scholarly journals Lupus clinical trial eligibility in a real-world setting: results from the British Isles Lupus Assessment Group-Biologics Register (BILAG-BR)

2021 ◽  
Vol 8 (1) ◽  
pp. e000513
Author(s):  
Sarah Dyball ◽  
Sophie Collinson ◽  
Emily Sutton ◽  
Eoghan M McCarthy ◽  
Ian N Bruce ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Real World ◽  
Renal Involvement ◽  
Standard Of Care ◽  
Phase Iii ◽  
British Isles ◽  
Eligibility Criteria ◽  
Low Disease Activity ◽  
Real World Setting ◽  
Biologics Register

ObjectiveTo quantify how well phase III randomised clinical trials in both SLE and lupus nephritis (LN) represents a real-world SLE cohort.MethodsLiterature reviews were performed of major published phase III SLE (n=12) and LN (n=6) clinical trials (ClinicalTrials.gov). Inclusion and exclusion criteria common across these trials were collated for non-renal SLE or LN trials, and applied to patients recruited to the British Isles Lupus Assessment Group-Biologics Register (BILAG-BR) starting either biological or standard-of-care (SOC) therapies.ResultsWe recruited 837 patients to the BILAG-BR from September 2010 to June 2018, starting either SOC (n=125, 15%) or a biological medication (n=712, 85%). Active LN, defined as a BILAG A in the renal domain occurred in 20% (n=166). Overall, 530 (63%) patients were ineligible to participate in non-renal SLE clinical trials and 72 (43%) patients with active LN would be ineligible for LN trials. The most common reasons for ineligibility from the non-renal lupus trials included active renal involvement (n=166, 20%) and low disease activity (n=114, 15%). For LN trials, the most common exclusion met was pre-existing renal impairment (n=15, 9%). Patients with fewer comorbidities were more likely to be eligible to participate in non-renal SLE trials.ConclusionsIn this national register of patients with moderate-to-severe SLE, nearly two-thirds would not be eligible for recruitment to key SLE clinical trials nor would almost half of those with active LN. Eligibility criteria may excessively constrain enrolment and thus, how we can generalise trial results in a real-world setting.

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

Rheumatology ◽  
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.

scholarly journals Real-world validity of randomized controlled phase III trials in newly diagnosed glioblastoma: to whom do the results of the trials apply?

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Erlend Skaga ◽  
Marthe Andrea Skretteberg ◽  
Tom Børge Johannesen ◽  
Petter Brandal ◽  
Einar O Vik-Mo ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Real World ◽  
Performance Status ◽  
Geographical Area ◽  
Eastern Cooperative Oncology Group ◽  
University Hospital ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Eligibility Criteria ◽  
Phase Iii Trials

Abstract Background The survival rates in population-based series of glioblastoma (GBM) differ substantially from those reported in clinical trials. This discrepancy may be attributed to that patients recruited to trials tend to be younger with better performance status. However, the proportion and characteristics of the patients in a population considered either eligible or ineligible for trials is unknown. The generalizability of trial results is therefore also uncertain. Methods Using the Cancer Registry of Norway and the Brain Tumor Database at Oslo University Hospital, we tracked all patients within a well-defined geographical area with newly diagnosed GBM during the years 2012–2017. Based on data from these registries and the medical records, the patients were evaluated for trial eligibility according to criteria employed in recent phase III trials for GBM. Results We identified 512 patients. The median survival was 11.7 months. When we selected a potential trial population at the start of concurrent chemoradiotherapy (radiotherapy [RT]/ temozolomide [TMZ]) by the parameters age (18–70 y), passed surgery for a supratentorial GBM, Eastern Cooperative Oncology Group (ECOG) ≤2, normal hematologic, hepatic and renal function, and lack of severe comorbidity, 57% of the patients were excluded. Further filtering the patients who progressed during RT/TMZ and never completed RT/TMZ resulted in exclusion of 59% and 63% of the patients, respectively. The survival of patients potentially eligible for trials was significantly higher than of the patients not fulfilling trial eligibility criteria (P < .0001). Conclusions Patients considered eligible for phase III clinical trials represent a highly selected minority of patients in a real-world GBM population.

Using real-world cohorts to assess the generalizability and relevance of randomized clinical trials (RCTs).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6540-6540 ◽  
Author(s):  
Caroline Savage Bennette ◽  
Nathan Coleman Nussbaum ◽  
Melissa D. Curtis ◽  
Neal J. Meropol
Keyword(s):  
Clinical Trials ◽  
Real World ◽  
Randomized Clinical Trials ◽  
Treatment Options ◽  
Metastatic Breast ◽  
Standard Of Care ◽  
Real World Data ◽  
Eligibility Criteria ◽  
Relevance Score ◽  
World Data

