FDA's Expedited Approval Mechanisms for New Drug Products

A. History of the FDA approval process

The modern safety and efficacy requirements that govern FDA's review and approval of a new drug ⁹ product evolved out of a series of legislative enactments, beginning in 1938 with the Federal Food, Drug and Cosmetic Act of 1938 (the FDCA), after the tragic deaths of more than 100 people from a poisonous ingredient in Elixir Sulfanilamide. ¹⁰ The law overhauled the regulatory system that had existed for almost 30 years. Recognizing that post-marketing monitoring alone was insufficient to protect the public's health from dangerous drugs, the FDCA required manufacturers to apply to FDA to market a new drug. ¹¹ If a specified period of time passed without action by FDA, the law deemed the application to be approved. ¹² The law also required a manufacturer to show that a new product was safe. ¹³

In October 1962, following the tragic discovery that a drug marketed as a sleeping pill led to substantial malformations in thousands of newborns in Western Europe, Congress expanded the pre-market requirements for manufacturers of new drug and biologic products through the Kefauver-Harris Drug Amendments to the FDCA. ¹⁴ The amendments replaced the automatic approval provisions if FDA failed to act with a requirement for affirmative FDA approval. ¹⁵ The law further mandated that manufacturers demonstrate substantial evidence of efficacy for a new drug, laying the foundation for the current system of development and clinical trial phases. ¹⁶ Numerous acts have amended the FDCA since 1962, but the heart of these two requirements remains the same.

B. The safety and efficacy standards for new drug product approval

To receive approval for marketing, a sponsor must show that a new drug is safe ¹⁷ and effective. ¹⁸ To establish effectiveness, the sponsor must present “substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof.” ¹⁹ “Substantial evidence” is:

evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. ²⁰

By its terms, § 505(d) of the FDCA permits FDA to find that data from one adequate and well-controlled clinical investigation and confirmatory evidence constitutes substantial evidence of effectiveness, ²¹ but FDA has typically only applied this provision where the lone study was statistically significant at a very high level or for products addressing orphan diseases, where more than one trial is not logistically feasible. ²² In determining whether an investigation is adequate and well-controlled, FDA considers specific characteristics, including whether the study design permits a valid comparison between the investigational drug and the control to permit quantitative assessment of the drug's effect and whether the recruitment, allocation to treatment arms, observation of patients, and method of analysis permit inference, by, for example, limiting bias and assuring comparability. ²³

A sponsor must also establish safety “for use under conditions prescribed, recommended, or suggested in the proposed labeling.” ²⁴ Neither the statutes nor regulations governing marketing approval define safety. To assess safety, FDA uses a risk-benefit framework. ²⁵ This analysis weighs the benefits against the risks of approving a new compound and considers all of the evidence submitted regarding safety and efficacy, the type and severity of the condition the new compound addresses, other available therapies for that condition, and risk management tools that potentially could ensure the benefits outweigh the risks. ²⁶

C. Clinical trials and phases of drug development

To develop the evidence necessary to satisfy the FDCA's safety and efficacy requirements, sponsors use a series of pre-clinical and three pre-marketing human clinical trial phases. ²⁷ Each phase builds on data from the prior phases and examines a different component of the drug's mechanisms, safety, and efficacy. ²⁸ While the three human clinical trial phases are theoretically distinct experiments, some modern investigations have blurred the lines between them or excluded components altogether. ²⁹

The process begins with preclinical research through in vitro (test tube) tests, tissue cell cultures, computer driven data analysis, and/or live animal models to obtain basic information about the new drug's toxicity, pharmacodynamics, and pharmacokinetics. ³⁰ If these studies appear sufficiently promising, the manufacturer files an Investigational New Drug (IND) Application to obtain an exemption from the FDCA's prohibition against shipping experimental drugs without FDA approval in interstate commerce and to allow FDA to assess the safety of the study. ³¹

After the submission of an IND, the investigator introduces the investigational drug to humans for the first time in Phase 1. ³² These trials are small, typically composed of about twenty to eighty healthy individuals, and are not controlled. ³³ The investigator seeks to assess the safety (including significant short-term side-effects), toxicity, dosage range, and the pharmacokinetics of the investigational drug. ³⁴ Some studies may have an extension component, in which the optimal dose determined from a dose escalation series is tested without controls in a group of study participants.

For those investigational drugs that survive Phase 1, the investigator then generally conducts a randomized, controlled trial of 80 to 200 subjects who have the disease or condition the drug is intended to treat. ³⁵ Phase 2 trials provide more information on safety, and, by testing on patients with the disease or condition of interest, these trials present the first data on the efficacy of the investigational drug and any dose-response relationships. ³⁶ The success of Phase 2 relies on the adequacy of the design of Phase 1. For example, if Phase 1 provided inadequate information on dosage levels, Phase 2 may test the investigational drug “for activity at too low or [too] high a dose.” ³⁷

