United States: FDA Finalizes Guidance Document On Expedited Programs For Serious Conditions

Last Updated: June 10 2014
Article by Colleen Heisey

On May 30, 2014, FDA finalized its Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics. The draft guidance document, issued in June 2013, was required by the FDA Safety and Innovation Act of 2012 ("FDASIA") and replaces guidance issued in 2006 (Fast Track Drug Development Programs – Designation, Development, and Application Review). The guidance document defines certain concepts for expedited drug development and spells out the processes for fast-track designation, breakthrough-therapy designation, accelerated approval, and priority review designation—FDA's four programs for expediting the development and review of new drugs for serious conditions. Concepts defined in the guidance document include "serious condition," "unmet medical need," and "available therapy." The guidance document also explains the policies and threshold criteria for each expedited program and sets forth general considerations for products that might utilize an expedited program, such as manufacturing and product quality as well as nonclinical and clinical inspection. FDA has indicated the guidance document is "the single resource on expedited programs and [will] replace two existing guidance documents [on] fast-track development and available therapy."

Concepts Defined in the Guidance Document

Serious condition: a disease or condition associated with morbidity that has substantial impact on day-to-day functioning or that is life-threatening. FDA has used the same definition in the past in other accelerated programs since 1992. 21 C.F.R. §312.300(b)(1). A drug utilizing an expedited program must be intended to have an effect on a serious aspect of a condition. For example, a diagnostic product intended to improve diagnosis or detection of a serious condition in a way that would lead to improved outcomes would meet the requirement. Products that mitigate or prevent serious treatment-related side effects or avoid a serious adverse event associated with available treatments would also be eligible for the expedited programs, as would a product for prevention of a serious condition or progression to a more advanced stage of the disease.

Available therapy: any therapy approved or licensed in the United States for the same indication and relevant to the standard of care. FDA applies this definition to determine whether there are satisfactory alternative therapies for a serious condition. The guidance document also clarifies that it may give expedited consideration to therapies targeting a subset of a broader disease population for whom the "available therapy" is less effective, but the burden is on the drug development program to provide this evidence. FDA will also take into account evolving standards of care based on developments "at the time of the relevant regulatory decision" and encourages industry sponsors to bring available therapy considerations to its attention. This definition updates FDA's Available Therapy Guidance issued in 2004 in response to FDASIA and applies to all four expedited programs, providing greater flexibility compared to the earlier regulations.

Unmet medical need: a condition for which treatment or diagnosis is not adequately addressed by available therapy, including an immediate need for a defined population or a longer-term societal need. For example, drugs developed in anticipation of antibiotic resistance would qualify for expedited consideration because they serve a longer-term societal need. Where there is no available therapy, an unmet medical need is obvious. Where there is an available therapy, a new treatment must fall into at least one of the following categories: (1) positively affects a serious outcome of the condition without an available therapy; (2) improves a serious outcome of the condition as compared with the available therapy; (3) positively affects a serious outcome of a condition in patients unable to tolerate or unresponsive to available therapy; (4) reduces toxicity or potentially harmful drug interactions associated with available therapy; (5) improves compliance or adds another documented benefit1 , even where the product has comparable safety and efficacy; or (6) addresses an emerging or anticipated public health need. A drug granted accelerated approval based on a surrogate or clinical endpoint and for which clinical benefit has been verified is not considered available therapy. Accelerated approval (restricted distribution) or approval with a Risk Evaluation and Mitigation Strategy ("REMS") is considered available therapy only if the study population for the new drug is eligible to receive the drug.

Overview of Expedited Programs

Like the draft guidance document, the finalized guidance document provides a table comparing FDA's four expedited programs for serious conditions and notes that a drug development program may qualify for more than one expedited program. The chart compares the programs on the basis of qualifying criteria, timing for submission and FDA response, special features, and additional considerations, such as when FDA may rescind a designation for failure to meet the criteria. After this overview in chart form, the guidance document goes on to explain each of the four expedited programs in more detail and provides an appendix laying out the administrative processes for each.

Fast Track: Section 506(b) of the Federal Food, Drug, and Cosmetic Act ("FD&C Act") provides for fast-tracking a drug product "if it is intended, whether alone or in combination with one or more other drugs, for the treatment of a serious or life-threatening disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition." Fast-tracked drugs could include new uses of an already approved drug. In order to qualify for this designation, a sponsor must demonstrate the drug's potential to address unmet medical need, which will depend on the stage of drug development. Whereas early requests for designation could be supported by evidence of activity in a nonclinical model, a mechanistic rationale, or pharmacologic data, requests made later in the drug's development process will require clinical data demonstrating potential to address an unmet medical need. Sponsors of drugs designated for the fast-track program will enjoy frequent interactions with the review team, rolling reviews, and eligibility for priority review for drug approval.

