Intermediate Clinical Endpoints Research Articles

EVIDENCE meta-analysis: evaluating minimal residual disease as an intermediate clinical endpoint for multiple myeloma

Estimating progression-free survival (PFS) and overall survival (OS) superiority during clinical trials of multiple myeloma (MM) has become increasingly challenging as novel therapeutics have improved patient outcomes. Thus, it is imperative to identify earlier endpoint surrogates that are predictive of long-term clinical benefit to expedite development of more effective therapies. Minimal residual disease (MRD)-negativity is a common intermediate endpoint that has shown prognostic value for clinical benefit in trials of patients with multiple myeloma (MM). This meta-analysis was based on the FDA guidance for considerations for a meta-analysis of MRD as a clinical endpoint and evaluates MRD-negativity as an early endpoint reasonably likely to predict long-term clinical benefit. Eligible studies were phase 2 or 3 randomized controlled clinical trials measuring MRD negativity as an endpoint in patients with MM, with follow-up of ≥6 months following an a priori defined time point of 12±3 months post-randomization. Eight newly diagnosed MM-(NDMM)-studies evaluating 4,907 patients were included. Trial-level associations between MRD-negativity and PFS were R2WLSiv (95% CI) 0.67 (0.43-0.91) and R2copula 0.84 (0.64->0.99) at the 12-month timepoint. The individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 4.02 (95% CI: 2.57-5.46). For relapse/refractory MM-(RRMM), there were four studies included, and the individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 7.67 (4.24-11.10). A clinical trial demonstrating a treatment effect on MRD is reasonably likely to eventually demonstrate a treatment effect on PFS, suggesting that MRD may be an early clinical endpoint reasonably likely to predict clinical benefit in MM, that may be used to support accelerated approval and thereby expedite the availability of new drugs to patients with MM.

Intermediate clinical endpoints in early-stage breast cancer: an analysis of individual patient data from the Gruppo Italiano Mammella and Mammella Intergruppo trials

Intermediate clinical endpoints (ICEs) are frequently used as primary endpoint in randomised trials (RCTs). We aim to assess whether changes in different ICEs can be used to predict changes in overall survival (OS) in adjuvant breast cancer trials. Individual patient level data from adjuvant phase III RCTs conducted by the Gruppo Italiano Mammella (GIM) and Mammella Intergruppo (MIG) study groups were used. ICEs were computed according to STEEP criteria. Using a two-stage meta-analytic model, we assessed the surrogacy of each ICE at both the outcome (i.e., OS and ICE are correlated irrespective of treatment) and trial (i.e., treatment effects on ICE and treatment effect on OS are correlated) levels. The following ICEs were considered as potential surrogate endpoints of OS: disease-free survival (DFS), distant disease-free survival (DDFS), distant relapse-free survival (DRFS), recurrence-free survival (RFS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), breast cancer-free interval (BCFI), and invasive breast cancer-free survival (IBCFS). The estimates of the degree of correlation were obtained by copula models and weighted linear regression. Kendall's τ and R2≥0.70 were considered as indicators of a clinically relevant surrogacy. Among the 12,397 patients enrolled from November 1992 to July 2012 in six RCTs, median age at enrolment was 57 years (interquartile range (IQR) 49-65). After a median follow-up of 10.3 years (IQR 6.4-14.5), 2131 (17.2%) OS events were observed, with 1390 (65.2%) attributed to breast cancer. At the outcome-level, Kendall's τ ranged from 0.69 for BCFI to 0.84 for DRFS. For DFS, DDFS, DRFS, RFS, RFI, DRFI, BCFI, and IBCFS endpoints, over 95% of the 8-year OS variability was attributable to the variation of the 5-year ICE. At the trial-level, treatment effects for the different ICEs and OS were strongly correlated, with the highest correlation for RFS and DRFS and the lowest for BCFI. Our results provide evidence supporting the use of DFS, DDFS, DRFS, RFS, RFI, DRFI, and IBCFS as primary endpoint in breast cancer adjuvant trials. This analysis was supported by the Italian Association for Cancer Research ("Associazione Italiana per la Ricerca sul Cancro", AIRC; IG 2017/20760) and by Italian Ministry of Health-5×1000 funds (years 2021-2022).

