Some of the largest entities in the pharmaceutical industry, including pharmaceutical manufacturer GlaxoSmithKline and industry trade groups BIO and PhRMA, are weighing in on a recent draft guidance published by US regulators, saying minor changes are needed to reflect the clarity of the guidance and its lifespan.
Their comments reference a 3 January 2013 draft revision of guidance for industry that would require all new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologic licensing applications (BLAs) and investigational new drug applications (INDs) use the electronic common technical document (eCTD) format.
The form has been in use by FDA since 2003, and was always meant to be the ultimate successor to the paper-based CTD, which can be considerably more time-consuming to review and analyze, thereby slowing down approval for some applications.
But under the FDA Safety and Innovation Act of 2012 (Sec. 1136), FDA was given the authority to require submissions in eCTD format starting "no earlier than" two years after the publication of final guidance in the Federal Register.
The implementation of the eCTD requirements will be phased in, with new drug applications (NDAs), abbreviated new drug applications (ANDAs) and biologics licensing applications (BLAs) required within 24 months, and investigational new drug applications (IND) submissions due in eCTD format 36 months after the final guidance is published.
Notably, the guidance will not make the same requirements of drug master files (DMFs) or promotional labeling submissions, though FDA said it "accepts and strongly encourages the submission" of both on a voluntary basis.
The guidance is also unusual in that Congress specified that it needed to establish a legally binding submission format (eCTD 3.2.2.). Under normal circumstances, guidance documents cannot, by law, establish legally enforceable responsibilities. The other parts of the draft guidance are still not legally enforceable, FDA noted.
And while industry generally had good things to say about the draft guidance-by all accounts one that will heavily affect the industry-some entities took issue with parts of the guidance.
The Biotechnology Industry Organization (BIO), for example, said that the guidance could use more specificity in parts, particularly in regards to referencing "specific software versions and formats for all data formats and specifications as opposed to referencing additional technical resources found on FDA's eCTD website."
"While we understand and appreciate FDA's intent to provide the additional technical specifications as separate, stand-alone […], BIO believes that reference to the FDA website for technical specifications documents and other resources that are subject to change without notice, not only undermines the intent and spirit of the PDUFA V Agreement, but also hinders the successful implementation of data standardization efforts by removing the security that comes with clear and transparent requirements and requests," BIO wrote, referencing the Prescription Drug User Fee Act (PDUFA V) contained within FDASIA.
Added BIO, "Without such security, both industry and FDA are inhibited from undertaking long-term planning decisions and making the necessary technology investments that truly improve the efficiency of the review process."
Industry group PhRMA, meanwhile, had more issues with the guidance than did BIO. For example, the group said it was not of the opinion that FDA should automatically assume that the 3.2.2 eCTD standard was without problems. In particular, PhRMA noted significant backwards compatibility issues between the 3.2.2 standards and the impending 4.0 standard, which it said could require companies to support two simultaneous sets of standards when version 4.0 finally comes out.
"With the release of this draft guidance and the anticipated issuance of final guidance, a December 2015 (if not earlier) timeline has been established for the requirement that all applications be submitted electronically using eCTD v3.2.2," the group noted. "Given the magnitude of this change to required eCTD submissions and the burden on industry to make significant investments in information technology to comply with the mandate, PhRMA strongly urges the FDA to support use of eCTD v3.2.2 for a minimum of five years. Therefore, PhRMA is unlikely to support a transition to eCTD v4.0 earlier than 2020, unless eCTD v4.0 presents substantial benefits to both FDA and industry that support an earlier transition date."
In addition, because guidance documents are almost never used to convey requirements, PhRMA said it recommended splitting the guidance document into two separate guidances: one for general considerations on the completion of the eCTD, and another for which standards are required of companies.
The agency also needs to take care to ensure standards are adopted uniformly across its own agency, PhRMA said, noting that electronic submission can often be inconsistent across centers and offices. This is particularly true for the submission of advertising, promotional and labeling materials to the agency, it said.
GSK, too, had several issues with the guidance, largely mirroring the primary concerns raised by BIO that references to standards and specifications were too vague.
"This guidance needs to be more explicit as to which version of the referenced documents sponsors should be using as the basis for eCTD creation," it wrote. "Directing sponsors to use the most recent version of specifications will add to confusion about when and if a standard should be used."
GSK, too, mirrored PhRMA's comments regarding the 3.2.2. standards, saying it would "strongly encourage the acceptance of the […] 3.2.2. standard through the conclusion of PDUFA V in 2017.
"We would like to ensure that frequent updates to standards to not occur and that a single standard can be used globally. Any proposed changes including the adoption of eCTD 4.0 should be tested with industry and software vendors," it added.