CDER Expedited Pathways: Why Do Some Drugs Get Approved Quicker Than Others?
Many new drugs that get to market today are reviewed and approved under one of the Center for Drug Evaluation and Research’s (CDER) expedited approval pathways. In 2015, 27 of the 45 new drugs approved by the FDA were reviewed through an expedited approval pathway. These pathways were developed after criticism from patient groups during the AIDS epidemic in the 1980s that the Food and Drug Administration (FDA) took too long to approve potentially life-saving new drugs. The four main expedited pathways – Fast Track, Breakthrough Therapy, Accelerated Approval, and Priority Review – offer several opportunities for Sponsors to gain expedited approval and extra incentives when submitting New Drug Application (NDA) applications for drugs intended to treat serious conditions. The programs aim to get important treatments to patients in need as quickly as possible, while still maintaining careful control over safety and efficacy.
So how exactly do these pathways work? What products are eligible for them? When do Sponsors need to apply?
Fast Track Designation
Fast Track designation was introduced by the FDA Modernization Act (FDAMA) in 1997 and amended by the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012. Fast Track designation is granted for drugs that are intended to treat serious or life-threatening conditions, with data that demonstrate the potential to address an unmet medical need. “Serious conditions,” according to the guidance document, are persistent or recurrent and associated with morbidity that substantially impacts day-to-day functioning, and an unmet medical need is a condition for which available therapy does not provide adequate treatment.
The goal of Fast Track designation is to get important new products to patients faster than traditional NDA approval. One of the benefits of Fast Track designation is a rolling review, in which FDA allows Sponsors to submit their NDA in sections as they complete them. Fast Track also increases the probability of Priority Review (see below), and other actions to expedite development and review, such as more opportunities for interactions with FDA.
Sponsors may request Fast Track designation with their Investigational New Drug (IND) application or after, and ideally no later than the pre-NDA meeting. The FDA provides a designation response within 60 days of receipt of the request. Importantly, FDA can revoke Fast Track designation at any time if the product no longer meets the designation criteria.
In 2014, CDER granted a total of 90 Fast Track designations. In 2015, 14 of the 25 new drugs approved had been granted Fast Track designation. Examples of recent Fast Track approvals include Cerexa’s Avyzcaz (ceftazidime/avibactamratories) for complicated intra-abdominal infections and complicated urinary tract infections and Amgen’s Corlanor (ivabradine) for chronic heart failure.
Breakthrough Therapy Designation
Breakthrough Therapy designation is the newest expedited pathway and was also enacted as part of FDASIA in 2012. A drug is considered a Breakthrough Therapy if it is intended to treat a serious or life-threatening condition, and when preliminary clinical evidence indicates that it may be more effective on at least one clinically significant endpoint than existing therapies. Like Fast Track designation, the goal of Breakthrough Therapy designation is to bring new potentially life-saving drugs to patients quicker than with traditional NDA applications.
With Breakthrough Therapy designation, FDA offers Sponsors intensive guidance on efficient drug development. The agency also offers an organizational commitment involving senior managers (i.e. experienced management staff from FDA collaborate with the Sponsor to expedite development), and rolling review. It is important to note that Breakthrough Therapy designation does not absolve the Sponsor from providing clinical data to support substantial evidence of efficacy and safety (see Accelerated Approval).
Sponsors can submit requests for Breakthrough Therapy designation with their IND or after, and ideally no later than the End-of-Phase 2 (EOP2) meeting. FDA provides a response within 60 calendar days of receipt of the request. Like Fast Track designation, FDA can also revoke Breakthrough Therapy designation if the product no longer meets the qualifying criteria.
In 2014, CDER received a total of 96 Breakthrough Therapy designation requests and granted 31. In 2015, CDER approved 10 new drugs through the Breakthrough Therapy designation pathway, including Vertex’s Orkambi (ivacaftor) for cystic fibrosis.
The Accelerated Approval Program began in 1992 under 21 CFR 314, subpart H and was later amended by FDASIA in 2012. Accelerated Approval is granted for drugs intended to treat serious conditions that provide a meaningful advantage over available therapies. Accelerated Approval allows approval based on surrogate endpoints, which are clinical endpoints that can be measured earlier than irreversible morbidity or mortality. However, the surrogate endpoints should predict the long-term endpoints. For example, progression-free survival is often considered a surrogate endpoint for overall survival in cancer trials.
The use of surrogate endpoints can expedite the time to approval of a new drug. Still, Sponsors must confirm clinical benefit in a confirmatory study or the drug may be withdrawn from the market. Sponsors should discuss the potential for Accelerated Approval early on in development, as studies need to be designed using established surrogate endpoints, and FDA does not have a set timeline for response.
In both 2014 and 2015, CDER only approved six NDAs with Accelerated Approval. These approvals included Novartis’ Farydak for the treatment of multiple myeloma and Pfizer’s Ibrance (palbociclib) for advance breast cancer.
Priority Review Designation
Priority Review Designation was initiated under the Prescription Drug User Fee Act (PDUFA) of 1992 to grant faster review to drugs that offer major advances in treatment or treatment for conditions with no existing adequate treatment. As dictated by PDUFA V, standard NDA review time is ten months, and six months for applications with Priority Review. There are additional avenues to obtaining Priority Review, such as the use of Priority Review vouchers, which are very valuable and therefore often sold to other companies.
Sponsors need to request Priority Review with the submission of their NDA. As noted above, Fast Track designation increases the likelihood that a product will be granted Priority Review. This, however, is not guaranteed, and the Sponsor must still apply for the designation. FDA responds to the request within 60 calendar days of the date of NDA submission.
In 2014, 25 of the 41 novel drugs approved were granted Priority Review. Similarly, in 2015, 24 of the 45 novel drugs approved were granted Priority Review. Priority Review approvals from 2015 include Astellas’ Cresemba (isavucanazole sulfate) for invasive aspergillosis and invasive mucormycosis and Merck’s Bridion (sugammadex) for reversal of neuromuscular blockade.
Overall, CDER’s expedited pathways offer Sponsors the opportunity to potentially bring their drugs to market quicker and with more guidance from FDA. The pathways are fairly similar, so it is important to note key differences (highlighted in Table 1) to determine where your product may fit. With the exception of Priority Review, the expedited pathways must be requested before NDA submission and can have an impact on the entire development process. While the main goal of these expedited pathways is to benefit patients in need, Sponsors can potentially benefit from lower clinical trial costs, more time on the market, and market exclusivity.
- FDA New Novel Drugs 2015 Summary. January 2016. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm474696.htm
- About FDA: Number of Fast Track designation requests granted. Available at: http://www.accessdata.fda.gov/scripts/fdatrack/view/track.cfm?program=cder&id=CDER-RRDS-Number-of-Fast-Track-Designations-granted
- CDER Breakthrough Therapy Designation Requests. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/INDActivityReports/ucm373559.htm
- FDA New Novel Drugs 2014 Summary. January 2015. Available at: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM430299.pdf
ABOUT THE AUTHOR
Lara Burgess, PhD, RAC, is a certified Regulatory Affairs professional with a PhD in Behavioral Neuroscience. She uses her academic research background and strong technical writing skills to prepare regulatory documents, including FDA Advisory Committee briefing books. Lara has experience writing and editing in many areas of research and statistics including grant proposals, research protocols, and conference abstracts. Connect with Lara on LinkedIn.