Premarket Pivotal Trial End Points and Postmarketing Requirements for FDA Breakthrough Therapies

Key Points Question What are the premarket end points and postmarketing requirements for US Food and Drug Administration (FDA) breakthrough therapy–designated approvals? Findings In this cross-sectional study of 157 original indications with breakthrough therapy designation, all accelerated approvals and 58% of traditional approvals were based on pivotal trials using surrogate markers as primary end points. Whereas all breakthrough therapy–designated accelerated approvals had FDA-required postmarketing studies, only 7% of traditional approvals based on surrogate marker primary end points had such studies. Meaning These findings suggest that frequent use of surrogate markers as primary end points in pivotal studies without requiring postmarketing studies to verify clinical benefit could create uncertainties for patients and clinicians around the use of breakthrough therapy–designated drugs.


Introduction
2][3] In contrast with clinical outcomes, which measure therapeutic effects by assessing how patients feel, function, or survive, surrogate markers (eg, laboratory measurements or imaging findings) serve as a proxy measure in lieu of directly measuring clinical outcomes and are thought to be predictive of clinical benefits. 4,5der the regulatory pathway of accelerated approval, the FDA explicitly allows the use of surrogate markers "reasonably likely to predict clinical benefit" as primary efficacy end points in clinical trials supporting approval for drugs and biologics addressing serious diseases. 6Sponsors of therapeutics for indications that receive accelerated approval are required to conduct postmarketing trials to confirm the expected clinical benefit. 6However, surrogate markers may also be used as primary end points in pivotal trials for therapeutics approved outside of accelerated approval, including traditional approval in which the surrogate markers are known to predict clinical benefit. 710][11] Surrogate markers can also be used in the FDA's determination of another special regulatory pathway, the breakthrough therapy designation.Established under the FDA Safety and Innovation Act of 2012 to expedite the development and review of therapeutics intended to treat serious conditions, the FDA grants the breakthrough therapy designation during the drug development process when preliminary clinical evidence demonstrates potential for substantial improvement over existing therapies on clinically significant end points, including certain surrogate markers. 12,13Receipt of this designation grants sponsors eligibility for more frequent meetings and written feedback around the drug's development, agency commitment "involving senior managers," and rolling review of application materials as the drug is being developed. 14Receipt of the breakthrough therapy designation has also been shown to significantly shorten clinical development periods to a median of 5.2 years compared with 7.2 years for therapeutic approvals using no expedited program. 15 prior studies evaluating the breakthrough therapy-designated indications approved in the first years of the program, investigators found that pivotal trials for these indications often were nonrandomized, used surrogate markers as primary end points, and enrolled small numbers of participants. 16,17However, little is known about whether the FDA requires additional postmarketing studies to confirm clinical benefit for breakthrough therapy-designated indications approved on the basis of surrogate markers.Accordingly, we evaluated the primary end points used in pivotal clinical trials supporting all FDA breakthrough therapy-designated approvals for original indications since the inception of the designation in 2012 until December 31, 2023, along with their approval pathways.We also further examined whether the FDA required or requested additional postmarketing studies to confirm clinical efficacy for indications approved based on pivotal trials that used surrogate markers as primary end points.These findings will be particularly informative in the context of recently enacted legislation through the Food and Drug Omnibus Reform Act of 2022, which strengthened the FDA authority over postmarketing requirements for drugs that receive accelerated approval, in part

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Premarket Pivotal Trial End Points and Postmarketing Requirements for FDA Breakthrough Therapies because of prior compliance failures, 18 but does not address breakthrough therapy-designated indications that receive traditional approval.

Methods
In accordance with the Common Rule, the Yale School of Medicine deemed this cross-sectional study exempt from ethics review and informed consent because it used public, nonidentifiable data and was not human participant research.The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Data Sources and Study Sample
Using the FDA Breakthrough Therapy Approvals reports, 19 we identified all original approvals for breakthrough therapy-designated drugs and biologics as of December 31, 2023.Next, we used approval letters in the Drugs@FDA database 20 to identify the approval pathway (ie, accelerated or traditional approval).For each indication, we identified the pivotal efficacy trials supporting the FDA approval and the corresponding primary end points using the clinical review documents within the drug approval packages, also located in the Drugs@FDA database.

