scholarly journals Underreporting of Symptomatic Adverse Events in Phase I Clinical Trials

2021 ◽  
Author(s):  
Zachary W Veitch ◽  
Daniel Shepshelovich ◽  
Christina Gallagher ◽  
Lisa Wang ◽  
Albiruni R Abdul Razak ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Survival Data ◽  
Reporting Rate ◽  
Phase I Trials ◽  
Phase I Clinical Trials ◽  
Best Response ◽  
Patient Reported ◽  
Limb Edema ◽  
Reporting Frequency

Abstract Background Clinician reporting of symptomatic adverse events (AEs) in phase I trials uses the Common Terminology Criteria for Adverse Events (CTCAE). The utility of the patient-reported outcomes (PROs) version of the CTCAE (PRO-CTCAE) in this setting is unknown. This prospective, observational study compared patient- and clinician-reported symptomatic AEs in phase I patients. Methods Phase I study–eligible patients at Princess Margaret were surveyed with the PRO-CTCAE full-item library (78 symptomatic AEs) at baseline (BL), mid-cycle 1, and mid-cycle 2 (C2). Patient and trial characteristics, best response, and survival data were collected. Presence or absence of patient- (PRO-CTCAE) or clinician-reported symptomatic AEs were compared (kappa) at defined timepoints and overall (BL+ mid-cycle 1 + C2). Results Of 292 patients approached from May 2017 to January 2019, a total of 265 (90.8%) were consented, with 243 (91.7%) evaluable and 552 PRO-CTCAE surveys (completion rate = 98.7%) included in analyses. Evaluation of overall patient-reported symptomatic AEs identified 50 PRO-CTCAE and 11 CTCAE items with 10% or greater reporting frequency. Nineteen CTCAE items were reported as 1% or less despite matched PRO-CTCAE items reporting as 10% or greater. Underreported categories included sexual health, bodily emissions, and cognition. Clinician- relative to patient-reporting frequency (ratio) demonstrated 9 symptomatic AEs with a 50-fold or more lower clinician reporting rate. Overall patient–clinician agreement for individual symptomatic AEs ranged from poor (κ = 0.00-0.19) to moderate (κ = 0.40-0.59), with discordance driven by lack of clinician reporting. Dyspnea (κ = 0.54) and peripheral neuropathy (κ = 0.63) at BL and limb edema (κ = 0.55) at C2 demonstrated the highest patient–clinician agreement. Conclusions Poor to moderate patient–clinician agreement for symptomatic AEs suggests clinician underreporting in phase I trials. Analyses of severity and interference PRO categories are ongoing.

A pilot study of the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) in a phase I clinical trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6587-6587 ◽  
Author(s):  
Rui Qin ◽  
Amylou C. Dueck ◽  
Daniel Satele ◽  
Julian R. Molina ◽  
Charles Erlichman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Pilot Study ◽  
Adverse Events ◽  
Phase I ◽  
Patient Reported Outcomes ◽  
Point Of View ◽  
Phase I Clinical Trial ◽  
Phase I Clinical Trials ◽  
Patient Reported

6587 Background: Recently the Patient-Reported Outcomes version of the CTCAE was developed to augment clinically graded adverse events with information reported directly by patients on clinical trials (Basch, 2009). The validation and potential application of PRO-CTCAE in phase I clinical trials are of great interest as toxicity is the primary endpoint. Methods: Selected PRO-CTCAE items (21 items measuring 12 symptomatic adverse events) corresponding to the major adverse events required to be graded clinically were collected in an ongoing phase I clinical trial of weekly cilengitide and paclitaxel in patients with advanced solid malignancies (NCT01276496). PRO-CTCAE was administered in a paper booklet by a clinical research associate prior to treatment on days 1, 8 and 15 of their regular visits. These PRO-CTCAE items were summarized descriptively in comparison to clinician-assessed CTCAE ver 4.0 (NCI, 2009) during the first cycle. As a pilot study to assess feasibility of PRO-CTCAE in phase I trials, PRO-CTCAE was not intended for determination of dose-limiting toxicity. Results: Twelve patients were accrued to two separate doses of cilengitide and paclitaxel. The median age was 56 (range 36—67) and half of patients were female. All patients had an ECOG performance score <= 1. Over 90% of patients had received prior surgery and chemotherapy. All but one patient completed weekly PRO-CTCAE during the first cycle, the only patient refused to complete weeks 2 and 3 did not give a reason. PRO-CTCAE captured most of the symptomatic adverse events reflected in clinician-assessed CTCAE. Some symptomatic adverse events were not reported clinically by CTCAE but were reported by patients by PRO-CTCAE. Overall, PRO-CTCAE items indicated slightly more severe degree of symptoms experienced by patients than those reported in CTCAE. Conclusions: This is the first study that PRO-CTCAE items were integrated within regular study visits in a phase I trial. The administration of PRO-CTCAE has been proved feasible and fruitful, providing consistent and enhanced symptomatic toxicity from the patient point of view. The addition of PRO-CTCAE did not significantly increase patient burden. Clinical trial information: NCT01276496.

