Trial Design Features Research Articles

Modern trials are most useful when they are pragmatic and explanatory - there is no continuum

Over half a century ago, the terms “pragmatic” and “explanatory” were introduced to biomedicine by Schwartz and Lellouch, presenting two distinct conceptual approaches to trial design. Today, we frequently say that there are pragmatic trials and there are explanatory trials. Pragmatic trials inform decision-making in practice, explanatory trials aim to understand the mechanism of an intervention. They are often perceived as diametral extremes of a continuum.In this commentary, we argue that with the digitalization of health care and clinical research ways for modern trial designs were were paved and new avenues opened, and that there is no such continuum. Since the groundbreaking work of Schwartz and Lellouch, new approaches and methods have become available that allow researchers to address pragmatic and explanatory questions in parallel in the same trial. Emerging availability of routinely collected “real-world” data, development of decentralized trial techniques, and creation of digital biomarkers allow to observe health outcomes with minimal or no interference in real-world care. This overcomes previous limitations to study mechanisms of interventions in routine care and makes the idea of a continuum obsolete. We argue that pragmatism and explanatorism need to be understood as two distinct but compatible conceptual dimensions to open new perspectives for using novel technologies to design the most informative clinical trials and making better clinical and regulatory decisions.We base our argument on an analysis of the concept of a continuum and highlight its limitations. We review key trial design features and introduce a new concept that sees explanatory design features as fundamental, invasive or non-invasive, sufficient or insufficient. We describe their impact on pragmatism and explanatorism and show how multidimensional pragmatic-explanatory trials that are most useful are possible today.

Patient Enrollment per Month (Accrual) in Clinical Trials Leading to the FDA Approval of New Cancer Drugs.

Insufficient patient enrollment per month (=accrual) is the leading cause of cancer trial termination. To identify and quantify factors associated with patient accrual in trials leading to the US Food and Drug Administration (FDA) approval of new cancer drugs. All anti-cancer drugs with FDA approval were identified in the Drugs@FDA database (2000-2022). Data on drug indication's background-, treatment-, disease-, and trial-related factors were collected from FDA labels, clinicaltrials.gov, and the Global Burden of Disease study. The association between patient accrual and collected variables was assessed in Poisson regression models reporting adjusted rate ratios (aRR). We identified 170 drugs with approval in 455 cancer indications on the basis of 292 randomized and 163 single-arm trials. Among randomized trials, median enrollment per month was 38 patients (interquartile range [IQR]: 26-54) for non-orphan, 21 (IQR: 15-38, aRR 0.88, p = 0.361) for common orphan, 20 (IQR: 10-35, aRR 0.73, p <0.001) for rare orphan, and 8 (IQR 6-12, aRR 0.30, p < 0.001) for ultra-rare orphan indications. Patient enrollment was positively associated with disease burden [aRR: 1.0003 per disability-adjusted life year (DALY), p < 0.001), trial sites (aRR: 1.001 per site, p < 0.001), participating countries (aRR: 1.02 per country, p < 0.001), and phase 3 vs. 1/2 trials (aRR: 1.64, p = 0.037). Enrollment was negatively associated with advanced-line vs. first-line treatments (aRR: 0.81, p = 0.010) and monotherapy vs. combination treatments (aRR: 0.80, p = 0.007). Patient enrollment per month was similar between indications with and without a biomarker (median: 27 vs. 32, aRR 0.80, p = 0.117). Patient enrollment per month was substantially lower in government-sponsored than industry-sponsored trials (median: 14 vs. 32, aRR 0.80, p = 0.209). Enrollment was not associated with randomization ratios, crossover, and study blinding. Disease incidence and disease burden alongside the number of study sites and participating countries are the main drivers of patient enrollment in clinical trials. For rare disease trials, greater financial incentives could help expedite patient enrollment. Novel trial design features, including skewed randomization, crossover, or open-label masking, did not entice patient enrollment.