3 Young Investigator Awardee - Intermediate clinical endpoints in early-stage breast cancer: an analysis of individual patient data from the Gruppo Italiano Mammella (GIM) and Mammella Intergruppo trials (MIG)

3 Young Investigator Awardee - Intermediate clinical endpoints in early-stage breast cancer: an analysis of individual patient data from the Gruppo Italiano Mammella (GIM) and Mammella Intergruppo trials (MIG)

Dose selection for biological enzyme replacement therapy indicated for inborn errors of metabolism.

This paper summarizes key features of the dose-finding strategies used in the development of 11 approved new molecular entities that are first-in-class enzyme replacement therapy (ERT), with a goal to gain insight into the dose exploration approaches to inform efficient dose-finding in future development of biological products for Inborn Errors of Metabolism (IEM). Dose exploration should preferably begin in invitro studies, followed by testing multiple doses in an appropriate animal disease model, when available, which can provide important information for dose assessment in humans. Performing adequate dose-finding in early phase clinical studies in a well-defined study population, including pediatric subjects, is generally critical to inform dose selection for pivotal trials; alternatively, additional dose exploration can be incorporated as part of a pivotal trial. Two important considerations for successful dose selection include (1) identifying appropriate disease-specific endpoints, including pharmacodynamic (PD) end points and intermediate clinical end points or clinical end points, and (2) designing a study with adequate treatment durations for evaluating these end points. Appropriately selected PD biomarkers is useful for dose selection, and early development of these biomarkers can facilitate the overall clinical development program. Optimization of ERT doses, as well as evaluations of patient intrinsic factors and/or immune tolerance strategies may be necessary to overcome antibody responses or increase efficacy in IEM.

Intermediate endpoints as surrogates for outcomes in cancer immunotherapy: a systematic review and meta-analysis of phase 3 trials

Cancer immunotherapy shows unique efficacy kinetics that differs from conventional treatment. These characteristics may lead to the prolongation of trial duration, hence reliable surrogate endpoints are urgently needed. We aimed to systematically evaluate the study-level performance of commonly reported intermediate clinical endpoints for surrogacy in cancer immunotherapy. We searched the Embase, PubMed, and Cochrane databases, between database inception and October 18, 2022, for phase 3 randomised trials investigating the efficacy of immunotherapy in patients with advanced solid tumours. An updated search was done on July, 15, 2023. No language restrictions were used. Eligible trials had to set overall survival (OS) as the primary or co-primary endpoint and report at least one intermediate clinical endpoint including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and 1-year overall survival. Other key inclusion and exclusion criteria included: (1) adult patients (>18 years old) with advanced solid tumour; (2) no immunotherapy conducted in the control arms; (3) follow-up is long enough to achieve OS; (4) data should be public available. A two-stage meta-analytic approach was conducted to evaluate the magnitude of the association between these intermediate endpoints and OS. A surrogate was identified if the coefficient of determination (R2) was 0.7 or greater. Leave-one-out cross-validation and pre-defined subgroup analysis were conducted to examine the heterogeneity. Potential publication bias was evaluated using the Egger's and Begg's tests. This trial was registered with PROSPERO, number CRD42022381648. 52,342 patients with 15 types of tumours from 77 phase 3 studies were included. ORR (R2=0.11; 95% CI, 0.00-0.24), DCR (R2=0.01; 95% CI, 0.00-0.01), and PFS (R2=0.40; 95% CI, 0.23-0.56) showed weak associations with OS. However, a strong correlation was observed between 1-year survival and clinical outcome (R2=0.74; 95% CI, 0.64-0.83). These associations remained relatively consistent across pre-defined subgroups stratified based on tumour types, masking methods, line of treatments, drug targets, treatment strategies, and follow-up durations. No significant heterogeneities or publication bias were identified. 1-year milestone survival was the only identified surrogacy endpoint for outcomes in cancer immunotherapy. Ongoing investigations and development of new endpoints and incorporation of biomarkers are needed to identify potential surrogate markers that can be more robust than 1-year survival. This work may provide important references in assisting the design and interpretation of future clinical trials, and constitute complementary information in drafting clinical practice guidelines. None.