Adverse Events

2020 ◽  
Author(s):  
Jill A. Fisher
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Healthy Volunteers ◽  
Social Inequalities ◽  
New Drugs ◽  
Phase I Trials ◽  
Phase I Clinical Trials ◽  
Racial Inequalities ◽  
Investigational Drugs ◽  
The Social

Phase I clinical trials test the safety and tolerability of new pharmaceuticals and typically pay healthy people to enroll as research participants. In addition to being exposed to the risks of taking investigational drugs, healthy volunteers are confined to residential research facilities for some portion of the clinical trial. Most healthy volunteers are African American and Hispanic men in their late twenties to early forties. Motivated by pervasive economic insecurity and racial discrimination, these individuals often enroll serially in Phase I trials to stay afloat or to get ahead. This book reveals not only the social inequalities on which Phase I trials rest, but also depicts the important validity concerns inherent in this mode of testing new pharmaceuticals. Healthy volunteers are enrolled in highly controlled studies that bear little resemblance to real-world conditions. Moreover, in these studies everyone—from the pharmaceutical companies sponsoring the studies, to the clinics conducting them, and the healthy volunteers paid to participate—is incentivized to game the system, with the effect that new drugs appear safer than they really are. Providing an unprecedented view of the intersection of US racial inequalities with pharmaceutical testing, Adverse Events calls attention to the dangers of this research enterprise to social justice and public health.

Immuno-oncology and the elderly: A comparative analysis of participation and toxicities of senior adults aged 65 years and above vs mid age and adolescent/young adult patients on immunotherapy-based phase I clinical trials.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10034-10034
Author(s):  
Ishwaria Mohan Subbiah ◽  
Kenneth R. Hess ◽  
Takeo Fujii ◽  
Anas Alshawa ◽  
Anna Lui ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Young Adult ◽  
Adverse Events ◽  
Phase I ◽  
Early Phase ◽  
Low Grade ◽  
Phase I Trials ◽  
High Grade ◽  
Senior Adults ◽  
Phase I Clinical Trials

10034 Background: Senior adults ≥ 65 yrs remain underrepresented in early phase clinical trials in particular trials with novel immunotherapies. One general limitation to enrollment is the concern for immune-related toxicities in the context of older age and comorbidities. We analyzed the enrollment and incidence of toxicities of seniors in comparison to mid age and adolescent/young adult (AYA) pts enrolled in phase 1 immunotherapy trials. Methods: We identified 422 consecutive pts w advanced cancer treated on immunotherapy-based phase I trials bw 04/2009-09/2015. We divided pts into 3 cohorts based on age at start of trial (AYA 15-39y, mid age 40-64y, seniors 65y+) and collected pt/disease characteristics and immune-related adverse events (irAE) including endocrinopathies, diarrhea/colitis, pneumonitis, constitutional (eg fatigue, fever, anorexia), myalgia, and dermatitis. Results: Of 422 patients treated, 116 were seniors (27%, median 70y), 50 AYA (12%, median 30y), 256 mid age (61%, median 56y). Most common cancers were GI (n = 108, 26%), thoracic/head/neck (n = 84, 20%), GU (n = 54, 13%), and GYN (n = 47, 11%). Median PFS was comparable in all 3 cohorts (2.4m seniors, 2.1m AYA, 2.1m mid age). The incidence of irAE was higher in elderly than mid age or AYA (low grade [G1/2] 49% vs 34% vs 34%, p 0.02; high grade [G3/4] 19% vs 11% vs 12%. p 0.14). When comparing irAE rates of seniors to AYA and mid age pts, the odds ratio of high grade events was 1.81 (95% CI 1.01, 3.24; p 0.05) and low grade events was 1.85 (95% CI 1.20, 2.85; p 0.0055). Most common G1/2 irAE among all cohorts was fatigue (n = 76, 18%), dermatitis (n = 59, 14%), fever (n = 29, 7%) and anorexia (n = 28, 7%) with seniors having a greater incidence of low grade fatigue (25% vs 15%, OR 1.84, 95% CI 1.09, 3.10, p 0.025). Conclusions: Senior adults accounted for < 1/3 of pts on immunotherapy-based phase I trials. When compared to mid age and AYA pts, seniors had a higher likelihood of experiencing a toxicity. Early phase immunotherapy trials may be an option for older adults but with a particular vigilance for adverse events in this population.

