scholarly journals Zelen design clinical trials: why, when, and how

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Gregory E. Simon ◽  
Susan M. Shortreed ◽  
Lynn L. DeBar
Keyword(s):  
Public Health ◽  
Clinical Trials ◽  
Usual Care ◽  
Real World ◽  
Randomized Clinical Trials ◽  
Specific Treatment ◽  
Health Benefit ◽  
Institutional Review Boards ◽  
Random Assignment ◽  
Engagement Interventions

Abstract Background In 1979, Marvin Zelen proposed a new design for randomized clinical trials intended to facilitate clinicians’ and patients’ participation. The defining innovation of Zelen’s proposal was random assignment of treatment prior to patient or participant consent. Following randomization, a participant would receive information and asked to consent to the assigned treatment. Methods This narrative review examined recent examples of Zelen design trials evaluating clinical and public health interventions. Results Zelen designs have often been applied to questions regarding real-world treatment or intervention effects under conditions of incomplete adherence. Examples include evaluating outreach or engagement interventions (especially for stigmatized conditions), evaluating treatments for which benefit may vary according to participant motivation, and situations when assignment to a control or usual care condition might prompt a disappointment effect. Specific practical considerations determine whether a Zelen design is scientifically appropriate or practicable. Zelen design trials usually depend on identifying participants automatically from existing records rather than by advertising, referral, or active recruitment. Assessments of baseline or prognostic characteristics usually depend on available records data rather than research-specific assessments. Because investigators must consider how exposure to treatments or interventions might bias ascertainment of outcomes, assessment of outcomes from routinely created records is often necessary. A Zelen design requires a waiver of the usual requirement for informed consent prior to random assignment of treatment. The Revised Common Rule includes specific criteria for such a waiver, and those criteria are most often met for evaluation of a low-risk and potentially beneficial intervention added to usual care. Investigators and Institutional Review Boards must also consider whether the scientific or public health benefit of a Zelen design trial outweighs the autonomy interests of potential participants. Analysis of Zelen trials compares outcomes according to original assignment, regardless of any refusal to accept or participate in the assigned treatment. Conclusions A Zelen design trial assesses the real-world consequences of a specific strategy to prompt or promote uptake of a specific treatment. While such trials are poorly suited to address explanatory or efficacy questions, they are often preferred for addressing pragmatic or policy questions.

scholarly journals Perceptions of Community Hematologists/Oncologists on Barriers to Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Diffuse Large B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2198-2198
Author(s):  
Ajeet Gajra ◽  
Richard Sweat ◽  
Yolaine Jeune-Smith ◽  
Jonathan K. Kish ◽  
Bruce A Feinberg
Keyword(s):  
Clinical Trials ◽  
B Cell ◽  
Annual Meeting ◽  
Real World ◽  
Randomized Clinical Trials ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
The United States ◽  
Large B Cell Lymphoma ◽  
Car T

