Generalizability of clinical trials in metastatic melanoma.

e21004 Background: Results from clinical trials are not always generalizable to real world patients (pts). Clinicians may not adhere to the studies’ original inclusion/exclusion criteria because of differences in clinical circumstances or institutional variations in treatment policies. Our aims were to determine the pattern in which melanoma trial findings are applied in a population-based setting and to describe the treatment outcomes of these pts. Methods: We focused on melanoma as several novel therapies have been recently introduced. Pts with unresectable disease from 2013 to 2014 and referred to any 1 of 6 cancer centers in British Columbia were reviewed. Based on eligibility criteria as described in registration trials of vemurafenib (Vem) and ipilimumab (Ipi), we classified pts into trial eligible (TE) and ineligible (TI) and those treated and untreated with these agents. During the study period, Vem was approved for 1st line use in BRAF mutant pts and Ipi was funded for 2nd line use. Results: We identified 185 pts with known BRAF status for the Vem analysis and 114 pts for the Ipi analysis: median ages 64 and 59 years, 57% and 61% men, and 89% and 88% ECOG 0-1, respectively. For Vem, BRAF wild type was the most common reason for being TI. Of the remaining 86 BRAF mutant pts, 59 (69%) were considered TE of whom 51 (86%) received treatment. For Ipi, poor ECOG including rapidly progressive disease was a prevalent cause of being TI. In the Ipi cohort, 96 (84%) cases were deemed TE of whom 63 (66%) received therapy. Factors most frequently associated with non-treatment in both Vem and Ipi TE pts included comorbidities (41%), pt refusal (23%), and toxicities from prior treatments (14%). Compared to TI pts as well as those considered TE but did not receive treatment, pts deemed TE and received treatment achieved the best survival (adjusted HR 0.53, 95% CI 0.28-1.00 for Vem and adjusted HR 0.33, 95% CI 0.13-0.83 for Ipi). Conclusions: There was favorable uptake of new melanoma treatments, but a fair number of pts were considered TI, suggesting the need for trials with better external validity. Non-use of novel agents in TE pts was due to physician factors, pt preferences, and concerns about toxicities, highlighting areas that limit real world effectiveness of new melanoma drugs.

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P166 Multimorbidity in SLE, a barrier to clinical trial eligibility: results from the BILAG-BR

Rheumatology ◽

10.1093/rheumatology/keab247.162 ◽

2021 ◽

Vol 60 (Supplement_1) ◽

Author(s):

Sarah Dyball ◽

Sophie Collinson ◽

Emily Sutton ◽

Eoghan McCarthy ◽

Ben Parker ◽

...

Keyword(s):

Clinical Trials ◽

Real World ◽

Phase Iii ◽

Research Support ◽

Exclusion Criteria ◽

Eligibility Criteria ◽

Chi Squared ◽

The Mean ◽

Double Blinded ◽

Age And Sex

Abstract Background/Aims Stringent inclusion and exclusion criteria are employed in SLE clinical trials. Organ dysfunction and co-morbidities are common exclusion criteria which may affect how representative trials are of real-world SLE populations. We aimed to apply published trial eligibility criteria to patients with SLE in a large national register. Methods A literature review of all major published double-blinded randomised phase III trials in non-renal SLE was performed. Common inclusion and exclusion criteria were applied to all patients recruited to the BILAG-Biologics Register (BILAG-BR), a large UK-wide register of SLE patients. Data on comorbidities for all patients registered was collected. The mean (SD) number of co-morbidities was calculated. Patients were then classified as being eligible or ineligible. Groups were compared initially using a chi-squared or Wilcoxon rank-sum test and logistic regression model was used to test the age and sex adjusted association between trial eligibility and comorbidities. Results Common inclusion and exclusion criteria were identified from 12 published trials. When applied to the 837 patients recruited to BILAG-BR, 562 (67%) patients would not be eligible for inclusion in these trials. Ineligible patients had a shorter disease duration (2.9 vs. 5.1 years, p < 0.01), but were similar in age (P = 1.0), sex (P = 0.7) and ethnicity (p = 0.5) to those who were eligible. Of eligible patients, 128 (53%) had 1 or more comorbidities compared with 340 (60%) who were ineligible (p = 0.05). The mean (SD) number of comorbidities was 0.9 (1.2) vs 1.2 (1.3) for eligible and ineligible patients respectively. After adjusting for age and sex, inclusion in clinical trials was associated with fewer comorbidities (OR 0.81, 95% CI 0.70, 0.94, p < 0.01). Conclusion Patients with multi-morbidity are more likely to be ineligible for SLE clinical trials. Evidence from real world studies and registers are therefore needed to fully understand the safety and effectiveness of new therapies. Our data also underscores the need to develop more pragmatic eligibility criteria for clinical trials. Disclosure S. Dyball: None. S. Collinson: None. E. Sutton: None. E. McCarthy: None. B. Parker: Consultancies; GSK, AstraZenica, UCB, Abbvie, Pfizer, BMS, Celltrion. Grants/research support; GSK, Sanofi Genzyme. I. Bruce: Consultancies; GSK, Medimmune, AstraZenica, Eli Lilly, Merck Serono, UCB, ILTOO. Member of speakers’ bureau; AstraZeneca, Medimmune, GSK, UCB. Grants/research support; GSK, Genzyme Sanofi, UCB.

