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Navigating the Initiatives

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.


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.


  1. US Food and Drug Administration, January 2006, Independent Evaluation of FDA’s First Cycle Review Performance – Retrospective Analysis Final Report Text, available at userfees/prescriptiondruguserfee/ ucm119469.htm
  2. US Food and Drug Administration, 30 April 2009, Issues and Communication: Independent Evaluation of FDA’s First Cycle Review Performance – Final Report, available at prescriptiondruguserfee/ucm127153.htm
  3. US Food and Drug Administration, April 2012, PDUFA Reauthorization Performance Goals and Procedures – Fiscal Years 2013 through 2017, available at prescriptiondruguserfee/ucm270412.pdf
  4. US Food and Drug Administration, 2011, Performance Report to the President and Congress for the Prescription Drug User Fee Act, available at www. 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:

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.


Nina Baluja
George Hemsworth
Mehri Hezari-Adam
Pat Mann
Henrietta Ukwu
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