Conditional early approval for new drug applications in Japan: Current and emerging issues.

Conditional early approval for new drug applications in Japan: Current and emerging issues.

Meta-Analysis of Candidate Surrogate End Points in Advanced Prostate Cancer

BackgroundThe Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group identified metastasis-free survival as a valid surrogate end point for overall survival (OS) for patients with localized prostate cancer. No comparably validated surrogate end points exist in advanced prostate cancer.MethodsWe searched for trials in advanced prostate cancer, defined as node-positive, metastatic castration-sensitive, nonmetastatic, or metastatic castration-resistant prostate cancer. Eligible randomized trials reported OS and one or more intermediate clinical end points, including biochemical failure (BF), clinical failure, biochemical failure–free survival (BFS), progression-free survival (PFS), and radiographic PFS. Candidacy for surrogacy was assessed by using the second condition of the meta-analytic approach; R2 was weighted by the inverse variance of the log intermediate clinical end point hazard ratio and defined as R2>0.70.ResultsA total of 143 randomized trials (n=75,601 patients) were included. No candidate end points met the criteria for surrogacy (R2 BF [n=28,922], 0.42 [95% confidence interval (CI), 0.18 to 0.64]; BFS [n=25,741], 0.57 [95% CI, 0.37 to 0.73]; clinical failure [n=22,616], 0.31 [95% CI, 0.075 to 0.56]; PFS [n=52,639], 0.50 [95% CI, 0.35 to 0.63]; and radiographic PFS [n=52,548], 0.50 [95% CI, 0.35 to 0.63]). Within preplanned subgroups according to castration-sensitive or castration-resistant disease or according to treatment type, neither BFS nor PFS consistently met criteria for surrogacy. Sensitivity analyses showed that candidacy for surrogacy of all end points tested did not change over time.ConclusionsOur aggregate screening method for surrogate end points in advanced prostate cancer showed that commonly used clinical end points are not clear valid surrogate end points for OS. (Funded by the Prostate Cancer Foundation and the National Cancer Institute.)

Radiographic progression-free survival (rPFS) and time to radiographic progression (TTrP) as surrogate endpoints in docetaxel-naïve metastatic castrate resistant prostate cancer (mCRPC): A pooled analysis of COU-AA-302 and ACIS.

136 Background: rPFS is often used as an intermediate clinical endpoint (ICE) for overall survival (OS) in randomized trials in mCRPC. However, the current literature shows conflicting results on the surrogacy of rPFS for OS. Moreover, it remains unknown if TTrP, which does not consider death as an event, is an ICE for OS. We performed a combined analysis of COU-AA-302 and ACIS to determine if TTrP and rPFS can be used as ICE. Methods: In COU trial, docetaxel-naïve mCRPC patients were randomized to abiraterone (abi) versus placebo. In ACIS, a similar patient population was randomized to abi alone or abi with apalutamide (abi+apa). We applied weighted Cox regression models to evaluate the effect of treatment on TTrP and OS and used landmark analyses to determine the if the treatment effect on OS is mediated by that on radiographic progression. We estimated a semiparametric Spearman correlation between the ICE and OS at the patient level. We determined the trial level correlation of treatment effect on the ICE and OS in the 2 trials where each of them was subdivided into 9 pseudo-trial centers and then calculating the adjusted R2 between center level estimates of treatment effect for ICE and OS. The procedure of creating pseudo-trial centers was repeated 500 times and the presented R2 is the average across 500 repetitions after excluding those with negative association. Results: Overall, 2016 patients were eligible for this study – 1053 from COU and 963 from ACIS. Abi was associated with superior TTrP (HR 0.55 [95%CI 0.45-0.66]) and OS (HR 0.80 [0.70-0.92]). Similar results were seen with abi+apa (0.51 [0.41-0.64], 0.77 [0.65-0.91]). Radiographic progression was associated with significantly higher hazard of death in the state arrival extended Markov proportional hazard model (3.64 [1.54-8.62]) while longer TTrP was associated with reduced hazard of death (0.94 [0.93-0.95]). At the patient level, the correlation between TTrP & OS and rPFS & OS was 0.58 [0.54-0.63] and 0.68 [0.65-0.71], in the overall cohort. In the abi and abi+apa group, the correlation between TTrP and OS was 0.60 [0.53-0.66] and 0.73 [0.66-0.79] and that for rPFS and OS was 0.72 [0.67-0.75] and 0.79 [0.74-0.83], respectively. At the trial level, the treatment effect on rPFS & OS and TTrP & OS were correlated with average R2 of 0.84, 0.84, 0.85, and 0.86, respectively. The mean surrogate threshold effect over 500 permutations for HRrPFS and HRTTrP was 0.78 and 0.70 in ACIS and 0.54 and 0.45 in the COU-AA-302 trials, respectively. Conclusions: TTrP and rPFS were found to have significant association with OS in chemo-naïve mCRPC patients. We noted a modest to strong correlation between the treatment effect on both the ICE and OS at the trial level. Larger meta-analytic studies are needed to validate these findings.