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Real-World Data for Planning Eligibility Criteria and Enhancing Recruitment: Recommendations from the Clinical Trials Transformation Initiative

Therapeutic Innovation & Regulatory Science ◽

10.1007/s43441-020-00248-7 ◽

2021 ◽

Author(s):

Scott R. Evans ◽

Dianne Paraoan ◽

Jane Perlmutter ◽

Sudha R. Raman ◽

John J. Sheehan ◽

...

Keyword(s):

Clinical Trials ◽

Real World ◽

Real World Data ◽

Eligibility Criteria ◽

World Data ◽

Study Planning ◽

Efficiency And Effectiveness ◽

Multi Stakeholder ◽

Functional Teams ◽

Data Driven Decisions

AbstractThe growing availability of real-world data (RWD) creates opportunities for new evidence generation and improved efficiency across the research enterprise. To varying degrees, sponsors now regularly use RWD to make data-driven decisions about trial feasibility, based on assessment of eligibility criteria for planned clinical trials. Increasingly, RWD are being used to support targeted, timely, and personalized outreach to potential trial participants that may improve the efficiency and effectiveness of the recruitment process. This paper highlights recommendations and resources, including specific case studies, developed by the Clinical Trials Transformation Initiative (CTTI) for applying RWD to planning eligibility criteria and recruiting for clinical trials. Developed through a multi-stakeholder, consensus- and evidence-driven process, these actionable tools support researchers in (1) determining whether RWD are fit for purpose with respect to study planning and recruitment, (2) engaging cross-functional teams in the use of RWD for study planning and recruitment, and (3) understanding patient and site needs to develop successful and patient-centric approaches to RWD-supported recruitment. Future considerations for the use of RWD are explored, including ensuring full patient understanding of data use and developing global datasets.

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Effectiveness and Safety of Immune Checkpoint Inhibitors for Patients with Advanced Non Small-Cell Lung Cancer in Real-World: Review and Meta-Analysis

Cancers ◽

10.3390/cancers13061388 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1388

Author(s):

Manlio Mencoboni ◽

Marcello Ceppi ◽

Marco Bruzzone ◽

Paola Taveggia ◽

Alessia Cavo ◽

...

Keyword(s):

Clinical Trials ◽

Real World ◽

Group Performance ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Small Cell ◽

