scholarly journals Are Quality of Randomized Clinical Trials and ESMO-Magnitude of Clinical Benefit Scale Two Sides of the Same Coin, to Grade Recommendations for Drug Approval?

2021 ◽  
Vol 10 (4) ◽  
pp. 746
Author(s):  
Adela Rodriguez ◽  
Francis Esposito ◽  
Helena Oliveres ◽  
Ferran Torres ◽  
Joan Maurel
Keyword(s):  
Clinical Trials ◽  
Clinical Benefit ◽  
Randomized Clinical Trials ◽  
Progression Free Survival ◽  
Drug Approval ◽  
New Drugs ◽  
Phase Iii ◽  
European Medicines Agency ◽  
Clinical Benefits

The approval of a new drug for cancer treatment by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) is based on positive, well-designed randomized phase III clinical trials (RCTs). However, not all of them are analyzed to support the recommendations. For this reason, there are different scales to quantify and evaluate the quality of RCTs and the magnitude of the clinical benefits of new drugs for treating solid tumors. In this review, we discuss the value of the progression-free survival (PFS) as an endpoint in RCTs and the concordance between it and the overall survival (OS) as a measure of the quality of clinical trial designs. We summarize and analyze the different scales to evaluate the clinical benefits of new drugs such as the The American Society of Clinical Oncology value framework (ASCO-VF-NHB16) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the concordance between them, focusing on metastatic colorectal cancer (mCRC). We propose several definitions that would help to evaluate the quality of RCT, the magnitude of clinical benefit and the appropriate approval of new drugs in oncology.

scholarly journals Blinded Independent Central Review of Progression-Free Survival in Phase III Clinical Trials: Important Design Element or Unnecessary Expense?

2008 ◽  
Vol 26 (22) ◽  
pp. 3791-3796 ◽  
Author(s):  
Lori E. Dodd ◽  
Edward L. Korn ◽  
Boris Freidlin ◽  
C. Carl Jaffe ◽  
Lawrence V. Rubinstein ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Treatment Effectiveness ◽  
Progression Free Survival ◽  
Informative Censoring ◽  
Phase Iii ◽  
General Strategy ◽  
Design Element ◽  
Free Survival ◽  
Using Data

Progression-free survival is an important end point in advanced disease settings. Blinded independent central review (BICR) of progression in randomized clinical trials has been advocated to control bias that might result from errors in progression assessments. However, although BICR lessens some potential biases, it does not remove all biases from evaluations of treatment effectiveness. In fact, as typically conducted, BICRs may introduce bias because of informative censoring, which results from having to censor unconfirmed locally determined progressions. In this article, we discuss the rationale for BICR and different ways of implementing independent review. We discuss the limitations of these approaches and review published trials that report implementing BICR. We demonstrate the existence of informative censoring using data from a randomized phase II trial. We conclude that double-blinded trials with consistent application of measurement criteria are the best means of ensuring unbiased trial results. When such designs are not practical, BICR is not recommended as a general strategy for reducing bias. However, BICR may be useful as an auditing tool to assess the reliability of marginally positive results.

Lenalidomide (L) in Combination with Dexamethasone (D) Improves Survival and Time to Progression in Elderly Patients (pts) with Relapsed or Refractory (rel/ref) Multiple Myeloma (MM).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3551-3551 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Donna Weber ◽  
Meletius Dimopoulos ◽  
Christine Chen ◽  
Reuben Niesvizky ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Median Time ◽  
Clinical Benefit ◽  
Randomized Clinical Trials ◽  
The Elderly ◽  
Elderly Group ◽  
Phase Iii ◽  
Time To Progression ◽  
Overall Response

