President and CTO
Hayward, Calif. T oday nearly 84 percent of all prescriptions filled in the U.S. are generic. The generic industry’s trade group, the Generic Pharmaceutical Association (GPhA), has released figures that show the impact of generic drugs:
To that end, in January 2014, the FDA published in the
Federal Register1 that it is seeking input from key stakeholders
on how to improve the Abbreviated New Drug Application
(ANDA) submission process.
The agency has cited poor and incomplete ANDA submissions as a significant impediment to generic drug approvals.
Specifically, the FDA is interested in hearing about any difficulties sponsors are having developing and preparing their
ANDA submissions that the agency could help address, by
providing more or better information to industry.
The FDA defines a generic drug product as one that is comparable to an innovator drug product in dosage form, strength, route
of administration, quality, performance characteristics, and
intended use. Generic drug applications are termed “
abbreviated” because they are generally not required to include preclinical
(animal) nor clinical (human) data to establish safety and effectiveness. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent – that it performs in
the same manner as the innovator drug.
Clinical performance alone may demonstrate that the drug is
capable of being bioequivalent, but it is the manufacturer’s diligence
in ensuring consistency of materials and processing along with
their quality management system (QMS) that certify the quality
and efficacy of a lot on an on-going commercial basis. Historically,
these elements were based upon a documentation-intensive quality
philosophy predicated on a system of inspection and testing. The
framework that supported this quality approach has always been a
key component of the ANDA submission.
In 2004, after extensive industry dialogue, the FDA changed
the paradigm and issued its revised cGMP guidance
Pharmaceutical cGMPs for the 21st Century- A Risk Based
Approach advocating a science-based rather than inspec-tion-based approach to product quality and control.
With this new philosophy the FDA instituted a framework to
raise the level of science associated with generic drug develop-
ment and drug applications that it termed question-based review
(QbR). QbR provides generic drug manufacturers with a list of
specific requirements essential to creating an approvable ANDA
and emphasizing the chemistry, manufacturing, and controls
(CMC) evaluation. This QbR process began in early 2005 shortly
after the issuance of the 2004 guidance to achieve the objectives
of product quality through performance-based specification, con-
tinuous improvement through risk assessment, standardization
of review questions, and reduced CMC review. The spirit of this
guidance is to speed access to generic medicines.
The GPhA echoes the principles of the 2004 guidance citing a commitment to the principles of scientific rigor directly
in its website discussion on quality. 2
The drive to improve the system is not altruistic by any measure but rather is a direct result of the Generic Drug User Fee
Amendments (GDUFA) signed into law on July 9, 2012.3 With
the enactment of GDUFA, the Office of Generic Drugs (OGD)
committed to expedite the availability of high-quality, lower cost
generic drugs by bringing greater predictability to the review
times for ANDAs and associated amendments and supplements.
The OGD agreed to specific performance review metrics to
reduce the time to bring a generic drug to market compared
to typical pre-GDUFA review times. However, OGD’s review is
often hindered by the quality of the ANDA submissions.
Despite the QbR approach, the FDA has seen continuing
issues with ANDA applications. The agency provided a summary of the six largest reoccurring issues in the notice; filing,
chemistry, sterility assurance, bioequivalence, fatal flaws in the
design itself, and drug master file discrepancies.
While there are procedural deficiencies cited regarding
incomplete or missing forms, some of the recurring issues are
alarming and contradict any notion of a commitment to scientific understanding as a basis for drug quality.
Another look at ANDA
To assist in revamping the ANDA process, the FDA has asked
the public and industry to answer some basic questions.
These four questions reflect an agency that is not only
interested in collaborating with the generic industry to debug
the process but also knows that the GDUFA funds will give
them the ability to follow through on any changes agreed on.
1. What aspects of the ANDA application process are confusing or not well-defined?
2. What problems do ANDA applicants encounter when developing a submission that FDA could help address?
3. Prior to GDUFA, were ANDA submissions consistently slowed or
stalled at certain recurring review points post-filing? If so, why?