CLINICAL TRIALS VERSUS THE REAL WORLD

Abstract Background: Immune checkpoint inhibitors (CPIs) are being used to effectively treat a growing number of cancers but can cause immune related adverse events (irAE). Thyroid dysfunction is the most common endocrine irAE. A meta-analysis of clinical trials estimated that following CPI exposure, 6.6% will become hypothyroid and 2.9% will have hyperthyroidism1. It is unclear if this reflects the real-world incidence of these irAEs. We used electronic health record (EHR) data to identify patients who developed thyroid dysfunction after CPI to estimate the real-world incidence of these irAEs. Methods: Data were derived from the EHR of a large U.S. academic center. We identified subjects treated with CPIs between 2012 and 2018 and excluded those with thyroid cancer or pre-existing thyroid disease. Thyroid dysfunction was identified as either a TSH > 10, an abnormal free T4 or a prescription for thyroid hormone replacement or anti-thyroid medication. Those with thyroid dysfunction were then categorized as having pre-existing disease or a new-onset thyroid irAE based on the timing of CPI initiation. Logistic regression was used to evaluate the association of thyroid irAE with age, gender, CPI and type of cancer. Results: In total, 1146 individuals without pre-existing thyroid disease that received CPIs were assessed. Pembrolizumab was the most common treatment (45%), followed by nivolumab (20%). Less than 10% of subjects received atezolizumab, durvalumab, ipilimumab monotherapy, combined ipilimumab/nivolumab, or other combinations of CPIs. Melanoma was the most common cancer treated (32%), followed by non-small cell lung cancer (13%). The prevalence of any other cancer was < 10% each. Overall, 19% developed thyroid irAEs. After adjustment for gender and age, the type of cancer was significantly associated with new onset thyroid dysfunction (p=0.01). The rates of thyroid irAEs ranged from 10% in glioblastoma to 40% in renal cell cancer. Although there was no significant association between irAEs and specific CPIs in the overall analysis, thyroid irAEs were more common in subjects who received combined ipilimumab/ nivolumab (31%) compared to pembrolizumab (18%, p=0.03), nivolumab (18%, p<0.01) and ipilimumab (15%, p=0.02). Conclusion: Thyroid irAEs are much more common in real world practice than in clinical trials and there is emerging evidence that certain cancer types incur a higher risk of thyroid irAEs even after adjustment for CPI exposure. Clinicians and patients should be educated about these risks. Future work should focus on exploring the reasons underlying the differing rates of thyroid irAEs among different cancers including effect on cancer outcomes. 1Barroso-Sousa et al. Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens. JAMA Oncol. 2017; 02215: 1–10.

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Do the Safety and Efficacy Outcomes Reported in the Clinical Trials of Direct Oral Anticoagulants (DOAC) Translate to the Real-World?

Blood ◽

10.1182/blood.v126.23.2335.2335 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2335-2335

Author(s):

Shammim Haji ◽

Jignesh P Patel ◽

Vivian Auyeung ◽

Lara N Roberts ◽

Julia Czuprynska ◽

...

Keyword(s):

