Expedited programs for drug development and approval

Abstract

The United States Food and Drug Administration (FDA) has long recognized the key role it plays in ensuring patients have timely access to safe and effective drugs. Over the past 25 years, FDA has developed multiple programs, including Fast Track, Accelerated Approval, and Priority Review, to expedite the development and review of new drugs for the patients who need them. With the passage of the Food and Drug Administration Safety and Innovation Act (FDASIA) in 2012, FDA has an additional tool to foster efficient drug development, Breakthrough Therapy designation. Building on past successes, like Fast Track, Breakthrough focuses on early collaboration and communication between drug developers and FDA. These programs reflect the growing recognition that robust scientific drug development must also be efficient and as timely as possible. FDA continues to look for opportunities to streamline drug development, especially in areas with unmet need, while focusing on those products that show real promise to positively impact patients' health.

Keywords::

• drug approval
• Food and Drug Administration
• orphan drugs
• rare diseases

1. Expedited programs for drug development and approval

The United States (US) Food and Drug Administration (FDA) has long recognized the need to expedite the availability of novel agents intended to treat serious or life-threatening conditions, especially when no satisfactory therapies exist, a philosophy first codified in regulation in the late 1980s [1]. During the 1990s, formal programs were developed through statute and codified in regulation when the Fast Track, Accelerated Approval, and Priority Review provisions were enacted in the US [2-4]. These provisions, intended to speed the development of new drugs (all references to drugs include both human drugs and biological products) and FDA's review process, were patterned after efforts in the 1980s to speed development and approval of novel compounds for the treatment of human immunodeficiency virus (HIV), with the overall goal of providing seriously ill patients earlier access to promising new drugs. In the approximately 20 years since these provisions were enacted, they have been applied to a variety of other drug development programs for serious or life-threatening conditions, with the greatest emphasis in HIV and cancer.

In July 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) became law [5]. Underscoring the importance of expediting the development of drugs for serious and life-threatening conditions, FDASIA contains provisions to further define the Accelerated Approval process and a new provision—Breakthrough Therapy designation (Breakthrough)—which is an additional tool for expediting development of innovative drugs intended to address unmet medical needs. Although all of these expedited programs are available to all new drugs intended to treat serious conditions, rare diseases is one area in particular where these programs have great potential to favorably effect new drug development. Most rare diseases are serious or life-threatening conditions, many of which have no approved therapies available for their treatment and for which new therapies are urgently needed [6].

2. FDA's expedited programs

FDA has a number of programs to expedite drug development and approval (Table 1). Although there are similarities between some of the programs, each program has its unique application. Fast Track and Breakthrough predominantly apply to developmental phase programs, offering the opportunity to expedite development. Accelerated Approval is unique because it allows for the demonstration of efficacy to depend on evaluation of a surrogate reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (IMM) and that is reasonably likely to predict an effect on IMM or other clinical benefit. If successful, Accelerated Approval allows marketing of a promising new drug intended to address an unmet medical need before the definitive trials to demonstrate clinical benefit are completed. Priority Review is applicable when the application is submitted and has the goal of shortening the review time.

Table 1. Expedited programs.

Program	Eligibility	Description
Fast track	Drug to treat a serious disease and fill an unmet medical need* Designation may be granted on the basis of preclinical or clinical data	Process designed to facilitate development and expedite review. Fast Track designated drugs are eligible for: More frequent interactions with FDA (meetings or written correspondence) during drug development Rolling review, whereby companies can submit completed sections of marketing applications for FDA review, rather than waiting until every section is complete
Breakthrough	Drug intended, alone or in combination with other drugs, to treat a serious or life-threatening disease and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies	Breakthrough drugs are eligible for: All of the Fast Track provisions Intensive FDA guidance on an efficient drug development program Organizational commitment involving senior managers and experienced cross-disciplinary review staff
Priority review	Drug offers a major advance in treatment or provides a treatment when no adequate therapy exists* Designation is assigned at the time of application filing	Goal to complete marketing application reviews in 6 months, rather than the standard goal of 10 months
Accelerated approval	Drug to treat a serious or life-threatening illness and provides meaningful therapeutic benefit over existing treatments Although assessed during marketing application review, plans to use the Accelerated Approval pathway should be discussed with FDA during drug development	Marketing approval may be granted on the basis of adequate and well-controlled clinical trials that establish an effect of the drug on: Surrogate endpoint reasonably likely to predict clinical benefit, or Clinical endpoint other than irreversible morbidity or mortality (IMM) Accelerated Approval requires that the drug be studied further in the postmarket period to verify and describe its clinical benefit or effect on IMM

*In addition to the eligibility criteria included in this table, there are some types of drugs or drug development programs that have been mandated to receive Fast Track and/or Priority Review status by statute, e.g., qualified infectious disease products under Title VIII of FDASIA entitled “Generating Antibiotic Incentives Now” [5].

2.1 Fast track and breakthrough designation

One of the major goals of developmental phase programs (Fast Track and Breakthrough) is to foster and encourage early engagement and ongoing communication between drug developers and FDA. Early and frequent communication has been shown to result in higher approval rates for marketing applications, and evidence suggests that, for approved applications, efficiency may be enhanced and clinical development shortened [7,8]. It is important to note that communication during earlier phases of development may have a greater impact on clinical development time than those interactions that occur later on [8]. Communication may be particularly valuable for therapeutic areas where no established regulatory precedent exists, that is, when there are no prior approvals for the disease indication. Compared to common disease drug development programs, rare disease programs often have no regulatory precedent and may benefit most from enhanced communication [9].