In the usual case, the safety and efficacy data from these two phases do not in themselves satisfy FDA's requirements of “adequate tests by all methods reasonably applicable to show whether or not such drug is safe” and of “substantial evidence” of efficacy, making Phase 3 trials necessary. ³⁸ Phase 3 clinical trials are expanded controlled and uncontrolled studies. ³⁹ Phase 3 trials involve significantly more patients (on the order of hundreds to thousands of patients) and apply stricter exclusionary criteria to the patients who may enroll than Phase 2 trials. ⁴⁰ These trials provide more extensive data on safety and efficacy, including any side effects associated with long-term use, to enable FDA “to evaluate the overall benefit-risk relationship of the drug …” ⁴¹

One particularly important component of Phase 3 trials is the primary endpoint used to measure the benefit from a drug product. ⁴² Under the regular approval mechanisms, FDA approves New Drug Applications (NDAs) based on either a direct clinical efficacy endpoint or a validated surrogate endpoint. ⁴³ A clinical endpoint “is a characteristic or variable that directly measures a therapeutic effect of a drug—an effect on how a patient feels (e.g., symptom relief), functions (e.g., improved mobility), or survives.” ⁴⁴ A clinical benefit “is a positive therapeutic effect that is clinically meaningful in the context of a given disease. The clinical benefit must be weighed against a treatment's risks to determine whether there is an overall benefit for patients (i.e., positive benefit-risk profile).” ⁴⁵ Quintessential primary clinical efficacy endpoints include improved overall survival and symptomatic improvement (such as time to progression of cancer symptoms). ⁴⁶

An intermediate clinical endpoint is a measure of how a patient feels or functions, but is not the ideal endpoint that a drug product seeks to affect. ⁴⁷ A surrogate endpoint is an alternative endpoint that measures the effect of a drug product on a distant biological marker that is predicted to relate with some degree of certainty to a clinical efficacy endpoint. ⁴⁸ A validated surrogate endpoint “is known to predict clinical benefit” for a certain disease state and for a certain type of intervention. ⁴⁹ It has been suggested that to be a validated surrogate endpoint, the biological marker “must be correlated with the clinical endpoint” and “must fully capture the net effect of the intervention on the clinical-efficacy endpoint” for a specific disease setting and class of interventions. ⁵⁰ Blood pressure reduction, for example, is a validated surrogate for risk of stroke in patients with cardiovascular disease for well-studied classes of antihypertensive agents such as beta-blockers and low-dose diuretics with known favorable safety profiles. ⁵¹

Following Phase 3 trials, a sponsor may submit an NDA seeking approval to market the compound. A sponsor also may conduct Phase 4 studies after FDA approves an NDA and the new drug enters the market. Phase 4 studies seek “to gather information on the drug's effect in various populations and any side effects associated with long-term use.” ⁵²

At various points during this development process, FDA and the sponsor of a new drug product may meet to discuss questions and issues that arise. For any type of new drug product, a sponsor may request meetings at the end of Phase 2 (EOP2 meeting) to discuss the safety of proceeding to Phase 3, the Phase 3 plan and protocol, and any additional information needed to support a marketing application, among other topics; they may also seek to meet with FDA prior to the submission of a NDA (pre-NDA meeting) to discuss any major unresolved problems, statistical analysis methods, and the best approach to formatting and presenting the data in the NDA. ⁵³

D. Pressures on drug development and innovation: time and cost of full marketing approval for a new drug product

The length and cost of the traditional development and approval process varies between products, and comparisons of the length of the development process across time periods are complicated by different methods of analysis and different data. But, there is nonetheless evidence and an accepted belief that both have been increasing. ⁵⁴ According to some estimates, in the 1960s and 1970s, clinical development of a new compound through marketing approval took respectively 7.9 years and 8.2 years, on average. ⁵⁵ Although one study assessing data for the 1980s and 1990s estimated that it had decreased to approximately 7.5 years, much of this reduction may have been due to shorter FDA approval times in the 1990s following the passage of the Pharmaceutical Development User Fee Act of 1992 (PDUFA), which established time goals for regulatory approval. ⁵⁶ Indeed, the length of the period between the start of clinical testing and submission of an NDA or biological licensing application (BLA) with FDA was on average six years (72.1 months) in the 1980s and early 1990s, 3.5 months longer than the same period in the 1970s and early 1980s. ⁵⁷ Another analysis suggested that the average development time from patent filing through market launch in the U.S. and 15 European Union countries spanned 9.7 years for products launched in the 1990s and increased to 13.9 years for those which began marketing in 2000 or later. ⁵⁸

In addition to an increase in the length of clinical trials, the cost of developing new compounds has risen dramatically. According to one study led by DiMasi, the average out-of-pocket cost to develop a new compound that receives marketing approval by FDA, taking into account the costs of other failed research over the same time period, was $403 million (in 2000 U.S. dollars), or $802 million capitalized, for drugs first tested in humans between 1983 and 1994 and receiving marketing approval on or about 1997. ⁵⁹ The estimated total capitated cost was more than twice as high as that calculated by the author in an earlier study for drugs first tested in humans a decade earlier (between 1970 and 1982) and receiving marketing approval on or around 1984, which itself was more than twice as high as figures calculated for new compounds generally approved in the 1970s. ⁶⁰ Notably, evidence suggests that costs associated with time accounted for half of these total costs. ⁶¹ Moreover, evidence indicates that clinical testing expenses significantly drive the increased costs of developing a new compound to marketing approval. ⁶²

