Research Letter
Oncology “Me-Too” Drugs Compared With Original Drugs in Randomized Clinical Trials
Timothée Olivier, Calvin Smith, Vinay Prasad, et al
JAMA Intern Med Published Online: July 14, 2025
doi: 10.1001/jamainternmed.2025.2892
The development of “me-too” or “next-in-class” drugs in oncology may offer benefits including improved efficacy, better safety profiles, or economic competition.1,2 Additionally, these drugs may be approved for broader indications and expand access. However, these advantages can remain theoretical without direct comparative evidence. Because little is known about how often randomized clinical trials (RCTs) compare next-in-class and first-in-class drugs, this study examined the share of next-in-class US Food and Drug Administration (FDA) anticancer drug approvals with an RCT-based comparison with the first-in-class drug and characteristics of such RCTs.
Methods
We analyzed all anticancer FDA approvals between 2009 and 2020, including biologics but excluding supportive care treatments, biosimilars, and novel routes of administration approvals. Statistical analysis was conducted on April 3, 2025. We included approvals of next-in-class drugs—a new compound within an existing drug class—for a specific tumor type.
We first identified approvals (eFigure in Supplement 1); for each included approval, another search was conducted to identify whether any corresponding head-to-head RCT was conducted, which could be as part of the approval (ie, supporting it) or later. Therefore, each RCT corresponded to 1 approval. We abstracted whether the identified RCTs met their end point—whether they showed statistically positive results according to their prespecified design (eMethods in Supplement 1). Because we used publicly available data, and this is not human subjects research in accordance with 45 CFR §46.102(f), we did not submit this study to an institutional review board or require informed consent. The study followed the STROBE reporting guidelines. Analyses were conducted with Excel version 16.75.2 (Microsoft).
Results
We found 27 approvals with a direct RCT comparison with an in-class counterpart. Overall, there were 23 regular approvals and 4 accelerated approvals.
Of the 27 approvals with in-class comparison RCTs, 12 were published at the time of FDA approval, while 15 had an RCT published after. Overall, 6 trials (22.2%) showed a survival benefit, and another 14 trials (51.9%) met a nonsurvival primary end point. Six additional trials (22.2%) failed to meet their primary end point, and 1 trial is still ongoing (Figure).
Figure. Network Diagram of Randomized Clinical Trials That Have Tested an Approved Next-In-Class Anticancer Drug Against an In-Class Comparator (N = 27)
The size of each circle represents the number of patients for 1 drug. When drugs were tested in more than 1 trial, the size of the circle represents the total number of patients who participated in these trials. Each arrow represents 1 comparative trial, with the arrow pointing toward the comparator group; the FLAURA trials2,3 are represented with 2 circle-arrows, as the comparator group included 2 drugs. T-DXd and T-DM1 are antibody drug conjugates: monoclonal antibodies linked to cytotoxic agents for targeted drug delivery. Dauno-cyta indicates daunorubicin and cytarabine; deci-ceda, combined oral decitabine and cedazuridine; IV, intravenous; lip-dauno-cyta, liposome-encapsulated combination of daunorubicin and cytarabine; OS, overall survival; T-DM1, trastuzumab emtansine; and T-DXd, trastuzumab deruxtecan.
aOne trial comparing ponatinib with imatinib was terminated early.
For regular approvals (n = 23), 10 trials (43.5%) were conducted as part of the approval, 13 (56.5%) were published after approval (median, 2.8 [range, 1.6-7.1] years postapproval), and 1 (4.3%) is ongoing (Table). For accelerated approvals (n = 4), 2 trials were conducted as part of the approval and 2 were conducted and published after approval (median, 3.3 [range, 3.3-3.4] years postapproval). Among regular approvals designed as superiority trials (n = 17), 11 (64.7%) met their end points. Among accelerated approval trials designed as superiority trials (n = 4), 3 met their end point. The remaining 6 of 27 trials (22.2%), all corresponding to regular approvals, were not designed as superiority trials and met their primary end points. This group included 4 noninferiority studies and 2 comparative pharmacological studies.
