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Key Points

Question听 What are the premarket end points and postmarketing requirements for US Food and Drug Administration (FDA) breakthrough therapy鈥揹esignated approvals?

Findings听 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鈥揹esignated accelerated approvals had FDA-required postmarketing studies, only 7% of traditional approvals based on surrogate marker primary end points had such studies.

Meaning听 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鈥揹esignated drugs.

Importance听 The US Food and Drug Administration (FDA) awards the breakthrough therapy designation to expedite development and review of therapeutics intended to treat serious conditions when preliminary clinical evidence demonstrates potential substantial improvement over existing therapies on clinically significant end points. Under the 21st Century Cures Act of 2016, the FDA is required to publish and routinely update a list of surrogate markers to provide industry sponsors with indication-specific information about end points that were or may be considered for approval. Therapeutics that are granted breakthrough therapy designation can receive accelerated or traditional approval; however, little is known about those approved through the latter pathway, where postmarketing confirmatory studies are typically not required, regardless of the end point used.

Objective听 To evaluate the primary end points used in premarket pivotal trials supporting FDA breakthrough therapy鈥揹esignated approvals and to determine whether postmarketing studies confirming efficacy were required for approvals based on pivotal trials using surrogate markers as primary end points.

Design, Setting, and Participants听 This cross-sectional study used data from the Drugs@FDA database for all original breakthrough therapy鈥揹esignated approvals from inception to December 31, 2023, in the US. The first designation was approved on November 1, 2013. Data analysis was performed in January 2024.

Main Outcomes and Measures听 Descriptive analyses were used to characterize the breakthrough therapy鈥揹esignated indication approval pathways, the primary end points of pivotal efficacy trials, and their postmarketing requirements or commitments.

Results听 From 2013 to 2023, the FDA approved 157 original indications with breakthrough therapy designation. Of these, 52 (33%) were granted accelerated approval and 105 (67%) were granted traditional approval. All accelerated approvals were based on pivotal trials using surrogate markers as primary end points and had FDA-required postmarketing studies to confirm efficacy. Of these 52 indications, 51 (98%) were approved based on surrogate end points listed in the FDA table of surrogate end points for the same indication. Among traditional approvals, 61 (58%) were based on pivotal trials using surrogate markers as primary end points, of which 4 (7%) had FDA-required postmarketing studies to confirm efficacy and 39 (64%) were approved based on surrogate end points listed in the FDA table for the same indication.

Conclusions and Relevance听 In this cross-sectional study of original FDA breakthrough therapy鈥揹esignated approvals from 2013 to 2023, trials supporting these approvals often used surrogate markers as primary end points (even when not approved via accelerated approval) and lacked FDA-required postmarketing studies to verify clinical benefit. These findings suggest that requiring postmarketing studies for breakthrough therapy鈥揹esignated indications approved based on surrogate markers, regardless of approval pathway, may increase patient and clinician certainty of the expected clinical benefit.

The US Food and Drug Administration (FDA) determines drug efficacy on the basis of pivotal clinical trials and has increasingly granted approval based on studies using surrogate markers as primary efficacy end points.^1-3 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.^4,5

Under the regulatory pathway of accelerated approval, the FDA explicitly allows the use of surrogate markers 鈥渞easonably likely to predict clinical benefit鈥� as primary efficacy end points in clinical trials supporting approval for drugs and biologics addressing serious diseases.⁶ Sponsors of therapeutics for indications that receive accelerated approval are required to conduct postmarketing trials to confirm the expected clinical benefit.⁶ However, 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.⁷ Nevertheless, prior studies have raised questions around the association between surrogate markers and their predicted clinical outcomes, for both oncology and nononcology therapeutics, finding that surrogate markers used to inform FDA approval for these indications are not consistently correlated with clinical outcomes such as overall survival or quality of life.^8-11

Surrogate markers can also be used in the FDA鈥檚 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.^12,13 Receipt of this designation grants sponsors eligibility for more frequent meetings and written feedback around the drug鈥檚 development, agency commitment 鈥渋nvolving senior managers,鈥� and rolling review of application materials as the drug is being developed.¹⁴ Receipt 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

In prior studies evaluating the breakthrough therapy鈥揹esignated 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.^16,17 However, little is known about whether the FDA requires additional postmarketing studies to confirm clinical benefit for breakthrough therapy鈥揹esignated 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鈥揹esignated 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 because of prior compliance failures,¹⁸ but does not address breakthrough therapy鈥揹esignated indications that receive traditional approval.