A. The original prioritization matrix

Following the Kefauver-Harris Amendments, FDA internally began to use a matrix of chemical type and therapeutic potential to classify and prioritize the review of INDs and NDAs. The matrix was formalized in 1974, and a version of it was utilized until January 1, 1992. ⁶³ The chemical classification represented a “fixed, objective rating that describe[d] FDA's assessment of the drug's relationship to active moieties already marketed and approved in the U.S.” ⁶⁴ Chemical types were identified with a number ranging from one, for a new molecular entity, to six, for already marketed drug seeking a new indication. Although generally mutually exclusive, some compounds received more than one type of chemical classification. ⁶⁵

Therapeutic classification was a subjective rating of the drug's therapeutic value, which could change during drug development based on the evidence before FDA. ⁶⁶ Initially, compounds were assigned a mutually exclusive Therapeutic Potential designation of A, B, or C, based on whether the compound would provide important, modest, or little to no therapeutic gains over existing products. Important gains included “effective therapy or diagnosis (by virtue of greatly increased effectiveness or safety) for a disease not adequately treated or diagnosed by any marketed drug” and “improved treatment of a disease through improved effectiveness or safety (including decreased abuse potential).” ⁶⁷ A modest therapeutic gain entailed real gains, which ranged from greater convenience to a large reduction in cost or usefulness for a subpopulation. ⁶⁸ If a compound “essentially duplicate[d] the medical importance and therapeutic usage” of something already on the market in the U.S, it was classified as Type C. ⁶⁹ The therapeutic system also provided for the inclusion of other important information, such as a drug's status as an orphan drug, its likely use in children, or the existence of important toxicity problems. ⁷⁰

The higher the therapeutic classification, the greater the precedence a reviewer would give the NDA. ⁷¹ High classifications also provided other benefits to a sponsor. The classification system was a factor “in determining which drugs [would] be submitted to advisory committee review and which [would] be candidates for ‘End of Phase II’ conferences and priority review.” ⁷² New “[d]rugs which [met] the criteria for priority review [also could] make an early submission of NDA manufacturing and controls information.” ⁷³

The classification matrix reportedly reduced review times for some applications. ⁷⁴ In 1978, for example, FDA approved the 21 NDAs that it had classified as new molecular entities, on average, in 21 months; at that time, FDA generally required 32 months, on average, to approve an NDA. ⁷⁵

B. The AIDS epidemic

In the 1980s, a new tragedy—one that “typifies the diseases of the future: slow, subtle, complex, and rooted in lifestyles and genes”—propelled changes in the new drug regulatory scheme to enable faster approval for certain new products. ⁷⁶ A series of cases of homosexual men suffering from rare diseases that typically afflicted the elderly led the medical community to identify a new syndrome, the Human Immunodeficiency Virus and Acquired Immune Deficiency Syndrome (HIV/AIDS). ⁷⁷ For several years following this initial discovery period (roughly 1981 to 1984), HIV/AIDS patients had no scientifically established or FDA-approved treatments to halt the progression of the virus, leading society to view HIV/AIDS as lethal. ⁷⁸ Those suffering from the syndrome had a significantly lower risk threshold than the average American; in other words, sufferers were willing to take greater risks in the safety of treatments in the hopes of obtaining any therapeutic benefit. ⁷⁹ Patients began seeking out any therapy that had anecdotal evidence of benefit, joining black market buying clubs and cooking medicine themselves. ⁸⁰

These patients and the pharmaceutical industry increasingly criticized FDA as being far too slow, conservative, and risk-averse in the circumstances. ⁸¹ Indeed, the demands of the FDCA drug development process added significant challenges to the marketing approval of a new drug compound for HIV/AIDS. Individuals lived with HIV/AIDS for years without knowing of their infection until symptoms developed leading to a diagnosis. ⁸² Under the traditional developmental framework, potential therapies, like zidovudine (better known now as AZT) could not meet the risk-benefit requirements, or show the lack of long-term toxic side effects quickly enough given the progression to mortality rate of HIV/AIDS. ⁸³ Ultimately, FDA collaborated with the sponsor to facilitate a focused development and review program that led to the approval of zidovudine in approximately two years. ⁸⁴

C. Creation of Priority Review, Accelerated Approval, and Fast Track designation

The activism of the often socially marginalized HIV/AIDS patients ultimately produced several reforms by FDA and Congress. ⁸⁵ FDA promulgated Subpart E in 1988, modeled on the zidovudine clinical development process. ⁸⁶ The regulations recognized the need for the “broadest flexibility in applying the statutory standards” and the altered risk-benefit threshold of patients with life-threatening and seriously debilitating diseases. ⁸⁷ They provided for early and close consultation between FDA and the drug product's sponsor, listing “procedures such as pre-IND and end of Phase 1 meetings as methods to improve the efficiency of preclinical and clinical development, and focus on efforts…to reach early agreement on the design of major clinical efficacy studies …” ⁸⁸ They further provided for the use of medical risk-benefit judgment in the approval decision, including the consideration of the severity of the disease and the lack of a satisfactory alternative. ⁸⁹

