in-house or outsourcing submissions, sponsors should ask:
- What does your technology look like?
- Can your submission building tool support cross-application linking?
- Is there life-cycling functionality available to automatically carry the 'virtual' link to the latest document version should
the reference document in the IND be updated after the NDA link has been established?
- Do you have a process defining the quality control steps taken to verify the link function under a variety of process circumstances
and business cases? If so, what are the business-case captures of the quality control process?
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