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 () reporting guideline.

Using the FDA Breakthrough Therapy Approvals reports,¹⁹ we identified all original approvals for breakthrough therapy鈥揹esignated drugs and biologics as of December 31, 2023. Next, we used approval letters in the Drugs@FDA database²⁰ 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.

Primary end points were classified as either clinical outcomes or surrogate markers according to the FDA definition of clinical trial end points.⁴ Under 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.⁷ For 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, 鈥淧atient Population鈥� in the FDA table).⁷ If 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.

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.²¹ We 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 File²² and subsequent approval letters to determine the status of the studies required in the postmarketing setting, using previously described methods.²³ According 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).²⁴ We then calculated the duration from the approval date until the fulfillment of postmarketing requirements or commitments, if applicable.

We used descriptive analyses to characterize the breakthrough therapy鈥揹esignated 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).

Since the inception of the breakthrough therapy designation in 2012 until December 31, 2023, the FDA approved 157 original indications with this designation, with the first indication being approved on November 1, 2013. Of these indications, 52 (33%) were granted accelerated approval and 105 (67%) were granted traditional approval (Table 1). Among the 52 indications granted accelerated approval, 29 (56%) were drugs and 23 (44%) were biologics; 49 (94%) were approved for hematologic and oncologic indications, 1 (2%) for an infectious disease, 1 (2%) for a neurologic and psychiatric indication, and 1 (2%) for a genetic and metabolic disease. Among those granted traditional approval, 72 (69%) were drugs and 33 (31%) were biologics; 38 (36%) were approved for hematologic and oncologic indications, 19 (18%) for infectious diseases, 14 (13%) for neurologic and psychiatric indications, 7 (7%) for pulmonologic indications, and 13 (12%) for other indications.

All 52 breakthrough therapy鈥揹esignated 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 (Table 2). 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 3).

For all 52 breakthrough therapy鈥揹esignated 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 26 fulfilled requirements, the median duration from approval to fulfillment was 27.6 (IQR, 17.1-36.4) months. The median duration since approval for the 7 indications with pending (not initiated) postmarketing efficacy requirements was 13.3 (IQR, 9.2-15.3) months, as of January 20, 2024.

Among the 105 breakthrough therapy鈥揹esignated 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). Among the 61 indications approved based on surrogate markers, 42 (69%) were included in the FDA table of surrogate end points. Of these 42 indications, 39 (93%) were approved based on surrogate end points listed for the same indication, 2 (5%) were approved based on surrogate end points that differed from the end point listed in the FDA table for that specific indication but were listed for another indication, and 1 (2%) was approved based on an end point that was not listed in the FDA table for any indication. Of the 61 indications, 19 (31%) were not listed in the FDA table; of these, 10 (53%) were approved based on surrogate end points listed in the FDA table for a different indication, and 9 (47%) were approved based on surrogate end points that were not included in the FDA table for any indications (Figure 2).

Of the 61 breakthrough therapy鈥揹esignated 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 indication (3%) (reduction of all antihypertensive medication for the treatment of unresectable, locally advanced, or metastatic pheochromocytoma or paraganglioma) was not listed in the FDA table for any indication. A total of 13 of 61 approvals (21%) were for infectious disease indications based on trials that used surrogate markers as primary end points, including sustained virologic response, proportion of patients with a 0.5 or greater log₁₀ decrease in viral load, mean adjusted decrease in viral load, viremia clearance, and parasitemia clearance. Of these 13 approvals, 3 end points鈥攃orresponding to 3 indications (23%) (parasitemia clearance for radical cure of Plasmodium vivax malaria, mean adjusted decrease in viral load for treatment of HIV-1 infection, and viral clearance for treatment of posttransplant cytomegalovirus infection)鈥攚ere not listed in the FDA table for any indications. Of the 61 approvals, 7 (11%) were for pulmonology indications, based on change in percent predicted forced expiratory volume in 1 second or change in forced vital capacity; both surrogate markers were listed in the FDA table for the same approved indications.

