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International Clinical Trials
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Pharmaceutical and biotechnology companies need to be familiar with the
changes in the Prescription Drug User Fee Act in order to prepare for
any impact on the costs of their drug development programmes, as well as
the timeline requirements.
Two decades ago, the Food and Drug Administration (FDA) was facing
massive review backlogs due to significant increases in the number and
complexity of new drug applications (NDAs). To remedy this issue, the US
Government passed Prescription Drug User Fee Act (PDUFA) in 1992.
The Act has since gone through several reauthorisations, as the FDA has
sought to improve review metrics, increase transparency, provide better
funding to management, and enhance drug safety and risk management
processes. The current legislation, PDUFA IV, expires this year, but US
President Obama has signed PDUFA V, which will go into effect on 1
January 2013, and will be valid through 2017.
This article will examine the key changes affecting drug developers.
These changes relate to FDA metrics for review cycle times, user fees,
rare diseases, transparency and access to reviewers, and technological
requirements, such as electronic submissions. In addition to this, an
extensive summary of the changes to each section of PDUFA, as well as a
listing of the key highlights is included (see Table 2, page 62).
Key Changes in PDUFA V
Review Period and First-Cycle Approval Performance
One concern for drug manufacturers is the low rate of first-cycle
approval, which is often a result of technical deficiencies in the
application, lack of communication during the review process and
insufficient time to respond to challenges to documentation, rather than
technical problems with the drug or clinical data (1). Though nearly 80
per cent of drug applications are eventually approved, only 50 per cent
are approved during the first-cycle review period. While no specific
metrics for first-cycle approval rates are stated in PDUFA V, proposed
changes include the addition of a 60-day administrative review period,
and enhanced communication between drug developers and the FDA during
the review process.
60-Day Validation Period
The 60-day administrative review period, which was previously included
in the six-month priority and 10-month standard application review
periods, will now take place before formal review begins. This means
that the overall application review period will be extended by two
months, which will offer an additional opportunity to address potential
administrative and technical issues. Sponsors will still need to
carefully prepare applications and ensure that they are ready for review
and in alignment with FDA requirements to avoid additional delays.
Enhanced FDA/Sponsor Communications
To improve communication, PDUFA V will include a midcycle review
meeting. The purpose of this meeting is for the FDA to communicate any
identified issues to the sponsor and allow time for discussion of
resolution before an advisory committee convenes, or, if no advisory
committee meeting is planned, before a complete response letter is
issued.
The incorporation of a communication milestone in the FDA review process
– the 74-day filing letter – provides detailed correspondence to
sponsors regarding any significant deficiencies noted by the agency
during their initial 60-day preliminary review of new marketing
applications. Sponsors should be aware the FDA will not reiterate any
deficiencies previously identified during other formal agency
interactions, such as the End-of-Phase 2 (EOP2), Pre-New Drug
Application (PreNDA) or Biologics License Application (BLA) meetings.
Sponsors need to enact remediation and comprehensive response plans as
soon as possible upon receipt of this letter to mitigate delays in
application approval. This enhanced communication process is expected to
foster the opportunity for an increased percentage of first-cycle
approvals.
Review Performance Goals
To address the lag in review rates that developed between 2005 and 2007,
one of the goals of PDUFA V is to maintain a high rate of review of new
molecular entity (NME), NDA and original BLA submissions (3).
Specifically, the FDA now will be committed to reviewing and acting on
90 per cent of standard NME, NDA and BLA submissions within 12 months,
and on priority NME, NDA and original BLA submissions within six months,
after completion of the 60- day administrative review period.
Original biosimilar application review and regulatory pathways will
continue to be challenging. The 2013 goal is to review 70 per cent of
those applications within 10 months of application receipt, with an
increase to 80 per cent in 2015 and 90 per cent in 2017. Robust
preparation for advisory meetings, as well as product development
meeting outcomes, will be essential in preventing delays.
User Fee Increase
The proposed improvements to review metrics and communication will come
at a cost. The historic reason for the lag in review rates has been an
increase in overall workload, without an equivalent increase in the
staffing of review teams. To ensure that the metrics set out in PDUFA V
are met, the FDA will need to hire and train additional reviewers, which
will be funded by raising user fees. PDUFA V is expected to increase
the amount of user fees collected by the FDA to $3 billion, up from the
$2.9 billion specified in PDUFA IV. This will allow for additional new
reviewers, with the goal of more timely reviews and enhanced
communication between sponsors and the FDA. Sponsors will need to be
prepared to cover these additional costs.
Improved Support for Rare Diseases
Other provisions in PDUFA V will help support developers of drugs for
rare diseases. By the end of 2013, the FDA will complete a staffing and
implementation plan for the Center for Drug Evaluation and Research’s
(CDER) rare disease programme. With the goal of streamlining the review
process for drugs for rare diseases and ensuring understanding of the
regulatory pathways as well as the complexity of these unique drugs, the
professionals in the CDER’s rare disease programme will develop and
disseminate guidance related to advancing the development of drugs and
biologics for rare diseases. These actions will include:
- Improving understanding among FDA reviewers of approaches to studying drugs for rare diseases
- Considering non-traditional clinical development programmes, study design, endpoints and statistical analysis
- Recognising particular challenges of post-market studies
- Encouraging flexibility and scientific judgment, as appropriate,
on the part of reviewers evaluating investigational studies and
marketing applications for drugs for rare diseases
Sponsors should benefit from the FDA’s increased scientific and technical knowledge and understanding in this area.