Table. Approval and Study Characteristics of US Food and Drug Administration–Approved Next-In-Class Anticancer Drugs With In-Class Comparator Trials
| Approval characteristic | No. (%) | ||
|---|---|---|---|
| All approvals (N = 27) | Accelerated approvals (n = 4) | Regular approvals (n = 23) | |
| Comparison timing | |||
| At the time of approval | 12 (44.4) | 2 (50.0) | 10 (43.5) |
| After approval | 15 (55.5) | 2 (50.0) | 13 (56.5) |
| Comparison met primary end point | |||
| Yes | 20 (74.1) | 3 (75.0) | 17 (74.0) |
| No | 6 (22.2) | 1 (25.0) | 5 (21.7) |
| Ongoing | 1 (3.7) | 0 | 1 (4.3) |
| Comparison primary end point | |||
| Progression-free survival | 17 (63.0) | 3 (75.0) | 14 (61.0) |
| Overall survival | 3 (11.1) | 0 | 3 (13.0) |
| Response rate | 3 (11.1) | 0 | 3 (13.0) |
| Metastasis-free survival | 1 (3.7) | 0 | 1 (4.3) |
| Serum asparaginase activity | 1 (3.7) | 0 | 1 (4.3) |
| Cytogenetic response | 1 (3.7) | 0 | 1 (4.3) |
| Major molecular response | 1 (3.7) | 1 (25.0) | 0 |
| Comparison end point design | |||
| Superiority | 21 (77.8) | 4 (100) | 17 (73.9) |
| Noninferiority trials and pharmacological comparisons | 6 (22.2) | 0 | 6 (26.1) |
| Tumor type | |||
| Hematologic | 8 (29.6) | 1 (25.0) | 7 (30.4) |
| NSCLC | 8 (29.6) | 3 (75.0) | 5 (21.7) |
| Breast | 3 (11.1) | 0 | 3 (13.0) |
| RCC | 3 (11.1) | 0 | 3 (13.0) |
| Prostate | 2 (7.4) | 0 | 2 (8.7) |
| GIST | 2 (7.4) | 0 | 2 (8.7) |
| HCC | 1 (3.7) | 0 | 1 (4.3) |
| Approval target | |||
| Cell cycle | 5 (18.5) | 0 | 5 (21.7) |
| Pan-kinase | 4 (14.8) | 0 | 4 (17.4) |
| EGFR | 4 (14.8) | 1 (25.0) | 3 (13.0) |
| ERBB2 | 3 (11.1) | 0 | 3 (13.0) |
| ALK | 3 (11.1) | 2 (50.0) | 1 (4.3) |
| BCR-ABL | 2 (7.4) | 1 (25.0) | 1 (4.3) |
| Othera | 6 (22.2) | 0 | 6 (26.1) |
Discussion
Study findings raise important questions about the value of next-in-class oncology drugs. These agents may offer benefits in specific scenarios, including overcoming resistance variants, such as osimertinib for EGFR T790M variants,3 or improving safety profiles like alectinib, which compares favorably with crizotinib.4 However, in cases where head-to-head RCTs were lacking, it is difficult to assess the true therapeutic value of next-in-class drugs.
Two limitations of this study are the development of next-in-class drugs may occur in parallel, making head-to-head trials between agents not feasible, and some comparative trials may have been conducted after the analysis and are therefore not captured in the study. These results suggest a need for regulatory bodies to incentivize within-class RCTs. Such evidence would help determine whether next-in-class drugs provide meaningful advances in cancer care. This is particularly important given that me-too drugs have not led to price competition in oncology,5 and many are approved through single-group trials or studies using suboptimal controls.6 Although not always possible if drug development happened concurrently, future regulatory frameworks should consider mandating head-to-head trials against existing in-class agents whenever feasible.