Fast Track designation is intended to provide opportunities for frequent interactions (meetings and written correspondence) between FDA and drug developers during developmental phases. Fast Track also contains provisions to expedite the review of marketing applications. For example, Fast Track-designated applications are eligible for “Rolling Review,” which allows for the submission of portions of a marketing application in completed sections (e.g., Quality module), rather than having to wait until every section is complete before submitting the application.

Breakthrough is also intended to provide increased opportunities for communication during developmental phases. Drugs with Breakthrough designation are eligible for all of the Fast Track provisions. Breakthrough differs from Fast Track, however, in that in order to receive Breakthrough designation, there must be some preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over existing therapies. Sponsors of Breakthrough drugs will receive intensive guidance to help create an efficient drug development program. FDA intends to involve senior managers and experienced cross-disciplinary review staff in a proactive, collaborative manner, and FDA has agreed to devote considerable resources toward the development of Breakthrough therapies. Products intended to treat serious or life-threatening disorders, both rare and common, are eligible for Breakthrough designation; however, given the intensive level of communication for Breakthrough-designated products, rare disorders with unmet needs and with no available approved therapies may be particularly likely to benefit from these interactions. This enhanced communication may also allow for greater involvement of disease-specific experts throughout the development process. Given that rare disorders often have a very limited community of physicians, researchers and other knowledgeable experts available to contribute to rare disease drug development, this presents another opportunity to support and facilitate this challenging area of research and development.

2.2 Accelerated approval and priority review

Accelerated Approval is an approval pathway by which a product can be marketed if it treats a serious condition, provides meaningful therapeutic benefit over existing therapies, and demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than an effect on IMM. Accelerated Approval is most useful when the disease has a long clinical course and an extended period of time would be required to measure the intended clinical benefit of a drug, whereas the effect on the surrogate or clinical endpoint other than IMM would occur more rapidly. Granted by FDA at the time of initial submission of a marketing application, Priority Review ensures that FDA devotes resources to shortening review times for those products that, if approved, would offer a significant improvement over existing therapies.

3. Impact of FDA's expedited programs

The older expedited programs (Fast Track, Accelerated Approval, Priority Review) have generated substantial interest among drug developers over the years. In fact, because designation for one of these programs does not exclude drug sponsors from participation in other programs, often sponsors with novel drug development programs, including new molecular entities and original biological products, have availed themselves of several expedited programs plus other incentives (e.g., Orphan drug designation) [10]. For example, in 2012, FDA's Center for Drug Evaluation and Research (CDER) approved 39 novel drug and biological products. Of these 39 products, 21 (54%) took advantage of at least one expedited program. For the 39 drugs approved in 2012, 31% used two or more programs, and 9 of these products (23%) received additional incentives, like orphan drug designation [11]. Expedited programs have been very successful and are having the intended effect of providing patients earlier access to novel drugs [10]. In addition, marketing application review times have progressively decreased since 1992 and are typically shorter than for other regulatory agencies [12].

In the months since becoming available, Breakthrough has also generated substantial interest. As of April 2013, FDA has received more than 40 requests for Breakthrough designation. This program has been particularly well embraced by developers of drugs to treat rare diseases [13]. Among the initial Breakthrough designations that have been publically announced are several candidate therapies for rare diseases. Although it is too soon for definitive conclusions, preliminary experience suggests that the Breakthrough program is having the intended impact—helping to identify the most promising therapies and ensuring that both the developers and FDA devote especially close attention to these products.

4. Conclusion

Everyone agrees that drugs should be developed as efficiently as possible, but efficiency is of particular importance for drugs intended to treat serious or life-threatening conditions. Fortunately, it is increasingly recognized that speed and precision in developing the clinical evidence needed to support regulatory approval are not mutually exclusive goals. Upholding the highest scientific and regulatory standards demands a thoughtful approach to drug development. Experience gained during the 1980s from efforts to speed development of novel compounds for the treatment of HIV and, more recently, with cancer drugs, has demonstrated that flexibility in interpretation and practice, a long-standing policy at FDA, is integral to achieving such an approach. This is proving to be the case especially for rare disease drug development programs [14].

Approval of marketing applications, the most effective way of providing access to therapies, is only possible—and benefits to patients will only be realized—when drugs are truly effective and their benefits outweigh their risks when used appropriately. Patients with rare diseases are entitled to expect the same quality of treatment as patients with more common diseases. While we have seen how efficiency and expediency in drug development are more apt to be fully realized when drug sponsors and FDA work together, communication is only one factor in expediting drug development. While FDASIA has created a new program for expediting drug development, it also has reaffirmed the need to maintain high standards for safety and effectiveness in drug approval. Demonstration of comprehensive scientific evidence of product quality, effectiveness, and safety and careful assessment of this evidence by FDA remain the most important determinants for application approvals. Efforts by all working in the pharmaceutical research ecosystem must continue to focus on the scientific tools, new approaches, and foundational biomedical work needed to inform the design of rigorous clinical development programs that can meet approval standards and expeditiously move novel drugs to the patients who need them.

Article highlights.

• Since the 1980s, FDA has expedited drug development using a number of programs.

• In 2012, the Food and Drug Administration Safety and Innovation Act created a new program, Breakthrough Therapy designation, for drugs intended to treat a serious condition that preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies.

• All of these expedited programs are available to all drugs intended to treat serious conditions, it is in the area of rare diseases where these programs have the greatest potential to favorably effect new drug development.

• Speed and precision in developing the clinical evidence needed to support regulatory approval are not mutually exclusive goals.

• Demonstration of comprehensive scientific evidence of product quality, effectiveness, and safety and careful assessment of this evidence by FDA remain the most important determinants for application approvals.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript. The FDA supplied a medical writer to edit the manuscript.

Notes

This box summarizes key points contained in the article.