The utility of recruitment incentives in early Alzheimer's disease trials.

Amid recent approvals, early Alzheimer's disease (AD) remains an active area of treatment development. We performed a conjoint experiment to compare preferences among 26 patients with mild cognitive impairment for four trial features including designs incorporating active aducanumab-control (vs. placebo), returning tau positron emission tomography (PET) results (vs. no disclosure), remote study partner participation (vs. in person), and increased risk of brain swelling (vs. lower risk). We used a generalized estimating equation to model the utility of factor levels. Returning tau PET results had the highest utility (est: 0.47; 95% confidence interval [CI]: 0.13, 0.81; P=0.007); remote study partner participation showed a similar trend (est: 0.29; 95% CI: -0.05, 0.63; P=0.097). Trials with active-controlled design (est: 0.01; 95% CI: -0.33, 0.35; P=0.956) did not demonstrate utility and higher risk of brain swelling had negative utility (est: -0.64; 95% CI: -0.99, -0.30; P<0.001). Returning additional biomarker results may increase willingness to enroll in early AD trials. We compared mild cognitive impairment participant preferences for four trial design features. Returning tau positron emission tomography results had the highest utility. Remote study partner participation showed a positive, albeit non-significant, trend. No utility was observed for an active aducanumab-control design.

Predictors of urine toxicology and other biologic specimen missingness in randomized trials of substance use disorders

BackgroundHigh levels of missing outcome data for biologically confirmed substance use (BCSU) threaten the validity of substance use disorder (SUD) clinical trials. Underlying attributes of clinical trials could explain BCSU missingness and identify targets for improved trial design. MethodsWe reviewed 21 clinical trials funded by the NIDA National Drug Abuse Treatment Clinical Trials Network (CTN) and published from 2005 to 2018 that examined pharmacologic and psychosocial interventions for SUD. We used configurational analysis—a Boolean algebra approach that identifies an attribute or combination of attributes predictive of an outcome—to identify trial design features and participant characteristics associated with high levels of BCSU missingness. Associations were identified by configuration complexity, consistency, coverage, and robustness. We limited results using a consistency threshold of 0.75 and summarized model fit using the product of consistency and coverage. ResultsFor trial design features, the final solution consisted of two pathways: psychosocial treatment as a trial intervention OR larger trial arm size (complexity=2, consistency=0.79, coverage=0.93, robustness score=0.71). For participant characteristics, the final solution consisted of two pathways: interventions targeting individuals with poly- or nonspecific substance use OR younger age (complexity=2, consistency=0.75, coverage=0.86, robustness score=1.00). ConclusionsPsychosocial treatments, larger trial arm size, interventions targeting individuals with poly- or nonspecific substance use, and younger age among trial participants were predictive of missing BCSU data in SUD clinical trials. Interventions to mitigate missing data that focus on these attributes may reduce threats to validity and improve utility of SUD clinical trials.

A Systematic Review of Adaptive Seamless Clinical Trials for Late-Phase Oncology Development.

Although oncology has seen large scientific and clinical advances over the last decade, it also has one of the lowest success rates for novel agents across therapeutic areas. Adaptive clinical trial design has been a popular option for increasing clinical trial efficiency and the chances of trial success. Seamless clinical trial design are studies in which two or more clinical trial phases are combined into a single study with a pre-specified transition between stages. This integration of phases may enhance efficiency. To understand the precedent for the use of seamless designs, this working group was formed to conduct a comprehensive literature search on seamless clinical trials conducted with confirmatory intent in oncology. Trial design features were extracted into a database and analyzed with descriptive statistics. A literature search identified 68 clinical trials meeting inclusion and exclusion criteria. The most common design feature was a gate on treatment efficacy, where the trial would only proceed to the second stage if sufficient efficacy was observed in the first. The next most common feature was a selection of a dose or treatment regimen. Inferentially and operationally seamless designs were approximately equally represented. Key statistical considerations for seamless phase II/III designs include optimizing design choices by evaluating and comparing operating characteristics across design alternatives as well as showing control of overall Type I error rates. Executing the transition between phases should be evaluated for issues related to accrual, drug production, and procedures to maintain trial integrity. While there are unique statistical, regulatory, and operational considerations for seamless designs they are also uniquely suited to many development settings. These include, for example, addressing dose selection under FDA's Project Optimus and addressing the growing use of biomarkers and personalized medicine approaches in cancer treatment.