Small Cell Lung ◽

Eligibility Criteria

Immunotherapy based on anti PD-1/PD-L1 inhibitors is the new standard of advanced non-small cell lung cancers. Pembrolizumab, nivolumab and atezolizumab are used in clinical practice. The strict eligibility criteria of clinical trials do not allow researchers to fully represent treatment effects in the patients that will ultimately use these drugs. We performed a systematic review and a meta-analysis to evaluate the effectiveness and safety of these drugs, and more generally of ICIs, as second-line therapy in NSCLC patients in real world practice. MEDLINE, PubMed, Scopus and Web of Science were searched to include original studies published between January 2015 and April 2020. A total of 32 studies was included in the meta-analysis. The overall radiological response rate (ORR), disease control rate (DCR), median progression-free survival (PFS) and overall survival (OS) were 21%, 52%, 3.35 months and 9.98 months, respectively. The results did not change when analysis was adjusted for Eastern Cooperative Oncology Group performance status (ECOG PS) and age. A unitary increase in the percent of patients with liver and CNS metastases reduced the occurrence of DCR by 7% (p < 0.001) and the median PFS by 2% (p = 0.010), respectively. The meta-analysis showed that the efficacy and safety of immunotherapy in everyday practice is comparable to that in clinical trials.

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A Comparison of the Randomized Clinical Trial Efficacy and Real-World Effectiveness of Tofacitinib for the Treatment of Inflammatory Bowel Disease: A Cohort Study

10.1101/19007195 ◽

2019 ◽

Author(s):

Vivek A. Rudrapatna ◽

Benjamin S. Glicksberg ◽

Atul J. Butte

Keyword(s):

Ulcerative Colitis ◽

Clinical Trials ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Real World ◽

Controlled Trials ◽

Real World Data ◽

Eligibility Criteria ◽

Primary Endpoints ◽

Three Phase

AbstractBackgroundReal-world data are receiving attention from regulators, biopharmaceuticals and payors as a potential source of clinical evidence. However, the suitability of these data to produce evidence commensurate with randomized controlled trials (RCTs) and the best practices in their use remain unclear. We sought to compare the real-world effectiveness of Tofacitinib in the treatment of IBD against efficacy rates published by corresponding RCTs.MethodsElectronic health records at the University of California, San Francisco (UCSF) were queried and reviewed to identify 86 Tofacitinib-treated IBD patients through 4/2019. The primary endpoint was treatment effectiveness. This was measured by time-to-treatment-discontinuation and by the primary endpoints of RCTs in Ulcerative Colitis (UC) and Crohn’s Disease (CD). Endpoints were measured and analyzed following a previously published protocol and analysis plan.Findings86 patients (68 with UC, 18 with CD) initiated Tofacitinib for IBD treatment. Most of the data needed to calculate baseline and follow-up disease activity indices were documented within the EHR(77% for UC, 91% for CD). Baseline characteristics of the UCSF and RCT cohorts were similar, except for a longer disease duration and 100% treatment failure of Tumor Necrosis Factor inhibitors in the former. None of the UCSF cohort would have met the RCT eligibility criteria due to multiple reasons.The rate of achieving the RCT primary endpoints were highly similar to the published rates for both UC(16%, P=0·5) and CD (38%, P=0·8). However, treatment persistence was substantially higher: 69% for UC (week 52) and 75% for CD (week 26).InterpretationAn analysis of routinely collected clinical data can reproduce published Tofacitinib efficacy rates, but also indicates far greater treatment durability than suggested by RCTs including possible benefit in CD. These results underscore the value of real-world studies to complement RCTs.FundingThe National Institutes of Health and UCSF Bakar InstituteResearch in ContextEvidence before this studyTofacitinib is the most recently approved treatment for Ulcerative Colitis. Data related to treatment efficacy for either IBD subtype is generally limited, whether from controlled trials or real-world studies. A search of clinicaltrials.gov was performed in January 2019 for completed phase 2 or 3, interventional, placebo-controlled clinical trials matching the terms “Crohn’s Disease” OR “Ulcerative Colitis” in the conditions field, and matching “Placebo” AND “Tofacitinib” OR “CP-690,550”) in the Interventions field. We identified three Phase 3 trials for UC (OCTAVE trials, all initially reported in a single article in 2016) and three Phase 2 trials of CD (two published in the same article in 2017, one reported in 2014). The Phase 3 UC trials reported 57·6% pooled clinical response rate in the Tofacitinib-assigned groups after 8 weeks (induction), and a 37·5% pooled remission rate among eligible induction trial responders in the Tofacitinib-assigned groups at 52 weeks. The 2017 CD trial reported a 70·8% pooled rate of response or remission in the Tofacitinib-assigned groups after 8 weeks, and a 47·6% pooled rate of response or remission among enrolled induction-trial responders at 26 weeks. A bias assessment of both UC and CD trials indicated a high risk of attrition bias and unclear risk of bias related to conflicts of interest. We also performed a search of pubmed.gov in January 2019 using search terms (“Colitis” OR “Crohn’s”) AND (“Tofacitinib” OR “CP-690,550”) OR “real-world” to identify cohort studies of Tofacitinib efficacy in routine clinical practice. No studies meeting these criteria were identified.Added value of this studyThis is one of the early studies to closely compare the results of clinical trials with the continuously-updated data captured in the electronic health records, and the very the first to assess the efficacy-effectiveness gap for Tofacitinib. We found that none of the patients treated at our center thus far would have qualified for the clinical trial based on published eligibility criteria. We found that the drug appeared to perform similarly to its efficacy when using the endpoints reported in clinical trials, but treatment persistence was significantly greater than would have been expected from the reported trial outcomes: 69% for UC at week 52 and 75% for CD at week 26.Implications of all the available evidenceTofacitinib is an effective treatment for the Ulcerative colitis and may be efficacious for Crohn’s disease. Controlled trials may not be representative of real-world cohorts, may not be optimally designed to identify efficacious drugs, and may not accurately predict patterns of use in clinical practice. Further studies using real-world data as well as methods to enable their proper use are needed to confirm and continuously monitor the efficacy and safety of drugs, both for on- and off-label use.

