Flexibility and innovation in the FDA’s novel regulatory approval strategies for hematologic drugs

The US Food and Drug Administration (FDA) negotiates the evidence necessary for drug approval with pharmaceutical sponsors. The resulting data package submitted in support of approval includes labeling that conveys the benefits and risks of a particular agent. Recent approvals in hematology illustrate the FDA's flexibility partnering with pharmaceutical sponsors to use innovative approaches when developing products for treatment of patients with life-threatening diseases. In addition, the FDA’s new Oncology Center of Excellence (OCE) unites experts from across the FDA to conduct expedited review of drugs, biologics, and devices for the treatment of malignancies, offering opportunities for greater collaboration and flexibility.

FDA has 2 approval pathways for drugs and biological products that treat serious and life-threatening diseases. Both require substantial evidence for approval from adequate and well-controlled investigations. Regular approval is based on demonstration of clinical benefit, defined as an effect on an end point that provides a direct clinical benefit to patients (eg, prolongation of life, a better quality of life, an established surrogate for at least 1 of these).^1-3  Accelerated approval (AA) can be granted based on a surrogate end point that is not considered established, but is reasonably likely to predict clinical benefit. Following AA, FDA requires the drug sponsor to conduct and submit a postmarketing study demonstrating that the treatment is indeed associated with clinical benefit.

Here we provide descriptions and requirements of FDA approval pathways and expedited programs, and offer examples of flexibility and innovation in recent drug approvals for hematological diseases.

Four FDA programs are available to expedite development and review of new drugs to address an unmet medical need in the treatment of a serious or life-threatening condition: Fast Track (FT) Designation, Breakthrough Therapy Designation (BTD), AA, and priority review (Table 1).³  These programs are intended to ensure that transformative therapies are available earlier to patients who have a life-threatening disease and few other treatment options. Key is the demonstration of how the product addresses an unmet medical need (ie, being better than available therapy if available therapy exists). Available therapy is one that is approved or licensed in the United States for the same indication being considered for the drug and is relevant to current US standard of care for the proposed indication. Pharmaceutical sponsors requesting these programs must provide adequate justification. These programs are available for new drug applications (NDAs) as well as supplemental drug applications. Table 2 provides a list of those new molecular entity products approved from 2010 to 2016 that used these programs.

FT Designation provides for designation of a drug as an FT 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.”³  The designation can be based on preclinical or clinical evidence, depending upon the ability of the model to predict effectiveness. FT designation denials occur because of failure to adequately address an unmet medical need, failure to provide requisite preclinical or clinical evidence, or failure to provide a prospective development program that would enable approval. FT designation provides for frequent interactions with the review team, including end-of-phase 1 and end-of-phase 2 meetings to discuss study design, extent of safety data required to support approval, dose-response concerns, and use of biomarkers. An FT product also could be eligible for rolling submissions and priority review if supported by clinical data at the time of the Biological License Application, NDA, or efficacy supplement submission. Rolling submissions are agreements with the applicant wherein the FDA may review portions of a marketing application before submission of the complete application containing all data needed for approval.

BTD was created in the FDA Safety & Innovation Act of 2012.³  BTD is granted for drugs intended to treat a serious condition in which preliminary clinical evidence indicates substantial improvement on a clinically significant end point over available therapy. Denial of BTD requests can occur for a variety of reasons, such as no product available, IND status is on clinical hold, no development plan, and lack of clinical evidence of a substantial improvement over available therapy, which may include a review of the literature and off-label use of other products. The designation offers an all-hands-on-deck approach within the FDA, including multiple meetings with the applicant to deal with the challenge of manufacturing readiness with a compressed development timeline, and is of greatest value early in development (before end-of-phase 2 meetings). BTD is not a guarantee of future approval and may be rescinded if criteria are no longer met. Of the 59 BTD products that FDA’s Center for Drug Evaluation and Research has approved since 2012, a majority are for hematology and oncology indications.⁴  Within the OCE, additional assistance is given through the preliminary breakthrough designation advice in which applicants have the opportunity to present their case for BTD and see their development program in the context of other promising drugs.