A Closed-Loop Digital Health Tool to Improve Depression Care in Multiple Sclerosis: Iterative Design and Cross-Sectional Pilot Randomized Controlled Trial and its Impact on Depression Care.

People living with multiple sclerosis (MS) face a higher likelihood of being diagnosed with a depressive disorder than the general population. Although many low-cost screening tools and evidence-based interventions exist, depression in people living with MS is underreported, underascertained by clinicians, and undertreated. This study aims to design a closed-loop tool to improve depression care for these patients. It would support regular depression screening, tie into the point of care, and support shared decision-making and comprehensive follow-up. After an initial development phase, this study involved a proof-of-concept pilot randomized controlled trial (RCT) validation phase and a detailed human-centered design (HCD) phase. During the initial development phase, the technological infrastructure of a clinician-facing point-of-care clinical dashboard for MS management (BRIDGE) was leveraged to incorporate features that would support depression screening and comprehensive care (Care Technology to Ascertain, Treat, and Engage the Community to Heal Depression in people living with MS [MS CATCH]). This linked a patient survey, in-basket messages, and a clinician dashboard. During the pilot RCT phase, a convenience sample of 50 adults with MS was recruited from a single MS center with 9-item Patient Health Questionnaire scores of 5-19 (mild to moderately severe depression). During the routine MS visit, their clinicians were either asked or not to use MS CATCH to review their scores and care outcomes were collected. During the HCD phase, the MS CATCH components were iteratively modified based on feedback from stakeholders: people living with MS, MS clinicians, and interprofessional experts. MS CATCH links 3 features designed to support mood reporting and ascertainment, comprehensive evidence-based management, and clinician and patient self-management behaviors likely to lead to sustained depression relief. In the pilot RCT (n=50 visits), visits in which the clinician was randomized to use MS CATCH had more notes documenting a discussion of depressive symptoms than those in which MS CATCH was not used (75% vs 34.6%; χ21=8.2; P=.004). During the HCD phase, 45 people living with MS, clinicians, and other experts participated in the design and refinement. The final testing round included 20 people living with MS and 10 clinicians including 5 not affiliated with our health system. Most scoring targets for likeability and usability, including perceived ease of use and perceived effectiveness, were met. Net Promoter Scale was 50 for patients and 40 for clinicians. Created with extensive stakeholder feedback, MS CATCH is a closed-loop system aimed to increase communication about depression between people living with MS and their clinicians, and ultimately improve depression care. The pilot findings showed evidence of enhanced communication. Stakeholders also advised on trial design features of a full year long Department of Defense-funded feasibility and efficacy trial, which is now underway. ClinicalTrials.gov NCT05865405; http://tinyurl.com/4zkvru9x.

Palliative Care Interventions for Persons With Neurodegenerative Disease: A Scoping Review of Clinical Trial Study Design Features.