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Eyes that Do Not Meet the Eligibility Criteria of Clinical Trials on Age-Related Macular Degeneration: Proportion of the Real-World Patient Population and Reasons for Exclusion

Journal of Ophthalmology ◽

10.1155/2021/6635467 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Jae Hui Kim ◽

Jong Woo Kim ◽

Chul Gu Kim

Keyword(s):

Clinical Trials ◽

Visual Acuity ◽

Real World ◽

Age Related Macular Degeneration ◽

Subretinal Hemorrhage ◽

Neovascular Amd ◽

Eligibility Criteria ◽

Type 3 Neovascularization ◽

Age Related ◽

Type 3

Background. To evaluate the proportion of eyes that do not meet the eligibility criteria of clinical trials on neovascular age-related macular degeneration (AMD) and the reasons for exclusion. Methods. This retrospective, observational study included 512 eyes of 463 patients diagnosed with treatment-naïve neovascular AMD. The proportion of eyes that did not meet the eligibility criteria of the Vascular Endothelial Growth Factor Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) studies were evaluated. The two most common reasons for exclusion were also evaluated in each subtype of neovascular AMD (typical neovascular AMD, polypoidal choroidal vasculopathy (PCV), and type 3 neovascularization). Results. Among the 512 eyes, 229 (44.7%) did not meet the eligibility criteria. In all the included eyes, the most common reasons for exclusion were good or poor visual acuity (169 eyes, 33.0%), followed by the presence of subretinal hemorrhage (47 eyes, 9.5%). Moreover, good or poor visual acuity was the most common reason for exclusion in all three subtypes of neovascular AMD. The second most common reason was a fovea-involving scar or fibrosis in typical neovascular AMD, subretinal hemorrhage in PCV, and other vascular diseases affecting the retina in type 3 neovascularization. Conclusions. Among the included cases, 44.7% did not meet the eligibility criteria for VIEW study, suggesting that the conclusion derived from clinical trials may not directly reflect the real-world outcomes. Additionally, the reasons for ineligibility differed among the different subtypes of neovascular AMD.

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Strategy for addressing research-site overlap in pragmatic clinical trials: lessons learned from the NIH-DOD-VA Pain Management Collaboratory (PMC)

Trials ◽

10.1186/s13063-020-04941-8 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Mary Geda ◽

◽

Steven Z. George ◽

Diana J. Burgess ◽

Dylan V. Scarton ◽

...

