expedited programs for drug development and approval

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1. Expedited programs for drug development and approval 2. FDA’s expedited programs 3. Impact of FDA’s expedited programs 4. Conclusion Editorial Expedited programs for drug development and approval Anne R Pariser , Melissa Robb & Rachel E Sherman Office of New Drugs, Center for Drug Evaluation and Research (CDER), Food and Drug Administration, Silver Spring, MD, USA 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 effec- tive 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 devel- opment, 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 rec- ognition 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 Expert Opinion on Orphan Drugs (2013) 1(7):507-510 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 pro- cess, 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 (FDA- SIA) became law [5]. Underscoring the importance of expediting the development of drugs for serious and life-threatening conditions, FDASIA contains provisions to fur- ther 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]. 10.1517/21678707.2013.805124 © 2013 Informa UK, Ltd. e-ISSN 2167-8707 507 All rights reserved: reproduction in whole or in part not permitted Expert Opinion on Orphan Drugs Downloaded from informahealthcare.com by McMaster University on 11/10/14 For personal use only.

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Page 1: Expedited programs for drug development and approval

1. Expedited programs for drug

development and approval

2. FDA’s expedited programs

3. Impact of FDA’s expedited

programs

4. Conclusion

Editorial

Expedited programs for drugdevelopment and approvalAnne R Pariser†, Melissa Robb & Rachel E Sherman†Office of New Drugs, Center for Drug Evaluation and Research (CDER), Food and Drug

Administration, Silver Spring, MD, USA

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 effec-

tive 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 devel-

opment, 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 rec-

ognition 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

Expert Opinion on Orphan Drugs (2013) 1(7):507-510

1. Expedited programs for drug development and approval

The United States (US) Food and Drug Administration (FDA) has long recognizedthe need to expedite the availability of novel agents intended to treat serious or life-threatening conditions, especially when no satisfactory therapies exist, a philosophyfirst codified in regulation in the late 1980s [1]. During the 1990s, formal programswere 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 referencesto drugs include both human drugs and biological products) and FDA’s review pro-cess, were patterned after efforts in the 1980s to speed development and approval ofnovel compounds for the treatment of human immunodeficiency virus (HIV), withthe overall goal of providing seriously ill patients earlier access to promising newdrugs. In the approximately 20 years since these provisions were enacted, theyhave been applied to a variety of other drug development programs for serious orlife-threatening conditions, with the greatest emphasis in HIV and cancer.

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

10.1517/21678707.2013.805124 © 2013 Informa UK, Ltd. e-ISSN 2167-8707 507All rights reserved: reproduction in whole or in part not permitted

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Page 2: Expedited programs for drug development and approval

2. FDA’s expedited programs

FDA has a number of programs to expedite drug developmentand approval (Table 1). Although there are similarities betweensome of the programs, each program has its unique application.Fast Track and Breakthrough predominantly apply to develop-mental phase programs, offering the opportunity to expeditedevelopment. Accelerated Approval is unique because it allowsfor the demonstration of efficacy to depend on evaluation of asurrogate reasonably likely to predict clinical benefit or on aclinical endpoint that can be measured earlier than irreversiblemorbidity or mortality (IMM) and that is reasonably likely topredict an effect on IMM or other clinical benefit. If successful,Accelerated Approval allows marketing of a promising newdrug intended to address an unmet medical need before thedefinitive trials to demonstrate clinical benefit are completed.Priority Review is applicable when the application is submittedand has the goal of shortening the review time.

2.1 Fast track and breakthrough designationOne of the major goals of developmental phase programs(Fast Track and Breakthrough) is to foster and encourageearly engagement and ongoing communication betweendrug developers and FDA. Early and frequent communica-tion has been shown to result in higher approval rates for mar-keting applications, and evidence suggests that, for approvedapplications, efficiency may be enhanced and clinical develop-ment shortened [7,8]. It is important to note that communica-tion during earlier phases of development may have a greaterimpact on clinical development time than those interactionsthat occur later on [8]. Communication may be particularlyvaluable for therapeutic areas where no established regulatory

precedent exists, that is, when there are no prior approvals forthe disease indication. Compared to common disease drugdevelopment programs, rare disease programs often have noregulatory precedent and may benefit most from enhancedcommunication [9].