By January 1992, FDA also had amended its internal prioritization system, combining the Type A and B classifications into a Type P (“Priority Review, therapeutic gain”) category, and renaming Type C as Type S (“Standard Review, substantially equivalent”). ⁹⁰ In addition to these two mutually exclusive classifications, FDA retained two additional classifications created in 1988. ⁹¹ One was a specific top priority classification, Type AA, for a drug “indicated for the treatment of AIDS or HIV-related disease.” ⁹² The other was a broader category Type E (“Subpart E drug”) for a drug developed and/or evaluated under 21 CFR Part 312 Subpart E.” ⁹³

In response to the AIDS epidemic, Congress also looked into the allegations of a “drug lag.” ⁹⁴ Recognizing that the delay arose in part from FDA's dearth of resources, in October 1992, Congress passed the Prescription Drug User Fee Act of 1992 (PDUFA). ⁹⁵ PDUFA established a system of user fees paid by manufacturers to FDA for the review of NDAs. The funds were dedicated to hiring new personnel. ⁹⁶ In exchange, FDA committed to review timetables in which to complete its analysis of applications. ⁹⁷ As part of that scheme, PDUFA codified two of FDA's prioritization categories of NDAs: Priority Review and Standard Review. ⁹⁸

In December 1992, FDA also created the Accelerated Approval mechanism for full NDA approval through regulations. ⁹⁹ This mechanism applied to the approval of new drug products for serious or life-threatening conditions that provide meaningful therapeutic benefit to patients over existing treatments. ¹⁰⁰ It permitted the sponsor to show efficacy through clinical trials demonstrating an effect on an unvalidated surrogate endpoint that, nonetheless, was “reasonably likely to predict clinical benefit,” rather than a validated surrogate endpoint or clinical efficacy endpoint. ¹⁰¹ For example, a study might evaluate the effect of a treatment on progression-free survival (PFS) rather than mortality. ¹⁰² The use of a surrogate marker may substantially shorten the duration of a trial where the disease would take a long time to progress to the ultimate clinical efficiency endpoint, such as mortality. ¹⁰³

The Fast Track designation evolved out of the Subpart E regulations and was codified in 1997 when Congress passed the Food and Drug Administration Modernization Act of 1997 (FDAMA). ¹⁰⁴

Finally, Congress created the Breakthrough Therapy designation in 2012 through the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA). ¹⁰⁵ In addition to creating this new designation, FDASIA authorized a broader use of Accelerated Approval. ¹⁰⁶

D. Development of Breakthrough Therapy designation

The concept of the Breakthrough Therapy mechanism arose from several factors, including the dramatic advances in science and economic pressures on the pharmaceutical industry. Prior to 1981, when HIV/AIDS was uncovered, scientists developed the vast majority of new therapies from the disease itself or from substances found in nature, through a trial-and-error process, rather than through intentional design. ¹⁰⁷ The core of the modern drug and biological product regulatory system developed against this backdrop. In 1981, however, FDA licensed a revolutionary new product, the first ACE inhibitor, which was modeled to fit a specific protease enzyme. ¹⁰⁸ Gradually, scientists embarked on a process of designing therapeutic compounds with an increasing understanding of biochemistry, pharmacology, and genetics. “The advent of genomic sciences, rapid DNA sequencing, combinatorial chemistry, cell-based assays, and automated high throughput screening (HTS)…led to a ‘new’ concept of drug discovery.” ¹⁰⁹ The completion of the human genome in 2001 has likely contributed to that new direction. ¹¹⁰ Indeed, one of the most notable new scientific advancements in drug development is the increase in molecularly targeted therapies, which target “subgroups of patients (within the larger population with a given disease) who are predicted to benefit from them.” ¹¹¹ The increased specificity and potential for substantially greater benefits over other therapies provide great promise, but also may lead to tension between the regulatory requirements and ethics, time, costs, and patient perspectives. ¹¹²

One drug in particular epitomized this tension. Roche and Plexxikon, Inc. developed a new product intended to treat metastatic melanoma (vemurafenib) ¹¹³ by targeting a specific gene mutation that reportedly occurs in 40 to 60 percent of metastatic melanoma patients. ¹¹⁴ In a Phase 1 dose-escalation clinical trial in 2008 and 2009, over 80 percent of the 32 extension patients with metastatic melanoma and the gene mutation benefited clinically through tumor shrinkage. ¹¹⁵ In the context of cancer, where the standard of care treatments slowed the growth of tumors in only 10 to 20 percent of metastatic melanoma patients, and the average survival for one of the treatments was less than eight months, these early clinical results were compelling. ¹¹⁶

Although some suggested that Roche and Plexxikon, Inc. apply for Accelerated Approval, the companies decided to complete a small Phase 2 clinical trial and a traditional randomized, controlled Phase 3 clinical trial. ¹¹⁷ The performance of these trials in which many patients were randomly given a treatment that early clinical evidence had shown to be dramatically inferior to the investigatory drug, and the general advances in science, pharmacogenetics, and pharmacogenomics, prompted debates in the scientific community and popular press on whether the traditional regulatory framework fit the new scientific methods and whether its use was ethical. ¹¹⁸