1375P Intermediate clinical endpoints (ICE) as potential surrogates for overall survival (OS) in men with metastatic hormone-sensitive prostate cancer (mHSPC)

We have previously shown that radiographic progression-free survival is potentially a valid surrogate of OS. Here, we explore whether castrate-resistant free survival (CRFS) and time to castrate-resistant disease (TCRD) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite phase 3 clinical trials. This hypothesis was investigated by the STOPCAP M1 Collaboration.

Metastasis Within Three Years from Radical Nephroureterectomy as a Potential Surrogate for Overall Survival.

The only phase III trial that evaluated the role of adjuvant chemotherapy following radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) was terminated early. Thus, eventual overall survival (OS) surrogacy, as per Prentice, cannot be assessed in this setting. We aimed to identify an intermediate clinical endpoint (ICE) that could serve as an OS surrogate after RNU for UTUC. We retrospectively analyzed 823 high-grade UTUC patients treated with RNU at 8 tertiary referral centers. We explored the role of any recurrence (aR), defined as recurrence in the urinary tract or in the resection bed as well the presence of distant metastasis (DM), defined as metastatic disease outside the urinary tract and regional lymph nodes, on OS through a time-varying Cox regression analyses fitted at the landmark points of 1, 2, 3, and 4 years from RNU. Models' discrimination was assessed using Harrell's c index, after internal validation. Median follow-up for survivors was 5.6 years (interquartile range: 2.0-8.8). Overall, 391 and 212 patients experienced aR and DM, respectively. In a time-varying model, aR and DM were predictors of OS: hazard ratio [HR]:1.20, 95% confidence interval [CI]: 1.13-1.28 (P < .001) and HR:1.26, 95% CI: 1.18-1.34 (P < .001), respectively. Progression to DM within 3 years from RNU was the most informative ICE for predicting OS (c index: 0.81; HR: 4.40; 95%CI: 2.45-7.92; P < .001), compared to DM within 1, 2, and 4 years (c indexes: 0.74, 0.76, and 0.78, respectively). Progression to DM within 3 years from RNU was further found superior for predicting OS compared to aR at any landmark points. Progression to DM within 3 years represents a potential OS surrogate for surgically-treated UTUC. This information could help in patient counseling, future study design and expedite results release of ongoing randomized controlled trials.

Progression-free survival is an adequate endpoint for clinical trials of locally advanced and metastatic urothelial carcinoma.

To evaluate intermediate clinical endpoints that have been proposed as potential surrogates for overall survival amongst patients with locally advanced and metastatic urothelial carcinoma. Several endpoints have been proposed as potential surrogates for overall survival. They are: pathologic downstaging or complete response after neoadjuvant treatments and progression-free survival in the adjuvant setting and metastatic setting. Formal surrogacy, as per Prentice, has not been established among any of the aforementioned intermediate clinical endpoints and overall survival. Despite that, regulatory agencies have recently approved adjuvant nivolumab for patients with high-risk muscle invasive bladder cancer, based on the results of a trial that had disease-free survival as primary endpoint. Despite the lack of proven surrogacy between progression-free survival and overall survival, this endpoint seems adequate for trial design and medication approval, as the recent case of adjuvant nivolumab demonstrates.