Assessment of Pivotal Trial End Points
Primary end points were classified as either clinical outcomes or surrogate markers according to the FDA definition of clinical trial end points. 4Under the 21st Century Cures Act of 2016, the FDA is required to publish and routinely update a table of surrogate end points to provide industry sponsors with indication-specific information about surrogate markers that were or may be considered by the agency for approval. 7For each indication approved based on pivotal trials with only surrogate markers as primary end points, we determined whether the FDA table of surrogate end points included the surrogate marker for the same indication (ie, "Patient Population" in the FDA table). 7If the end point was not the same or if the indication was not listed in the FDA table, we determined whether that surrogate marker was listed for another indication.

Assessment of Postmarketing Requirements and Commitments
For indications approved based on trials using surrogate markers as primary end points, we determined whether approval letters outlined any postmarketing requirements or commitments describing studies explicitly focused on confirming efficacy.Postmarketing requirements are studies that the FDA requires sponsors to complete by a prespecified deadline, whereas postmarketing commitments are studies that sponsors have voluntarily agreed to conduct but are not required by statute or regulation. 21We excluded postmarketing requirements describing studies evaluating efficacy in a subpopulation of the patient population (eg, those with a specific demographic background or with a certain genotype) and those focused on pharmacokinetics, pharmacodynamics, safety, or tolerability.For approvals with postmarketing requirements or commitments to confirm efficacy, we then searched the FDA Postmarketing Requirements and Commitments Downloadable Database File 22 and subsequent approval letters to determine the status of the studies required in the postmarketing setting, using previously described methods. 23cording to the FDA definition, the status of postmarketing requirements was classified as follows: (1) released (ie, no longer obligated to conduct the study because the study is no longer feasible or would not provide useful data), (2) fulfilled (ie, after reviewing the final study report, the FDA confirmed the fulfillment of the requirements) or submitted (ie, the final study report was submitted to the FDA), (3) terminated (ie, the study was ended before completion, and the final study report has not yet been submitted to the FDA), ( 4) delayed (ie, study progression was behind the original schedule), ( 5) ongoing (ie, study progression was according to or ahead of the original schedule), and (6) pending (not initiated). 24We then calculated the duration from the approval date until the fulfillment of postmarketing requirements or commitments, if applicable.

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Premarket Pivotal Trial End Points and Postmarketing Requirements for FDA Breakthrough Therapies

Statistical Analysis
We used descriptive analyses to characterize the breakthrough therapy-designated indications included in our sample, the primary end points of pivotal efficacy trials, and their postmarketing requirements or commitments.Data analysis was performed in January 2024 using Excel, version 16.79 (Microsoft Inc).
For all 52 breakthrough therapy-designated indications granted accelerated approval, the FDA had required postmarketing studies to confirm efficacy.As of January 20, 2024, the status of these 52 requirements was as follows: 6 (12%) were released (ie, no longer obligated to conduct the study as the study was no longer feasible or would not provide useful data), 26 (50%) were fulfilled (ie, after reviewing the final study report, the FDA confirmed the fulfillment of the requirements), 1 (2%) was submitted (ie, final study report was submitted to the FDA), 5 (10%) were delayed (ie, study progression was behind the original schedule), 7 (13%) were ongoing (ie, study progression was according to or ahead of the original schedule), and 7 (13%) were pending (not initiated).Among the