Concerns about the economics of modern drug development, supply chain security if development efforts migrated outside the United States, and job security also contributed to the public debate over the requirements of the regulatory process. ¹¹⁹ Since the passage of PDUFA, FDA reported tremendous progress in shortening review times and reversing the drug lag in FDA review of NDAs in comparison to other regulatory agencies. ¹²⁰ Nonetheless, concern existed over the unpredictability, financial costs, and length of the drug development and approval process. ¹²¹ In a report issued shortly after the passage of FDASIA, a group of experts concluded that developing a new compound still required more time and money than in the past, in part because of the inefficiency of the clinical trial system and the need for large and long trials to establish the necessary safety and efficacy data. ¹²² Ominously, it also found that resources available for new compound development were dwindling, due to the loss of revenue of many pharmaceutical companies as a large segment of drugs lost their patent exclusivity (without any new compounds to replace the lost revenue) and a decline in venture capital investment, reportedly due to concerns over unfavorable returns on investment. ¹²³ A high rate of candidate compound failure and regulatory uncertainty further complicated the innovation ecosystem, according to the report. ¹²⁴ The basic concern was that these factors would cause venture capitalists to decrease their investments in small biological and pharmaceutical companies and lead established manufacturers to withdraw from certain fields of development due to diminished financial incentives. Such losses risked not only the public health but also threatened the U.S. economy. Pharmaceutical products represent one of the most significant exports for the United States, and the industry employs a significant number of workers directly and indirectly. ¹²⁵

The Breakthrough Therapy mechanism originated during a discussion at a conference co-hosted by Friends of Cancer Research and the Brookings Institute in 2011 regarding potential new approaches to speed up the FDA approval process for certain promising new drugs. ¹²⁶ A panel of experts that included Janet Woodcock, the Director of the Center for Drug Evaluation and Research (CDER) at FDA, identified a potential development and full approval strategy for obtaining reliable information on safety and efficacy for new therapies that demonstrated large treatment effects early in the development process by considering three new compounds, including vemurafenib. ¹²⁷

In the spring of 2012, after Friends of Cancer Research advocated before Congress for updated mechanisms to respond to the rapid advancement of science, including the Breakthrough Therapy designation, ¹²⁸ members of Congress introduced two bills in the Senate and House, which sought to amend the FDCA to add a new breakthrough therapy designation, ¹²⁹ and which were ultimately incorporated into the Food and Drug Administration Safety and Innovation Act. FDASIA made two significant and general changes to the expedited approval mechanisms then-available for drug products. First, it authorized FDA to apply the Accelerated Approval mechanism more broadly. ¹³⁰ Second, it created an altogether new mechanism, the Breakthrough Therapy designation. ¹³¹

A. Priority Review

Under the two-tier Priority Review framework, FDA classifies all original NDAs, original BLAs, and efficacy supplements for either priority or standard review, whether or not the sponsor requests a specific designation. ¹³² Under FDA's Guidance and the updated CDER MAPP 6020.3, to receive Priority Review, the new product must treat a serious or life-threatening condition and “provide significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions compared to available therapies,” if approved. ¹³³ FDA determines whether a new drug product represents a significant improvement on a case-by-case basis, but it may consider evidence of increased effectiveness, elimination or substantial reduction of a treatment-limiting adverse reaction, improved patient compliance that is expected to improve a serious outcome, or evidence of safety or effectiveness in a new subpopulation. ¹³⁴

Although FDA expects the source of this evidence to be randomized superiority trials, comparing the new drug product to the currently available therapy, FDA has some flexibility in the types of evidence that will establish a significant improvement. ¹³⁵ It notes in its Final Guidance on the four expedited approval mechanisms, for example, that a trial that demonstrates effective treatment of a subpopulation using an historical control may be persuasive. ¹³⁶

FDA independently decides whether to give Priority Review to a new drug product whether or not specifically requested, but a sponsor may request Priority Review when it submits its original NDA or efficacy supplement. ¹³⁷ All original NDAs and efficacy supplements that do not meet the criteria for Priority Review receive the Standard Review designation. ¹³⁸

The primary benefit of receiving Priority Review is a reduction of four-months in the projected review time by FDA. FDA aims to complete review of an NDA for a compound with a Priority Review designation within six months; the goal for a compound with a Standard Review designation is to complete review within ten months. ¹³⁹ In addition, FDA intends “to direct overall attention and resources to the evaluation of applications for” Priority Review drug products. ¹⁴⁰

B. Accelerated Approval

For a new compound to qualify for Accelerated Approval ¹⁴¹ following the enactment of FDASIA, it must address a serious or life-threatening condition and demonstrate an effect on a surrogate endpoint or an intermediate clinical endpoint other than a direct measure of mortality or survival. ¹⁴² The surrogate endpoint or intermediate clinical endpoint must be “reasonably likely to predict” the clinical benefit or an effect on irreversible morbidity or mortality. ¹⁴³

In its Final Guidance, FDA has interpreted an intermediate clinical endpoint to be “a measurement of a therapeutic effect that can be measured earlier than an effect on IMM [irreversible morbidity and mortality] and is considered reasonably likely to predict the drug's effect on IMM or other clinical benefit.” ¹⁴⁴ FDA appears to anticipate that most studies using an intermediate clinical endpoint to demonstrate clinical benefit would be a basis for traditional approval, leaving only a narrow slice of circumstances for accelerated approval. ¹⁴⁵ It believes that Accelerated Approval based on an intermediate clinical endpoint may be appropriate where “[a] study demonstrates a relatively short-term clinical benefit in a chronic disease setting…[and] the short-term benefit is considered reasonably likely to predict long-term benefit or where ‘[a] clinical endpoint demonstrates a clinical benefit that is reasonably likely to predict an effect on IMM…[where] it is essential to confirm the effect on IMM’” for example, “because available therapy has established effects on IMM.” ¹⁴⁶