Clinical Trials ◽

Major Bleeding ◽

Real World ◽

Research Funding ◽

Oral Anticoagulants ◽

Phase Iii ◽

World Population ◽

Safety And Efficacy ◽

The Real ◽

Pooled Data

Abstract Do the safety and efficacy outcomes reported in the clinical trials of direct oral anticoagulants (DOAC) translate to the 'real-world'? Background: A number of DOACs are now available for clinicians to prescribe in clinical practice. Whilst the results from large clinical trials demonstrate that these agents are as effective as vitamin K antagonists, there is some concern that the patients studied in the trials were not representative of patients, clinicians encounter in everyday practice. The aim of our study was to compare the real-world clinic population commenced on a DOAC to that from the clinical trials for these agents, in order to assess potential differences in safety and efficacy. Patients and methods: A retrospective observational cohort study was undertaken. Patients who were initiated on a DOAC (apixaban, dabigatran and rivaroxaban) at a large teaching hospital in South East London between 1st August 2012 and 31st July 2014 were identified through pharmacy issue data with those followed-up for a minimum of 6 months included. Baseline demographic data, rates of stroke/VTE and rates of major/non-major clinically relevant (NMCR) (ISTH definition) bleeding were assessed and compared to pooled data reported from the corresponding Phase III trials. Differences between groups were compared using t-tests or chi-squared tests. Results: During the review period, 748 patients were initiated on a DOAC, 365 for atrial fibrillation (AF) and 383 for venous thromboembolism (VTE). In terms of demographic differences, the real-world AF population comprised more females, were significantly older, had poorer renal function and a lower body weight. In contrast, the real-world VTE population typically had a higher body weight and poorer renal function, compared to the trial population, (table 1). Efficacy of DOACs was found to be similar across both the VTE and AF populations. With respect to safety, the real-world AF population experienced similar rates of major bleeding and a significantly lower rate of NMCR bleeding compared to the trial populations. In contrast, the real-world VTE population experienced a significantly higher rate of major bleeding, particularly gastrointestinal bleeding. Although the rate of NMCR bleeding was similar, there was a significantly higher rate of urogenital bleeding in the real-world VTE population, specifically heavy menstrual bleeding in women. Conclusions: The efficacy outcomes of DOAC use in a real-world AF and VTE population are consistent with the Phase III trials, despite some significant differences in baseline characteristics. However, a significantly increased rate of major bleeding was observed in the real-world VTE population, which requires further investigation. Table 1. Baseline demographic characteristics, efficacy and safety outcomes in the real-world population versus the trial population Atrial Fibrillation Venous Thromboembolism Trial population+N=28,342 Real-world population Trial population++ Real-world population N=365 N=8,716 N=383 Baseline Demographics, mean (SD) unless otherwise specified Age, years 72 (9.6) 76.8 * (12.1) 56.9 (14.2) 55.6 (18.7) Female (%) 10451 (36.9) 215 * (58.9) 3753 (43.1) 184 (48.0) Weight, kg 82.7 (19.5) 77.3 * (22.6) 84.9 (19.6) 88.2 * (23.0) Creatinine clearance, mL/min 69 (26.7) 58.1 * (26.9) 105.8 (40.7) 91.1 * (37.6) Concomitant aspirin therapy 10341 (36.5) 49 * (13.4) - 0 (0) Previous VKA use (%) 15711 (55.4) 193 (52.9) - 85 (22.2) Efficacy (%) All-cause mortality 1695 (6.0) 37 * (9.1) 160 (1.8) 10 (2.5) Stroke 676 (2.4) 8 (2.0) - 1 (0.3) VTE 39 (0.1) 1 (0.2) 192 (2.2) 7 (1.8) Safety (%) Major Bleeding 1419 (5.0) 17 (4.2) 79 (0.9) 15 * (3.8) Intracranial 170 (0.6) 1 (0.2) 6 (0.1) 2 * (0.5) Gastrointestinal 644 (2.3) 8 (2.0) 8 (0.1) 8 * (2.0) Non-major Clinically relevant (NMCR) bleeding 4824 (17.0) 30 * (7.4) 540 (6.2) 26 (6.6) Gastrointestinal - 9 (2.2) 53 (4.2) 10 (2.5) Urogenital 296 (4.2) 16 (3.9) 100 (2.5) 38 * (9.6) +Pooled data from ARISTOTLE, RE-LY and ROCKET-AF trials ++Pooled data from AMPLIFY, RE-COVER and EINSTEIN-PE/DVT trials *p<0.05 Disclosures Patel: Bayer plc: Research Funding. Auyeung:Bayer PLC: Research Funding. Arya:Bayer plc: Research Funding.

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Hepatitis C (HCV) Treatment and SVR: The Gap Between Clinical Trials and the Real-World

The American Journal of Gastroenterology ◽

10.14309/00000434-201410002-00418 ◽

2014 ◽

Vol 109 ◽

pp. S125

Author(s):

Madiha Tahir ◽

Fatima Alvi ◽

Imtiaz Alam

Keyword(s):

Clinical Trials ◽

Hepatitis C ◽

Real World ◽

Hcv Treatment ◽

The Real

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Survival among metastatic colorectal patients in clinical trials compared to the real world.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.673 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 673-673

Author(s):

Ziwei Wang ◽

Lindsay Hwang ◽

James Don Murphy

Keyword(s):