AA, as with RA, requires substantial evidence of safety and efficacy, demonstrating that a product provides “meaningful therapeutic benefit… over existing therapies” through well-controlled clinical trials.⁵  However, although regular approval requires demonstration of an improvement in prolongation of life, a better life, or an established surrogate, AA may be based on a “surrogate endpoint… reasonably likely… to predict clinical benefit.”⁶  AA is granted with the requirement that the applicant study the drug further through postmarketing clinical trials, which should usually be under way at the time of AA and be carried out with due diligence. These confirmatory trials may be conducted in a different stage of disease than that for which AA was granted. Equipoise may not exist with respect to conducting a randomized controlled trial in the same disease setting. Often, AA is granted when preliminary efficacy data are based upon response rate in refractory disease, with the confirmatory trial performed in a less refractory disease setting.

A benefit of AA is the ability to use an unestablished surrogate end point, which usually results in smaller, quicker trials. Sponsors negotiate an AA strategy with the FDA. The risk of AA is that the applicant must demonstrate that the product is better than available therapy, and the applicant must complete postmarketing trials and confirm meaningful clinical benefit or the product could be withdrawn. Approximately 10% of AAs in oncology have been withdrawn for failure to confirm clinical benefit.⁷  The FDA does not consider this a failure of the AA program, but an anticipated tradeoff for earlier availability of promising anticancer agents.

Priority review designation means the FDA’s goal is to take action on the marketing application within 8 months of receipt, compared with 12 months under standard review. This designation may be granted to a drug that treats a serious condition and, if approved, would provide a “significant improvement” in safety or effectiveness. Examples include evidence of increased effectiveness in treatment, prevention, or diagnosis of a condition; elimination or substantial reduction of a treatment-limiting adverse reaction; documented enhancement of patient compliance that is expected to lead to an improvement in serious outcomes; or evidence of safety and effectiveness in a new subpopulation.³ 

Demonstrating improvement in overall survival is not always practical for diseases such as multiple myeloma or chronic lymphocytic leukemia, and its use as an end point could delay development of effective therapies. Thus, innovative approaches are required for clinical trial design, analysis, and end points.

Clinical trial designs used in drug development include single arm, window of opportunity, randomized, active or placebo-controlled, randomized discontinuation, add-on, and pick-the-winner designs. Trial design choice depends on the clinical situation and development needs. Practical comparator arm considerations include whether there would be equipoise with respect to treatment arms if placebo or supportive care were the alternative to the experimental treatment. Unbalanced treatment arm withdrawals affect the ability of the trial to make conclusions. Ideally, the same trial should answer important regulatory and scientific questions using current standard of care controls.

Recent novel development approaches include umbrella or basket trials, or master protocol trials with the potential for expansion cohorts, such as Beat AML.⁸  These novel trial designs offer the hope that early identification of promising agents or new uses for approved products can lead to more efficient development and approval. Recently, FDA has recommended that sponsors consider common control studies with multiple experimental arms using a single comparator for those situations in which a confirmatory trial is needed to establish clinical benefit.^9,10 

Combination product development intended to treat a serious disease, such as a hematologic malignancy, represents a new paradigm wherein sponsors provide justifications: strong biological rationale for the combination and a compelling reason the investigational drugs cannot be developed independently. Because regulatory flexibility will be used, the FDA recommends early interaction (eg, pre-IND meetings) to reach agreement on how nonclinical and clinical development can achieve the expected scientific goals of the traditional development program.¹¹ 

Developing novel end points or development pathways can start with the goal in mind, ie, considering what an effective individual product would be expected to do in a disease setting, and then working with the pharmaceutical developer and academicians to develop an appropriate end point to capture the benefit. Successful development depends on a well-thought out plan with go/no-go algorithms based on early clinical data. The following examples are illustrative of well-focused pharmaceutical development and regulatory flexibility in trial design and end points.