FDA defines a “surrogate endpoint” in its Final Guidance as “a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure, that is thought to predict clinical benefit, but is not itself a measure of clinical benefit.” ¹⁴⁷ As examples, FDA highlights “[c]learance of bacteria from the blood stream as evidenced by a laboratory measurement of bacteria in the blood” for clinical resolution of infection, “[o]utcomes of 6-month follow-up treatment (i.e., sputum culture status and infection relapse rate” for pulmonary tuberculosis resolution, “[d]ecrease in iron stores for patients with iron overload caused by thalassemia” for “a decrease in transfusion-related adverse events caused by iron overload in the body,” and “[r]adiographic evidence of tumor shrinkage (response rate) in certain cancer types” as a prediction of “improvement of overall survival.” ¹⁴⁸

The type of evidence a sponsor can rely on to establish the necessary relationship between the surrogate or intermediate endpoint and the clinical efficacy endpoint includes “epidemiological, pathophysiological, therapeutic, pharmacologic, or other evidence developed using biomarkers, for example, or other scientific methods or tools,” ¹⁴⁹ although “[e]vidence of pharmacologic activity alone is not sufficient.” ¹⁵⁰

In addition, unlike the FDA regulations, § 506(c) of the FDCA does not expressly require that a new drug product provide meaningful therapeutic benefit to patients over existing treatments. ¹⁵¹ Rather, it permits FDA to take into account “the availability or lack of alternative treatments,” as well as “the severity, rarity, or prevalence of the condition.” ¹⁵² In its Final Guidance, however, FDA explains that it interprets § 506(c) as broadening the use of Accelerated Approval in several ways. ¹⁵³ These include providing (1) “additional flexibility concerning the implications of available therapy on eligibility for accelerated approval,” (2) clarifying “the use of [intermediate] clinical endpoints…as a basis for accelerated approval,” (3) explicitly allowing FDA “to consider pharmacologic or other evidence developed using biomarkers or other scientific methods or tools, in conjunction with other data,” in determining whether to approve a product, and (4) “indicating that FDA should take into account, “… the severity, rarity, or prevalence of the condition …” ¹⁵⁴

Further, § 506(c) of the FDCA permits, but does not require, FDA to hinge Accelerated Approval on verifying the predicted effect on irreversible morbidity or mortality or other clinical benefit through post-approval studies. ¹⁵⁵ Nonetheless, FDA appears to continue to require confirmatory post-approval trials, “completed with due diligence.” ¹⁵⁶

FDA may withdraw approval in several circumstances, including if the sponsor does not “conduct a required postapproval study of the drug with due diligence,” ¹⁵⁷ the study “fails to verify and describe” the “predicted effect on irreversible morbidity or mortality or other clinical benefit,” ¹⁵⁸ “[o]ther evidence demonstrates that the product is not shown to be safe or effective under the conditions of use,” ¹⁵⁹ or “[t]he applicant disseminates false or misleading promotional materials relating to the product.” ¹⁶⁰

The Accelerated Approval mechanism benefits a sponsor or manufacturer by facilitating shorter clinical trials. Rather than waiting for data on a clinical endpoint, Accelerated Approval permits a sponsor or manufacturer to utilize an event that may occur earlier in time. ¹⁶¹

C. Fast Track approval

An investigational new drug product is eligible for Fast Track designation 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 …” ¹⁶² The type of evidence required may be nonclinical or clinical and varies with the stage of development of the product; it could include “theoretical rationale, mechanistic rationale (based on nonclinical data) or evidence of nonclinical activity …” ¹⁶³ A sponsor may request Fast Track designation when the sponsor files an IND application or any time thereafter prior to the receipt of marketing approval. ¹⁶⁴ If a new drug product meets these criteria, Fast Track designation is mandatory. However, FDA may rescind the designation if emerging data no longer supports it. ¹⁶⁵

Fast Track designation provides several benefits to a sponsor. Section 356(b)(1) of the FDCA requires FDA to “facilitate the development and expedite the review of” a Fast Track drug product. ¹⁶⁶ The statute itself provides one such benefit explicitly. Rolling review of a Fast Track product's NDA may be possible if FDA finds that a “fast track product may be effective” based on a “preliminary evaluation of clinical data submitted by the sponsor,” and other administrative criteria ¹⁶⁷ are met. ¹⁶⁸ This enables FDA to review “portions of[] an application for the approval of the product before the sponsor submits a complete application,” potentially expediting the review process. ¹⁶⁹

In addition, Fast Track designation permits frequent interaction between a sponsor and the FDA review team. Meetings are possible prior to submitting an IND application, at the end of Phases 1 and 2 and at other times, as appropriate. ¹⁷⁰ They may cover topics such as “study design, extent of safety data required to support approval, dose-response concerns, [] use of biomarkers,…accelerated approval, the structure and content of an NDA, and other critical issues … .” ¹⁷¹