Standardisation of Electronic Submission Data
When PDUFA V takes effect, the steps toward making electronic
submissions a requirement will be set into motion. The FDA is expected
to require electronic submissions by 2015. That requirement will be
phased-in over the coming years, with draft guidance on standards and
format of electronic submissions released by the end of 2012. Final
guidance will follow no later than 12 months after the close of the
public comment period on the draft guidance, in 2014. The guidance
documents will be developed in support of the transition timeline for
both clinical trial applications and marketing applications (IND and
NDA/BLA, respectively).
Implementing systems to produce electronic submissions in electronic
common technical document (eCTD) format is no small feat. While many
well-established sponsors and manufacturers have implemented the
technologies and necessary capabilities, achieving readiness to fully
prepare and manage electronic submissions requires a significant
investment of time, resources, systems and effort. Reaching full
capability may prove to be a significant hurdle for many smaller
companies. As an alternative, companies may choose to consider
outsourcing the preparation of their submissions. This will also require
additional time and effort to identify and select a service provider
that best matches the needs of the company. Both approaches offer
advantages, so companies will need to plan carefully to discern the best
approach for the circumstances they face. Overall, electronic
submission is expected to simplify and expedite the review process,
while also reducing the review challenges inherent in paper submission
formats.
Conclusion
Pharmaceutical and biotechnology companies should be encouraged by
initiatives to improve the rate of first-cycle approvals and to increase
access to reviewers through the new mid- and late-review cycle
communications. However, the cost will be higher user fees and the
extension of some review timelines. In addition to this, all
stakeholders will need to ensure that they have the technological
solutions needed to meet the FDA’s new electronic submissions standards,
which are expected to be implemented in 2015. Overall, careful planning
and a well thought-out submission strategy will help companies
successfully navigate the new goals and initiatives set out in PDUFA V.
References
- US Food and Drug Administration, January 2006, Independent
Evaluation of FDA’s First Cycle Review Performance – Retrospective
Analysis Final Report Text, available at www.fda.gov/forindustry/
userfees/prescriptiondruguserfee/ ucm119469.htm
- US Food and Drug Administration, 30 April 2009, Issues and
Communication: Independent Evaluation of FDA’s First Cycle Review
Performance – Final Report, available at
www.fda.gov/forindustry/userfees/ prescriptiondruguserfee/ucm127153.htm
- US Food and Drug Administration, April 2012, PDUFA Reauthorization
Performance Goals and Procedures – Fiscal Years 2013 through 2017,
available at www.fda.gov/downloads/forindustry/userfees/
prescriptiondruguserfee/ucm270412.pdf
- US Food and Drug Administration, 2011, Performance Report to the
President and Congress for the Prescription Drug User Fee Act, available
at www. fda.gov/downloads/aboutfda/reportsmanualsforms/
reports/userfeereports/performancereports/pdufa/ ucm294101.pdf
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Nina Baluja, Director of Global
Regulatory Consulting for PPD, has a medical degree from the Armed
Forces Medical College, Pune, India, and a Masters in Oncology from
Bombay University, India. She has more than 20 years of experience in
healthcare and pharmaceuticals in the areas of clinical development,
medical marketing and regulatory affairs, including post-approval
requirements, paediatric clinical trials and in-licensing opportunities.
George Hemsworth is Director of
Global Regulatory Consulting for PPD. He holds a Doctoral degree from
Miami University and has nearly 40 years of diverse pharmaceutical
industry experience. His background includes more than 25 INDs/CTAs,
including clinical development, new drug application defense and
labelling negotiation and achieving approved NDAs/sNDAs in the
management of a range of conditions. Email: george.hemsworth@ppdi.com
Mehri Hezari-Adam, Director of Global
Regulatory Development for PPD, has more than 15 years of experience in
regulatory affairs. She has been involved in all phases of drug
development, providing strategic consulting to sponsors, participating
in different aspects of investigational new drugs and new drug
applications. She hold a Bachelor’s degree and a PhD in Pharmacy from
the University of Texas at Austin.
Pat Mann is a Director of
Regulatory Affairs at PPD, serving as a technical project leader and
scientifi c liaison. She has more than 30 years of experience in global
quality assurance and regulatory affairs in the generic, medical device
and pharmaceutical industries. She holds a Bachelor’s degree in plant
pathology from the University of Delaware, an MBA in global management
from the University of Phoenix and a Six Sigma Greenbelt Certifi cation
from Villanova University.
Henrietta Ukwu, a physician,
infectious diseases expert, pharmaceutical industry executive and
thought leader, is Senior Vice President and Head of Global Regulatory
Affairs for PPD. She has more than 20 years of pharma and global
regulatory experience. She completed her residency in internal medicine
at Baptist Hospital, and her fellowship in infectious diseases at
Vanderbilt University, both of which are in Nashville, Tennesee.
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