FDA’s Expedited Review Process: The Need for Speed

The FDA currently uses four programs to expedite reviews of drugs for serious and life-threatening diseases. Whether accelerated approval, priority review, fast track, or breakthrough therapy, each program has specific requirements and benefits, and can be used in various combinations. At the start of any drug development program, an in-depth understanding of these options is critical to ensuring the most efficient path to approval.

Accelerated approval allows the use of surrogate endpoints

In response to the AIDS crisis in the late 1980s, the FDA drafted initiatives to accelerate drug delivery and cut costs for new drugs treating serious and life-threatening illnesses and conditions, granting approval to drugs after extended Phase II trials. In 1992, in response to a push by AIDS advocates to make the investigational anti-AIDS drug azidothymidine (AZT) accessible, the FDA enacted "Subpart H" commonly referred to as accelerated approval; giving rise to expedited review of drugs by the FDA. This legislation allowed new drug applications (NDAs) to be approved based on surrogate endpoints in clinical trials including 1) markers that would be expected to confer a clinical benefit such as improved overall survival, prolonged suppression of HIV viral load in HIV, or tumor shrinkage in cancer, or 2) an intermediate clinical endpoint; a measurement of a therapeutic effect considered reasonably likely to predict clinical benefit, such as an effect on irreversible morbidity or mortality.

There is no formal application process for designating a product for development through the accelerated approval pathway. Drug sponsors that decide to pursue this pathway meet with the FDA early in drug development and agree on the following criteria:

• The unmet need that exists in the patient population being studied

• The surrogate endpoints that will be assessed

• The magnitude of benefit that must be observed using the agreed-upon surrogate endpoint

• Post-marketing commitments

Acceleration of oncology drug approval:

Accelerated approval has been vital in expediting access primarily to drugs for cancer patients. From 2000 to 2012, 53% of accelerated approvals were for cancer drugs, 18% were for HIV, and 29% for "other," with cardiovascular leading the "other" category. As of July 1, 2010, 35 oncology products had obtained accelerated approval for 47 indications, and 26 were converted to full approval with an average time of conversion of 4.7 years. Following post-marketing analysis, three oncology drugs that were granted accelerated approval have been withdrawn or relabeled because of unexpected safety or apparent lack of efficacy; however, the majority of accelerated approvals have confirmed clinical benefit.

Priority review shortens FDA review timelines

In 1992, under the Prescription Drug User Fee Act (PDUFA), the FDA agreed to improve drug review timelines, and created a two-tiered system of review times: priority review and standard review. To improve review timelines, the agency grants a priority review to applicants for drugs that 1) treat a serious condition and 2) would provide a significant improvement in the safety or efficacy for a serious condition. Priority review shortens the target period for FDA review from 10 months to six months, and this designation is often used in combination with other expedited review processes.

Fast track designation for drugs with potential to address unmet medical needs

The expedited process "fast track" was implemented under the FDA Modernization Act (FDAMA) of 1997. The designation targets drugs that are intended 1) to treat a serious condition and 2) for which data demonstrate the potential to address an unmet medical need. Fast track addresses the need to approve treatment for a broad range of serious diseases, including AIDS, Alzheimer's, cancer, epilepsy, and diabetes. An application for fast-track designation can be submitted at any time during the drug development process and can use preclinical or clinical data to show potential to address an unmet medical need. The FDA must respond to the application within 60 days. With fast-track status, sponsors benefit from the opportunity for early and frequent interactions with the FDA review team and from the "rolling review" process where portions of an application can be submitted for review prior to submitting the complete application.

Overview of FDA's Expedited Drug Approval Programs

Fast track of Ebola vaccines: Recently the FDA has been under pressure to fast track experimental drugs and vaccines for the Ebola virus, of which there is no known cure, following the spread of the virus in Western Africa with 8,795 reported deaths as of the end of January, according to the CDC. In October 2014, the FDA approved the use of an experimental antiviral drug which has successfully treated Ebola in lab tests. The drug has also been tested by the CDC and the NIH, though it is not expected to win approval for wide public use until late 2016. Another drug, produced by a Canadian drugmaker, has also been approved under the fast track provision and was used to treat a patient in Atlanta.

Breakthrough therapy for drugs with substantial superiority

FDASIA also introduced the breakthrough therapy designation into the FDA portfolio of expedited programs to address new trends in drug discovery and development, particularly targeted therapies (including biomarkers), often paired with companion diagnostics, for treatment of cancer, genetic diseases, and increasingly other diseases. The breakthrough therapy designation is similar to fast track and accelerated approval in that it requires the investigational drug be used for a serious or life-threatening disease. Breakthrough therapy also allows "rolling review" of drug development material being submitted to the FDA. Breakthrough therapy designation differs from the other expedited review processes by requiring the use of a clinically significant endpoint that demonstrates substantial superiority of the drug over available therapies. The breakthrough therapy designation offers more expansive benefits than the other expedited processes in that once a drug receives the tag, it is assigned an FDA committee, which meets regularly with the sponsor to devise the most efficient way to generate additional safety and efficacy data to move development forward. It is an "all hands on deck" approach, with frequent communication between the drug developer and the FDA, at the division level and across all levels of FDA management.

Between July 2012 and December 2013, the FDA received 135 breakthrough therapy requests, 41% of which were for cancer therapies.

- Shahza Somerville, Medical Writer and Clinical Research Specialist at Technical Resources International (TRI), and Jessica Holden Kloda, Associate Director of Regulatory Affairs at TRI