D. Breakthrough Therapy designation

The fourth expedited approval mechanism—the Breakthrough Therapy designation—applies to a new drug product if it “is intended, alone or in combination with 1 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 1 or more clinically significant endpoints.” ¹⁷²

In its Final Guidance, FDA has interpreted “preliminary clinical evidence” to mean 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.” ¹⁷³ This generally will require more than data from in vitro studies or animal models. ¹⁷⁴ FDA expects preliminary clinical evidence to come from Phase 1 or 2 clinical trials. ¹⁷⁵ Data from human clinical trials “should involve a sufficient number of patients to be considered credible,” though the data may not be definitive at the time of a Breakthrough Therapy designation. ¹⁷⁶ The strongest preliminary clinical evidence would come from a study, comparing the new compound to an available therapy or placebo (where no therapy exists) or the new compound with the standard of care to the standard of care alone; clinical data showing a large difference between a new compound and an historical control may be persuasive, as well. ¹⁷⁷ In addition to evidence of clinical benefit, nonclinical evidence could be supportive. ¹⁷⁸

According to FDA's Final Guidance on its four expedited approval mechanisms, “substantial improvement” generally means a “clear advantage over available therapy” and depends on both the size of the treatment effect and “the importance of the observed effect to the treatment of the serious condition or serious aspect of the condition.” ¹⁷⁹ FDA has interpreted a “clinically significant endpoint” relatively broadly. It “generally [] refer[s] to an endpoint that measures an effect on irreversible morbidity or mortality (IMM) [,] on symptoms that represent serious consequences of the disease,” or “on findings that suggest an effect on IMM or serious symptoms …” ¹⁸⁰ Among other findings, these could be an effect on a surrogate or intermediate clinical endpoint that meets the Accelerated Approval requirements or on a pharmacodynamics biomarker that “strongly suggests the potential for a clinically meaningful effect on the underlying disease.” ¹⁸¹

A sponsor may apply for the Breakthrough Therapy designation when it files an IND application or anytime thereafter. ¹⁸² If the sponsor's application satisfies the Breakthrough Therapy designation requirements, designation of the new drug product as a breakthrough therapy is mandatory. The designation entitles a sponsor to “appropriate actions [by FDA] to expedite the development and review of an application for approval of a breakthrough therapy.” ¹⁸³ FDASIA lists several examples of potential actions that FDA may take. These focus on creating a collaborative and close process between FDA and the sponsor through the commitment of timely communication and meetings, experienced and senior FDA personnel, an FDA employee responsible for coordinating the review within FDA, and efforts by FDA to make the trials as efficient and small as practicable. ¹⁸⁴ In its Final Guidance, FDA has reiterated these benefits and added that a Breakthrough Therapy product may obtain rolling review and “could be eligible for priority review if supported by clinical data at the time of BLA, NDA, or efficacy supplement submission.” ¹⁸⁵

A. Breakthrough Therapy and Fast Track designations

FDASIA creates a hierarchy, placing the Breakthrough Therapy designation at a level above the Fast Track designation, but only for a subset of Fast Track products. To receive the Breakthrough Therapy designation, the evidentiary requirements are stricter at an earlier point in the development process than Fast Track. For both designations, a sponsor may request the designation as early as with the filing of the IND application. Whether a sponsor requests Breakthrough Therapy designation at the IND stage or some later point, a sponsor always must present clinical evidence of improvement over existing therapies. ¹⁸⁸ In contrast, while FDA will likely require available clinical data to accompany a request for Fast Track designation later in the development process, at an early developmental stage, a sponsor may be able to obtain a Fast Track designation with “evidence of activity in a nonclinical mechanism, a mechanistic rationale, or pharmacologic data.” ¹⁸⁹ Moreover, for Breakthrough Therapy designation, the improvement demonstrated must be substantial, while Fast Track designation requires only the potential for improvement. ¹⁹⁰

The subset of new drug products that qualify for the Breakthrough Therapy designation also receive more benefits than Fast Track products. First, the sponsors of Breakthrough Therapy products enjoy a closer, more-collaborative relationship with FDA. FDA has specifically identified in its Final Guidance possible meetings for Fast Track products that are earlier in the development process than for non-expedited products: these include pre-IND and EOP1, at which the sponsor may discuss the design of studies, data required by FDA, use of biomarkers, and other issues. ¹⁹¹ FDASIA, the Final Guidance, and CDER's Good Review Practice on Management of Breakthrough Therapy-Designated Drugs and Biologics provide for even greater, more-frequent meetings for Breakthrough Therapy products. As FDA explains in its Final Guidance, “FDA will seek to ensure that the sponsor … receives timely advice and interactive communications in order to help the sponsor design and conduct a development program as efficiently as possible” and this communication can occur “throughout drug development.” ¹⁹² Indeed, FDA suggests that sponsors of Breakthrough Therapy products have an initial comprehensive multidisciplinary breakthrough therapy meeting with all relevant FDA disciplines ¹⁹³ to discuss “the overarching, high-level plan for drug development” and topics such as “planned clinical trials and endpoints, plans for expediting the manufacturing development strategy, and studies that potentially could be completed after approval.” ¹⁹⁴ Further, FDA anticipates subsequent discipline-specific meetings outside of the critical IND milestone meetings. ¹⁹⁵ These meetings provide a forum to discuss important issues “at different development phases.” ¹⁹⁶ And, importantly, the sponsor and FDA can determine their frequency in a unique communication plan. ¹⁹⁷ Critical IND milestone meetings also can occur earlier than in other cases. ¹⁹⁸ Thus, a Breakthrough Therapy designation appears to permit the opportunity for earlier meetings and FDA's assurance of timely advice and interactions on a much-more-continuous basis throughout development than Fast Track products receive.