Background: Within palliative care research, best practice guidelines to conduct scientifically rigorous clinical trials for neurodegenerative diseases are underexplored. This patient population experiences unique challenges, including fluctuations in cognitive capacity, care partner (CP) and proxy involvement, and high adverse events (AEs), that necessitate special consideration when designing clinical trials. Objective: The objective of this study was to describe and identify clinical trial design features that have been documented in studies involving a neuropalliative intervention for persons with neurodegenerative diseases, highlighting features that have been adapted for this unique patient population. Design: We conducted a scoping review of clinical trials with a neuropalliative intervention for persons with neurodegenerative disease. We searched Cochrane, Web of Science, EMBASE, Scopus, and PubMed (MEDLINE) databases for articles published in English between 1950 and 2023. Two reviewers screened, extracted, and synthesized data from the included articles. A third reviewer adjudicated instances of conflict. The data were analyzed using a thematic framework approach. Results: Of 1025 texts, 44 articles were included. Seven study design features were analyzed: (1) consent, (2) proxies and CPs, (3) recruitment strategies, (4) retention strategies, (5) choice of comparator, (6) AEs, and (7) internal validity. This scoping review found disparities in study design features around structured consent, proxies and CPs, comparators, and AEs. Conclusions: To date, neuropalliative care clinical trials have had varied study designs and the majority of research has focused on dementia. Research guideline development for high-quality neuropalliative care clinical trials is greatly needed across the range of neurodegenerative diseases. To increase the scientific rigor of clinical trials and neuropalliative care, we recommend a standardized capacity assessment for consent, defining conditions for the CP, proxy, and AEs, systematizing appropriate comparators, and outlining preemptive recruitment and retention strategies to address the broader unpredictable challenges of palliative care research.

Preventing Respiratory Viral Illness Invisibly (PRiVII): protocol for a pragmatic cluster randomized trial evaluating far-UVC light devices in long-term care facilities to reduce infections

BackgroundRespiratory viral illness (RVI)—e.g., influenza, COVID-19—is a serious threat in long-term care (LTC) facilities. Standard infection control measures are suboptimal in LTC facilities because of residents’ cognitive impairments, care needs, and susceptibility to loneliness and mental illness. Further, LTC residents living with high degrees of frailty who contract RVIs often develop the so-called atypical symptoms (e.g., delirium, worse mobility) instead of typical cough and fever, delaying infection diagnosis and treatment. Although far-UVC (222 nm) light devices have shown potent antiviral activity in vitro, clinical efficacy remains unproven.MethodsFollowing a study to assay acceptability at each site, this multicenter, double-blinded, cluster-randomized, placebo-controlled trial aims to assess whether far-UVC light devices impact the incidence of RVIs in LTC facilities. Neighborhoods within LTC facilities are randomized to receive far-UVC light devices (222 nm) or identical placebo light devices that emit only visible spectrum light (400–700 nm) in common areas. All residents are monitored for RVIs using both a standard screening protocol and a novel screening protocol that target atypical symptoms. The 3-year incidence of RVIs will be compared using intention-to-treat analysis. A cost-consequence analysis will follow.DiscussionThis trial aims to inform decisions about whether to implement far-UVC light in LTC facilities for RVI prevention. The trial design features align with this pragmatic intent. Appropriate additional ethical protections have been implemented to mitigate participant vulnerabilities that arise from conducting this study. Knowledge dissemination will be supported through media engagement, peer-reviewed presentations, and publications.Trial registrationClinicalTrials.gov NCT05084898. October 20, 2021.

Comparison of efficacy discrepancy between early-phase clinical trials and phase III trials of PD-1/PD-L1 inhibitors

BackgroundPhase III clinical trials are pivotal for evaluating therapeutics, yet a concerning failure rate has been documented, particularly impacting oncology where accelerated approvals of immunotherapies are common. These failures are...

Alcohol-focused and transdiagnostic treatments for unhealthy alcohol use among adults with HIV in Zambia: A 3-arm randomized controlled trial.

