Citations

11030 Background: Drug regulators operate on their own timelines to assess the safety and efficacy of new drugs and/or extensions to existing indications, such that there are delays between regulators. During such a gap, patients in the “early” domain have access to the approved drug, while those in the “late” domain do not, outside of compassionate use. Our study aimed to quantify the “opportunity lost” for new therapies approved by FDA and EMA, assuming patients in the late domain receive standard-of-care (SOC) therapy – which is presumably inferior to the new drug – during the gap. Methods: Anticancer drugs approved by both FDA and EMA were identified through the HemOnc knowledgebase. Inclusion criteria included: 1) drugs approved in both domains based on the same randomized clinical trial (RCTs) for the same indication; 2) a primary time-to-event endpoint; and 3) a quantitated median time-to-event for the primary endpoint. For each included trial, the approval gap between FDA and EMA in days and the ratio of approval gap to median control arm time-to-event duration was calculated. A ratio ≥2 implies that, on average, no late domain patients starting treatment in the first half of the gap would be expected to have access to the new drug prior to an event. Results: Of 60 eligible RCTs, 59 had calculable median event durations. 25 (42%) had a primary overall survival endpoint; the most common surrogate endpoint was progression-free survival (PFS; 29/59; 49%). The median (interquartile range [IQR]) approval gap was 186 (124-271) days, with FDA being the first approver in 56/59 (95%) cases. The median (IQR) ratio of approval gap to median control arm event duration was 0.63 (0.35-1.11). Drugs with ratio ≥2 (Table) were targeted or immunotherapies; 7/8 (88%) were approved with PFS endpoint; 5/8 (62.5%) were approved for second line or later. Conclusions: Our study shows that FDA approves most drugs prior to EMA and a nontrivial number of patients may experience progression or death events while awaiting access to anticancer therapies already approved in another domain. The analysis does not take into consideration scenarios in which the new therapy is inferior to SOC or delays in patient access (due to slow uptake; regulatory barriers [in Europe/UK]; or patient affordability [in US]). Further regulatory collaboration (e.g., Project Orbis) between FDA and EMA could help to reduce and potentially ameliorate this differential in access to new cancer drugs in the future. [Table: see text]

11023 Background: Randomized clinical trials (RCTs) in cancer typically compare experimental to control arm regimens. The choice of an appropriate control (ctrl) arm can have a major impact on the expected success of an RCT. The frequency with which cancer RCTs use control arms based on established dosing and scheduling protocols has not been described. Methods: The HemOnc knowledgebase (KB) was used to identify systemic anti-cancer therapy (SACT) regimen variants, defined as regimens with identical components that differ in dosing, scheduling, and/or route. Non-cancer, nonrandomized, and non-SACT studies were excluded. Study publication year was used to define standard variants as those evaluated in the experimental arm of a positive phase 3 RCT >1 year prior to publication as a control arm, regardless of cancer type or context of treatment. Study-variant dyads were evaluated to determine whether the variant was standard. Success rates of RCTs with standard vs non-standard control arms were evaluated with Fisher’s exact test. Results: 5221 studies were associated with ≥1 named variant in the HemOnc KB, as of 2024-02-06. After exclusions, there were 3511 study-variant dyads (2386 studies; 1714 variants). The 9 most common regimens are shown in the Table. The median (IQR) number of variants per regimen was 2 (1-3); carboplatin & paclitaxel (CP) had the most variants (n=33). Across all control arm study-variant dyads, 2228/3492 (64%) utilized non-standard variants. For example, 60/97 studies (62%) of docetaxel as control used the 75 mg/m2 q3wk variant after it was established in 2000, whereas n=27 others used 19 non-standard variants. Trials that used a standard control arm had a numerically higher success rate, 45% vs 42% (OR 1.10, 95% CI 0.92-1.32). Conclusions: Non-standard regimen variants are frequently used in cancer RCTs. Reasons for this could include toxicity, patient convenience, or emerging data from smaller studies that establish comparable efficacy or improved toxicity to standard variants. However, the a priori efficacy of non-standard control arms is less rigorously established, and trials with standard control arms might be more successful. Future directions include quantifying the granular differences between standard and non-standard variants and investigating whether certain types of non-standard variation (e.g. fewer cycles, lower doses) associate with trial success rates. [Table: see text]

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment of chronic myeloid leukemia (CML). Optimal conditioning intensity for allo-HCT for CML in the era of tyrosine kinase inhibitors (TKIs) is unknown. Using the Center for International Blood and Marrow Transplant Research database, we sought to determine whether reduced-intensity/nonmyeloablative conditioning (RIC) allo-HCT and myeloablative conditioning (MAC) result in similar outcomes in CML patients. We evaluated 1395 CML allo-HCT recipients between the ages of 18 and 60 years. The disease status at transplant was divided into the following categories: chronic phase 1, chronic phase 2 or greater, and accelerated phase. Patients in blast phase at transplant and alternative donor transplants were excluded. The primary outcome was overall survival (OS) after allo-HCT. MAC (n = 1204) and RIC allo-HCT recipients (n = 191) from 2007 to 2014 were included. Patient, disease, and transplantation characteristics were similar, with a few exceptions. Multivariable analysis showed no significant difference in OS between MAC and RIC groups. In addition, leukemia-free survival and nonrelapse mortality did not differ significantly between the 2 groups. Compared with MAC, the RIC group had a higher risk of early relapse after allo-HCT (hazard ratio [HR], 1.85; P = .001). The cumulative incidence of chronic graft-versus-host disease (cGVHD) was lower with RIC than with MAC (HR, 0.77; P = .02). RIC provides similar survival and lower cGVHD compared with MAC and therefore may be a reasonable alternative to MAC for CML patients in the TKI era.