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Expediting drug development: a quick look at drug designations and classifications.

The FDA recognizes four distinct approaches for expediting drug development to address unmet medical needs in the treatment of serious or life-threatening conditions, these are:

1. Fast-track Designation

2. Breakthrough Therapy Designation

3. Accelerated Approval Pathway

4. Priority Review Designation

The FDA considers the definition of serious or life-threatening conditions to be those associated with morbidity that substantially impact day-to-day functioning, while unmet medical needs are conditions that are not adequately addressed with current and available therapies, or for which no therapies currently exist.


While fast-track and priority review designations, and the accelerated approval pathway approaches have been established since the 1990's, breakthrough therapy designation is a relatively new approach recognized by the FDA in 2012 to accelerate the development of drugs indicated for serious or life-threatening conditions, where preliminary clinical evidence indicates that the drug demonstrates substantial improvement on at least one clinically significant endpoint when compared to existing marketed drugs.

This designation allows for all the features of fast-track designation, plus intensive guidance from the FDA and organizational commitment from senior FDA managers. As with other FDA recognized designations, breakthrough therapy status can be withdrawn by the FDA at a later time if the specific drug/indication combination does not continue to meet qualifying criteria.

To receive this designation, sponsors submit a request to the FDA at the initial Investigational New Drug Application stage or later in clinical development but, ideally, no later than end-of-phase 2 meetings. The FDA then has sixty days after receiving a breakthrough therapy designation request to provide a designation or non-designation letter.

As with other expedited development approaches, timely and frequent communication with the FDA is critical to ensure that development of a drug and eventually market approval, if justified, proceeds as rapidly as possible. However, the quality of the drug cannot be compromised for speed. Pharmaceutical and analytical aspects of the drug are expected to meet current Good Manufacturing Practices and comply with applicable regulations as would be expected from drugs developed in non-expedited programs. If a sponsor anticipates requesting one of the expedited approaches from the FDA, it needs to ensure that other aspects of development will be able to support the accelerated timelines such as:

* Analytical method validation

* Stability studies

* Drug substance process performance qualification

* Drug product process performance qualification

* Prior approval inspections

* Business considerations


Another designation recognized by the FDA is that of orphan drugs. Orphan drug designations are intended to encourage and facilitate the development of drugs for rare diseases or conditions and, in general, are defined as a drug intended to treat a condition that affects fewer than 200,000 patients. Orphan drug designation is not a recognized expedited development designation but specific drug product(s) and indication combinations may also qualify for these designations. However, the designation can result in smaller clinical studies and faster market submission reviews resulting in shorter development times compared to the development of non-orphan drugs. The shortened timelines mean that development programs for drugs with orphan designations take on many of the characteristics of those with expedited designations. In general, many indications that would qualify for orphan status are serious or life-threatening conditions which might also qualify for expedited designations.

Orphan drug designation may be requested at any time in clinical development. The designation allows for seven years of market exclusivity after approval and can result in FDA fee waivers, protocol assistance, and tax credits. If the drug and target indication do not continue to meet qualifying criteria however, the designation may be withdrawn by the FDA.

If sponsors do not have the pharmaceutical, analytical, packaging, and project management resources and infrastructure in-house, maintaining a development program at a rate that takes full advantage of the benefits of receiving an expedited designation from FDA may be challenging. A solution to these development challenges may be to contract for the additional resources and/or services required. However, contracting these services from several vendors can be difficult and seamlessly integrating the development program can be problematic if the vendor company is not experienced in managing such programs, and working closely alongside sponsors to construct development programs that meet project deadlines. Contract vendors that have integrated offerings at one site can provide significant advantages through efficiencies of scale and experience.

Undertaking programs with shortened timelines to the required quality and regulatory standards can prove challenging. Having worked on a number of these projects at Catalent Pharma Solutions' Kansas City, Missouri, a number of critical factors have become apparent and best practice procedures adopted. Because of the shortened timelines associated with drugs with expedited and orphan designations, programs are established with a single, cross-functional team that can drive development from early-phase all the way through to commercialization. By utilising a team based approach, with specialists in fields ranging from formulation, pharmaceutics and analytics to packaging and project management integrating seamlessly with the sponsors' teams, potential root causes and optimum solutions can be identified quicker keeping programs on-track. Of course, development speed is worthless without regulatory compliance and a robust quality system. Contract providers should be able to demonstrate a successful track-record of audits and pre-approval inspections from the FDA, EMA and other regulatory bodies, and across multiple drug products with expedited or orphan designations.

To summarize, several expedited program designations and approaches are available from the FDA, of which breakthrough therapy designation is the latest. A sponsor needs to ensure that all aspects of its development programs can support expedited designations before pursuing them. If specialist development support is needed, sponsors need to have close, honest relationships with the contract vendors to enable close working relationships and rapid communication. Risk assessment and mitigation/contingency planning is essential. An integrated development program approach under one quality system with single-point project management can be used to leverage risk and reduce time-lines to get maximum benefit from receiving expedited drug designations.


Richard J. Ho/I, PhD, is Director of the Pharmaceutics ll group at Ca talent Pharma Solutions in Kansas City, Missouri, where he manages a group of twenty scientists and technicians involved in contract pharmaceutical development and manufacture. He has been at his current position for the past 6 years, having been previously employed at several large and small pharmaceutical companies throughout his career including Cephalon.

His professional experience has concentrated on discovering novel drug delivery systems and in developing robust pharmaceutical formulations and manufacturing processes. Marketed products that he has been involved in developing include OnsoIlse and Amrix[R]. He is a listed inventor on 33 US and international patents or patent applications. He has been involved in development of multiple injectable, topical, transmucosal, and oral drug products and the processes used in their manufacture. One particularly interesting project involved designing an experimental module for pharmaceutical processing that flew on board the U.S. Space Shuttle.He received his doctorate degree in chemical engineering from Auburn University and his undergraduate chemical engineering degree from the University of Florida. *

* By Richard J. Holl, PhD; Director of the Pharmaceutics II Group, Catalent Pharma Solutions
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Title Annotation:DEVELOPMENT
Author:Holl, Richard J.
Publication:Pharmaceutical Processing
Date:Apr 1, 2014
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