Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

FDA programs to expedite innovative drug development and review process: Fast Track, Priority Review and Accelerated Approval ***

Dr. Maria Teresa Piccini (Abschlußjahr: 2009)

Language: English

To expedite the availability on the market of innovative therapeutics is of outmost importance for patients, especially for those suffering of serious or life-threatening conditions for which no treatment exists or when all available treatments have failed.

To address this important issue in the United States, the Food and Drug Administration has introduced in the past two decades several distinct approaches to speed up the development and approval of new drugs and biologics. This master thesis intends to describe and analyze the FDA programs: Accelerated Approval Regulation, Fast Track Drug Development Programs and Priority Review Policies.

The Accelerated Approval regulation, introduced in 1992, allows both the possibility of an approval of drugs or biologics with restrictions to assure safe use and the approval based on surrogate endpoints that reasonably predict that the therapy provides clinical benefit. This clinical benefit is then to be confirmed through additional human studies that will be completed after marketing approval. The use of a surrogate endpoint can decrease the complexity of late stage clinical trials and thus can decrease the time required to conduct the necessary clinical studies. The accelerated approval procedures are available for drug and biological products that have been studied to treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments.

The Fast Track drug development program, introduced as part of the FDA Modernization Act in 1997, is designed to facilitate the development and expedite the review of drug and biological products that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. Fast Track designation may be requested by sponsors at any time during the drug development process. Once a product receives designation, early and frequent communication between FDA and the sponsor is encouraged throughout the entire drug development and review process. Moreover Fast Track products are eligible of a rolling review, i.e., the possibility to submit individually completed sections of an application (NDA/BLA) before all sections of the application are completed. Only Fast Track designated products are eligible for rolling review. Furthermore, Fast Track products are eligible for both accelerated approval and priority review.

The Priority Review classification and policies have been established in 1997. The Priority Review designation is intended to direct overall attention and resources to the evaluation of applications for products that have the potential for providing a significant treatment, preventive or diagnostic therapeutic advance, as compared to standard applications. Priority Review status can apply both to drugs that are used to treat serious diseases and to drugs for less serious conditions. Priority applications are given a six-month review and action goal, standard applications are given a ten-month action and review goal.
The objective of the FDA initiatives Fast Track, Priority Review and Accelerated Approval is to shorten time to market for new important drugs, i.e. to shorten development and review / approval times.

Using the available data from FDA web page and from recent scientific publications, the impact of these programs has been assessed.

Data show that the median total approval times for approved products which participated to FDA initiatives Fast Track, Priority Review and Accelerated Approval had in average shorter approval times compared to standard NDAs/BLAs. As most of the candidates participating to Fast Track or Accelerated Approval initiatives were also granted Priority Review, the shorter review and approval times are most likely to be attributed to a Priority Review "effect".

Considering the FDA initiatives which aim to reduce development time, i.e. Fast Track and Accelerated Approval, data show that:

• the average clinical development time for Fast Track designated indications approved during 1998-2007 was of 6% longer than it was for non designated indications. On the other hand, considering the overall clinical development and approval times for Fast Track designated drugs approved during the same period, this was in average 5% shorter than for all drugs approved (NDAs/BLAs). This would lead to the conclusion, that the larger benefit in speeding up the overall process to market for the fast track products has been the expedite review/approval phase rather than an expedite clinical development phase.
• during 1992-2005 the median development time for drugs approved under Accelerated Approval rule was about 50 and 60 months for cancer and HIV indications respectively. This was considerably shorter as the average for all FDA approved drugs in the same period (87 months). Considering other therapeutic categories, for cardiovascular indications receiving accelerated approval the median development time was about 70 months. However, for other indications under Accelerated Approval rule (about 20% of the total), the median development time was about 100 months, which is considerably longer than the average for all FDA approved products.

As a conclusion, data show that the FDA initiatives over the past years were well effective in reducing the review and approval phase, but only in part successful in reducing development and clinical development times.

Some controversial aspects of the FDA programs have also come under criticism in the past years.
It has been shown that drug sponsors public announcements of Fast Track designation often correlate with very short-term stock price increase. Small and lesser-valued companies would benefit relatively more from this so-called Fast Track effect. It has been argued, that some companies may apply for fast track designation mainly as a business driven decision, seeking benefit from the publicity coming from designation announcement.

Controversial issues associates to the accelerated approval program, as the use of surrogate clinical end point and the compliance of sponsor companies in conducing post approval validation trials, are as well discussed in the thesis.

Despite some controversial aspects, FDA programs still have the potential to support and expedite the development and review of new and important medicinal products:

Priority Review policies have shown a positive impact in reducing significantly the review time for designated product compared to standard applications.

The close and early cooperation with FDA in the frame of Fast Track program is potentially a very valuable support, especially for small-to-medium size companies with less experience and expertise in development and regulatory field. A precondition to take the most advantage of the program options would be to seek designation, and thus cooperation, in an early development stage.

The Accelerated Approval program has shown in the past years the potential to reduce the clinical development time for several promising products However to assure in the future the efficacy and the credibility of the program, FDA has to address following issues:

• To make more transparent for the large public and the consumers (patients, practitioners), what exactly the Accelerated Approval imply; full information on the risk-benefit profile of the drug should be made immediately available and understandable, e.g. including this in the product label.
• To improve the compliance of product sponsors to perform validation, post approval clinical trials in a timely manner e.g. introducing the concept of a conditional approval, including annual status review and restrictive marketing until confirmatory studies are completed.

All things considered, the close cooperation between sponsors and the Agency will create in the future the value of the programs aimed to expedite development and review times.

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