Biochemical Failure Is Not a Surrogate End Point for Overall Survival in Recurrent Prostate Cancer: Analysis of NRG Oncology/RTOG 9601.

Metastasis-free survival (MFS), but not event-free survival, is a validated surrogate end point for overall survival (OS) in men treated for localized prostate cancer. It remains unknown if this holds true in biochemically recurrent disease after radical prostatectomy. Leveraging NRG/RTOG 9601, we aimed to determine the performance of intermediate clinical end points (ICEs) as surrogate end points for OS in recurrent prostate cancer. NRG/RTOG 9601 randomly assigned 760 men with recurrence after prostatectomy to salvage radiation therapy with 2 years of placebo versus bicalutamide 150 mg daily. ICEs assessed were biochemical failure (BF) per NRG/RTOG 9601 (prostate-specific antigen nadir + 0.3-0.5 ng/mL or initiation of salvage hormone therapy; [BF1]) and NRG/RTOG 0534 (prostate-specific antigen nadir+2 ng/mL; [BF2]), distant metastasis (DM), and MFS (DM or death). Surrogacy was assessed by the Prentice criteria and a two-stage meta-analytic approach (condition one assessed at the patient level with Kendall's τ and condition two assessed by randomly dividing the entire trial cohort into 10 pseudo trial centers and calculating the average R2 between treatment hazard ratios for ICE and OS). BF1, BF2, DM, and MFS satisfied the four Prentice criteria. However, with the two-condition meta-analytic approach, there was strong correlation between MFS and OS (τ = 0.86), moderate correlation between DM and OS (τ = 0.66), and weaker correlation between BF1 (τ = 0.25) or BF2 (τ = 0.40) and OS. Similarly, for condition two, the treatment effect of antiandrogen therapy on MFS and OS were correlated (R2 = 0.67), but this was not true for BF1 (R2 = 0.09), BF2 (R2 = 0.12), or DM (R2 = 0.18) and OS. MFS is also a strong surrogate for OS in men receiving salvage radiation therapy for recurrence after prostatectomy. Caution should be used when inferring survival benefit from effects on BF in biochemically recurrent prostate cancer. Lack of comorbidity data did not allow us to assess whether BF in men with no/minimal comorbidity could serve as a surrogate for OS.

Candidate surrogate endpoints in advanced prostate cancer: Aggregate meta-analysis of 143 randomized trials.

5039 Background: The Intermediate Clinical Endpoints (ICEs) in Cancer of the Prostate (ICECaP) working group identified metastasis-free survival as a valid surrogate endpoint for overall survival (OS) for patients with localized prostate cancer. No comparably validated surrogate endpoints for OS exist in advanced prostate cancer. Methods: In this meta-analysis, PubMed was searched for trials in advanced prostate cancer, defined as node positive (N1M0), metastatic castration-sensitive (mCSPC), non-metastatic (M0CRPC), or metastatic castration-resistant prostate cancer (mCRPC). Eligible randomized trials were required to report OS and ≥1 intermediate clinical endpoint (ICE). ICEs included biochemical-failure (BF), clinical failure (CF), BF-free survival (BFS), progression-free survival (PFS), radiographic PFS (radiographic +/- other study defined endpoints). Candidacy for surrogacy was assessed using the second condition of the meta-analytic approach, correlation of the treatment effect of the ICE and OS, using R2 weighted by the inverse variance of the log ICE hazard ratio and defined as an R2 &gt; 0.70. Results: A total of 143 randomized trials (n = 75,601 patients) were included. No candidate endpoints met criteria for surrogacy; R2 BF (n = 28,922) 0.42 (95%CI 0.18-0.64), BFS (n = 25,741) 0.57 (95%CI 0.37-0.73), CF (n = 22,616) 0.31 (95%CI 0.0075-0.56), PFS (n = 52,639) 0.50 (95%CI 0.35-0.63), and radiographic PFS (n = 52,548) 0.50 (95%CI 0.35-0.63). Within preplanned subgroups by castration sensitive or resistant disease, or by treatment type, neither BFS nor PFS met criteria for surrogacy. When assessing radiographically-defined progression (exclusive or with clinical progression), PFS for the overall group and by castration status did not meet criteria for surrogacy. Sensitivity analyses demonstrated that candidacy for surrogacy of all endpoints tested did not change over time. Conclusions: Our aggregate screening method for surrogate endpoints in advanced prostate cancer demonstrated commonly used clinical endpoints are not valid surrogate endpoints for OS, and further composite endpoint construction is necessary.