Colorectal Cancer ◽

Clinical Trial ◽

Clinical Trials ◽

Metastatic Colorectal Cancer ◽

Median Survival ◽

Real World ◽

Randomized Clinical Trials ◽

Phase Iii ◽

The Real ◽

Clinical Trial Results

673 Background: Randomized clinical trials play a central role in clinical research though only a small fraction of patients partake in clinical studies. Questions thus arise regarding the generalizability of clinical trial results to the remainder of the population. This study evaluated whether patient survival from randomized clinical trials in metastatic colorectal cancer reflects real world outcomes. Methods: A Pubmed search was used to identify randomized phase III clinical trials of first-line treatment for metastatic colorectal cancer published between 2005 and 2010. We excluded secondary or pooled analyses, second-line treatments, non-metastatic patients, non-English language, and non-randomized studies. Thirty-one clinical trials met these criteria, comprised of 79 distinct clinical trial arms. Overall survival among clinical trial patients was compared to metastatic colorectal cancer patients within the Surveillance, Epidemiology, and End Results (SEER) program. Within SEER, we restricted the analysis time-period and age of patients to match the enrollment period and age of patients within each individual clinical trial. Results: The clinical trials enrolled a total of 16,614 patients. Among all clinical trial arms the median survival ranged from 6.7-62 months, 1-year survival ranged from 30-97%, and 2-year survival ranged from 6-88%. Compared to SEER, the median survival was higher in 95% of the individual clinical trial arms by an average of 5.4 months (p<0.0001). The 1-year survival was higher in 94% of the clinical trial arms by an average of 16.7% (p<0.0001). The 2-year survival was higher in 71% of the clinical trial arms by an average of 7.2% (p<0.0001). Conclusions: This study found substantially improved survival among clinical trial participants compared to patients in the SEER database suggesting that survival estimates from clinical trials may not generalize to the “real world.” Potential patient factors such as differences in underlying comorbidity, performance status, disease burden, as well as variation in treatment could not be addressed in this study, though these factors likely explain some of the observed survival differences.

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MET meets the real world: design issues and clinical strategies in the Clinical Trials Network

Journal of Substance Abuse Treatment ◽

10.1016/s0740-5472(02)00255-6 ◽

2002 ◽

Vol 23 (2) ◽

pp. 73-80 ◽

Cited By ~ 53

Author(s):

Kathleen M. Carroll ◽

Chris Farentinos ◽

Samuel A. Ball ◽

Paul Crits-Christoph ◽

Bryce Libby ◽

...

Keyword(s):

Clinical Trials ◽

Real World ◽

Design Issues ◽

The Real ◽

Clinical Strategies

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The real-world outcomes of multiple myeloma patients treated with daratumumab

PLoS ONE ◽

10.1371/journal.pone.0258487 ◽

2021 ◽

Vol 16 (10) ◽

pp. e0258487

Author(s):

Agoston Gyula Szabo ◽

Tobias Wirenfeldt Klausen ◽

Mette Bøegh Levring ◽

Birgitte Preiss ◽

Carsten Helleberg ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Real World ◽

Randomized Clinical Trials ◽

Proteasome Inhibitors ◽

Median Number ◽

The Real ◽

Treatment Timing ◽

Risk Patients ◽

Standard Risk

Most patients cannot be included in randomized clinical trials. We report real-world outcomes of all Danish patients with multiple myeloma (MM) treated with daratumumab-based regimens until 1 January 2019. Methods Information of 635 patients treated with daratumumab was collected retrospectively and included lines of therapy (LOT), hematologic responses according to the International Myeloma Working Group recommendations, time to next treatment (TNT) and the cause of discontinuation of treatment. Baseline characteristics were acquired from the validated Danish Multiple Myeloma Registry (DMMR). Results Daratumumab was administrated as monotherapy (Da-mono) in 27.7%, in combination with immunomodulatory drugs (Da-IMiD) in 57.3%, in combination with proteasome inhibitors (Da-PI) in 11.2% and in other combinations (Da-other) in 3.8% of patients. The median number of lines of therapy given before daratumumab was 5 for Da-mono, 3 for Da-IMiD, 4 for Da-PI, and 2 for Da-other. In Da-mono, overall response rate (ORR) was 44.9% and median time to next treatment (mTNT) was 4.9 months. In Da-IMiD, ORR was 80.5%, and mTNT was 16.1 months. In Da-PI, OOR was 60.6% and mTNT was 5.3 months. In patients treated with Da-other, OOR was 54,2% and mTNT was 5.6 months. The use of daratumumab in early LOT was associated with longer TNT (p<0.0001). Patients with amplification 1q had outcome comparable to standard risk patients, while patients with t(4;14), t(14;16) or del17p had worse outcome (p = 0.0001). Multivariate analysis indicated that timing of treatment (timing of daratumumab in the sequence of all LOT that the patients received throughout the course of their disease) was the most important factor for outcome (p<0.0001). Conclusion The real-world outcomes of multiple myeloma patients treated with daratumumab are worse than the results of clinical trials. Outcomes achieved with daratumumab were best when daratumumab was used in combination with IMIDs and in early LOT. Patients with high-risk CA had worse outcomes, but patients with amp1q had similar outcomes to standard-risk patients.