Clinical and quality of life outcomes in people living with human immunodeficiency virus (PLWH) are undermined by unhealthy alcohol use (UAU), which is highly prevalent in this population and is often complicated by mental health (MH) or other substance use (SU) comorbidity. In sub-Saharan Africa, evidence-based and implementable treatment options for people with HIV and UAU are needed. We are conducting a hybrid clinical effectiveness-implementation trial at three public-sector HIV clinics in Lusaka, Zambia. Adults with HIV, who report UAU, and have suboptimal HIV clinical outcomes, will be randomized to one of three arms: an alcohol-focused brief intervention (BI), the BI with additional referral to a transdiagnostic cognitive behavioral therapy (Common Elements Treatment Approach [CETA]), or standard of care. The BI and CETA will be provided by HIV peer counselors, a common cadre of lay health worker in Zambia. Clinical outcomes will include HIV viral suppression, alcohol use, assessed by audio computer-assisted self-interview (ACASI) and direct alcohol biomarkers, Phophatidylethanol and Ethyl glucuronide, and comorbid MH and other SU. A range of implementation outcomes including cost effectiveness will also be analyzed. Hybrid and 3-arm trial design features facilitate the integrated evaluation of both brief, highly implementable, and more intensive, less implementable, treatment options for UAU among PLWH in sub-Saharan Africa. Use of ACASI and alcohol biomarkers will strengthen understanding of treatment effects.

WITHDRAWN: Evidence Synthesis to Advance Clinical Practice and Scientific Research: A CGH Pillar

WITHDRAWN: Evidence Synthesis to Advance Clinical Practice and Scientific Research: A CGH Pillar

Cold-stored Platelets for Bleeding Patients: Comment.

Cold-stored Platelets for Bleeding Patients: Comment.

The Effect of Biomarkers on Clinical Trial Risk in Gastric Cancer.

This study examined clinical trial success rates for new drug developments in gastric cancer since 1998. We also examined the clinical trial design features that may mitigate the risk of clinical trial failure. Clinical trial data was obtained from clinicaltrials.gov. Drugs were included if they entered testing between January 1, 1998 and January 1, 2022 and were excluded if they did not have a completed phase I trial or treated secondary effects of gastric cancer. Transition probabilities were calculated for each phase and compared with industry averages. Success rates were determined based on biomarker usage, drug target, type of therapy, and drug chemistry. Upon screening 1990 trials, 219 drugs met our inclusion criteria. The probability of a drug completing all phases of testing and obtaining FDA approval was 7%, which is below the 11% industry average. The use of biomarkers in clinical development resulted in nearly a 2-fold increase in the cumulative success rate. Biologics also exhibited higher success rates (17%) as opposed to small molecules (1%). This was true even when we compared both drug types that shared the same target. When comparing only receptor-targeted therapies, biologics (62%) continued to outperform small molecules (18%). Similarly, when narrowed down to drugs targeting solely HER2 receptors, biologics continued to prevail (64% vs. 24%). Implementing biomarkers, receptor-targeted therapies, and biologics in clinical development improves clinical trial success rates in gastric cancer. Thus, physicians should prioritize the enrollment of gastric cancer patients in clinical trials that incorporate the aforementioned features.

2,109 randomized oncology trials map continuous, meager improvements in progression-free and overall survival over 50 years

ObjectivesTo assess the patterns and time trends in overall survival and progression-free survival treatment effects across randomized controlled trials (RCTs) in oncology. Study Design and SettingA PubMed search for oncology network meta-analyses (NMAs) was carried (to September 30, 2021). Relevant hazard ratios were extracted for systemic treatments from RCTs in the NMAs. After removing duplicate results, relationships between treatment effects, year of publication, trial design, and other features were explored. ResultsFrom 241 oncology NMAs, 2,109 unique eligible RCTs provided analyzable data. On average, there was a 12%–14% reduction in hazard for overall survival and 27%–30% reduction for progression-free survival, with substantial heterogeneity across different malignancies. Correlation between overall survival and progression-free survival treatment effects was modest (r = 0.60, 95% confidence interval, 0.56–0.64). Over time, there was a suggestive trend of increased progression-free survival treatment effect, although overall survival treatment effects remained steady. Only one in five trials met criteria for clinically meaningful improvements in overall survival. Among 300 randomly selected trials, mean absolute improvement was 1.6 months for median progression-free survival and 1.4 months for median overall survival. ConclusionBroad patterns across the past 50 years of oncology research suggest continuous progress has been made, but few results meet clinically meaningful thresholds for overall survival improvement.

