scholarly journals Associations With Definitive Outcomes and Clinical Benefit of Cancer Drugs at the Time of Marketing Approval and in the Postmarketing Period

2021 ◽  
pp. 1-9
Author(s):  
Aida Bujosa ◽  
Consolación Moltó ◽  
Thomas J. Hwang ◽  
José Carlos Tapia ◽  
Kerstin N. Vokinger ◽  
...  
Keyword(s):  
Anticancer Drugs ◽  
Clinical Benefit ◽  
Checkpoint Inhibitors ◽  
Marketing Approval ◽  
Substantial Benefit ◽  
Level Data ◽  
Substantial Clinical Benefit ◽  
Surrogate Measures

Background: Most anticancer drugs are approved by regulatory agencies based on surrogate measures. This article explores the variables associated with overall survival (OS), quality of life (QoL), and substantial clinical benefit among anticancer drugs at the time of approval and in the postmarketing period. Methods: Anticancer drugs approved by the FDA between January 2006 and December 2015 and with postmarketing follow-up until April 2019 were identified. We evaluated trial-level data supporting approval and any updated OS and/or QoL data. We applied the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the ASCO Value Framework (ASCO-VF) to initial and follow-up studies. Results: We found that 58 drugs were approved for 96 indications based on 96 trials. At registration, approval was based on improved OS in 39 trials (41%) and improved QoL in 16 of 45 indications (36%). Postmarketing data showed an improvement in OS for 28 of 59 trials (47%) and in QoL for 22 of 48 indications (46%). At the time of approval, 25 of 94 (27%) and 26 of 80 scorable trials (33%) met substantial benefit thresholds using the ESMO-MCBS and ASCO-VF, respectively. In the postmarketing period, 37 of 69 (54%) and 35 of 65 (54%) trials met the substantial benefit thresholds. Drugs with companion diagnostics and immune checkpoint inhibitors were associated significantly with substantial clinical benefit. Conclusions: Compared with the time of approval, more anticancer drugs showed improved OS and QoL and met the ESMO-MCBS or ASCO-VF thresholds for substantial benefit over the course of postmarketing time. However, only approximately half of the trials met the threshold for substantial benefit. Companion diagnostic drugs and immunotherapy seemed to be associated with greater clinical benefit.

Factors associated with change in the magnitude of clinical benefit of anti-cancer drugs in the post-marketing period.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7052-7052
Author(s):  
Aida Bujosa Rodríguez ◽  
Consolacion Molto ◽  
Thomas J Hwang ◽  
Kerstin Noëlle Vokinger ◽  
Jose Carlos Tapia ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Multivariable Analysis ◽  
Drug Approval ◽  
Cancer Drug ◽  
Marketing Approval ◽  
Cancer Drugs ◽  
Companion Diagnostics ◽  
Substantial Clinical Benefit ◽  
Post Marketing

7052 Background: Initial drug approval is often based on surrogate endpoints. Definitive outcomes like Overall Survival (OS) or Quality of life (QoL) may not be available. Here, we evaluate changes in the magnitude of clinical benefit using the American Society of Clinical Oncology Value Framework (ASCO-VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) comparing the time of approval to the most recent available data for cancer drugs approved by the US Food and Drug Administration (FDA) between 2006 and 2015. Methods: We examined data on trials supporting FDA accelerated (AA) and regular (RA) cancer drug approvals between January 2006 and December 2015. We performed a systematic search of Pubmed and ClinicalTrials.gov to identify updated OS and/or QoL data, with follow up through April 2019. For AA drugs we analysed initial and confirmatory trials as follow-up. ASCO-VF and ESMO-MCBS grades were applied for trials at approval and after marketing. We explored variables associated with improved clinical benefit scores using multivariable logistic regression. Results: We identified 102 trials supporting the approval of 59 drugs for 96 solid tumour indications. Of these indications, 22 (23%) were granted AA and 21 (95%) were converted to RA. At time of approval, 38% of trials showed improved OS and 17% improved QoL. Substantial clinical benefit was observed in 26% of initial approval trials using ESMO-MCSB and in 34% using ASCO-VF. After a median post-marketing period of 3.3 years, updated results changed substantial clinical benefit in 20 trials with ESMO-MCBS (19 upgrades, 1 downgrade) and in 23 trials using ASCO-VF (19 upgrades, 4 downgrades). For 25% of trials no updated information was found. In the palliative setting, multivariable analysis showed association between improved ASCO-VF scores and initial approvals based on single-arm trials (OR 9.21, 95%CI 1.36-62.29, P=0.023), drugs with companion diagnostics (OR 4.95, 95%CI 1.01-24.22, P=0.049) and second or later lines (OR 7.80, 95%CI 1.35-45.02, P=0.022) while for ESMO-MCBS, drugs with companion diagnostics (OR 6.86, 95%CI 1.82-25.86, P=0.004) and immunotherapy drugs (OR 6.42, 95%CI 1.27-32.59, P=0.025) were associated with greater clinical benefit. Conclusions: Drugs with companion diagnostic tests, immunotherapy as well as approved based on single-arm trials were associated with increased clinical benefit after marketing approval. For a quarter of trials there were no updated data in the post-marketing period.