Idarucizumab, a humanized monoclonal antibody fragment targeting the direct thrombin inhibitor dabigatran, was a BTD product granted AA in 2015 and indicated in patients treated with dabigatran etexilate when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery, urgent procedures, or situations with life-threatening or uncontrolled bleeding.¹²  Practical considerations during development included lack of standardized tests measuring dabigatran’s anticoagulant effect and bleeding associated with anticoagulant use, which is usually from a lesion (eg, gastrointestinal, genitourinary). Initial development involved healthy volunteer studies because trials in patients who are actively bleeding would be confounded by the bleeding events. Modeling and understanding pharmacokinetics and pharmacodynamics in healthy volunteers allowed the design of additional trials that provided data for AA, which was based on a reduction in unbound dabigatran level and normalization of coagulation parameters. The NDA included the healthy volunteer studies in patients ages 18 to 80 years and an interim report from a real-world outcomes registry in patients, which provided sufficient data for AA. These registry data will provide bleeding and mortality outcomes based on the treatment regimen selected from the healthy volunteer studies.

Ruxolitinib, a kinase inhibitor of JAKs, JAK1 and JAK2, which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function,¹³  was the first product developed and approved to treat myelofibrosis. The lack of a distinct development pathway required significant discussion to define potential clinical benefit and possible approval pathways. A fundamental question was whether changes in spleen size or bone marrow fibrosis could be described as clinical benefit or merely surrogates. Negotiations with the FDA, pharmaceutical sponsor, and academicians led to the use of the Total Symptom Score, a validated patient-reported outcome instrument that focused on specific symptoms associated with the disease. The instrument rated the severity (on a scale from 1 to 10) of pertinent symptom categories. The regular approval was based on demonstration of a reduction in spleen size and a reduction in Total Symptom Score.

Asparaginase Erwinia chrysanthemi was developed for an ultra-rare population of pediatric patients with acute lymphoblastic leukemia (ALL) requiring an alternative to marketed Escherichia coli asparaginase and peg-asparaginase products because of significant hypersensitivity reactions.¹⁴  Approval was based on results of a single-arm, open-label, multiagent chemotherapy pharmacokinetic trial enrolling 59 pediatric patients with ALL and a history of clinically significant hypersensitivity. Trial results demonstrated that the therapy resulted in sustained asparaginase activity at or above levels resulting in depletion of plasma asparagine concentrations, which was accepted as a surrogate end point for this type of product. This end point was supported by significant data external to the trial and more than 30 years of clinical experience using asparaginase products.

Venetoclax was approved as a BCL-2 inhibitor indicated for treatment of patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least 1 prior therapy.¹⁵  Patients with CLL harboring the 17p deletion have a documented poorer prognosis compared with those with CLL without the mutation. Because the development plan targeted a subset of those with CLL, the sponsor partnered with a device developer to identify the select population. AA was based on demonstration of response in a disease setting in which there is no available therapy. The FDA Center for Drug Evaluation and Research and the FDA Center for Devices and Radiological Health negotiated with the pharmaceutical and device sponsors regarding the evidence necessary for simultaneous drug and device approval.

Blinatumomab is a bispecific CD19-directed CD3 T-cell engager indicated for the treatment of Philadelphia (Ph) chromosome-negative relapsed or refractory B-cell precursor ALL.¹⁶  The submitted data package was primarily based on an open-label, multicenter, single-arm study enrolling adult patients with Ph chromosome-negative relapsed or refractory B-precursor ALL demonstrating an impressive complete response rate of 32%, with support from a negative minimal residual disease (MRD) (polymerase chain reaction <1 × 10⁻⁴) of 80%. Because of a lack of information regarding durability of response, AA was granted rather than regular approval. The FDA and applicant agreed that a phase 3 randomized, open-label, active-controlled trial comparing blinatumomab with standard of care for treatment of patients with relapsed or refractory Ph-negative B-cell precursor ALL would be sufficient for granting regular approval.