Fast Track designation is intended to provide opportunitiesfor frequent interactions (meetings and written correspon-dence) between FDA and drug developers during develop-mental phases. Fast Track also contains provisions toexpedite the review of marketing applications. For example,Fast Track-designated applications are eligible for “RollingReview,” which allows for the submission of portions of amarketing application in completed sections (e.g., Qualitymodule), rather than having to wait until every section iscomplete before submitting the application.

Breakthrough is also intended to provide increased opportu-nities for communication during developmental phases. Drugswith Breakthrough designation are eligible for all of the FastTrack provisions. Breakthrough differs from Fast Track, how-ever, in that in order to receive Breakthrough designation, theremust be some preliminary clinical evidence indicating that thedrug may demonstrate substantial improvement over existingtherapies. Sponsors of Breakthrough drugs will receive intensiveguidance 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 towardthe development of Breakthrough therapies. Products intendedto treat serious or life-threatening disorders, both rare andcommon, are eligible for Breakthrough designation; however,given the intensive level of communication for Breakthrough-designated products, rare disorders with unmet needs andwith no available approved therapies may be particularly likelyto benefit from these interactions. This enhanced communica-tion may also allow for greater involvement of disease-specificexperts throughout the development process. Given that raredisorders often have a very limited community of physicians,researchers and other knowledgeable experts available to con-tribute to rare disease drug development, this presents anotheropportunity to support and facilitate this challenging area ofresearch and development.

2.2 Accelerated approval and priority reviewAccelerated Approval is an approval pathway by which aproduct can be marketed if it treats a serious condition, pro-vides meaningful therapeutic benefit over existing therapies,and demonstrates an effect on a surrogate endpoint that is rea-sonably likely to predict clinical benefit or on a clinical end-point that can be measured earlier than an effect on IMM.Accelerated Approval is most useful when the disease has along clinical course and an extended period of time wouldbe required to measure the intended clinical benefit of adrug, whereas the effect on the surrogate or clinical endpointother than IMM would occur more rapidly. Granted by FDAat the time of initial submission of a marketing application,

Article highlights.

. Since the 1980s, FDA has expedited drug developmentusing a number of programs.

. In 2012, the Food and Drug Administration Safety andInnovation Act created a new program, BreakthroughTherapy designation, for drugs intended to treat aserious condition that preliminary clinical evidenceindicates that the drug may demonstrate substantialimprovement over available therapies.

. All of these expedited programs are available to alldrugs intended to treat serious conditions, it is in thearea of rare diseases where these programs have thegreatest potential to favorably effect new drugdevelopment.

. Speed and precision in developing the clinical evidenceneeded to support regulatory approval are not mutuallyexclusive goals.

. Demonstration of comprehensive scientific evidence ofproduct quality, effectiveness, and safety and carefulassessment of this evidence by FDA remain the mostimportant determinants for application approvals.

This box summarizes key points contained in the article.

A. R. Pariser et al.

508 Expert Opinion on Orphan Drugs (2013) 1(7)

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Page 3: Expedited programs for drug development and approval

Priority Review ensures that FDA devotes resources to short-ening review times for those products that, if approved, wouldoffer a significant improvement over existing therapies.

3. Impact of FDA’s expedited programs

The older expedited programs (Fast Track, AcceleratedApproval, Priority Review) have generated substantial interestamong drug developers over the years. In fact, because desig-nation for one of these programs does not exclude drug spon-sors from participation in other programs, often sponsors withnovel drug development programs, including new molecularentities and original biological products, have availed them-selves 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 these39 products, 21 (54%) took advantage of at least one expe-dited 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 designa-tion [11]. Expedited programs have been very successful and

are having the intended effect of providing patients earlieraccess to novel drugs [10]. In addition, marketing applicationreview times have progressively decreased since 1992 and aretypically shorter than for other regulatory agencies [12].

In the months since becoming available, Breakthrough hasalso generated substantial interest. As of April 2013, FDA hasreceived more than 40 requests for Breakthrough designation.This program has been particularly well embraced by develop-ers of drugs to treat rare diseases [13]. Among the initial Break-through designations that have been publically announced areseveral candidate therapies for rare diseases. Although it is toosoon for definitive conclusions, preliminary experience sug-gests that the Breakthrough program is having the intendedimpact----helping to identify the most promising therapiesand ensuring that both the developers and FDA devoteespecially close attention to these products.