DBS of the PSA and the VIM in essential tremor

Neurology ◽  
2018 ◽  
Vol 91 (6) ◽  
pp. e543-e550 ◽  
Author(s):  
Michael T. Barbe ◽  
Paul Reker ◽  
Stefanie Hamacher ◽  
Jeremy Franklin ◽  
Daria Kraus ◽  
...  
Keyword(s):  
Side Effects ◽  
Essential Tremor ◽  
Clinical Benefit ◽  
Double Blind ◽  
Crossover Phase ◽  
Ventral Intermediate Nucleus ◽  
Frequency Of Stimulation

ObjectiveTo evaluate deep brain stimulation (DBS) of the posterior subthalamic area (PSA) in essential tremor (ET) and compare it to the ventral intermediate nucleus of the thalamus (VIM) in terms of stimulation efficacy, efficiency, and side effects.MethodsDBS leads were implanted such that contacts were placed in the VIM, on the intercommissural line, and in the PSA. Thirteen patients with ET entered a randomized, double-blind crossover phase and completed a 1-year follow-up.ResultsPSA-DBS significantly reduced tremor severity and improved quality of life. There were no relevant differences in quality and frequency of stimulation side effects between VIM and PSA, with a tendency toward greater tremor improvement with PSA stimulation. Clinical benefit was achieved at significantly lower stimulation amplitudes in the PSA. The majority of patients remained with PSA-DBS after 1 year.ConclusionIn accordance with previous retrospective investigations, our prospective data suggest that PSA-DBS is at least equally effective as but possibly more efficient than VIM-DBS.Classification of evidenceThis study provides Class I evidence that for patients with essential tremor, PSA-DBS is not significantly different from VIM-DBS in suppressing tremor, but clinical benefit from PSA-DBS is attained at lower stimulation amplitudes.

scholarly journals A tiered system using substantial clinical benefit and patient acceptable symptomatic state scores to evaluate 2-year outcomes of hip arthroscopy with the Hip Outcome Score

2020 ◽  
Vol 7 (1) ◽  
pp. 62-69
Author(s):  
RobRoy L Martin ◽  
Benjamin R Kivlan ◽  
John J Christoforetti ◽  
Andrew B Wolff ◽  
Shane J Nho ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Hip Arthroscopy ◽  
Self Report ◽  
Initial Assessment ◽  
Characteristic Analysis ◽  
Level Of Evidence ◽  
Outcome Score ◽  
Substantial Clinical Benefit ◽  
Tiered System

Abstract There is no information to define variations in hip arthroscopy outcomes at 2-year follow-up using the Hip Outcome Score (HOS). To offer a tiered system using HOS absolute substantial clinical benefit (SCB) and patient acceptable symptomatic state (PASS) scores for 2-year hip arthroscopy outcome assessment. This was a retrospective review of patients having hip arthroscopy for femoroacetabular impingement and/or chondrolabral pathology. On initial assessment and 2 years (±2 months) post-operatively, subjects completed the HOS activity of daily living (ADL) and Sports subscales, categorical self-rating of function and visual analog scale for satisfaction with surgery. Receiver operator characteristic analysis identified absolute SCB and PASS HOS ADL and Sports subscale scores. Subjects consisted of 462 (70%) females and 196 (30%) males with a mean age of 35.3 years [standard deviation (SD) 13] and mean follow-up of 722 days (SD 29). SCB and PASS scores for the HOS ADL and Sports subscales were accurate in identifying those at a ‘nearly normal’ and ‘normal’ self- report of function and at least 75% and 100% levels of satisfaction (area under the curve >0.70). This study provides tiered SCB and PASS HOS scores to define variations in 2-year (±2 months) outcome after hip arthroscopy. HOS ADL subscale scores of 84 and 94 and Sports subscale scores of 61 and 87 were associated with a ‘nearly normal’ and ‘normal’ self-report of function, respectively. HOS ADL subscale scores of 86 and 94 and Sports subscale score of 74 and 87 were associated with being at least 75% and 100% satisfied with surgery, respectively. Level of evidence: III, retrospective comparative study.