Introduction The ASH Annual Meeting is a venue for presentation of outcomes data from key clinical trials in hematologic malignancies and novel drug classes used to treat them. The approval of two CAR-T therapies, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel), in the treatment of large B-cell lymphoma (LBCL), including diffuse LBCL (DLBCL), has ushered in a new class of drugs, i.e. cellular therapy. At ASH 2018, Nastoupil et al. presented data from a retrospective analysis of the characteristics and outcomes of patients with relapsed/refractory LBCL, including DLBCL, treated with commercially available axi-cel CAR-T therapy at academic centers in the United States (Nastoupil LJ, et al. Blood. 2018;132[Suppl 1]:91). The authors found that early outcomes of real-world patients receiving axi-cel therapy were comparable to those observed in the clinical trial population, despite >40% of these patients failing to meet the clinical trial eligibility criteria. At a live meeting in February 2019, we sought the perceptions of community hematologists and oncologists (H/O) regarding their use of, referrals for and barriers to CAR-T therapy as well their perception of the value of the real-world evidence (RWE) presented. Methods A live meeting in February 2019 convened H/O with geographic representation from across the United States. The participants were shown data from selected oral and/or poster presentations from the 2018 ASH Annual Meeting and responded to questions regarding their perceptions of the data and its potential impact on current practice. Participants submitted their demographic responses via a web-based survey prior to the meeting and data impression responses via an audience response system at the live meeting. Results Among the 59 H/O who participated in this live market research program on February 22-23, 2019, 61% identified their primary specialty as hematology/oncology and 34% medical oncology. Only 27% of H/O had attended the 60th ASH Annual Meeting in December 2018. The participants were mostly community-based physicians, 50% in private community and 45% in community practices owned by a hospital or academic center. One-third have been in practice for over 20 years, one-third for 11-20 years and one-third for 10 or fewer years. This group sees an average of 20+ patients per day and reported B-cell non-Hodgkin lymphoma as one of the three most common hematologic malignancy they managed. 28% of H/O indicated that they have referred one patient and 24% have referred 2-5 patients for CAR-T therapy since the first approval on August 30, 2017. Of those H/O who had referred patients for CAR-T therapy, 45% indicated that none of their patients had yet received the infusion. The top two barriers to prescribing/recommending CAR-T therapy, as reported by the H/O, were the cumbersome logistics of administering therapy and following patients (52%), and the cost of the therapy (46%). Other concerns included high toxicity (24%) and lack of long-term survival data (19%), but not lack of knowledge of CAR-T therapy (2%). Furthermore, 87% of H/O agreed with the assertion that due to the limitations of randomized clinical trials, RWE is necessary to inform clinical practice. After review of the information presented on the real-world use of axi-cel, 73% of H/O indicated that this information is likely to cause them to recommend CAR-T therapy for more of their patients with DLBCL. Conclusions There is significant interest in adopting and using CAR-T therapies in LBCL amongst community H/O. This group does not perceive itself as lacking in knowledge regarding CAR-T therapy. The significant barriers of logistics and cost are potential deterrents to appropriate use. These results can inform stakeholders (manufacturers, payers, hospitals and practices) regarding the need to improve processes and develop payment models to address cost in order to facilitate access of these agents to the appropriate patients. RWE is viewed favorably by the vast majority of community H/O to inform clinical practice, due to the limitations of randomized clinical trials. Disclosures Gajra: Cardinal Health: Employment. Sweat:Cardinal Health: Employment. Jeune-Smith:Cardinal Health: Employment. Kish:Cardinal Health: Employment. Feinberg:Cardinal Health: Employment.

Chromosome 1q Amplification Is Associated with a History of Prior Malignancies Among Patients Newly Diagnosed with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2193-2193
Author(s):  
Elizabeth B Lamont ◽  
Andrew J. Yee ◽  
Stuart L. Goldberg ◽  
Andrew D Norden
Keyword(s):  
Prostate Cancer ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Usual Care ◽  
Real World ◽  
Research Funding ◽  
Newly Diagnosed ◽  
History Of ◽  
Equity Ownership ◽  
Prior Malignancy