Abstract Introduction: Treatment of elderly pts (age >65 years) with rel/ref MM remains a challenge due to concurrent comorbid conditions and poor tolerability to chemotherapy limiting therapeutic options. Recently, 2 phase III randomized clinical trials (MM-090 and MM-010) demonstrated superiority of the LD combination over D alone in previously treated MM pts. We examined the clinical benefit of LD combination in elderly pts enrolled in these 2 clinical trials. Methods: This is a retrospective data analysis of pts enrolled on the MM-090 and MM-010. All elderly pts (>65 years) were identified and parameters of clinical outcome (overall response, OR; time to progression, TTP; overall survival, OS) recorded. To determine the clinical benefit of L in elderly pt population, we compared the group of elderly pts who received LD combination with those who received D + placebo as well as with the group of younger pts who received the LD combination in these studies. Results: Collectively, 704 pts were enrolled with 285 identified as elderly. In the elderly group, 146 pts were randomized to LD combination and 139 to D + placebo. There were no significant differences in baseline characteristics of these two groups. In the elderly group who received LD, median time from diagnosis was 3.3 yrs (range 0.5–14.7) and 77.4% had received ≥ 2 prior therapies (prior D and/or thalidomide in 69% and 32% respectively). Using the Blade criteria, the overall response (ORR) was significantly better in pts on combination treatment vs. D alone (58.9% vs. 20.9%; p<0.001). On an intent-to-treat analysis, the median time to progression (TTP; primary endpoint) for pts treated with D alone was 20 vs. 60 wks on combination (p<0.001) and the median overall survival was 79 wks and has not been reached (p=<0.001) in the combination group, respectively. We then compared the elderly pts with the younger pts who received LD combination. The ORR and median TTP was (58.9% vs. 60.9%) and (60 wks vs. 47.3 wks), respectively. The OS was 128 wks in the younger pts and is not reached in the elderly. Conclusion: L when combined with D improves ORR, prolongs TTP and OS in elderly pts with rel/ref MM and thus offers an important treatment option for this pt population. This clinical benefit of L achieved in the elderly is comparable to that in the younger pts and thus is irrespective of age of the pt treated. The availability of L as an oral formulation provides an added benefit in the management of elderly pts population.

Are surrogate endpoints unbiased metrics compared to hazard ratio for death? An evaluation of clinical benefit scores (CBS) in the American Society of Clinical Oncology (ASCO) value framework.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6600-6600
Author(s):  
Mahin Iqbal Qureshi ◽  
Matthew C. Cheung ◽  
Sierra Cheng ◽  
Di Maria Jiang ◽  
Erica McDonald ◽  
...  
Keyword(s):  
Clinical Oncology ◽  
Clinical Benefit ◽  
Randomized Clinical Trials ◽  
Health Benefit ◽  
Progression Free Survival ◽  
Absolute Error ◽  
Hazard Ratio ◽  
European Medicines Agency ◽  
Average Deviation ◽  
American Society

6600 Background: Clinical benefit scores (CBS) are a key element of the American Society of Clinical Oncology (ASCO) value framework's Net Health Benefit valuation of cancer therapies. CBS are assigned based on a hierarchy of efficacy endpoints, from hazard ratio for death (HR OS), to median overall survival (mOS), HR for disease progression (HR PFS), median progression-free survival (mPFS), and response rate (RR). When HR OS is unavailable, other endpoints in the hierarchy are used as "surrogates" to calculate CBS via their scaling factors. We aim to examine whether surrogate-derived CBS offer unbiased scoring of clinical benefit compared to HR OS-derived CBS. Methods: CBS for advanced-disease settings were computed for randomized clinical trials (RCTs) of oncology drug approvals by the Food and Drug Administration, European Medicines Agency, and Health Canada, between 2006 and August 2015. Spearman's correlation assessed association between CBS derived from surrogates and HR OS. Mean bias (surrogate-derived CBS minus HR OS-derived CBS) evaluated the tendency for surrogate-derived CBS to over- or under- estimate clinical benefit. Mean absolute error (MAE), a measure of average deviation, assessed precision of surrogate-derived CBS in relation to HR OS-derived CBS. Results: Scored RCTs (n=104) yielded 69, 93, 88, and 89 paired CBS between HR OS and mOS, HR PFS, mPFS, and RR, respectively. See table for results. Restricting to RCTs reporting all endpoints (n=59) and RCTs without OS as primary endpoint (n=68) showed similar results. Conclusions: Findings suggest HR PFS-, mPFS-, and RR-derived CBS are poor "surrogates" as they are imprecise and weakly correlated to HR OS-derived CBS. HR PFS and particularly mPFS exhibit bias to overestimate CBS. [Table: see text]

Effect of subsequent chemotherapy on overall survival in first-line chemotherapy with targeted agents for patients with metastatic colorectal cancer: Systematic review and meta-analysis of randomized control trials.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 782-782
Author(s):  
Daisuke Sakai ◽  
Toshihiro Kudo ◽  
Aya Kato ◽  
Toshinori Sueda ◽  
Hidekazu Takahashi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Randomized Clinical Trials ◽  
Progression Free Survival ◽  
Cytotoxic Agents ◽  
Phase Iii ◽  
First Line ◽  
Line Chemotherapy