6540 Background: RCTs are the gold standard for understanding the efficacy of new treatments, however, patients (pts) in RCTs often differ from those treated in the real-world. Further, selecting a standard of care (SOC) arm is challenging as treatment options may evolve during the course of a RCT. Our objective was to assess the generalizability and relevance of RCTs supporting recent FDA approvals of anticancer therapies. Methods: RCTs were identified that supported FDA approvals of anticancer therapies (1/1/2016 - 4/30/2018). Relevant pts were selected from the Flatiron Health longitudinal, EHR-derived database, where available. Two metrics were calculated: 1) a trial’s pt generalizability score (% of real-world pts receiving treatment consistent with the control arm therapy for the relevant indication who actually met the trial's eligibility criteria) and 2) a trial’s SOC relevance score (% of real-world pts with the relevant indication and meeting the trial's eligibility criteria who actually received treatment consistent with the control arm therapy). All analyses excluded real-world pts treated after the relevant trial’s enrollment ended. Results: 14 RCTs across 5 cancer types (metastatic breast, advanced non-small cell lung cancer, metastatic renal cell carcinoma, multiple myeloma, and advanced urothelial) were included. There was wide variation in the SOC relevance and pt generalizability scores. The median pt generalizability score was 63% (range 35% - 88%), indicating that most real-world pts would have met the RCT eligibility criteria. The median SOC relevance score was 37% (range 15% - 74%), indicating that most RCT control arms did not reflect the way trial-eligible real-world pts in the US were actually treated. Conclusions: There is great variability across recent RCTs in terms of pt generalizability and relevance of SOC arms. Real-world data can be used to inform selection of control arms, predict impact of inclusion/exclusion criteria, and also assess the generalizability of the results of completed trials. Incorporating real-world data in planning and interpretation of prospective clinical trials could improve accrual and enhance relevance of RCT outcomes.

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

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.

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

Cancers ◽  
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.

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

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.

scholarly journals 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

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.

PP126 MEA In Italy: Correlation Between Time To Payment By Result And Time To Off Treatment Curve

2017 ◽  
Vol 33 (S1) ◽  
pp. 131-132
Author(s):  
Gabriele Vittoria ◽  
Antonio Fascì ◽  
Matteo Ferrario ◽  
Giovanni Giuliani
Keyword(s):  
Clinical Trials ◽  
Treatment Failure ◽  
Median Time ◽  
Real Life ◽  
Standard Of Care ◽  
Phase Iii ◽  
Experimental Drug ◽  
The Mean ◽  
Line Of Therapy ◽  
Mean Time

INTRODUCTION:Payment by result agreements have been quite widely used in Italy to provide access for high costs oncologic drugs and minimize uncertainties of real life benefits (1). The aim of this analysis was to overview the Roche experience in terms of Payment by Result (Pbr) in oncology and investigate the relation between timing for the evaluation of treatment failures and observed Time to Off Treatment (TTOT) from Phase III clinical trials (2).METHODS:A retrospective analysis of the Roche payment by results schemes in place in Italy was conducted. For each drug included in the analysis it was collected: (i) the negotiated timing to assess the treatment failure for payment by result, (ii) the median time to off treatment curve observed in clinical trials for the experimental drug, (iii) the median time to off treatment observed in clinical trials for the control arm. The mean ratios between timing to assess the treatment failure for payment by result and the time to off treatment observed for the experimental drug or the median time to off treatment observed in the control arm were calculated to identify potential correlations. High level of correlation was expected if ratio was close to 1 (±.2).RESULTS:Roche products or different indications of the same product were identified as candidates for the analysis from 2008 to 2016. The timing for the evaluation of treatment failures for Pbr varies between 2 and 9 months, depending on the type of tumor and line of therapy. The mean Time to Payment By Result (TTPbr) / Control arm Time To Off Treatment (cTTOT) ratio was 1.16 (±.37) while the mean Time to Payment By Result (TTPbr) / Experimental arm Time To Off Treatment (eTTOT) ratio was .71 (±.13). Data analysis according to different time periods shows that the mean TTPbr/cTTOT and TTPbr/eTTOT for drugs negotiated from 2008 to 2015 were respectively 1.07 and 1.39 whereas for drugs negotiated in 2016 were respectively and .63 and 1.CONCLUSIONS:Good level of correlation between TTPbr and cTTOT was found. This finding is in line with the methodology used by Italian Medicines Agency so far, leveraging the cTTOT as the most appropriate proxy to assess any incremental effect of a new drug compared to the previous Standard of Care. The analysis over time of TTPbr shows that in the first years of payment by result negotiation TTPbr is more correlated to the cTTOT whereas in the last years is moving closer to the experimental one.

scholarly journals Targeting Angiogenesis in Pancreatic Neuroendocrine Tumors: Resistance Mechanisms

2019 ◽  
Vol 20 (19) ◽  
pp. 4949 ◽  
Author(s):  
Pozas ◽  
San Román ◽  
Alonso-Gordoa ◽  
Pozas ◽  
Caracuel ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Neuroendocrine Tumors ◽  
Peptide Receptor Radionuclide Therapy ◽  
Standard Of Care ◽  
Initial Response ◽  
Somatostatin Analogues ◽  
Resistance Mechanisms ◽  
Phase Iii ◽  
Pancreatic Neuroendocrine Tumors ◽  
Optimal Sequence

Despite being infrequent tumors, the incidence and prevalence of pancreatic neuroendocrine tumors (P-NETs) has been rising over the past few decades. In recent years, rigorous phase III clinical trials have been conducted, allowing the approval of several drugs that have become the standard of care in these patients. Although various treatments are used in clinical practice, including somatostatin analogues (SSAs), biological therapies like sunitinib or everolimus, peptide receptor radionuclide therapy (PRRT) or even chemotherapy, a consensus regarding the optimal sequence of treatment has not yet been reached. Notwithstanding, sunitinib is largely used in these patients after the promising results shown in SUN111 phase III clinical trial. However, both prompt progression as well as tumor recurrence after initial response have been reported, suggesting the existence of primary and acquired resistances to this antiangiogenic drug. In this review, we aim to summarize the most relevant mechanisms of angiogenesis resistance that are key contributors of tumor progression and dissemination. Furthermore, several targeted molecules acting selectively against these pathways have shown promising results in preclinical models, and preliminary results from ongoing clinical trials are awaited.

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