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 FDA
unveiled a report in March that maps out strategies
for converting new biomedical discoveries into safe
and effective therapies more quickly and efficiently.
Although most of the specific proposals are not new
to those familiar with drug manufacturing practices,
the report shines a spotlight on the agency's desire
to eliminate roadblocks to the development and approval
of new drugs. This initiative to map "critical
pathways" to drug development lends support to
efforts by the Center for Drug Evaluation and Research
(CDER) to streamline regulatory policies and better
manage the review process.
Removing R&D obstacles
A main objective for FDA is to reverse the recent decline
in new drug applications (NDAs) filed with the agency,
especially for new molecular entities. Former FDA Commissioner
Mark McClellan frequently commented on the lag between
gains in genomic and other cutting-edge biomedical research,
and the development of new therapies able to improve
public health. One of McClellan's last acts at FDA was
to issue a report entitled "Innovation or Stagnation?--Challenge
and Opportunity on the Critical Path to New Medical
Products" which identifies obstacles and possible
solutions for moving potential new medical products
from laboratory concept to useful medicine (www.fda.gov/bbs/topics/news/2004/NEW01035.html).
The report notes growing interest in "translational
research" that can help speed basic biomedical
research into clinical testing. For the next step, FDA
wants to provide new tools related more to downstream
product development: preclinical safety testing, clinical
efficacy studies, and efforts to refine manufacturing
processes.
It is noteworthy that FDA identifies product industrialization
as the third dimension of this critical path in drug
development. Although researchers and industry professionals
often discuss the need to better assess drug safety
and efficacy to accelerate the R&D process, this
report also focuses on the difficulties in drug formulation,
delivery, and manufacturing that block many potential
medical products from reaching the market. FDA recognizes
that outdated manufacturing systems and tools can stymie
efforts to achieve high quality mass production of cutting-edge
therapies--a problem that FDA believes is "highly
underrated in the scientific community." In FDA's
opinion, the failure to solve difficulties in product
design, characterization, manufacturing scale-up, and
quality control may "routinely derail or delay
development programs and keep needed treatments from
patients"--particularly therapies using new technologies,
which frequently are more complex than traditional products
and lack standard assessment tools.
At a recent Drug Information Association conference
on chemistry, manufacturing, and controls (CMC) strategies,
Liam Feeley, director of pharmaceutical R&D at Abbott
Laboratories, estimated that up to 50% of the factors
causing attrition of drug candidates during development
could be related to CMC issues. He emphasized the importance
of investing more resources in product formulation,
characterization, and scale-up requirements to avoid
wasted clinical studies and later manufacturing problems.
Janet Woodcock, currently serving as FDA acting deputy
commissioner and author of the new critical pathways
report, wants to work with the industry to gain more
information about the root causes of product development
failures. If a drug does not show efficacy in Phase
III studies, she wonders how it got that far. Is the
failure due to poor bioavailability, or too much variability
in formulation? Gaining more insight into these issues
is an FDA priority.
Making a list
FDA's next step is to create a critical-path opportunities
list. Agency staffers are beginning to look for opportunities
to develop standards or policies able to remove or overcome
specific obstacles to drug development. FDA leaders
plan to seek additional suggestions from manufacturers,
academics, and National Institutes of Health officials
who are involved in its "roadmap" initiative
to improve clinical trials. One proposal, says Woodcock,
is to develop a better FDA database of how manufacturing
changes affect product performance, and to identify
changes that are most critical to success. These initiatives
were discussed at the April meeting of FDA's Science
Board, along with proposals to devote a portion of the
agency's $135-million research bud get to critical path
projects.
In addition to calling for new efforts to improve drug
development, the report acknowledges the need to build
on initiatives to improve manufacturing processes and
operations already underway.
Updating GMPs. FDA is continuing to implement this
initiative to modernize current good manufacturing practices
(GMP) standards, and plans to roll out additional policies
in upcoming months. Under this program, the agency has
established a pharmaceutical inspectorate and is training
field inspectors to conduct more-targeted GMP inspections.
A new high-level FDA panel has been formed to resolve
disputes involving manufacturing science issues, and
FDA is encouraging international harmonization of GMP
quality issues. FDA also has launched several collaborative
efforts with manufacturers and researchers to articulate
new approaches for understanding manufacturing science
and risk management techniques.
Promoting PAT. A high-profile component of the GMP
initiative is to encourage broader industry adoption
of process analytical technologies (PAT) to reduce costs
and increase the efficiency of drug manufacturing processes.
FDA issued a draft guidance in September 2003 outlining
a framework for agency review and oversight of PAT manufacturing
applications. Agency staffers are preparing a final
guidance, and also are developing scientific principles
and tools to support analytical and manufacturing control
innovations. CDER's Office of Pharmaceutical Science
(OPS) is establishing a PAT team to review applications
and inspect facilities with PAT components; OPS has
received six applications with PAT innovations and has
begun to conduct PAT field inspections.
New guidance. In addition to several guidances issued
as part of the GMP initiative (on PAT, 21 CFR Part 11,
aseptic processing, and comparability protocols, among
others), FDA is developing new policies related to process
validation and CMC review. In March, CDER published
a revised process validation policy to reduce requirements
that delayed the launch of innovative new drugs in the
past (see Sidebar, "New validation policy aims
to overcome roadblocks"). CDER also is working
with the industry to evaluate the best way to set product
specifications that reflect product risk and consistency
of manufacturing processes.
According to OPS Director Helen Winkle, these policy
proposals reflect a move by CDER to devise a risk-based
approach for submitting and reviewing CMC data. FDA
has been discussing this issue for some time and now
is stepping back to look at postapproval change requirements
and comparability protocols to formulate a more workable
approach. In the meantime, the agency may issue more
targeted, informal guidances that address specific CMC
issues raised in plant inspections.
More collaboration. A main objective of the critical
pathway initiative is to launch more joint efforts by
FDA and manufacturers to address product development
issues. FDA believes that its staff can help identify
problems common to similar products because they have
access to information about failed drug development
programs that is not publicly available. "FDA holds
the only broad, cross-cutting knowledge about how certain
investigational products fail, why certain therapeutic
areas remain under-developed, and when certain development
hurdles persist despite advances in technology that
could mitigate them," the report explains. The
agency seeks more public-private collaborative work
on genomics, proteomics, bioinformatics systems, and
new imaging technologies to help detect safety problems
early, identify patients likely to respond to therapy,
and address product design, characterization, and manufacturing
issues.
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