Breakthrough Therapy-Designated Indications With Traditional Approval
Among the 105 breakthrough therapy-designated indications that received traditional approval, 44 (42%) were approved based on pivotal trials that used at least 1 clinical outcome as a primary end point and 61 (58%) were approved based on pivotal trials that used only surrogate markers as primary end points (Figure 1).2).
Of the 61 breakthrough therapy-designated indications granted traditional approval based on pivotal trials using surrogate markers as primary end points, 29 (48%) were for hematologic and oncologic indications.The surrogate markers used to support approval of these indications included progression-free survival, overall response rate, complete remission rate, complete response rate, duration of severe neutropenia, major molecular response, event-free survival, and reduction of antihypertensive medications.Among these end points, a single end point corresponding to 1 Among the 61 breakthrough therapy-designated indications granted traditional approval based on pivotal trials using surrogate markers as primary end points, 4 (7%) had FDA-required postmarketing studies to confirm efficacy.These requirements included the following: (1) completion and submission of the final report for an ongoing observational study assessing resistance and durability of response to direct-acting antiviral agent therapy for chronic hepatitis C virus infection;  At least 1 clinical primary end point Only surrogate markers as primary end points (2) conducting a new study evaluating disease progression or survival for chemotherapy-induced myelosuppression; (3) conducting a safety analysis with efficacy results when treating chronic graftvs-host disease, using data from prior clinical trials; and (4) completion and submission of the final report for a randomized clinical trial and a single-group study to evaluate the efficacy and safety results for the treatment of paroxysmal nocturnal hemoglobinuria.As of January 20, 2024, the status of these 4 requirements was as follows: 1 study (25%) was fulfilled, 1 study (25%) was submitted, 1 study (25%) was pending (not initiated), and 1 study (25%) could not be located.Additionally, 3 indications had postmarketing efficacy requirements only in a subpopulation of the indicated population (eTable in Supplement 1).

Discussion
In this study of FDA breakthrough therapy-designated approvals between 2013 and 2023, two-thirds were based on pivotal trials that used surrogate markers as primary efficacy end points.For breakthrough therapy-designated indications granted traditional approval, more than half were based on surrogate markers, many of which are not currently listed in the FDA table of surrogate end points meant to guide sponsors about which surrogate have been or may be considered for indication approvals.Moreover, unlike with accelerated approvals in which the FDA required postmarketing studies to confirm the expected clinical benefit for all breakthrough therapydesignated indications, traditional approvals based on surrogate markers were generally not accompanied by FDA-required postmarketing efficacy studies.These findings underline the uncertainty that patients and clinicians may face when assessing the clinical benefits of breakthrough therapy-designated indications without the opportunity for further evidence to be generated after approval to confirm such clinical benefits.
Our study suggests that over a decade after the inception of the breakthrough therapy designation, the majority of the designated indications were approved based on clinical trials using only surrogate markers as the primary efficacy end points, including approvals through both the accelerated and traditional approval pathways.These findings were consistent with previous research examining approvals during the early years of the program. 16However, previous studies have raised concerns around the lack of a strong correlation between surrogate markers and clinical outcomes, 8,9,11,25 and the FDA has acknowledged that surrogate markers may provide incomplete information about the clinical benefits of therapeutics. 26[28] Despite recent research showing greater overall survival for breakthrough therapy-designated vs nondesignated cancer therapeutics, 29 concerns have also been raised that the designation may imply an exceptional magnitude of clinical benefit, creating a perception among the public as well as clinicians that these medications substantially improve patient by providing a cure for serious illnesses or improving patients' quality of life or survival. 30,31For instance, evidence suggests that a substantial proportion of physicians misinterpret the meaning of the breakthrough therapy designation in terms of the evidentiary standards, including that the designation automatically confers eligibility for receiving accelerated approval. 32Thus, when breakthrough therapy-designated indications are approved based on surrogate end points instead of clinical outcomes, without consistent postmarketing requirements to confirm benefit, this may hinder accurate and informed decision-making by patients and clinicians.
In fact, we found that the FDA consistently required additional studies to confirm clinical benefit for the originally indicated population only when breakthrough therapy-designated drugs were granted accelerated approval on the basis of pivotal trials using surrogate markers.For most breakthrough therapy-designated drugs using surrogate markers approved under the traditional pathway, the FDA did not require such postmarketing efficacy studies.Therefore, the FDA should encourage sponsors to use clinical outcomes as primary end points of pivotal trials, especially if the indication is being considered for traditional approval.Furthermore, for these approved indications awarded the breakthrough therapy designation with pivotal trials using surrogate markers as primary end points, the FDA should require sponsors to confirm the clinical benefits in the postmarket setting, regardless of approval pathway. 33This includes the traditional approval pathway where if surrogate end points are used as the basis of approval, they are typically considered to be validated. 4wever, prior studies on both oncology and nononcology indications have demonstrated that surrogate end points used as the basis of traditional approval often lack evidence or strong evidence of association with clinical outcomes, 9,11 underscoring the need for postmarketing efficacy studies to confirm clinical benefits for traditional approvals based on pivotal trials using surrogate markers.
To further improve transparency around these approvals, the FDA could include further justification for the approval decisions, particularly when they do not require postmarketing efficacy studies.
Finally, for those breakthrough therapy-designated treatments approved by the FDA based on surrogate markers as primary end points, the agency could require the surrogate marker end points to be among those listed for the specific indication within the FDA table of surrogate end points.
In addition to requiring postmarketing studies to confirm clinical benefit for breakthrough therapies approved on the basis of studies using surrogate markers as primary end points, regardless of approval pathway, the FDA should also enable their timely completion.The Food and Drug Omnibus Reform Act of 2022 has awarded the FDA several authorities to do so with accelerated approval while also requiring additional transparency from manufacturers regarding the status of confirmatory studies. 18Similar policies could also be established to address parallel concerns around residual uncertainty of clinical benefit of breakthrough therapy-designated indications approved based on surrogate markers as primary end points.