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Effects of low-dose pirfenidone on survival and lung function decline in patients with idiopathic pulmonary fibrosis (IPF): Results from a real-world study

PLoS ONE ◽

10.1371/journal.pone.0261684 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0261684

Author(s):

Eung Gu Lee ◽

Tae-Hee Lee ◽

Yujin Hong ◽

Jiwon Ryoo ◽

Jung Won Heo ◽

...

Keyword(s):

Clinical Trials ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Pulmonary Function ◽

Real World ◽

Low Dose ◽

Randomized Clinical Trials ◽

Laboratory Data ◽

Unknown Etiology ◽

The Real

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia of unknown etiology. In several randomized clinical trials, and in the clinical practice, pirfenidone is used to effectively and safely treat IPF. However, sometimes it is difficult to use the dose of pirfenidone used in clinical trials. This study evaluated the effects of low-dose pirfenidone on IPF disease progression and patient survival in the real-world. Methods This retrospective, observational study enrolled IPF patients seen at the time of diagnosis at a single center from 2008 to 2018. Longitudinal clinical and laboratory data were prospectively collected. We compared the clinical characteristics, survival, and pulmonary function decline between patients treated and untreated with various dose of pirfenidone. Results Of 295 IPF patients, 100 (33.9%) received pirfenidone and 195 (66.1%) received no antifibrotic agent. Of the 100 patients who received pirfenidone, 24 (24%), 50 (50%), and 26 (26%), respectively, were given 600, 1200, and 1800 mg pirfenidone daily. The mean survival time was 57.03 ± 3.90 months in the no-antifibrotic drug group and 73.26 ± 7.87 months in the pirfenidone-treated group (p = 0.027). In the unadjusted analysis, the survival of the patients given pirfenidone was significantly better (hazard ratio [HR] = 0.69, 95% confidence interval [CI]: 0.48–0.99, p = 0.04). After adjusting for age, gender, body mass index, and the GAP score [based on gender (G), age (A), and two physiological lung parameters (P)], survival remained better in the patients given pirfenidone (HR = 0.56, 95% CI: 0.37–0.85, p = 0.006). In terms of pulmonary function, the decreases in forced vital capacity (%), forced expiratory volume in 1 s (%) and the diffusing capacity of lung for carbon monoxide (%) were significantly smaller (p = 0.000, p = 0.001, and p = 0.007, respectively) in patients given pirfenidone. Conclusions Low-dose pirfenidone provided beneficial effects on survival and pulmonary function decline in the real-world practice.

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An observational study «FOLLITROPIN» comparing the efficacy of follitropin alpha biosimilar: the real-world data

Obstetrics Gynecology and Reproduction ◽

10.17749/2313-7347/ob.gyn.rep.2021.212 ◽

2021 ◽

Vol 15 (1) ◽

pp. 5-21

Author(s):

D. P. Kamilova ◽

M. M. Ovchinnikova ◽

E. Sh. Ablyaeva ◽

M. M. Leviashvili ◽

N. S. Stuleva ◽

...

Keyword(s):