Keyword(s):

Clinical Trials ◽

Pain Management ◽

Research Effort ◽

Health Care Systems ◽

Lessons Learned ◽

Exclusion Criteria ◽

Eligibility Criteria ◽

Recruitment Methods ◽

Research Site ◽

Pragmatic Clinical Trials

Abstract Background The Pain Management Collaboratory (PMC) is a multi-site network of pragmatic clinical trials (PCTs) focused on nonpharmacological approaches to pain management, conducted in health care systems of the US Department of Defense (DoD) and Department of Veterans Affairs (VA) and co-funded by the National Institutes of Health (NIH). Concerns about potential research-site overlap prompted the PMC investigator community to consider strategies to avert this problem that could negatively affect recruitment and contaminate interventions and thus pose a threat to trial integrity. Methods We developed a two-step strategy to identify and remediate research-site overlap by obtaining detailed recruitment plans across all PMC PCTs that addressed eligibility criteria, recruitment methods, trial settings, and timeframes. The first, information-gathering phase consisted of a 2-month period for data collection from PIs, stakeholders, and ClinicalTrials.gov. The second, remediation phase consisted of a series of moderated conference calls over a 1-month time period to develop plans to address overlap. Remediation efforts focused on exclusion criteria and recruitment strategies, and they involved collaboration with sponsors and stakeholder groups such as the Military Treatment Facility Engagement Committee (MTFEC). The MTFEC is comprised of collaborating DoD and university-affiliated PIs, clinicians, and educators devoted to facilitating successful pragmatic trials in DoD settings. Results Of 61 recruitment sites for the 11 PMC PCTs, 17 (28%) overlapped. Four PCTs had five overlapping Military Treatment Facilities (MTFs), and eight PCTs had 12 overlapping VA Medical Centers (VAMCs). We developed three general strategies to avoid research-site overlap: (i) modify exclusion criteria, (ii) coordinate recruitment efforts, and/or (iii) replace or avoid any overlapping sites. Potential overlap from competing studies outside of the PMC was apparent at 26 sites, but we were not able to confirm them as true conflicts. Conclusion Proactive strategies can be used to resolve the issue of overlapping research sites in the PMC. These strategies, combined with open and impartial mediation approaches that include researchers, sponsors, and stakeholders, provide lessons learned from this large and complex pragmatic research effort.

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Demographics, Treatment Patterns, Safety, and Real-World Effectiveness in Patients ≥70 Years of Age with Chronic Lymphocytic Leukemia Receiving Bendamustine with or without Rituximab,

Blood ◽

10.1182/blood.v118.21.3914.3914 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3914-3914

Author(s):

Kathryn S. Kolibaba ◽

Avani D. Joshi ◽

James A. Sterchele ◽

Michael Forsyth ◽

Erin Alwon ◽

...

Keyword(s):