The Biologics Price Competition and Innovation Act of 2009 created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with a US-licensed biological product. This abbreviated licensure pathway permits reliance on certain existing scientific knowledge about safety and effectiveness of the US-licensed product and enables licensing of a biosimilar biological product based on less than a full complement of product-specific preclinical and clinical data. FDA approved the first US biosimilar, filgrastim-sndz, on 6 March 2015.¹⁷  This approval was based on a totality of evidence approach requiring sufficient analytical similarity data to support a conclusion that the biological product is highly similar to the US-licensed product, notwithstanding minor differences in clinically inactive components. The applicant presented sufficient animal study data to support the demonstration of biosimilarity and presented sufficient human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other clinical safety and effectiveness data to demonstrate that there are no clinically meaningful differences between the biological product and the US-licensed product in terms of safety, purity, and potency.

The FDA welcomes discussion of regulatory use of novel end points, particularly how the novel end point provides direct clinical benefit for the patient. Scientific issues that must be addressed for novel end points include definition, technology standardization, measurement, reproducibility, and validation. Anchoring a novel end point to a more traditional end point in the same trial facilitates scientific understanding of the relationship and leads to acceptance and understanding among providers and patients. Reliable data on MRD and major molecular response (MMR) have been incorporated into FDA-approved labeling since March 2005, when MMR trial data were included based on results from patients with newly diagnosed chronic phase chronic myelogenous leukemia (CP-CML) treated with imatinib mesylate. Approval of tyrosine kinase inhibitors for the treatment of previously treated CP-CML was initially based on demonstration of an improvement in major cytogenetic response and hematologic response. With the interim results of the International Randomized Study of Interferon and STI571 trial,¹⁸  it became clear that time to progression as an end point for approval in trials conducted in patients with newly diagnosed CP-CML would not be feasible for the development of second and later generation tyrosine kinase inhibitors. Substantial external data supported achieving MRD negative status as a surrogate end point. Key to incorporation and regulatory use was the external supportive data, the quality and completeness of trial data, in addition to development of a standardized MMR definition, an MMR assay, and the successful pilot of the assay in the International Randomized Study of Interferon and STI571 trial. These steps led to regulatory acceptance of MMR as the basis for approval in CML. Novel regulatory end points and the breadth of external supportive data needed should be discussed with the FDA on a case-by-case basis. What is not entirely clear for diseases such as CLL is the relationship of the level of MRD achieved and clinical benefit. Clarifying this relationship is needed to understand the role this technology can play in CLL drug development.

The FDA has been increasingly involved in efforts to understand patient perspective on the disease. In February 2014, the FDA held a Patient Focused Drug Development meeting with patients who have sickle cell disease to understand what symptoms bother them the most. The anticipated outcome is that the identified symptoms can be incorporated into Patient Reported Outcome (PRO) instruments to be used in clinical trials to describe the patient experience. Regulatory discussion on using these instruments occurs in the setting of a drug demonstrated to have a clinical effect on the disease. Validated PROs provide evidence of a drug’s effect on disease-related symptoms or functional deficits as well as drug tolerance and quality of life. Hematologic diseases such as sickle cell disease can be an ideal situation for the use of PRO instruments to demonstrate clinical benefit. Validated PROs can be considered for other disease areas as well.

The OCE unites experts from across the FDA to evaluate products for prevention, screening, diagnosis, and treatment of cancer; support development of companion diagnostic tests and use of combinations of drugs, biologics, and devices; develop and promote use of methods created through the science of precision medicine; and facilitate incorporation of the patient view in regulatory decision-making.¹⁹  The OCE conducts the clinical review of applications for products in any expedited review program, such as BTD, AA, or priority review.

The National Cancer Moonshot task force and OCE priorities include modernization of eligibility criteria for clinical trials to include patients normally excluded, greater use of novel clinical trial designs such as large simple trials, site agnostic trials wherein different tumor types are eligible for a therapy based on presence of target, common controls and cohort trials, and the incorporation of “real-world data” and patient-reported outcomes to inform regulatory policy and product efficacy and safety.