Background: Over the past 20 years, observational data from usual care clinical oncology settings has been leveraged to inform estimates of cancer treatment-associated benefits and risks among patients not treated on clinical trials. Increasing genomic testing to inform treatment decisions in usual care settings now meaningfully augments traditional observational data, positioning it to provide insights beyond clinical care into tumor biology. We studied patients with newly diagnosed multiple myeloma (MM), comparing cytogenetic test patterns according to history of prior malignancy. Methods: In this retrospective cohort study, we identified 2,380 patients from the COTA real-world database (RWD) who were newly diagnosed with MM in the years 2010-2018. The COTA RWD is a de-identified composite of both abstracted electronic health record and administrative data pertaining to patients receiving their cancer care at one of COTA's clinical oncology practice partners. Among these patients, 1769 (74%) had evidence of MM-associated cytogenetic testing with fluorescent in-situ hybridization (FISH) within the 120 days surrounding their date of diagnosis. The 1,769 patients form the analytic cohort. We compared patients' FISH results for t(4;14), deletion(17p), t(14;16), deletion(13), t(14;20), t(6;14), t(11;14), deletion (1p), and amplification(1q) according to their history of prior malignancy. Results: Within the cohort, 263 prior malignancies were identified in 241 patients (14%, 241/1,769). Two-hundred and twenty-one patients (92%) had one prior malignancy, 28 (7.9%) had two prior malignancies, and one (<1%) had four prior malignancies. The most common prior malignancies were prostate (n=50), breast (n=19), melanoma (n=14), skin (n=13), and cervix (n=6). Amplification of the long arm of chromosome one (amp(1q)) was noted in 31% of patients (75/241) with a prior malignancy vs. 24% of patients (370/1,528) without (chi2 test p=0.02). Overall 25% of patients had amp(1q). No other translocations, amplifications, deletions were associated with prior cancers. A non-parametric test for trend revealed a strong positive association between patients' malignancy count (range 0-4) and amp1q (p<0.01). MM patients with prior lymphomas and prior melanomas also had high rates of amp(1q), though these were not significantly different from patients without these prior malignancies. In a multivariable logistic regression model that adjusted for patient demographic attributes, other known potentially collinear MM poor prognostic factors (i.e., revised ISS stage, IgA sub-type, lambda light chains) and adjusted standard errors for clustering of patients within treatment settings, a history of prostate cancer remained clinically and statistically significantly positively associated with amp(1q) (OR 2.1, 95% CI: 1.9-2.2) as did history of two or more prior malignancies (OR 2.8, 95% CI: 2.3-3.3). Of note, amp(1q) was positively associated with IgA subtype (OR 1.5, 95% CI: 1.3-1.6) and the presence of lambda subtype (OR 1.3, 95%CI: 1.3-1.4). Conclusions: Using RWD, we found that newly diagnosed MM patients with histories of prostate cancer and those with two or more prior malignancies were more likely to have amp(1q), a poor prognostic marker in MM. Gains in 1q have previously been identified among patients with prostate and lymphoid cancers, but to our knowledge this is the first study to identify an association with a prior history of cancer, especially prostate cancer, and amp(1q) in MM. This relationship is worth further exploration of whether there is a common pathway associated with for example risk of prostate cancer and amp(1q) in MM. Clinical trials are less likely to answer this question as patients with prior malignancies are often excluded from enrollment. Overall, the results reported suggest that RWD is an efficient and comparatively inexpensive tool to support research in cancer biology through hypothesis generating and testing analyses of linked real-world phenotypic and genotypic data. Disclosures Lamont: COTA: Employment. Yee:Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; Adaptive: Consultancy; Amgen: Consultancy, Honoraria. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy. Norden:COTA: Employment, Equity Ownership.

Treatment-related toxicities in patients with squamous cell carcinoma of the head and neck (SCCHN)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e17041-e17041
Author(s):  
M. Ulcickas Yood ◽  
P. Feng Wang ◽  
S. Hensley Alford ◽  
S. Oliveria ◽  
K. Wells ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Clinical Trials ◽  
Clinical Practice ◽  
Health System ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Medical Record ◽  
Squamous Cell ◽  
Real World ◽  
Randomized Clinical Trials

e17041 Background: Although treatment effects and toxicities have been reported from randomized clinical trials of patients with squamous cell carcinoma of the head and neck (SCCHN), little information is available from real-world clinical practice where heterogeneous treatment patterns and patient populations may lead to different estimates than those observed in clinical trials. Methods: Using a population-based tumor registry at a large, Midwestern integrated health system, we identified all cases of stage III or IV SCCHN diagnosed 2000–2006. The incidence/severity of acute and late toxicities associated with SCCHN treatment was obtained from detailed medical record review of health system encounters, including physician notes. Grading of toxicities (using CTCAE3 criteria), distinction between acute and late toxicity, and analyses by treatment are ongoing. The incidence and severity of toxicities will be presented by treatment regimen, tumor location and tumor stage. We presented here an interim analysis. Results: Among the target population of 194 patients that will ultimately be included in this study, 137 medical record reviews have been completed to date. The percentages of patients with toxicities, including 95% confidence intervals are presented in the table , below. Conclusions: Toxicity in patients with advanced SCCHN is common. Data from clinical practice quantifying the incidence are lacking, these data from an observational real-world study provide important baseline information on the incidence of toxicities in patients with advanced SCCHN and also call for safer effective treatment for SCCHN. [Table: see text] [Table: see text]

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

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.

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

PLoS ONE ◽  
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.

scholarly journals 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 ◽  
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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