Limitations
This study has several limitations.First, we only examined original indication approvals, whereas the breakthrough therapy designation could also be used for supplemental indications.Second, we relied on publicly available data, including the FDA table of surrogate end points, and did not have access to communications between the sponsors and the agency that might not be included as part of the approval packages and could have informed the selection of primary end points.Finally, we only evaluated the pivotal efficacy trials, which are the primary evidence informing FDA approval; however, the FDA may consider other studies and nonpublicly available data from the sponsors as supplementary efficacy data for its regulatory decision-making.

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Premarket Pivotal Trial End Points and Postmarketing Requirements for FDA Breakthrough Therapies

Figure 1 .
Figure 1.End Points for US Food and Drug Administration Breakthrough Therapy-Designated Indications Granted Traditional Approval, 2013 to 2023 (n = 105) 12

Figure 2 .
Figure 2. Surrogate End Points for US Food and Drug Administration (FDA) Breakthrough Therapy-Designated Indications Granted Traditional Approval, 2013 to 2023 (n = 61)

Table 1 .
Characteristics and Trial End Points for FDA-Approved Breakthrough Therapy-Designated Indications, 2013 to 2023 Abbreviation: FDA, US Food and Drug Administration.aIncludedgeneticand metabolic diseases, gastroenterology, nephrology, ophthalmology, and pain medicine.JAMA Network Open | Health PolicyPremarket Pivotal Trial End Points and Postmarketing Requirements for FDA Breakthrough Therapies Breakthrough Therapy-

Designated Indications With Accelerated Approval All
52 breakthrough therapy-designated indications that received accelerated approval had pivotal trials that used surrogate markers as primary end points.The surrogate markers used as primary efficacy end points in pivotal trials supporting the 51 accelerated approval indications (98%) were listed in the FDA table of surrogate end points for the same indication (Table2).One indication (2%) (to treat PIK3CA-related overgrowth spectrum) was not listed in the FDA table, and the corresponding surrogate marker used in the pivotal trial (reduction in the sum of measurable target lesion volume) was not listed in the FDA table for any other indication (Table

Table 2 .
Consistency of Surrogate End Points Used in Trials Supporting Breakthrough Therapy-Designated Approvals With the FDA Table for Surrogate End Points, 2013 to 2023 Premarket Pivotal Trial End Points and Postmarketing Requirements for FDA Breakthrough Therapies

Table 3 .
Breakthrough Therapy-Designated Indications Approved Based on Trials Using Surrogate End Points That Were Not Consistent With End Points Listed by the FDA (continued)

table Abbreviations :
CMV, cytomegalovirus; DFS, disease-free survival; DLCO, diffusing capacity of the lungs for carbon monoxide; FDA, US Food and Drug Administration; FVC, forced vital capacity; ORR, objective response rate; PFS, progression-free survival.
a Refers to the FDA table for surrogate end points.