Breakthrough Therapy: FDASIA's Title IX recently amended the FD&C Act to provide for the designation of a drug as a breakthrough therapy "if the drug is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development." The guidance document is FDA's first interpretation of this designation program, which has already proven popular with more than 60 requests in the pipeline.

Before issuing the draft guidance document, FDA designated 20 drugs as breakthrough therapies, leaving stakeholders wondering what the rationales were for granting or denying designations. The guidance document emphasizes that the qualifying criteria for the breakthrough therapy program and drug approval are not the same: the clinical evidence needed to support breakthrough designation is preliminary, and not all designated products will receive marketing approval after undergoing safety and efficacy testing. If later data shows that the designation is no longer supported, FDA may rescind the designation.

According to the guidance document, preliminary clinical evidence is evidence sufficient to indicate that the drug may demonstrate substantial improvement in effectiveness or safety over available therapies, but in most cases is not sufficient to establish safety and effectiveness for purposes of approval. Typically, this kind of evidence comes from Phase I or II trials and would ideally compare the investigational drug to an available therapy or placebo where there is no available therapy. Well-documented historical clinical data and nonclinical information are also persuasive and can support contemporary clinical data. In general, preliminary evidence should show a clear advantage over available therapy.

FDA goes on to say that a substantial improvement over an available therapy is a matter of judgment and depends on both the magnitude of the drug's effect on a clinically significant endpoint and the importance of the observed effect to the treatment of the serious condition or serious aspect of the condition. The guidance document then outlines six approaches to demonstrating substantial improvement that are similar to the unmet medical need criteria discussed above.

Because a breakthrough therapy relies upon a clinically significant endpoint, FDA also defines that term in the guidance document. It is an endpoint measuring an effect on irreversible morbidity or mortality or on symptoms representing serious consequences of the disease. An effect on an established surrogate endpoint typically used to support traditional approval is also acceptable, as is an effect on an "intermediate clinical endpoint considered reasonably likely to predict a clinical benefit." Where similar efficacy to an alternative therapy is shown, designation is available for drugs with a significantly improved safety profile. FDA expressed some doubts about using a pharmacodynamic biomarker as an endpoint, especially if another therapy is already available.

Features of breakthrough therapy designation will include intensive guidance on an efficient drug development program as early as Phase I, involvement of senior managers early in the review, availability of a rolling review process, and potential eligibility for priority review.

Accelerated Approval: FDASIA also contained accelerated approval provisions for "a product for a serious of life-threatening disease or condition . . . upon a determination that the product has an effect on a surrogate endpoint [or some other clinical endpoint] that is reasonably likely to predict clinical benefit . . . taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments." For this program, FDA typically requires postmarketing trials to confirm the anticipated clinical benefits. In the guidance document's discussion of accelerated approval, FDA notes that this program is used more often where the disease course is long, and an extended period of time is required to measure the clinical benefit of a drug, e.g., certain cancer and HIV treatments. Yet the program is also appropriate in acute disease settings in which the intended clinical benefit can be demonstrated only in a very large study.

In order to obtain designation for accelerated approval, a treatment must provide a meaningful therapeutic benefit over existing treatments. 21 C.F.R. §§ 314.500 and 601.40. Under this standard, an alternative therapy with comparable efficacy but a different mechanism of action could receive designation because a significant number of patients may respond differently to it. And the guidance document refers back to its discussion of unmet medical needs for examples of meaningful therapeutic benefit. Like the fast-track program, accelerated approval designation requires the use of certain endpoints, which FDA discusses in detail. The guidance document also lays out the evidentiary criteria for accelerated approval, i.e. the same standards applied to traditional approval.

Other conditions of accelerated approval include preclearance of promotional materials, confirmatory trials, and where those trials fail to verify the intended clinical benefit, FDA may withdraw the designation or ask the applicant to withdraw.

Priority Review: applications for drugs that treat a serious condition and, if approved, would provide a significant improvement in safety or effectiveness will receive this designation. FDA says the safety and efficacy determination is made on a case-by-case basis at the time of New Drug Application ("NDA"), Biologic License Application ("BLA"), or efficacy supplement filing. The guidance document defines significant improvement by way of four examples: (1) evidence of increased effectiveness in treatment, prevention, or diagnosis; (2) reduction of treatment-limiting adverse reactions; (3) enhanced patient compliance expected to lead to improved outcome; and (4) evidence of safety and effectiveness in a new subpopulation. Notably, priority review designation does not require clinical trial evidence of these significant improvements, rather "other scientifically valid information" will do. A priority review designation means FDA intends to take action on the marketing application within six months of receipt (40 percent faster than the standard review).