Currently, cancer clinical trials only enroll an estimated 3% of cancer patients. Potential participants are excluded because of central nervous system disease involvement, organ dysfunction or limited marrow reserve, HIV positivity, young or older age, or prior malignancy. Some exclusions are based on outdated concerns, such as brief life expectancy for patients with HIV or brain metastases. The OCE is involved in a collaboration between the American Society for Clinical Oncology, Friends of Cancer Research, and the FDA to study how to broaden eligibility criteria to provide greater access to trials and improve the generalizability of clinical trials while ensuring safety. A recent perspective encourages sponsors to use a rational approach to include some patients who were previously excluded from clinical trials.²⁰ 

Per-patient clinical trial costs have risen across all phases since 2008 (4). To reduce the time and cost burden, the concept of large simple trials has been proposed. These would be randomized trials conducted in context of routine cancer care in the postmarketing setting (phase 4), ask a limited number of clinically relevant questions, use focused data collection from electronic health records, and ideally would not be burdensome to clinicians or patients. These trials would benefit from a large sample size (ie, high level of power) to reliably estimate the risk-benefit of a drug.

Historically, oncology drug development has involved discrete phase 1, phase 2, and phase 3 trials. In the past five years, these phases have become more seamless, particularly for anti-PD-1/PD-L1 agents, which account for one-third of the first-in-human trials incorporating expansion cohorts seen in FDA’s oncology INDs involving >100 patients. Expansion cohorts are used to test dose/schedule refinements, expand the tumor types studied, increase the variety of molecularly defined subsets, and test a variety of drug combinations. Although expansion cohorts may offer greater efficiency, additional patient safeguards are needed to ensure that trials have clearly stated objectives, designs, and statistical analysis plans, and that informed consent is accurately updated. It has been proposed that in oncology and hematology, the FDA use the BT designation to identify therapies that justify a seamless design, because this designation offers more intensive interaction with the FDA throughout the drug’s development.¹⁰ 

Regulatory agencies serve the public health through innovative approaches and regulatory flexibility. BTD and AA are increasingly being used to expedite patient access to new therapies. Hematologic disorders affect populations of <100 to millions. These disorders range from those with known effective treatments to those with an unmet medical need. These factors and others are carefully considered when determining a development pathway. In the past 15 years, tremendous growth has occurred in our scientific knowledge of the treatment of hematologic diseases, translating into new therapeutics and an improved outlook. Before the first proteasome inhibitor approval, no product had been approved for the treatment of multiple myeloma in more than 40 years. Bortezomib’s success was followed by the immunomodulatory drugs, and more recently monoclonal antibodies. The monoclonal antibodies’ repertoire include the those with single targets such as programmed death receptor and novel combinatory approaches such as bispecifics that enhance cell–cell or factor–factor interaction. Over the next decade, the hematologic treatment landscape will encompass a number of new therapeutic possibilities, such as chimeric antigen receptor T cells, gene editing, targeted therapies, and immune therapeutics. New uses for old drugs, such as ruxolitinib for treatment of graft-versus-host disease, will also continue.²¹  Novel end points such as immune recovery response and other response criteria using emerging technologies will be defined and refined before eventual incorporation into clinical trials. Drug development for rare and ultrarare populations requires innovative scientific approaches and regulatory flexibility. Continued partnership with patients, clinicians, and the pharmaceutical industry will ensure development and approval will occur as expeditiously as possible.

Contribution: A.T.F. and R.P. conceived the paper. A.T.F. and K.B.G. wrote the paper and R.P. edited it.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

This is a US government work. There are no restrictions on its use.

Correspondence: Ann T. Farrell, US Food and Drug Administration, WO 22-2332, 10903 New Hampshire Ave, Silver Spring, MD 20993; e-mail: ann.farrell@fda.hhs.gov.