Integration of supportive care in immuno-oncology trials: Investigating the incidence and severity of immune-related toxicities among older adults versus mid-age patients on immunotherapy-based phase I clinical trials.

2017 ◽  
Vol 35 (31_suppl) ◽  
pp. 152-152
Author(s):  
Ishwaria Mohan Subbiah ◽  
Kenneth R. Hess ◽  
Takeo Fujii ◽  
Anna Lui ◽  
Vivek Subbiah ◽  
...  
Keyword(s):  
Older Adults ◽  
Clinical Trials ◽  
Adverse Events ◽  
Supportive Care ◽  
Phase I ◽  
Phase 1 ◽  
Low Grade ◽  
Phase I Trials ◽  
High Grade ◽  
Phase I Clinical Trials

152 Background: Older adults (65y+) with cancer are underrepresented in trials of novel drugs notably in phase I clinical trials with immunotherapies. The trepidation over immune-related toxicities in the context of older age and associated comorbidities may function as a barrier to participation. To that end, we investigated the enrollment and incidence of immune related adverse events of older adults enrolled in phase 1 immunotherapy trials. Methods: We identified 422 consecutive pts w advanced cancer treated on immunotherapy-based phase I trials bw 04/2009-09/2015, and collected pt/disease characteristics and immune-related adverse events (irAE) such as endocrinopathies, diarrhea/colitis, pneumonitis, constitutional (fatigue, fever, anorexia), myalgia, and dermatitis. Results: Older adults comprised 27% of trial participants (116 of 422 pts, median age 70y) while 256 pts were mid age (61%, median 56y). Most common cancers were GI (n = 108, 26%), thoracic/head/neck (n = 84, 20%), GU (n = 54, 13%), and GYN (n = 47, 11%). Median PFS was comparable among older pts (2.4m) and mid age (2.1m). Older adults had a higher incidence of irAE than mid age (low grade [G1/2] 49% vs 34%, p 0.02; high grade [G3/4] 19% vs 11%. p 0.14). The odds ratio of high grade events among older adults vs mid age pts was 1.81 (95% CI 1.01, 3.24; p 0.05) and low grade events was 1.85 (95% CI 1.20, 2.85; p 0.0055). Most common G1/2 irAE among all patients was fatigue (n = 76, 18%), dermatitis (n = 59, 14%), fever (n = 29, 7%) and anorexia (n = 28, 7%) with older adults having a greater incidence of low grade fatigue (25% vs 15%, OR 1.84, 95% CI 1.09, 3.10, p 0.025). Conclusions: Older adult participation remained under 30% for immunotherapy-based phase I trials. This early analysis suggests a higher incidence of toxicities among older adults, which calls for the urgent integration of comprehensive supportive care strategy to guide seniors through therapy. This work lays the foundation for future studies investigating the early involvement of supportive care through treatment on early phase clinical trials with immunotherapeutic agents.

Call to integrate supportive care and patient reported outcomes in early phase clinical trials: An exploration of adolescent and young adult (AYA) participation on phase I trials of novel anticancer agents.

2017 ◽  
Vol 35 (31_suppl) ◽  
pp. 149-149
Author(s):  
Ishwaria Mohan Subbiah ◽  
Chad Tang ◽  
Arvind Rao ◽  
Vivek Subbiah ◽  
Razelle Kurzrock ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Supportive Care ◽  
Phase I ◽  
Median Duration ◽  
Early Phase ◽  
Patient Reported Outcomes ◽  
Phase I Trials ◽  
Family Needs ◽  
Phase I Clinical Trials ◽  
Patient Reported