782 Background: One of recent standard first line chemotherapies for metastatic colorectal cancer is doublet of cytotoxic agents, fluorouracil and oxaliplatin or irinotecan, in combination with target agent, bevacizumab, or anti-EGFR antibody as cetuximab or panitumumab for KRAS or RAS wild type (WT). In this decade, nevertheless progression free survival (PFS) of clinical trials was little improved, overall survival (OS) had been increased. Methods: We analyzed data from 14 recently published phase III randomized clinical trials in mCRC to correlate the percentage of patients receiving subsequent chemotherapy with the reported OS. Results: Median PFS and OS were 10.3 and 25.0 months, respectively. In all comer trials, median OS is significantly correlated with the percentage of patients who received subsequent chemotherapy after first line chemotherapy of their disease [regression coefficient (R2) = 0.85 p = 0.0018]. In trials with KRAS WT, a correlation between OS and the rate of subsequent therapy was modest [r2 = 0.605, p = 0.0637]. Median PFS and RR were not correlated with median OS. Conclusions: Our results support the strategy of making salvage chemotherapy available to all patients with advanced CRC to maximize OS. In addition, our findings suggest that, with the availability of effective salvage options, PFS might no longer be regarded as the appropriate surrogate end point of OS by which to assess the efficacy of a palliative first-line treatment in CRC.

Progression-Free Survival Rate As Primary End Point for Phase II Cancer Clinical Trials: Application to Mesothelioma—The EORTC Lung Cancer Group

2006 ◽  
Vol 24 (19) ◽  
pp. 3007-3012 ◽  
Author(s):  
Julie Francart ◽  
Catherine Legrand ◽  
Richard Sylvester ◽  
Martine Van Glabbeke ◽  
Jan P. van Meerbeeck ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Survival Rate ◽  
Phase Ii ◽  
Progression Free Survival ◽  
New Drugs ◽  
Phase Iii ◽  
Cancer Clinical Trials ◽  
Phase Ii Trials ◽  
Free Survival ◽  
End Point

Purpose Phase II cancer clinical trials play a key role in the development of new drugs. These trials should be designed to accurately determine if the drug should be abandoned or if it is sufficiently promising for further investigation in phase III trials. With new cytostatic agents or when the response assessment is difficult, using the progression-free survival rate (PFSR) at a fixed time point, such as 3, 4, 5, or 6 months, instead of the response rate (RR) as the primary end point is an alternative approach. To design future phase II trials, reference values for PFSRs that correspond to drugs with insufficient (P0) and sufficient (P1) clinical activity (CA) are necessary. This article provides these values in mesothelioma. Materials and Methods The European Organisation for Research and Treatment of Cancer database registered ten closed mesothelioma trials (nine phase II trials and one phase III trial) with 523 total patients. Trials were grouped into three categories according to the published RR: significant (n = 259), moderate (n = 142), and insufficient (n = 122) CA. Results The PFSRs at 3, 4, 5, and 6 months, respectively, were as follows: 72%, 67%, 51%, and 43% in the group with significant CA; 59%, 51%, 42%, and 35% with moderate CA; and 52%, 40%, 34%, and 28% with insufficient CA. Conclusion These values may be used to define relevant P0 and P1 values in future phase II mesothelioma trials that use PFSR as the primary end point.

scholarly journals New approved drugs for psoriatic arthritis

Reumatismo ◽  
2016 ◽  
Vol 68 (2) ◽  
pp. 57 ◽  
Author(s):  
F.M. Perrotta ◽  
E. Lubrano
Keyword(s):  
Clinical Trials ◽  
Psoriatic Arthritis ◽  
Structural Damage ◽  
Randomized Clinical Trials ◽  
Poor Quality ◽  
Chronic Inflammatory Disease ◽  
New Drugs ◽  
Approved Drugs ◽  
Symptoms And Signs

Psoriatic arthritis (PsA) is a chronic inflammatory disease that possibly leads to structural damage and to a reduction of joint function and poor quality of life. Treatment of PsA has changed since its introduction of anti- TNF drugs, which have shown to reduce the symptoms and signs of the disease and slow the radiographic progression. However, recently, the discovery of new pathogenic mechanisms have made possible the development of new molecules that target pro-inflammatory cytokines involved in skin, joint and entheseal inflammation. New drugs like ustekinumab, secukinumab and apremilast inhibit interleukin axis and intracellular pathways and showed their efficacy and safety in randomized clinical trials. These drugs have been recently approved for the treatment of PsA and included in the new EULAR and GRAPPA treatment recommendations. The aim of this paper is to briefly review the clinical trials that led to their approval for PsA.