4. Conclusion

Everyone agrees that drugs should be developed as efficiently aspossible, but efficiency is of particular importance for drugsintended to treat serious or life-threatening conditions.

Table 1. Expedited programs.

Program Eligibility Description

Fast track Drug to treat a serious disease and fill an unmetmedical need*Designation may be granted on the basis ofpreclinical or clinical data

Process designed to facilitate development andexpedite review. Fast Track designated drugsare eligible for:More frequent interactions with FDA (meetingsor written correspondence) during drug developmentRolling review, whereby companies can submitcompleted sections of marketing applications forFDA review, rather than waiting until every sectionis complete

Breakthrough Drug intended, alone or in combinationwith other drugs, to treat a serious orlife-threatening disease and preliminaryclinical evidence indicates that the drug maydemonstrate substantial improvement overexisting therapies

Breakthrough drugs are eligible for:All of the Fast Track provisionsIntensive FDA guidance on an efficient drug developmentprogramOrganizational commitment involving senior managersand experienced cross-disciplinary review staff

Priority review Drug offers a major advance in treatment orprovides a treatment when no adequatetherapy exists*Designation is assigned at the time ofapplication filing

Goal to complete marketing application reviews in6 months, rather than the standard goal of 10 months

Accelerated approval Drug to treat a serious or life-threatening illnessand provides meaningful therapeutic benefitover existing treatmentsAlthough assessed during marketing applicationreview, plans to use the Accelerated Approvalpathway should be discussed with FDA duringdrug development

Marketing approval may be granted on the basis ofadequate and well-controlled clinical trials that establishan effect of the drug on:Surrogate endpoint reasonably likely to predict clinicalbenefit, orClinical endpoint other than irreversible morbidity ormortality (IMM)

Accelerated Approval requires that the drug be studiedfurther in the postmarket period to verify and describeits 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].

Expedited programs for drug development and approval

Expert Opinion on Orphan Drugs (2013) 1(7) 509

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Page 4: Expedited programs for drug development and approval

Fortunately, it is increasingly recognized that speed and preci-sion in developing the clinical evidence needed to support reg-ulatory approval are not mutually exclusive goals. Upholdingthe highest scientific and regulatory standards demands athoughtful approach to drug development. Experience gainedduring the 1980s from efforts to speed development of novelcompounds for the treatment of HIV and, more recently,with cancer drugs, has demonstrated that flexibility in interpre-tation and practice, a long-standing policy at FDA, is integralto achieving such an approach. This is proving to be the caseespecially for rare disease drug development programs [14].Approval of marketing applications, the most effective way

of providing access to therapies, is only possible----and benefitsto patients will only be realized----when drugs are truly effectiveand their benefits outweigh their risks when used appropriately.Patients with rare diseases are entitled to expect the same qual-ity of treatment as patients with more common diseases. Whilewe have seen how efficiency and expediency in drug develop-ment are more apt to be fully realized when drug sponsorsand FDA work together, communication is only one factor in

expediting drug development. While FDASIA has created anew program for expediting drug development, it also has reaf-firmed the need to maintain high standards for safety and effec-tiveness in drug approval. Demonstration of comprehensivescientific evidence of product quality, effectiveness, and safetyand careful assessment of this evidence by FDA remain themost important determinants for application approvals. Effortsby all working in the pharmaceutical research ecosystem mustcontinue to focus on the scientific tools, new approaches, andfoundational biomedical work needed to inform the design ofrigorous clinical development programs that can meet approvalstandards and expeditiously move novel drugs to the patientswho need them.

Declaration of interest

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

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AffiliationAnne R Pariser†1 MD, Melissa Robb2 &

Rachel E Sherman3 MD MPH†Author for correspondence1Associate Director for Rare Diseases,

Office of New Drugs, Center for Drug

Evaluation and Research (CDER),

Food and Drug Administration (FDA),

10903 New Hampshire Avenue,

Silver Spring, MD, 20993, USA

E-mail: [email protected] Director for Regulatory Affairs,

Office of Medical Policy Initiatives,

Office of Medical Policy (OMP), CDER, FDA,

10903 New Hampshire Avenue,

Silver Spring, MD, 20993, USA3Associate Director for Medical Policy,

OMP, CDER, FDA, 10903 New Hampshire

Avenue, Silver Spring, MD, 20993, USA

A. R. Pariser et al.

510 Expert Opinion on Orphan Drugs (2013) 1(7)

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