Clinical Trials ◽

Chronic Lymphocytic Leukemia ◽

Partial Response ◽

Real World ◽

Progressive Disease ◽

Lymphocytic Leukemia ◽

Social Security Administration ◽

Grade 3

Abstract Abstract 3914 Background Bendamustine is a unique, well-established alkylating agent with multifaceted actions leading to cancer cell death in several hematologic malignancies. In a phase 3 trial in treatment-naïve patients with chronic lymphocytic leukemia (CLL), rates of response and progression-free survival (PFS) were significantly superior to those for chlorambucil [Knauf WU et al. J Clin Oncol 2009;27:4378–84]. In vitro studies have found that the cytotoxic activity of bendamustine against CLL-derived cell lines is synergized by rituximab, an anti-CD20 monoclonal antibody [Demidem A et al. Cancer Biother Radiopharm 1997;12:177–86]. Older patients may demonstrate lower tolerance to chemoimmunotherapy [Foon KA & Hallek MJ. Leukemia 2010;24:500–11], and published clinical data on bendamustine-rituximab in CLL are scarce. Thus, this retrospective study sought to characterize a population of adults ≥70 years old with CLL receiving bendamustine with or without rituximab, describe patterns of care, assess data on real-world effectiveness outside of the controlled environment of clinical trials [Waldthaler C et al. Wien Klin Wochenschr 2011;123:269–275], and assess safety. Methods Records were extracted from US Oncology iKnowMed (iKM) record databases for all outpatients ≥70 years old with CLL (but no other tumor) and more than 1 visit recorded (but not enrolled in clinical trials) who received bendamustine between March 2008 and May 2010. Patients were classified as treatment-naïve or relapsed (including ≥ second-line therapy). To ascertain mortality, the iKM data were supplemented with vital-status data from the Social Security Administration Death Index. The overall response rate (ORR) included complete response (CR), nodal partial response (nPR), and partial response (PR). PFS was time from first bendamustine dose to progressive disease (change in line of therapy), relapse, or death from any cause. Data from patients who did not die, or had no progression and were lost to follow-up were censored. Results Among 91 patients, the mean (SD) initial age at beginning of first therapy was 77.4 (5.6) years, age at diagnosis was 70.3 (6.5) years, and 63.7% were male. Of the 16 (17.6%) treatment-naïve patients, 10 had received bendamustine monotherapy and 6 received bendamustine-rituximab. Of the 75 (82.4%) relapsed patients, 20 had received bendamustine monotherapy and 55 received bendamustine-rituximab. The observed ORR for treatment-naïve patients was 56.3% (n=9; 18.8% CR, 37.5% PR, and 0 nPR); 6.3% had progressive disease. For relapsed patients, the ORR was 58.7% (n=44; 13.3% CR, 44.0% PR, and 1.3% nPR); 24.0% had progressive disease. Among patients with data, median PFS for 16 treatment-naïve patients has not been reached (median follow-up 15.1 months); for 73 relapsed patients, PFS was 18.4 months. Kaplan-Meier estimates for PFS over time for each group are shown in the Figure. No unexpected toxicities were seen. The overall rate of blood/bone marrow toxicities (all grades) was 40.7%; grade 3/4 rates were 18.8% for treatment-naïve patients and 25.3% for relapsed patients. Other grade 3/4 adverse events (AEs) included upper respiratory infection and abdominal pain in the relapsed group as well as rash and sepsis in both groups (n=1 each). The most frequent nonhematologic AEs (≥5%, any grade) were fatigue (33.0%), weight loss (11.0%), infection (9.9%; herpes zoster [n=2]; cryptococcal sepsis, Klebsiella sepsis, and pneumonia [n=1 each]), gastrointestinal (8.8%), fever (8.8%), pulmonary (6.6%), and rash (5.5%). o = data censored. Conclusions In this retrospective chart review of patients ≥70 years old with CLL, bendamustine, either alone or with rituximab, provided meaningful response rates and was generally well tolerated. The length of PFS of both treatment-naïve and relapsed patients was clinically meaningful. This research was sponsored by and conducted in collaboration with Cephalon, Inc., Frazer, PA. Disclosures: Sterchele: Cephalon, Inc.: Employment. Beygi:Cephalon, Inc.: Employment. Kennealey:Cephalon, Inc.: Employment.

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A multicentered population-based analysis of outcomes of patients with metastatic renal cell carcinoma (mRCC) who do not meet eligibility criteria for clinical trials.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.353 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 353-353 ◽

Cited By ~ 4

Author(s):

Daniel Yick Chin Heng ◽

Toni K. Choueiri ◽

Jae-Lyun Lee ◽

Lauren Christine Harshman ◽

Georg A. Bjarnason ◽

...

Keyword(s):