scholarly journals Impact of Value Frameworks on the Magnitude of Clinical Benefit: Evaluating a Decade of Randomized Trials for Systemic Therapy in Solid Malignancies

2021 ◽  
Vol 28 (6) ◽  
pp. 4894-4928
Author(s):  
Ellen Cusano ◽  
Chelsea Wong ◽  
Eddy Taguedong ◽  
Marcus Vaska ◽  
Tasnima Abedin ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Benefit ◽  
Randomized Clinical Trials ◽  
Rapid Development ◽  
Progression Free Survival ◽  
Cancer Therapies ◽  
Primary Endpoints ◽  
Solid Malignancies ◽  
American Society ◽  
The Impact

In the era of rapid development of new, expensive cancer therapies, value frameworks have been developed to quantify clinical benefit (CB). We assessed the evolution of CB since the 2015 introduction of The American Society of Clinical Oncology and The European Society of Medical Oncology value frameworks. Randomized clinical trials (RCTs) assessing systemic therapies for solid malignancies from 2010 to 2020 were evaluated and CB (Δ) in 2010–2014 (pre-value frameworks (PRE)) were compared to 2015–2020 (POST) for overall survival (OS), progression-free survival (PFS), response rate (RR), and quality of life (QoL). In the 485 studies analyzed (12% PRE and 88% POST), the most common primary endpoint was PFS (49%), followed by OS (20%), RR (12%), and QoL (6%), with a significant increase in OS and decrease in RR as primary endpoints in the POST era (p = 0.011). Multivariable analyses revealed significant improvement in ΔOS POST (OR 2.86, 95% CI 0.46 to 5.26, p = 0.02) while controlling for other variables. After the development of value frameworks, median ΔOS improved minimally. The impact of value frameworks has yet to be fully realized in RCTs. Efforts to include endpoints shown to impact value, such as QoL, into clinical trials are warranted.

Quality of reports related to survival events in randomized clinical trials: A review of recent cancer trials published in eight major journals

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6611-6611
Author(s):  
S. Mathoulin-Pelissier ◽  
S. Gourgou-Bourgade ◽  
F. Bonnetain ◽  
A. Kramar
Keyword(s):  
At Risk ◽  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Relevant Information ◽  
Consort Statement ◽  
Phase Iii ◽  
Accurate Information ◽  
Survival Endpoints ◽  
Adequate Definition

6611 Background: About ten years ago, Altman pointed the low quality of survival analyses published in cancer journals. Despite the development of Consort statement, the lack of quality standards remained in the reports of randomized clinical trials (RCT).The aim of this study was to evaluate quality of definitions and reports of survival endpoints in recent cancer RCTs. Methods: A computerized search in Medline databases identified 274 cancer RCTs published from January 2004 to December 2004 in 4 general medical journals (BMJ, JAMA, Lancet, NEJM) and 4 clinical oncology journals (BJC, Cancer, JCO, JNCI). Eligible papers were these that reported primary analyses of RCT with survival endpoints. Three methodologists have reviewed and scored 1/3 of papers according to 7 key points: prevalence of adequate definition of survival end-points (time to origin, survival events, censures) and relevant information about their analyses (Kaplan-meier method, confidence interval, number of events, patients at risk). Reliability of scoring was checked among a random subsample of 30 papers with an independent biostatistician (kappa coefficient). Results: Following eligibility screening, 149 papers were not included. Among the 125 selected papers, 104 trials were of phase III (83%) and 98 publications (78%) were obtained from the 4 oncology journals. Among these RCTs, a total of 268 survivals endpoints were recorded and overall survival (OS) was the most frequent outcome (118 terms, 44%). Survival terms were adequately defined in 116 endpoints (43%) and OS was most frequent adequately defined (49%). Accurate information about analysis was found in 51 endpoints (19%). The less adequate information was patient's number at risk (55%). Finally, according to the 7 key methodological points, optimal quality of report was found in 19 of the endpoints (7 %) i.e.6 articles (kappa value: 0.65). Conclusions: Majority of published papers failed to provide an adequate definition and analysis reports of survival endpoints. Finally survival definitions add another source of variability actually not controlled. Readers should critically pay attention to the reported definitions since the lack of these elements may lead to misinterpretation of the RCT results. No significant financial relationships to disclose.