Assessing intermediate clinical endpoints (ICE) as potential surrogates for overall survival (OS) in men with metastatic hormone-sensitive prostate cancer (mHSPC).

5006 Background: We hypothesized that radiographic progression free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite phase 3 clinical trials. This hypothesis was investigated by the STOPCAP M1 Collaboration. Methods: We obtained individual patient data (IPD) from 13/26 eligible randomized trials comparing treatment regimens (androgen deprivation therapy (ADT) or ADT + docetaxel in the control or research arms) in mHSPC. We evaluated the surrogacy of rPFS and cPFS as potential ICEs. rPFS was defined as time from randomization to radiographic progression (defined per protocol) or death from any cause whichever occurred first; cPFS was defined as time from randomization to date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. OS was defined as time from randomization to death from any cause, if patients had not died they were censored at the date of last follow-up. We implemented a two-stage meta-analytic validation model where conditions of trial level and patient level surrogacy had to be met. We computed the surrogate threshold effect (STE), which is the minimum ICE treatment effect necessary to estimate a non-zero effect on OS. Results: IPD from 8592 patients randomized from 1994-2012 from 13 trials were pooled for a stratified analysis. There were 5377 deaths, of which 3971 (74%) were due to prostate cancer. The median follow-up for surviving patients was 75.6 months. In addition, there were 6227 rPFS and 6314 cPFS events. The median OS, rPFS and cPFS were 49.4, 26.8 and 25.2 months, respectively. The STE was 0.82 for rPFS and 0.84 for cPFS. Conclusions: Both rPFS and cPFS appear to be valid surrogate endpoints for OS. A surrogate threshold effect of 0.82 or higher makes it viable for either rPFS or cPFS to be used as the primary endpoint as a surrogate for OS in phase 3 mHSPC trials and would expedite trial conduct. Validation of these ICEs in trials with drugs having other mechanisms of action is planned. Clinical trial information: Several. [Table: see text]

Physician Perceptions of the FDA's Breakthrough Therapy Designation: An Update.

The US Food and Drug Administration developed the Breakthrough Therapy designation to expedite the development and review of drugs that show a clear advantage over available therapy for serious conditions. Prior research has shown that physicians tend to misunderstand that a drug may receive a Breakthrough Therapy designation based on preliminary clinical evidence (eg, effect on a surrogate endpoint or intermediate clinical endpoint that is likely to predict clinical benefit). The objective of this article is to examine whether physicians’ familiarity with and interpretation of the Breakthrough Therapy designation have changed since a survey on the topic was published in 2016. We replicated three of the questions in that study and explored beliefs that a Breakthrough Therapy designation automatically qualifies a drug for accelerated approval. We also draw comparisons by specialization (oncologists vs. primary care physicians). In general, physicians remain more likely than not to misunderstand the Breakthrough Therapy designation.

Evidence-based Urology: Surrogate Endpoints – For

The use of intermediate clinical endpoints and overall survival surrogates can shorten trial duration and related costs. This would potentially allow for an earlier introduction in practice of novel practice changing medications or treatments with a consequent impact on patient prognosis.

Fulfillment of Postmarketing Commitments for Novel Malignant Hematology Products Granted Accelerated Approval By the FDA between 2011-2016