Clinical Trials ◽

Targeted Therapy ◽

Brain Metastases ◽

Clear Cell ◽

Karnofsky Performance Status ◽

Performance Status ◽

Progression Free Survival ◽

Exclusion Criteria ◽

Eligibility Criteria ◽

Number Of Patients

353 Background: Clinical trials have strict eligibility criteria to maintain internal validity. These criteria exclude many patients to whom the trial results are later applied to in clinical practice. Patients that do not meet eligibility criteria are poorly characterized. Methods: mRCC patients treated with VEGF targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky Performance Status (KPS) < 70%, brain metastases, non-clear cell histology, hemoglobin ≤ 9 g/dL, creatinine > 2x the upper limit of normal, platelet count of < 100x103/uL, neutrophil count < 1500/mm3 or corrected calcium ≤ 12 mg/dL. Results: 894/2076 (43%) patients were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression free survival (PFS) and median overall survival of first-line targeted therapy were 21% vs 29%, 5.2 vs 8.8 months and 14.5 vs 28.8 months (all p < 0.0001), respectively. Second-line PFS (if applicable) was 3.2 months in the trial ineligible vs 4.4 months in the trial eligible patients (p = 0.0074). When adjusted by the Heng et al prognostic categories, the hazard ratio for death between trial ineligible vs trial eligible patients was 1.621 (95% CI = 1.431–1.836, p < 0.0001). If only KPS, brain metastases and non-clear cell histology were used as exclusion criteria, 672 (32%) patients were excluded and the results were similar. Conclusions: The number of patients that are ineligible for clinical trials is high and their outcomes are inferior. Designing more inclusive clinical trials for this “ineligible” patient population are needed. [Table: see text]

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Multidimensional Quantification of Exclusion Criteria to Reduce the Gap between Randomized Clinical Trial and Real-World Outcomes in Multiple Myeloma

Blood ◽

10.1182/blood-2021-148222 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4003-4003

Author(s):

Augusta Eduafo ◽

Leland Metheny ◽

Ravi Kyasaram ◽

Farhad Sanati ◽

James J. Driscoll ◽

...

Keyword(s):

Real World ◽

Research Funding ◽

Advisory Board ◽

P Value ◽

Single Institution ◽

Exclusion Criteria ◽

Eligibility Criteria ◽

Real World Evidence ◽

Index Treatment

Abstract Randomized clinical trials (RCTs) are considered the highest level of evidence to define the efficacy of newly developed treatments before their adoption into clinical practice. RCTs incorporate exclusion criteria that eliminate specific patient populations in order to reduce the incidence of serious adverse events and enhance the efficacy of a given anti-cancer strategy. However, exclusion criteria may lead to a significant gap between patients (pts) enrolled on RCTs and real world pt populations, which represent the ultimate stakeholders in cancer treatment. The analysis of real-world evidence to answer clinical questions has recently gained increased interest. Assessing different dimensions of this gap may help overcome barriers in trial recruitment and enhance the applicability of RCTs in daily practice. There has been significant advancement in treating multiple myeloma (MM) over the past two decades bringing multiple new mechanisms of action to the bedside. We selected ten recent RCTs: ASPIRE, TOURMALNE-MM01, ELOQUENT-2, ENDEAVOR, POLLUX and CASTOR, OCEAN, ICARIA, APOLLO and ELOQUENT-3 studies, which are pharma-sponsored landmark trials that provided the basis for FDA approval of anti-myeloma agents. Our objective was to quantify the gap in eligibility criteria between the ten RCTs and real world populations by examining these trials using a single institution database. Methods: Pts with relapsed MM that were initiated on a second (or later line) of therapy that were recognized, retrospectively. Eligibility criteria of the ten landmark RCTs was applied during the 21 day period before the index treatment date. Pts that received Len-containing regimens were tested as to be enrolled on trials with Len/Dex control arm, patients that received Bor-containing regimens were examined to be enrolled on Bor/Dex trials and subjects who had Pom-containing regimen were screened for Pom/Dex trials. Pts were then classified as "Trial eligible" or "Trial ineligible", accordingly and were monitored longitudinally from the index treatment date until death, loss to follow-up, or end of the follow up period. Ten commonly used eligibility criteria were examined (Fig. 1). Any cancer in the three years prior to the index treatment date was counted as "history of other malignancies", i.e., skin and prostate cancer were excluded. Concurrent infection was defined as use of any antibiotic other than acyclovir, ciprofloxacin or bactrim. To calculate area under the curve of the polygon graphs Shoelace algorithm was used. Results : 516 pts were studied between 2010 and 2020 and 153 were excluded due to missing values. 224, 136 and 98 pts were treated with Len-, Bor- or Pom-containing regimens, respectively. Overall, the trial-eligible cohort was more likely to have autologous stem cell transplant and to have had longer treatment-free period before index treatment date (p-value: 0.009). There was a substantial variation in the ineligibility rate for these ten RCTs among the study population (Fig. 1). The most common items that excluded a patient from a RCT were: other malignancy, current infection and renal dysfunction. Differences between trial-eligible and trial-ineligible pts stratified by trial are listed in Tables 1, 2 and 3 for trials with Len, Bor and Pom as control arms, respectively. The median follow-up for the Len, Bor and Pom cohorts was 31, 30 and 22 months, respectively. Trial-ineligible pts displayed a significantly worse OS (2-year rate 58% vs. 78%, p-value: 0.001) and 49% higher chance of death (HR 1.69, 90%, CI: 1.17-2.62) compared with trial-eligible cohort. Conclusion: Here, we assessed the multidimensional gap that exists between patient cohorts enrolled on RCTs and real world cohorts for ten landmark MM trials. We present a quantitative deviation score as a tool to calibrate the generalizability of these landmark trials against a single institution. Importantly, we show that trial-eligibility alone significantly correlates with superior OS across a variety of MM clinical trials across all ten MM RCTs. Furthermore, our results reveal that ineligibility rates were quite different among the ten trials which significantly limit cross-trial comparisons. We propose a uniform methodology to assess patient exclusion criteria and narrow the efficacy gap observed between RCTs and real world evidence. Figure 1 Figure 1. Disclosures Metheny: Pharmacosmos: Honoraria; Incyte: Speakers Bureau. Malek: Medpacto Inc.: Research Funding; Amgen: Honoraria; Janssen: Other: Advisory board ; Takeda: Honoraria; BMS: Honoraria, Research Funding; Cumberland Inc.: Research Funding; Bluespark Inc.: Research Funding; Sanofi: Other: Advisory Board.