Organ dysfunction (dys) and clinical outcomes in patients (pts) treated with immune checkpoint inhibitors (ICIs).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2569-2569
Author(s):  
QI LIU ◽  
Elad Sharon ◽  
Issam Zineh ◽  
Diqiong (Joan) Xie ◽  
Shrujal S. Baxi ◽  
...  
Keyword(s):  
Renal Function ◽  
Liver Function ◽  
Clinical Outcomes ◽  
Checkpoint Inhibitors ◽  
Stage Iv ◽  
Organ Function ◽  
Kaplan Meier ◽  
Level Data ◽  
The Impact

2569 Background: ICIs (anti-PD-L1/PD-1/CTLA-4) are approved in multiple cancers. The impact of organ dys on the pharmacokinetics of ICIs is known, but associated clinical outcomes are not well characterized. We compared real-world (rw) clinical outcomes in ICI-treated pts by liver and renal function. Methods: This retrospective study used longitudinal, patient-level data from community practices in the Flatiron Health electronic-health record (EHR)-derived database. We included pts diagnosed with advanced cancers (NSCLC, renal cell, melanoma, gastric/esophageal, or head and neck) on or after 1/1/2011, treated with an ICI with follow-up through 12/31/2018 and with baseline liver or renal function results in the EHR ≤30 days prior to ICI start. Organ function was stratified as normal, mild, moderate, or severe dys based on NCI CTCAE. We computed unadjusted median estimates for rw time to treatment discontinuation (rwTTD) for any reason and overall survival (OS) across baseline groups using the Kaplan-Meier method. Results: Of 15,979 pts, we identified 12,978/12,840 pts with evaluable renal/liver function, respectively; median follow-up was 5.1 mos and median age was 69.0 yrs (IQR: 61.0, 76.0) for both. Most pts had NSCLC (69.4/69.0%), were men (60.1/60.0%), white (73.5/73.6%), and diagnosed at stage IV (58.7%/58.6%). Most ICI was given in 1st-line (42.3/42.1%) (outcomes in Table). Conclusions: Pts with categorically worse baseline liver function had progressively worse on-treatment outcomes, including shorter OS, which differed from trends in renal dys. Whether baseline dys is prognostic or predictive of ICI outcomes should be further investigated in addition to reasons for discontinuation. Clinical outcomes (unadjusted median times, mos [95% CI]) by organ function. [Table: see text]

Overall survival, quality of life and magnitude of clinical benefit of breast cancer drugs over the last 25 years.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6571-6571
Author(s):  
J. Carlos Tapia ◽  
Aida Bujosa Rodríguez ◽  
Consolacion Molto ◽  
Arnoud J. Templeton ◽  
Daniel Shepshelovich ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Benefit ◽  
Cancer Drug ◽  
Cancer Drugs ◽  
Curative Intent ◽  
Substantial Clinical Benefit ◽  
Breast Cancer Drugs ◽  
Palliative Setting ◽  
Over Time