FDA closed its guidance document by discussing general considerations that apply to all four expedited programs. For example, when sponsors receive a designation, "they should be prepared to propose a commercial manufacturing program that will ensure the availability of quality product at the time of approval." And FDA "may exercise some flexibility," based on product characteristics, seriousness of the condition and medical need, manufacturing processes, the robustness of the sponsor's quality system, and the strength of the sponsor's risk-based quality assessment. FDA also added a provision allowing sponsors using one or more of the expedited programs to involve an in vitro companion diagnostic device.

Overall, the final guidance document hewed closely to the draft, but it appears that requests for more specific and concrete examples of the circumstances to which certain definitions or programs apply were heard by the Agency. The final guidance document added multiple lists of factors, principles, comparisons, and a variety of examples and counterexamples to aid sponsors in understanding FDA's thinking as it evaluates a treatment under its expedited programs.


1 The guidance discusses mechanistic diversity in particular, noting that a novel mechanism of action in a drug with comparable safety and effectiveness could provide advantages for some patients or for drugs that may become less effective over time. For example, infectious disease drugs or targeted cancer therapies could benefit patients who no longer respond to available therapy. So, FDA's evaluation is not strictly a head-to-head comparison.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

To print this article, all you need is to be registered on Mondaq.com.

Click to Login as an existing user or Register so you can print this article.

Colleen Heisey
In association with
Related Video
Up-coming Events Search
Font Size:
Mondaq on Twitter
Register for Access and our Free Biweekly Alert for
This service is completely free. Access 250,000 archived articles from 100+ countries and get a personalised email twice a week covering developments (and yes, our lawyers like to think you’ve read our Disclaimer).
Email Address
Company Name
Confirm Password
Mondaq Topics -- Select your Interests
 Law Performance
 Law Practice
 Media & IT
 Real Estate
 Wealth Mgt
Asia Pacific
European Union
Latin America
Middle East
United States
Worldwide Updates
Mondaq Ltd requires you to register and provide information that personally identifies you, including what sort of information you are interested in, for three primary purposes:
  • To allow you to personalize the Mondaq websites you are visiting.
  • To enable features such as password reminder, newsletter alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our information providers who provide information free for your use.
  • Mondaq (and its affiliate sites) do not sell or provide your details to third parties other than information providers. The reason we provide our information providers with this information is so that they can measure the response their articles are receiving and provide you with information about their products and services.
    If you do not want us to provide your name and email address you may opt out by clicking here
    If you do not wish to receive any future announcements of products and services offered by Mondaq you may opt out by clicking here

    Terms & Conditions and Privacy Statement

    Mondaq.com (the Website) is owned and managed by Mondaq Ltd and as a user you are granted a non-exclusive, revocable license to access the Website under its terms and conditions of use. Your use of the Website constitutes your agreement to the following terms and conditions of use. Mondaq Ltd may terminate your use of the Website if you are in breach of these terms and conditions or if Mondaq Ltd decides to terminate your license of use for whatever reason.

    Use of www.mondaq.com

    You may use the Website but are required to register as a user if you wish to read the full text of the content and articles available (the Content). You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these terms & conditions or with the prior written consent of Mondaq Ltd. You may not use electronic or other means to extract details or information about Mondaq.com’s content, users or contributors in order to offer them any services or products which compete directly or indirectly with Mondaq Ltd’s services and products.


    Mondaq Ltd and/or its respective suppliers make no representations about the suitability of the information contained in the documents and related graphics published on this server for any purpose. All such documents and related graphics are provided "as is" without warranty of any kind. Mondaq Ltd and/or its respective suppliers hereby disclaim all warranties and conditions with regard to this information, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. In no event shall Mondaq Ltd and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use or performance of information available from this server.

    The documents and related graphics published on this server could include technical inaccuracies or typographical errors. Changes are periodically added to the information herein. Mondaq Ltd and/or its respective suppliers may make improvements and/or changes in the product(s) and/or the program(s) described herein at any time.


    Mondaq Ltd requires you to register and provide information that personally identifies you, including what sort of information you are interested in, for three primary purposes:

    • To allow you to personalize the Mondaq websites you are visiting.
    • To enable features such as password reminder, newsletter alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
    • To produce demographic feedback for our information providers who provide information free for your use.

    Mondaq (and its affiliate sites) do not sell or provide your details to third parties other than information providers. The reason we provide our information providers with this information is so that they can measure the response their articles are receiving and provide you with information about their products and services.