149 Background: Adolescent and young adults (AYA) aged 15-39 years with cancer represent a patient population with very unique needs extending into the psychosocial realm. Consequently AYA participation on cancer clinical trials has been dismally low in recent decades, particularly on early phase trials with investigational agents. In an effort to better understand AYAs with advanced cancer, we analyzed their characteristics and participation on phase I clinical trials. Methods: We queried a department database to identify 1489 consecutive pts treated on phase I trials bw Dec 2004-July 2013 and then divided into 2 age-based groups (AYA 15-39y, mid age 40-64y) for analysis of their baseline characteristics, participation, time to treatment failure (TTF), and imaging response. We then calculated the odds ratios of achieving a favorable clinical benefit (defined as a RECIST response of prolonged SD≥6m+PR+CR) for AYAs vs mid-age pts. Results: AYAs represented 15% (n = 220) of participants treated on phase I trials while 67% (n = 991) were middle age. Most AYAs were women (63% female, 33% male) w median age being 32.6 years and a median of 3 prior therapies. AYAs most commonly had GYN (n = 41, 19%), sarcoma (n = 39, 18%), GI (n = 35, 16%), thoracic/head/neck (n = 31, 14%), melanoma (n = 27, 12%), and breast (n = 20, 9%) cancers. AYA had a comparable median TTF of 3.3m to mid age pts (3.5m). Overall, 369 (37%) mid age and 96 (44%) AYAs received a non-FDA approved agent. Imaging responses among AYAs showed 93 (42%) SD including 42 (19%) prolonged SD (median duration 9.7m), 34 (15%) PR (median duration 9.5m), and 2 AYAs with a CR lasting 36.2m and 50.1m. Conclusions: AYA patients represented just 15% of phase I clinical trials participants; none of these trials measured patient reported outcomes or quality of life indices, highlighting an urgent need for comprehensive supportive care integration into AYA care to tend to the unique psychosocial, economic, and family needs of this population to ultimately identify and overcome barriers to clinical trial participation.

scholarly journals Using Patient-Reported Outcomes to Describe the Patient Experience on Phase I Clinical Trials

2020 ◽  
Vol 4 (6) ◽  
Author(s):  
Ramy Sedhom ◽  
Betty Ferrell ◽  
Nora Ruel ◽  
Marianna Koczywas ◽  
Vincent Chung ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Phase I ◽  
Correlation Coefficient ◽  
Patient Reported Outcomes ◽  
Pearson Correlation ◽  
Phase I Trials ◽  
Phase I Clinical Trials ◽  
Distress Level ◽  
Patient Reported

Abstract Background Symptoms are common among patients enrolled in phase I trials. We assessed the validity of Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) items in relation to previously validated assessments of quality of life and psychological distress. We used data from a randomized trial testing a palliative care support intervention for patients enrolled on phase I trials. Methods Patients (n = 479) were accrued to the parent study prior to initiating a phase I clinical trial with data collected at baseline, 4, and 12 weeks. We determined the correlation of PRO-CTCAE with distress level, Functional Assessment of Cancer Therapy - General (FACT-G) total, and subscale domain scores. Results Patients were predominantly female (56.8%) and older than age 60 years, and 30.7% were from minority populations. The correlation coefficient for distress level for all PRO-CTCAE items was small to moderate (Pearson r = 0.33-0.46). Pearson correlation coefficient for FACT-G total was moderate (r = -0.45 to -0.69). Stronger associations were noted for mood items of the PRO-CTCAE only (with distress level, r = 0.55-0.6; with FACT-G, r = -0.54 to -0.6). PRO-CTCAE symptom interference scores had the strongest correlation with distress level (Pearson r = 0.46) and FACT-G total (Pearson r = -0.69). Correlations between PRO-CTCAE items and corresponding FACT-G (total and subscales) and distress levels reached statistical significance for all items (P &lt;.001). Conclusion Evidence demonstrates validity of PRO-CTCAE in a heterogeneous US sample of patients undergoing cancer treatment on phase I trials, with small to moderate correlations with distress level for all PRO-CTCAE items and moderate correlations with quality of life as measured by FACT-G total.

Validity of patient-reported outcomes to describe the symptom experience of patients enrolled on phase I clinical trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 12107-12107
Author(s):  
Ramy Sedhom ◽  
Betty R. Ferrell ◽  
Nora Ruel ◽  
Marianna Koczywas ◽  
Vincent Chung ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Palliative Care ◽  
Phase I ◽  
Correlation Coefficient ◽  
Patient Reported Outcomes ◽  
Assessment Tools ◽  
Phase I Trials ◽  
Phase I Clinical Trials ◽  
Distress Level ◽  
Patient Reported