Introduction: Between 2011 and 2016, 16 novel products were approved by the Food and Drug Administration (FDA) for malignant hematology indications. The FDA has created 4 review programs to expedite the development of new drugs that address unmet medical needs in the treatment of a serious or life-threatening conditions: Fast Track designation, Breakthrough Therapy designation, Priority Review designation, and Accelerated Approval. The data used to support Accelerated Approval may rely on surrogate or intermediate clinical endpoints that have been determined to reasonably predict clinical benefit, but postapproval confirmatory trials are often required. We aimed to examine the fulfillment of postmarketing commitments associated with novel drugs granted Accelerated Approval for malignant hematology indications.Methods: We reviewed FDA yearly approval reports between 2011-2016 to identify novel products for malignant hematology conditions, as well as use of expedited programs. FDA's Postmarketing Requirements and Commitments database was subsequently searched for products with Accelerated Approval. Moreover, the www.clinicaltrials.gov website was searched for postmarketing study status. Drug approval packages were then reviewed for further information on label changes.Results: Compared to products approved by the FDA for all other conditions, a significantly greater proportion of products approved for malignant hematology indications used any of the expedited programs (94% versus 56%), including Accelerated Approval (69% versus 10%). Of the 11 malignant hematology products granted Accelerated Approval, 9 were required to fulfill postmarketing commitments to collect additional clinical data, with 16 total clinical studies mandated. Significant safety issues were identified for 2 products in 3 studies (2 terminated [Zydelig], 1 fulfilled [Iclusig]), which resulted in changes to labeling for both drugs. One of the products (Iclusig) was temporarily pulled from the market, with the FDA requiring further studies, and a risk evaluation and mitigation strategy. Another postmarketing commitment study (for Beleodaq) is delayed; 1 study (for Blincyto) was terminated prematurely for nonsafety related reasons. In total, only 4 of the 16 postmarketing commitment studies have been fulfilled (see Table).Conclusions: Nearly all novel drug products for malignant hematology conditions approved by the FDA in the past 6 years utilized an expedited program. While most products were granted Accelerated Approval, only a fraction (25%) of the associated postmarketing commitments have been fulfilled. Serious safety concerns were identified in 2 of the 9 products with postmarketing commitments following Accelerated Approval. We argue that critical assessment of the FDA Accelerated Approval program is warranted as newer drugs continue to enter the market. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

BIIB093 (intravenous glibenclamide) for the prevention of severe cerebral edema.

Background: Vasogenic edema in the setting of acute ischemic stroke can be attributed to the opening of transient receptor potential 4 channels, which are expressed in the setting of injury and regulated by sulfonylurea receptor 1 (SUR1) proteins. Glibenclamide, also known as glyburide, RP-1127, Cirara, and BIIB093, is a second-generation sulfonylurea that binds SUR1 at potassium channels and may significantly reduce cerebral edema following stroke, as evidenced by recent clinical trials. This review provides a comprehensive analysis of clinical considerations of glibenclamide use and current patient outcomes when administered in the setting of acute ischemic stroke to reduce severe edema.Methods: National databases (MEDLINE, EMBASE, Cochrane, and Google scholar databases) were searched to identify studies that reported on the clinical outcomes of glibenclamide administered immediately following acute ischemic stroke.Results: The pharmacological mechanism of glibenclamide was reviewed in depth as well as the known indications and contraindications to receiving treatment. Eight studies were identified as having meaningful clinical outcome data, finding statistically significant differences in glibenclamide treatment groups ranging from matrix metalloproteinase-9 serum levels, midline shift, modified Rankin Scores, National Institute of Health Stroke Score, and mortality endpoints.Conclusion: Studies analyzing the GAMES-Pilot and GAMES-PR trials suggest that glibenclamide has a moderate, however, measurable effect on intermediate biomarkers and clinical endpoints. Meaningful conclusions are limited by the small sample size of patients studied.

Intermediate clinical endpoints for surrogacy in localised prostate cancer: an aggregate meta-analysis.

The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer. For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R2 was 0·7 or greater. 75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7-10·6). Biochemical failure (R2 0·38 [95% CI 0·11-0·64]), biochemical failure-free survival (R2 0·12 [0·0030-0·33]), biochemical failure and clinical failure (R2 0·28 [0·0045-0·65]), and local failure (R2 0·085 [0·00-0·37]) correlated poorly with overall survival. Progression-free survival (R2 0·46 [95% CI 0·22-0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R2 0·78 [0·59-0·89]) correlated strongly. Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date. Prostate Cancer Foundation and National Institutes of Health.

Intermediate clinical endpoints in localised prostate cancer.

Intermediate clinical endpoints in localised prostate cancer.