    Information Collection and Use

    We require site users to register with Mondaq (and its affiliate sites) to view the free information on the site. We also collect information from our users at several different points on the websites: this is so that we can customise the sites according to individual usage, provide 'session-aware' functionality, and ensure that content is acquired and developed appropriately. This gives us an overall picture of our user profiles, which in turn shows to our Editorial Contributors the type of person they are reaching by posting articles on Mondaq (and its affiliate sites) – meaning more free content for registered users.

    We are only able to provide the material on the Mondaq (and its affiliate sites) site free to site visitors because we can pass on information about the pages that users are viewing and the personal information users provide to us (e.g. email addresses) to reputable contributing firms such as law firms who author those pages. We do not sell or rent information to anyone else other than the authors of those pages, who may change from time to time. Should you wish us not to disclose your details to any of these parties, please tick the box above or tick the box marked "Opt out of Registration Information Disclosure" on the Your Profile page. We and our author organisations may only contact you via email or other means if you allow us to do so. Users can opt out of contact when they register on the site, or send an email to unsubscribe@mondaq.com with “no disclosure” in the subject heading

    Mondaq News Alerts

    In order to receive Mondaq News Alerts, users have to complete a separate registration form. This is a personalised service where users choose regions and topics of interest and we send it only to those users who have requested it. Users can stop receiving these Alerts by going to the Mondaq News Alerts page and deselecting all interest areas. In the same way users can amend their personal preferences to add or remove subject areas.


    A cookie is a small text file written to a user’s hard drive that contains an identifying user number. The cookies do not contain any personal information about users. We use the cookie so users do not have to log in every time they use the service and the cookie will automatically expire if you do not visit the Mondaq website (or its affiliate sites) for 12 months. We also use the cookie to personalise a user's experience of the site (for example to show information specific to a user's region). As the Mondaq sites are fully personalised and cookies are essential to its core technology the site will function unpredictably with browsers that do not support cookies - or where cookies are disabled (in these circumstances we advise you to attempt to locate the information you require elsewhere on the web). However if you are concerned about the presence of a Mondaq cookie on your machine you can also choose to expire the cookie immediately (remove it) by selecting the 'Log Off' menu option as the last thing you do when you use the site.

    Some of our business partners may use cookies on our site (for example, advertisers). However, we have no access to or control over these cookies and we are not aware of any at present that do so.

    Log Files

    We use IP addresses to analyse trends, administer the site, track movement, and gather broad demographic information for aggregate use. IP addresses are not linked to personally identifiable information.


    This web site contains links to other sites. Please be aware that Mondaq (or its affiliate sites) are not responsible for the privacy practices of such other sites. We encourage our users to be aware when they leave our site and to read the privacy statements of these third party sites. This privacy statement applies solely to information collected by this Web site.

    Surveys & Contests

    From time-to-time our site requests information from users via surveys or contests. Participation in these surveys or contests is completely voluntary and the user therefore has a choice whether or not to disclose any information requested. Information requested may include contact information (such as name and delivery address), and demographic information (such as postcode, age level). Contact information will be used to notify the winners and award prizes. Survey information will be used for purposes of monitoring or improving the functionality of the site.


    If a user elects to use our referral service for informing a friend about our site, we ask them for the friend’s name and email address. Mondaq stores this information and may contact the friend to invite them to register with Mondaq, but they will not be contacted more than once. The friend may contact Mondaq to request the removal of this information from our database.


    From time to time Mondaq may send you emails promoting Mondaq services including new services. You may opt out of receiving such emails by clicking below.

    *** If you do not wish to receive any future announcements of services offered by Mondaq you may opt out by clicking here .


    This website takes every reasonable precaution to protect our users’ information. When users submit sensitive information via the website, your information is protected using firewalls and other security technology. If you have any questions about the security at our website, you can send an email to webmaster@mondaq.com.

    Correcting/Updating Personal Information

    If a user’s personally identifiable information changes (such as postcode), or if a user no longer desires our service, we will endeavour to provide a way to correct, update or remove that user’s personal data provided to us. This can usually be done at the “Your Profile” page or by sending an email to EditorialAdvisor@mondaq.com.

    Notification of Changes

    If we decide to change our Terms & Conditions or Privacy Policy, we will post those changes on our site so our users are always aware of what information we collect, how we use it, and under what circumstances, if any, we disclose it. If at any point we decide to use personally identifiable information in a manner different from that stated at the time it was collected, we will notify users by way of an email. Users will have a choice as to whether or not we use their information in this different manner. We will use information in accordance with the privacy policy under which the information was collected.

    How to contact Mondaq

    You can contact us with comments or queries at enquiries@mondaq.com.

    If for some reason you believe Mondaq Ltd. has not adhered to these principles, please notify us by e-mail at problems@mondaq.com and we will use commercially reasonable efforts to determine and correct the problem promptly.

    By clicking Register you state you have read and agree to our Terms and Conditions