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Real world eligibility for cabozantinib (C), regorafenib (Reg), and ramucirumab (Ram) in hepatocellular carcinoma (HCC) patients after sorafenib (S).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.422 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 422-422 ◽

Cited By ~ 5

Author(s):

Andrea S. Fung ◽

Vincent C. Tam ◽

Daniel E. Meyers ◽

Hao-Wen Sim ◽

Jennifer J. Knox ◽

...

Keyword(s):

Real World ◽

Performance Status ◽

Outcome Data ◽

Prognostic Impact ◽

Eligibility Criteria ◽

Cancer Centre ◽

Kaplan Meier ◽

Real World Evidence ◽

Receive Treatment ◽

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422 Background: The CELESTIAL, RESORCE, and REACH-2 trials showed survival benefit of C, Reg, and Ram, respectively, when given after S to HCC patients. However, strict eligibility criteria (SEC) may limit generalizability. In clinical practice, modified eligibility criteria (MEC) may be used to offer treatments to select patients with slightly worse performance status (ECOG 2) or limited liver dysfunction (Child-Pugh (CP) B7). This study evaluated which patients in the real world would be eligible for these new treatments using SEC and MEC, and their prognostic impact. Methods: HCC patients who received S between 01/2008-06/2017 in British Columbia, Alberta, Princess Margaret Cancer Centre, and Sunnybrook Cancer Centre in Canada were included. Clinical, pathologic, laboratory and outcome data were collected. Patients were classified as eligible or ineligible based on available CELESTIAL, RESORCE, REACH-2 clinical trial SEC or MEC. Median overall survival (mOS) for these groups was assessed using the Kaplan-Meier method. Results: A total of 730 patients were identified. Using SEC, only 13.1% of patients would be eligible for C, Reg, or Ram (table). Expanding eligibility to include patients who meet MEC increased the proportion of eligible patients to 31.7%. Patients who met SEC had longer mOS compared to those who were ineligible. The most common reasons for not meeting SEC across all 3 trials were ECOG ≥ 2 (61.7%) and CP ≥ B (63.9%). Higher ineligibility for Reg or Ram was likely driven by strict trial-specific criteria, with 28.0% of patients ineligible for Reg due to S intolerance and 58.9% ineligible for Ram due to AFP < 400. Conclusions: Only a small proportion of real-world HCC patients would be eligible for C, Reg, or Ram based on SEC. More than twice as many patients would likely receive treatment if MEC were applied. If MEC are adopted, ongoing real-world evidence generation will be important to evaluate outcomes in these unstudied patient groups. [Table: see text]

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