Second, Breakthrough Therapy products also may receive greater access and coordination from FDA personnel. These products may have the commitment (where appropriate) of intensive involvement of “senior managers and experienced review staff in a proactive collaborative, cross-disciplinary review.” ¹⁹⁹ Breakthrough Therapy products also have a FDA cross-disciplinary project lead for the FDA review team. ²⁰⁰ The project lead facilitates an efficient review of the development program and serves as a scientific liaison between the review team and the sponsor. ²⁰¹ This level of coordination within FDA is not available for other products. ²⁰² In discussing the communication issues between FDA and sponsors, the PCAST report notes that “no single individual has authority and accountability for integrating the input, resolving conflicting opinions within the FDA, and communicating informally in a timely ongoing manner.” ²⁰³ Rather, many staff across divisions and offices participate in the review, leading potentially to communications to sponsors from different individuals, variable and unpredictable timeframes for reviews of applications and clinical holds, and possibly conflicting opinions within FDA on issues. ²⁰⁴ The addition of experienced and senior FDA personnel and an internal project lead provides a valuable asset to Breakthrough Therapy products because of the chance of significantly greater efficiency in the review and communications to the sponsor. ²⁰⁵

Third, FDA may permit both Fast Track and Breakthrough Therapy products to undergo Rolling Review. ²⁰⁶

Whether the additional meetings and commitment of senior and experienced FDA personnel meaningfully adds to the efficiency and quality of the development program depends on how FDA implements it, but Janet Woodcock, MD, reports that “Sponsors of designated products have remarked on the degree of FDA involvement and have also stated that their timelines for filing a market application have been accelerated as a result.” ²⁰⁷ Altogether, the Breakthrough Therapy designation has additional benefits available to its products that may facilitate the development and review process to a greater extent than for Fast Track products. ²⁰⁸

B. Breakthrough Therapy and Priority Review

A hierarchical relationship also exists between Breakthrough Therapy and Priority Review.

Differences exist between the two mechanisms, stemming largely from their different goals. Priority Review focuses on the review component of the pre-market phase of a new drug product, setting a shorter goal for completing review and providing greater resources. Breakthrough Therapy designation seeks to streamline the pre-review development process. ²⁰⁹ Thus, a sponsor requests these designations at different times. The evidence required to qualify for Breakthrough Therapy must exist far earlier in the development process than for Priority Review. Further, although not definitive, the clinical evidence must show a substantial improvement on a clinical endpoint for the Breakthrough Therapy designation, while a Priority Review drug must only show a significant improvement in effectiveness or safety. ²¹⁰

Overall, Breakthrough Therapy designation likely provides a greater chance of reducing the length (and potentially cost) of the entire pre-market process than Priority Review alone, because development currently demands the greatest amount of time during the pre-market process and because in many cases a Breakthrough Therapy product may qualify for Priority Review as well. Indeed, 11 of the 13 compounds with a Breakthrough Therapy designation that have been approved by FDA for marketing received Priority Review. ²¹¹

C. Breakthrough Therapy and Accelerated Approval

The Breakthrough Therapy designation has more differences relative to Accelerated Approval than to the Fast Track designation or Priority Review. Nonetheless, a subtle hierarchy exists between the two mechanisms. Accelerated Approval primarily aids a sponsor by permitting it to use an endpoint that is expected to occur more quickly than the true primary clinical endpoint of interest. This concrete tool can reduce the length of clinical trials, but does so through one design component. The Breakthrough Therapy designation provides for a close collaboration between the sponsor and FDA to discuss the overall design of the trials. This could potentially include Accelerated Approval and the use of a surrogate marker or intermediate clinical endpoint in trials to develop evidence to support marketing approval. But, it does not guarantee any concrete design elements or any design elements not otherwise available to any other product.

Further, because Accelerated Approval primarily benefits a sponsor by reducing the time to the endpoint of the trial, the products receiving Accelerated Approval generally address conditions with a long disease course and an extended period of time before clinical benefits can be measured. ²¹² The Breakthrough Therapy designation is not so limited.

Finally, FDA generally requires a sponsor to conduct post-marketing trials to confirm the relationship between the surrogate or intermediate clinical endpoint and the clinical benefit. ²¹³ Under Accelerated Approval, FDA may withdraw approval of a drug or biological product in an accelerated manner under certain circumstances, including post-marketing trials that do not verify the expected benefit. ²¹⁴ While FDA may require any new drug or biological product, including a Breakthrough Therapy product, to complete post-marketing studies, they may be required less often than for Accelerated Approval products. Thus, the Breakthrough Therapy designation potentially enables greater efficiency in the development phase of new product than does Accelerated Approval.