Gender-based disparities in clinical trials supporting FDA approval of oncology drugs.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2058-2058
Author(s):  
Marjorie Zettler ◽  
Bruce A. Feinberg ◽  
Jonathan Kish ◽  
Ajeet Gajra
Keyword(s):  
Clinical Trials ◽  
Prevalence Ratio ◽  
Drug Approval ◽  
Gender Disparity ◽  
New Drugs ◽  
Phase Iii ◽  
Gender Representation ◽  
Gender Distribution ◽  
Representation Of Women ◽  
Prescribing Information

2058 Background: Adequate gender representation in clinical trials of new drugs is critical in order to accurately detect possible differences in response and toxicity (Özdemir et al, JCO 2018). The under-representation of women in oncology clinical trials has been previously described, however data on registrational trials, which are the basis for drug approval and inform the prescribing information, is lacking. We conducted an analysis of the trials supporting Food and Drug Administration approval of oncology drugs over a 5-year period to evaluate the representation of women vs. men. Methods: Prescribing information for novel new drugs approved from 2014-2018 was reviewed for the proportions of men and women in the evaluable population of the supporting clinical trials. Sex-specific cancers were excluded. Prevalence estimates for the indications were obtained from the Surveillance, Epidemiology and End Results database and the published literature. A participation to prevalence ratio (PPR) was calculated for each trial by dividing the percentage of women in the trial by the percentage of women in the disease population. A PPR value closer to unity represents even gender distribution and the range 0.8-1.2 is considered to reflect an acceptable representation of women. Data are presented using descriptive statistics. Results: A total of 46 oncology drugs were approved based on 56 trials enrolling 13,862 patients (7941 [57%] men; 5,921 [43%] women). Of the 56 trials, 38 (68%) had a PPR within the 0.8-1.2 range, 15 (27%) fell between 0.4-0.7, and 3 (5%) had a PPR of 1.3. The proportion of trials with unbalanced gender representation was comparable for hematological malignancy and solid tumor indications and did not improve over time. Fewer unbalanced trials were Phase III or employed a randomized design. Nine of the 18 (50%) unbalanced trials enrolled <100 subjects, compared to 3 of the 38 (8%) balanced trials. Conclusions: A third of registrational trials for oncology drugs lacked balanced gender distribution. Of the trials lacking balance, the vast majority (80%) had under-representation of women. Phase I-II trials and smaller trials had greater gender disparity, a concerning finding in a precision medicine environment where an increasing number of registration trials have double digit accrual. Further research is needed to understand the implications of unbalanced gender accrual in registrational trials, and to develop strategies for preventing disparities.

End Points and Trial Design in Geriatric Oncology Research: A Joint European Organisation for Research and Treatment of Cancer–Alliance for Clinical Trials in Oncology–International Society of Geriatric Oncology Position Article

2013 ◽  
Vol 31 (29) ◽  
pp. 3711-3718 ◽  
Author(s):  
Hans Wildiers ◽  
Murielle Mauer ◽  
Athanasios Pallis ◽  
Arti Hurria ◽  
Supriya G. Mohile ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Geriatric Oncology ◽  
New Drugs ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Global Functioning ◽  
End Points ◽  
Advantages And Disadvantages ◽  
Oncology Research

Selecting the most appropriate end points for clinical trials is important to assess the value of new treatment strategies. Well-established end points for clinical research exist in oncology but may not be as relevant to the older cancer population because of competing risks of death and potentially increased impact of therapy on global functioning and quality of life. This article discusses specific clinical end points and their advantages and disadvantages for older individuals.Randomized or single-arm phase II trials can provide insight into the range of efficacy and toxicity in older populations but ideally need to be confirmed in phase III trials, which are unfortunately often hindered by the severe heterogeneity of the older cancer population, difficulties with selection bias depending on inclusion criteria, physician perception, and barriers in willingness to participate. All clinical trials in oncology should be without an upper age limit to allow entry of eligible older adults. In settings where so-called standard therapy is not feasible, specific trials for older patients with cancer might be required, integrating meaningful measures of outcome. Not all questions can be answered in randomized clinical trials, and large observational cohort studies or registries within the community setting should be established (preferably in parallel to randomized trials) so that treatment patterns across different settings can be compared with impact on outcome. Obligatory integration of a comparable form of geriatric assessment is recommended in future studies, and regulatory organizations such as the European Medicines Agency and US Food and Drug Administration should require adequate collection of data on efficacy and toxicity of new drugs in fit and frail elderly subpopulations.

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