Among the 61 breakthrough therapy鈥揹esignated 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; (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 graft-vs-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).

In this study of FDA breakthrough therapy鈥揹esignated approvals between 2013 and 2023, two-thirds were based on pivotal trials that used surrogate markers as primary efficacy end points. For breakthrough therapy鈥揹esignated 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 markers 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 therapy鈥揹esignated 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鈥揹esignated 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.¹⁶ However, 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 Certain treatments that have demonstrated clinical benefit for one indication might be ineffective or even harmful for others, often due to potentially unmeasured effects by the surrogate markers.^26-28

Despite recent research showing greater overall survival for breakthrough therapy鈥揹esignated 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 outcomes by providing a cure for serious illnesses or improving patients鈥� quality of life or survival.^30,31 For 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.³² Thus, when breakthrough therapy鈥揹esignated 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鈥揹esignated drugs were granted accelerated approval on the basis of pivotal trials using surrogate markers. For most breakthrough therapy鈥揹esignated 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.³³ This includes the traditional approval pathway where if surrogate end points are used as the basis of approval, they are typically considered to be validated.⁴ However, 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鈥揹esignated 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.¹⁸ Similar policies could also be established to address parallel concerns around residual uncertainty of clinical benefit of breakthrough therapy鈥揹esignated indications approved based on surrogate markers as primary end points.

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.

This cross-sectional study of FDA breakthrough therapy鈥揹esignated indication approvals between 2013 and 2023 showed that pivotal trials supporting the agency鈥檚 approvals for these indications often used surrogate markers as primary end points, even when not approved via the accelerated approval pathway, and lacked FDA-required postmarketing studies to confirm the expected clinical benefit. These concerns highlight the uncertainties for patients and clinicians around the quality of evidence supporting FDA approvals of breakthrough therapy鈥揹esignated indications. Requiring postmarketing requirements for breakthrough therapy鈥揹esignated indications approved based on surrogate markers, regardless of approval pathway, would ensure that clinical benefits are confirmed.

Accepted for Publication: July 3, 2024.

Published: August 27, 2024. doi:10.1001/jamanetworkopen.2024.30486

Open Access: This is an open access article distributed under the terms of the CC-BY License. 漏 2024 Mooghali M et al. 糖心vlog Open.

Corresponding Author: Maryam Mooghali, MD, MSc, Yale Center for Outcomes Research and Evaluation, 195 Church St, New Haven, CT 06510 (maryam.mooghali@yale.edu).

Author Contributions: Dr Mooghali had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Mooghali, Ramachandran.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Mooghali.

Critical review of the manuscript for important intellectual content: Wallach, Ross, Ramachandran.

Statistical analysis: Mooghali.

Obtained funding: Ross, Ramachandran.

Administrative, technical, or material support: Ramachandran.

Supervision: Ramachandran.

Conflict of Interest Disclosures: Dr Wallach reported receiving grants from the National Institute on Alcohol Abuse and Alcoholism, Johnson & Johnson (through the Yale Open Data Access project), and the US Food and Drug Administration (FDA) (through the Yale-Mayo Center for Excellence in Regulatory Science and Innovation) outside the submitted work. In addition, Dr Wallach reported receiving consulting fees from Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC outside the submitted work. Dr Ross reported receiving grants from the FDA, Johnson & Johnson, the Medical Devices Innovation Consortium, the Agency for Healthcare Research and Quality (AHRQ), and the National Heart, Lung, and Blood Institute outside the submitted work. In addition, Dr Ross reported serving as an expert witness at the request of the relator鈥檚 attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc that was settled September 2022. Dr Ramachandran reported receiving grants from the Stavros Niarchos Foundation and the FDA as well as consulting fees from the ReAct-Action on Antibiotic Resistance Strategic Policy Program outside the submitted work. In addition, Dr Ramachandran serves as chair of the FDA Task Force for Doctors for America and as board president of Universities Allied for Essential Medicines North America, both of which are unpaid volunteer positions. No other conflicts were reported.

Funding/Support: This work was supported by grants from Arnold Ventures to the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.