Analysis of Supportive Evidence for US Food and Drug Administration Approvals of Novel Drugs in 2020

In recent years, drug approvals have been based on fewer, smaller, and less rigorous pivotal trials. Less robust preapproval testing raises questions about the efficacy and clinical value of these drugs. To assess the regulatory context, pivotal design characteristics, and postmarket requirements (PMRs) and postmarket commitments (PMCs) of novel 2020 drug approvals to characterize the state of evidence at the time of approval. This cohort study identified novel drugs approved by the US Food and Drug Administration's (FDA) Center for Drug Evaluation and Research in 2020. The Drugs@FDA database was used to extract key characteristics of each drug's pivotal trials. Drug approval packages provided regulatory information. The prevalence of key trial design features was compared between oncology and nononcology drugs. Drug names, date of approval, indication on labeling, and clinical and regulatory details. Number of pivotal trials, pivotal trial design (randomization, masking, groups), trial comparator, trial hypothesis, trial end points, results, number and type of expedited pathway designations, and number and type of PMRs and PMCs. The 49 novel therapeutics approved in 2020 were supported by 75 pivotal trials. More than half of drugs (28 [57.1%]) were supported by a single pivotal trial. Trial sizes ranged from 19 to 2230 participants. More than three-fourths of trials (57 [76.0%]) had a randomization component, and nearly two-thirds (46 [61.3%]) were double-masked. Most used a superiority approach. Roughly half (39 [52.0%]) compared the novel therapeutic with a placebo or vehicle control; 13 (17.3%), an active control; 2 (2.7%), both a placebo and active control; and 21 (28.0%), a historical, external, or other control. Nearly half of pivotal trials (34 [45.3%]) used a surrogate measure as a primary end point. Pivotal trials supporting oncology approvals were much more likely to have historical controls than nononcology approvals (13 of 18 [72.2%] vs 8 of 57 [14.0%]; P < .001) and to use at least 1 surrogate measure as a primary end point (17 [94.4%] vs 17 [29.8%]; P < .001). Forty drugs had at least 1 PMR or PMC, accounting for 178 PMRs and PMCs across the cohort. These findings suggest that the increased flexibility in the characteristics of acceptable preapproval evidence can be partially explained by the increase in trials of drugs for rare and other serious conditions that require flexible testing strategies as well as the associated regulatory changes that have accumulated over time. The FDA and consumers may benefit from a revised approach that better balances time to market with ensuring that approved drugs show evidence of efficacy.

Abstract ES6-1: Approving New Therapies for Early Breast Cancer

Abstract The approval of a therapy by the US Food and Drug Administration (FDA) for the treatment of early breast cancer (EBC) requires substantial evidence of efficacy and an acceptable benefit-to risk evaluation from adequate and well-controlled investigations. There are two different regulatory pathways by which the FDA may approve drugs and biologics for the treatment of cancer. Regular or traditional approvals are based on the demonstration of direct clinical benefit, such as an improvement in survival or disease-related symptoms, or an improvement in an established surrogate. Examples of endpoints used for regular approval in EBC include invasive disease-free survival (IDFS) and event free survival (EFS). In 1992, new regulations were implemented, allowing for the accelerated approval (AA) of drugs for serious or life-threatening diseases in which the drugs seem to provide benefit over available therapy. AA is based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. A post marketing requirement to confirm the effect on a direct clinical benefit is required. An example of an endpoint used for AA in EBC is pathologic complete response (pCR). Pertuzumab, neratinib, ado-trastuzumab emtansine and pembrolizumab have all received approvals for treatment of breast cancer in the neo/adjuvant setting over the last decade. Some of these approvals will be discussed to highlight various efficacy endpoints and clinical trial design features that may be used in the early breast cancer setting. Citation Format: S Wedam. Approving New Therapies for Early Breast Cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES6-1.

