Making Sense of FDA’s Expedited Drug Approval Pathways and Designations – for the Non-Regulatory Professional

One of the fundamental responsibilities of the US Food and Drug Administration (FDA) is to approve effective medicines for people who need them, while upholding high standards for safety. That mission also demands that the FDA work efficiently and not delay approval of life-saving medical advances. Today, the FDA is reviewing applications for approval of new medicines faster than ever, and that’s a welcome change from the status quo 25 years ago. In the era from 1962 (immediately following the thalidomide recall) to the early 1990s, FDA review times for a New Drug Application (NDA) or Biologic License Agreement (BLA) were often measured in years rather than months. In 1993, the standard review time (from NDA or BLA submission to decision) for a new molecular or biologic entity (parlance for a drug not previously approved for any other use) was about 28 months,¹ and in some cases, approvals were delayed for many years.

Starting in the late 1980s, the US Congress sought to tackle that problem and create incentives for the pharma industry by establishing programs designed to empower the FDA to expedite approval of new drugs for the treatment of serious conditions (those associated with irreversible morbidity that has substantial impact on day-to-day functioning).^2,3 The Prescription Drug User Fee Act (PDUFA) of 1992 took the first major step in that direction by establishing application fees,⁴ which allowed the FDA to increase their internal resources. At the same time, however, it also established a deadline for FDA decisions, known as the PDUFA date.⁴ Several other legislative acts followed, and these programs finally came to full fruition with the passage of the 2012 Safety and Innovation Act (FDASIA).⁵

Today the FDA has 4 key programs in place: known as “priority review,” “fast track designation,” “breakthrough therapy designation,” and the “accelerated approval” pathway. The success of these programs is reflected in shorter review times (now 6‑10 months) and an option to grant accelerated approval to drugs much sooner than would be possible otherwise. But what do these programs actually do to facilitate and shorten the approval process, and how can companies take advantage of them? Let’s take a closer look at what each one is intended to do.

• Priority Review Designation was enacted in 1992 as part of PDUFA I.³ It shortens the time that FDA has to review a sponsor’s NDA or BLA by 2 months compared with a standard submission. Total time from submission to approval is substantially shorter for priority reviews. In 1993, for example, standard reviews were taking about 28 months, whereas priority reviews were only taking about 13 months.¹ By 2011, review times had been shortened to 10 months for standard reviews and only 6 months for priority reviews.^1,6 To be eligible for priority review, a drug must provide a significant improvement in safety or effectiveness compared with currently available therapies. Sponsors can request priority review at the time of NDA/BLA submission. So when a sponsor has data from their pivotal phase 3 program showing a significant clinical benefit compared with available therapies, they are smart to request priority review.
• Fast Track Designation was enacted as part of the FDA Modernization Act of 1997 and is intended to facilitate and expedite the process by which a sponsor submits their data to the Agency.³ It allows for a rolling submission, which means a sponsor can submit some sections of their NDA or BLA ahead of the final data. This allows the Agency to begin their review early and head off any issues with the data package. Fast Track Designation can be requested as early as the time of filing the Investigational New Drug application (IND) or anytime thereafter, and the rolling submission usually begins around the time of the pre-NDA meeting with the Agency. Sponsors often use this program to get early feedback on their submission and avoid any surprises later on.
• Breakthrough Therapy Designation is the latest innovation, established in 2012 by FDASIA, and incorporates all the features of Fast Track Designation,³ but the benefits of Breakthrough Therapy Designation go way beyond that. This program is intended to facilitate close collaboration between sponsors and the Agency throughout the development process, and the FDA commits to providing intensive guidance to the sponsor on best practices of efficient drug development. To be eligible, the sponsor must provide preliminary evidence that the investigational drug may demonstrate a substantial improvement over existing therapy based on a clinically significant endpoint(s).³ Just like Fast Track, the request for Breakthrough Therapy Designation can be submitted as early as the IND submission, or anytime thereafter. Granting of Breakthrough Therapy Designation is a big boost to a sponsor’s drug development program because they know they have FDA support.
• Accelerated Approval was also established as part of the 1997 FDA Modernization Act,³ partly in response to pressure from the HIV patient advocacy community, and it has had a dramatic impact on development of drugs that provide a meaningful advantage over currently available therapies. This program doesn’t shorten FDA review time, instead it allows sponsors to substantially shorten their drug development timeline, sometimes by several years. It does this by permitting use of a “surrogate endpoint” in the pivotal trial to show that the drug is “reasonably likely” to provide clinical benefit.³ The surrogate endpoint is usually something that can be measured much earlier than a clinically meaningful endpoint such as a morbid event or death. It may be a biomarker or some other measure of disease progression or worsening. However, as a condition for accelerated approval, the sponsor must agree to conduct a confirmatory trial designed to demonstrate that the new drug does in fact provide a clinically meaningful benefit, and FDA can revoke the approval if the confirmatory trial fails to do so. Most importantly, sponsors are encouraged to discuss their desire to pursue accelerated approval with the FDA as early as possible and to gain consensus with the Agency regarding the proposed surrogate endpoint. This program is increasingly being used by sponsors developing drugs that fulfill important unmet needs. It is particularly useful in situations where demonstrating clinical benefit based on clinically meaningful endpoints, such as overall survival or occurrence of a heart attack or stroke, would require many years of follow-up.

Sponsors can take advantage of one or all of these programs. Together these innovative programs have vastly improved the efficiency of the FDA approval process for drugs that treat serious conditions and have helped the Agency achieve its critical mission.

Jeff Riegel, PhD, combines his scientific expertise in molecular biology with 20 years of global healthcare agency experience to guide medical and regulatory communication strategies for biopharma companies large and small. Jeff has developed strategies, messages, and presentations for multiple FDA Advisory Committee meetings. He also directs publications planning and execution in oncology and other therapeutic areas. Connect with Jeff on LinkedIn.

References

1. Jenkins JK. Center for Drug Evaluation and Research (CDER) New Drug Review: 2012 Update. http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM331454.pdf. December 10, 2012. Accessed September 10, 2015.
2. Food and Drug Administration, Interim Rule, Investigational New Drug, Antibiotic, and Biological Drug Product Regulations; Procedures for Drugs Intended to Treat Life-Threatening and Severely Debilitating Illnesses (53 FR 41516, October 21, 1988). First Clinical Research LLC Web site. http://firstclinical.com/regdocs/doc/?showpage=3&db=FDA_Guidance_Expedited_Programs. Accessed September 10, 2015.
3. US Department of Health and Human Services. Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf. Published May 2014. Accessed September 10, 2015.
4. Prescription Drug User Fee Act (PDUFA). US Food and Drug Administration Web site. http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/. Updated August 20, 2015. Accessed September 15, 2015.
5. Food and Drug Administration Safety and Innovation Act (FDASIA). US Food and Drug Administration Web site. http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/ucm20027187.htm. Updated September 15, 2015. Accessed September 16, 2015.
6. Gaffney A. Report: FDA drug, device approval times improving. Regulatory Affairs Professionals Society Web site http://www.raps.org/Regulatory-Focus/News/2015/01/27/21188/Report-FDA-Drug-Device-Approval-Times-Improving. Posted January 27, 2015. Accessed September 10, 2015.