Clinical Trials ◽

Clinical Practice ◽

Observational Study ◽

Clinical Efficacy ◽

Real World ◽

Ovarian Stimulation ◽

Successful Implementation ◽

Efficacy And Safety ◽

The Real ◽

Real Clinical Practice

Introduction. The efficacy and safety of biosimilar follitropin alpha have been demonstrated in randomized blinded prospective clinical trials of phases I and III. Unfortunately, there is a gap between the clinical trials and real clinical practice data. The real-world patient data helps to create an evidence-based background for successful implementation of medicine at everyday practice in a nonselected population.Aim: to investigate the efficacy of follitropin alpha biosimilar therapy (Primapur®) in nonselected real-world population.Materials and Methods. A retrospective observational anonymized cohort study of follitropin alpha biosimilar (Primapur®) as a pre-filled pen injector with a dose adjustment of 5 IU, aimed to investigate its efficacy and safety in a nonselected population with indications to assisted reproductive technologies (ART) was carried out. The ovarian stimulation (OS) protocols included: monotherapy protocols with using only Primapur®; mixed protocols (recombinant and urinary-derived gonadotropins); short protocols with using antagonists of gonadotropin-releasing hormone (GnRH) and long protocols with GnRH agonists. The stimulation protocols were analyzed with Primapur® application for at least 5 days.Results. The overall clinical efficacy of ovarian stimulation cycles (N = 5484) was: oocytes retrieved - 9.5 ± 7.2, mature (MII) - 6.8 ± 6.6, fertilized (2PN) - 6.1 ± 5.8, clinical pregnancy per ET (PR) - 38.4 %. Mixed gonadotropin protocols (N = 2625) vs. monotherapy with Primapur® (N = 2859): oocytes retrieved - 8.6 ± 6.8 vs. 10.3 ± 7.4 (p < 0.001), mature (MII) - 6.7 ± 6.2 vs. 7.7 ± 6.9 (p < 0.001), fertilized (2PN) - 5.8 ± 5.2 vs. 7.2 ± 6.2 (p < 0.001). There were statistically significant differences between oocyte yields in mixed vs. monotherapy protocols due to subgroup differences, including age, body mass index (BMI) and IVF/ICSI attempts. No statistically significant differences were found for PR: 39.3 % vs. 37.6 % (p = 0.314). Monotherapy protocols with GnRH antagonist OS (N = 2183) vs. GnRH agonist (N = 676) revealed: oocytes retrieved - 10.5 ± 7.5 vs. 9.6 ± 7.0 (p = 0.032), mature (MII) - 7.6 ± 6.9 vs. 6.7 ± 5.7 (p < 0.001), fertilized (2PN) - 7.3 ± 6.3 vs. 5.7 ± 5.0 (p < 0.001). There were statistically significant differences between BMI and IVF/ICSI attempts. No statistically significant differences were found for PR: 37.9 % vs. 35.9 % (p = 0.482). All medicines were well tolerated and no serious adverse reactions were reported.Conclusion. This was the largest retrospective observational study conducted in the field of fertility in Russia and involved 5484 ovarian stimulation protocols at 35 IVF clinics. The obtained results demonstrated similar clinical efficacy for follitropin alpha biosimilar Primapur® in different OS protocols in real clinical practice.

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Impact of the COVID-19 pandemic on the oncologic activities (diagnosis, treatment, clinical trials enrollment) of a general hospital in a district with high prevalence of SARS-COV-2 in Italy

Supportive Care in Cancer ◽

10.1007/s00520-021-06667-y ◽

2022 ◽

Author(s):

Massimo Ambroggi ◽

Chiara Citterio ◽

Stefano Vecchia ◽

Alessandra Riva ◽

Patrizia Mordenti ◽

...

Keyword(s):

Clinical Trials ◽

Clinical Research ◽

Cancer Patients ◽

General Hospital ◽

Cancer Diagnosis ◽

Real World ◽

Oral Treatment ◽

The Real ◽

High Prevalence ◽

Research Studies

Abstract Purpose Little is known about the real impact of the COVID-19 outbreak on the qualitative and quantitative fall-out on the management of cancer patients. Our objective was to provide evidence of the effects of SARS-COV-2 on the management of cancer patients in the real world. Methods In a general hospital in a district in Italy with high prevalence of COVID-19 during the first wave, we retrospectively analyzed the data of oncologic activity, namely new cancer diagnosis, types of treatment (intravenous or by mouth), clinical research studies, and drug utilization, and compared the findings with those of 2019, before the pandemic. The data have been summarized in boxplot figures for median and interquartile range. Results In 2020, a significant reduction in new cancer diagnosis was demonstrated when compared with 2019, with 17.4% fewer cancer diagnoses, 84.5% fewer patients enrolled in clinical trials, a 10.6% reduction in intravenous antitumor treatment, and a 42.7% increase in oral anticancer treatment. Conclusion Our data indicate a significant reduction in cancer diagnosis, antitumor venous treatment, and patients enrolled in clinical research studies in 2020 compared with 2019, although there was a significant increase in oral treatment. These data suggest that the COVID-19 pandemic had a deep impact on the real-world management of cancer patients in a district of Italy with a high prevalence of COVID-19.

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