Association of study design features and treatment effects in trials of chronic medical conditions: a meta-epidemiological study

ObjectivesTo evaluate the association of study design features and treatment effects in randomised controlled trials (RCTs) evaluating therapies for individuals with chronic medical conditions.DesignMeta-epidemiological study.SettingRCTs from meta-analyses published in the...

The berry health tool chest - an evidence map and interactive resource.

Berry consumption is linked to diverse health benefits, but numerous questions remain regarding mechanism of action, dose efficacy, and optimal duration and frequency of intake. Addressing these outstanding questions requires an organized assessment of current research, to inform future study designs and fill critical knowledge gaps. Tools that organize such information will also facilitate consumer messaging, targeted nutritional health initiatives, and dietary intake guidelines. This review aimed to describe the development and utility of the "Berry Health Tool Chest," an evidence map summarizing trial design features of studies characterizing the impact of berry consumption upon human health biomarkers. A systematic search strategy identified relevant high-quality human feeding studies, whose study design parameters were collected and compiled into an evidence map that is freely available as an interactive online interface enabling tabulated data to be interrogated, filtered, and exported. Of the 231 included studies, approximately 70% were of less than 3 months' duration and/or fewer than 50 participants, illustrating research gaps that could potentially inform the design of future studies.

Clinical Trial Design Features of Myelofibrosis Trials during the Last Decade: Comprehensive Review of Clinicaltrials.Gov Data 2010-2019

Introduction: FDA approval of JAK2-inhibitors for myelofibrosis (MF) has changed the landscape for treatment introducing possible increased complexity of clinical trial designs in MF. Many patients with MF will have insufficient response or intolerance to ruxolitinib, opening an opportunity for testing of novel agents alone or in combination. Novel trial designs exist for early stage (phase 1 and 2) studies. The Myeloproliferative Neoplasms Research Consortium (MPN-RC) is an NCI-funded academic group of laboratory and clinical scientists working to develop and evaluate treatments that will improve the survival of patients with MPNs focused on early stage trials in MF. This review was undertaken to understand the landscape of MF clinical trials and improve our approach to trial design. Methods: Studies with "myelofibrosis" as a condition were abstracted from clinicaltrials.gov using an application programming interface from 2010-2019 and reviewed for phase, trial design features, and endpoints. Trial design review captured such features as presence of dose escalation and approach (rule-based versus model-based/assisted) in the phase 1 setting. Observational and behavioral based studies were excluded. A total of 165 treatment interventional studies including MF patients (either MF as the primary cohort, or MF along with other MPN, myelodysplastic syndrome, or hematologic malignancies related cohorts) were reviewed. Primary and secondary endpoints were reviewed for quality of life, symptoms, or other patient-reported outcomes (PRO). Results: A median of 16.5 (range 13-20) trials were initiated per year; 92 (56%) phase 2, 54 (33%) phase 1; 17 (10%) phase 3 and 2 (1%) phase 4, with 77 (47%) industry sponsored (Figure 1). Among phase 1 trials, 41/54 (76%) included dose escalation, the majority employing a standard 3+3 design (or other rule-based design) or not specifically detailing the dose escalation schema. Less than 5 dose escalation trials were explicitly described as model-based or model-assisted. Almost half of the phase 1 trials (23/54; 43%) included combination treatment, with 17/23 (74%) using ruxolitinib or fedratinib. Among phase 2 trials, 82 (89%) were non-randomized and 10 (11%) randomized trials; 35/92 (38%) involved combination treatment and 57 (62%) single agent. Median actual/target enrollment for the phase 3 trials (n=16) was 192 patients (range 49-2233 patients); only 2 phase 3 trials were &amp;gt; 500 patients. Median number of total outcomes was 6.0 (range 1-28) across all studies with a median of 5.5 (range 1-28) for 2010-2014 versus 7.0 (range 1-22) for 2015-2019 (p=0.09). Overall 63/165 (38%) studies included at least one PRO endpoint; 15 (28%) phase 1, 33 (36%) phase 2 and 14 (82%) phase 3. Inclusion of PRO endpoints for years 2010-2014 was similar to studies started in years 2015-2019 [31/82 (38%) and 32/83 (39%)]. Industry sponsored studies included PRO endpoints more frequently [46/77 (60%) versus 17/88 (19%); p&amp;lt;0.001] than non-industry sponsored trials but this is primarily due to a higher proportion of phase 3/4 trials (n=17) being conducted by industry versus non-industry (n=2) (Figure 2). Conclusions: For phase 1 trials in MF, few dose-escalation trials included model-based or model-assisted methods. These designs are encouraged in order to maximize therapeutic benefits in MF, a rare cancer. Clinical trial designs in myelofibrosis have shifted in recent years as evidenced by an increase in number of endpoints, likely to accommodate new challenges in the post JAK2-inhibitors approval era. Use of patient-reported outcomes including quality of life and symptom assessment was high in the phase 3 setting, and continued use should be encouraged as endpoint assessments in MF clinical trial designs. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Mesa:LaJolla Pharma: Consultancy; Novartis: Consultancy; Sierra Onc: Consultancy; Abbvie: Research Funding; Celgene: Research Funding; CTI: Research Funding; Genetech: Research Funding; Incyte: Research Funding; Promedior: Research Funding; Samus: Research Funding. Hoffman:Dompe: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Forbius: Consultancy; Protagonist: Consultancy.