12107 Background: Symptoms are common among patients enrolled in phase I trials. To integrate the patient perspective, the National Cancer Institute developed a patient-reported outcomes version of the CTCAE (PRO-CTCAE) to capture symptomatic adverse events (AEs) directly from patients; however, the tool has not been used often in early phase trials or in palliative care studies. Our overall objective was to assess the validity of PRO-CTCAE items to previously validated assessments of quality of life (FACT-G) and psychological distress (Distress Thermometer). We utilized data from a randomized trial testing a palliative care intervention for patients with cancer enrolled on phase I trials. Methods: Patients (n = 481) were accrued to the parent study prior to initiating a Phase I clinical trial with data collected at baseline, 4, and 12 weeks. We determined the correlation of PRO-CTCAE with Distress Level, FACT-G total and subscale domain scores. Aggregate scores using PRO-CTCAE were calculated to explore the effect of overall symptom frequency, severity, and interference by calculating the total of all scored items classified within each of those domains. We used these metrics to identify associations between this and other validated tools. Results: Patients were predominantly female (56.8%), over age 60, and 30.7% were minority populations. Correlations between PRO-CTCAE items and corresponding FACT-G (total and subscales) and Distress levels reached statistical significance for all items (p < 0.001). Importantly, many of symptoms captured would have been missed using HRQOL assessment tools. Some of these symptoms affected nearly 50% of patients and were frequently rated as severe or very severe. The correlation coefficient for Distress Level for all PRO-CTCAE items was small to moderate (Pearson r = 0.33 to 0.46). Pearson’s correlation coefficient for FACT-G total was moderate ( r = -0.45 to -0.69). Mood items of the PRO-CTCAE had stronger associations (Pearson r > 0.5). PRO-CTCAE symptom interference scores had the strongest correlation with Distress (Pearson r = 0.46) and FACT-G Total (Pearson r = -0.69). Conclusions: Patients entering Phase I trials are willing to report on symptoms they experience as a result of advancing disease and adverse effects from experimental treatment. Evidence demonstrates favorable validity of PRO-CTCAE in a heterogeneous US sample of patients undergoing cancer treatment on phase I trials. The granular assessment of symptomatic AEs may be on increasing importance as we enter a new therapeutic era in oncology. Clinical trial information: NCT01828775 .

scholarly journals Healthy Volunteers’ Perceptions of the Benefits of Their Participation in Phase I Clinical Trials

2018 ◽  
Vol 13 (5) ◽  
pp. 494-510 ◽  
Author(s):  
Jill A. Fisher ◽  
Lisa McManus ◽  
Megan M. Wood ◽  
Marci D. Cottingham ◽  
Julianne M. Kalbaugh ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Healthy Volunteers ◽  
Employment Status ◽  
Qualitative Interviews ◽  
Trial Participation ◽  
Phase I Trials ◽  
Phase I Clinical Trials ◽  
Financial Compensation ◽  
Trial History

Other than the financial motivations for enrolling in Phase I trials, research on how healthy volunteers perceive the benefits of their trial participation is scant. Using qualitative interviews conducted with 178 U.S. healthy volunteers enrolled in Phase I trials, we investigated how participants described the benefits of their study involvement, including, but not limited to, the financial compensation, and we analyzed how these perceptions varied based on participants’ sociodemographic characteristics and clinical trial history. We found that participants detailed economic, societal, and noneconomic personal benefits. We also found differences in participants’ perceived benefits based on gender, age, ethnicity, educational attainment, employment status, and number of clinical trials completed. Our study indicates that many healthy volunteers believe they gain more than just the financial compensation when they accept the risks of Phase I participation.

scholarly journals Race and ethnicity representation in clinical trials: findings from a literature review of Phase I oncology trials

2021 ◽  
Author(s):  
D Ross Camidge ◽  
Haeseong Park ◽  
Karen E Smoyer ◽  
Ira Jacobs ◽  
Lauren J Lee ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Predominantly White ◽  
Race And Ethnicity ◽  
Phase I Trials ◽  
Minimal Representation ◽  
Phase I Clinical Trials ◽  
Demographic Representation ◽  
The Usa ◽  
Race Ethnicity

Aim: To provide an assessment of published literature on the demographic representation in Phase I trials of biopharmaceutical oncology agents. Materials & methods: We conducted a rapid evidence assessment to identify demographic representation reported in Phase I clinical trials for biopharmaceutical oncology agents published in 2019. Results: Globally, the population was predominantly White/Caucasian (62.2%). In the USA, the distribution was heavily skewed toward White/Caucasian (84.2%), with minimal representation of Blacks/African–Americans (7.3%), Asians (3.4%), Hispanics/Latinos (2.8%) or other race/ethnicity groups. Conclusion: Our data highlight that Phase I oncology trials do not reflect the population at large, which may perpetuate health disparities. Further research is needed to understand and address barriers to participation, particularly among under-represented groups

Non-Clinical Safety Evaluation and Adverse Events in Phase I Trials

2007 ◽  
pp. 75-84
Author(s):  
Patricia M. Reed ◽  
Stuart J. Mair ◽  
Stephen Freestone
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Safety Evaluation ◽  
Phase I Trials ◽  
Clinical Safety
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