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 The draft guidance document, issued in June 2013, was required by the FDA Safety and Innovation Act of 2012 ("FDASIA") and replaces guidance issued in 2006 (Fast Track Drug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.
 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 guidance document defines concepts for expedited drug development and spells out processes for fast-track designation, breakthrough-therapy designation, accelerated approval, and priority review designation...".