PIK3CA mutation status and progression-free survival in advanced hormone receptor positive (HR+)/ human endocrine receptor negative (HER2–) metastatic breast cancer (mBC): A meta-analysis of published clinical trials.

1069 Background: Approximately 40% of HR+/HER2- mBC patients harbor PIK3CA mutation. Associations between PIK3CA mutation status and clinical outcomes among patients with HR+/HER2- mBC have been heterogeneous across clinical trials. We synthesized available evidence from clinical trials to estimate the association between PIK3CA status and progression-free survival (PFS) using a meta-analysis adjusting for study design differences. Methods: Randomized clinical trials reporting PFS stratified by PIK3CA status in HR+/HER2- mBC were identified via a systematic literature review. Trial arms receiving PIK3CA targeted therapies were excluded. Median PFS, 6-, 12- and 18-month PFS rates, and data on trial design features were extracted. Associations between PIK3CA status and PFS were estimated adjusting for study follow-up duration, PIK3CA testing method (ctDNA vs tissue ) and study treatment using multi-level random effects meta-regression. Results: The analyzed data included 3,238 patients from 33 study arms across 11 trials ( PIK3CA mutated (MT): 1,386, wild type (WT): 1,852). PIK3CA mutation was overall associated with shorter median PFS (difference [95% CI] (months): -2.15 [-4.14, -0.15]) with substantial heterogeneity across studies ( I2 = 98.34%). The direction of this association was robust to adjustment for study treatment (-1.27 [-2.22, -0.32]). The association was stronger for ctDNA testing (-2.16 [-3.65, -0.66]; N (total patients): 1,876) than for tissue testing (-0.65 [-2.2, 0.91]; N: 998). Findings were similar for 6-month PFS rates (absolute rate difference -9.17% [-14.22, -4.12], N: 3,179; MT: 1,366, WT: 1,813). Associations were directionally consistent but not statistically significant at 12 months (N = 2,487; MT: 1,056, WT: 1,431) and 18 months (N = 1,745; MT: 811, WT: 934), potentially due to the decreasing precision towards the tails of the PFS curves and significant heterogeneity across studies. Conclusions: Pooling evidence across multiple studies, PIK3CA mutation was associated with shorter PFS, especially when ctDNA testing was used. These findings suggest a negative prognostic value of PIK3CA mutation in patients with HR+/HER2- mBC.