6571 Background: The American Society of Clinical Oncology Cancer Research Committee (ASCO-CRC), the ASCO Value Framework Net Health Benefit score version 2 (ASCO-VF), and the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS) are validated tools quantifying the clinical benefit for cancer drugs. Here, we assess the overall survival (OS), quality of life (QoL) and magnitude of clinical benefit of trials supporting breast cancer drug approval by the US Food and Drug Administration (FDA) in the last 25 years. Methods: We searched Drugs@FDA website for all breast cancer drug approvals from January 1, 1995 to December 30, 2020. Drug labels and reports of registration trials were reviewed. We collected data on trial characteristics, efficacy, toxicity and QoL. When more than one study supported a single indication, we preferred efficacy-oriented endpoints (typically OS) to QoL. We excluded trials supporting accelerated-approval indications if these were converted to regular approval during the study period. We scored clinical benefit using the ASCO-CRC in palliative setting, and ASCO-VF and ESMO-MCBS in both curative and palliative setting. Substantial clinical benefit was defined as: OS gains ≥2.5 months and progression-free survival gains ≥ 3 months for ASCO-CRC criteria; ASCO-VF scores ≥ 45 and grade of A or B for trials of curative intent and 4 or 5 for those of non-curative intent using ESMO-MCBS. Trends over time were assessed using Chi-squared test for trend. Results: We identified 51 trials supporting the approval of 32 individual drugs for 51 indications; 12 (24%) were in the curative setting and 39 (76%) in the palliative setting. At the time of approval, 8 (16%) trials reported significant improvement in OS. QoL was reported in 22 trials (43%). Among these, 8 (36%) showed improvement in QoL. For curative intent, we applied ASCO-VF and ESMO-MCBS score to 11 (92%) trials, finding clinical benefit in 10 (91%) and 2 (18%) trials, respectively. In the palliative setting, we used ASCO-CRC, ASCO-VF and ESMO-MCBS scores to rate 32 (82%), 33 (85%) and 38 (97%) trials. Substantial clinical benefit was observed in 20 (63%), 12 (36%) and 7 (19%) trials, respectively. Over time, there has been a decrease in the number of trials supporting approval based on OS (1996-2003 50% vs 2004-12 38% vs 2013-20 13%, P trend = 0.033). There were no statistically significant changes over time in QoL, ASCO-CRC, ASCO-VF and ESMO-MCBS scores. Conclusions: For palliative intent, most trials supporting FDA approval of breast cancer drugs do not meet the ASCO-VF or ESMO-MCBS criteria for substantial clinical benefit. There is substantial inter-framework variability in the assessment of clinical benefit in the curative setting. Over time, there has been a substantial shift towards use of surrogate endpoints as the basis for approval without a clear improvement in substantial clinical benefit.

Baseline neutrophil-to-eosinophil ratio (NER) and its association with clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (CPI).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16569-e16569
Author(s):  
Deepak Ravindranathan ◽  
Yuan Liu ◽  
Dylan J. Martini ◽  
Jacqueline T Brown ◽  
Bassel Nazha ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Clinical Benefit ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
P Value ◽  
Proportional Hazard ◽  
Free Survival ◽  
Cox Proportional Hazard ◽  
Significant Difference

e16569 Background: Inflammatory markers have been studied as prognostic markers in patients with mRCC treated with CPIs. Recently, eosinophilia has been found to be associated with improved survival of patients with melanoma treated with CPIs. We reported baseline NER in patients with mRCC treated with CPIs and its association with clinical outcomes. Methods: We conducted a retrospective analysis of patients with mRCC treated with CPIs at Winship Cancer Institute from 2015-2018. Clinical outcomes were measured as overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). OS and PFS were calculated from CPI-initiation to date of death and radiographic or clinical progression, respectively. Patients with baseline NER were categorized into high or low; high defined as NER > 49.2 and low defined as NER < 49.2. Univariate (UVA) and multivariate (MVA) analyses were carried out for OS and PFS using Cox proportional hazard model. Results: A total of 184 patients were studied with a median follow up of 25.4 months. Median age was 63 years old with 72% male and 20% black. About 25% were in high NER group. The high NER patients had significantly shorter OS in both UVA (HR: 0.58, p-value=0.017) and MVA (HR: 0.62, p-value=0.046) (Table). There was no significant difference between groups for PFS. Clinical benefit was seen in 47.3% of patients with low baseline NER and 40% with high NER. Conclusions: High baseline NER was associated with worse OS in patients with mRCC treated with CPIs. Larger, prospective studies are warranted to validate this hypothesis generating data.[Table: see text]

The effect of length of follow-up on substantial clinical benefit thresholds in patients undergoing surgery for cervical degenerative myelopathy

2019 ◽  
Vol 62 ◽  
pp. 88-93
Author(s):  
Morgan P. Spurgas ◽  
Syed F. Abbas ◽  
Benjamin S. Szewczyk ◽  
Benjamin Yim ◽  
Ashar Ata ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Substantial Clinical Benefit ◽  
Degenerative Myelopathy

scholarly journals The likelihood of reaching minimum clinically important difference and substantial clinical benefit at 2 years following a 3-column osteotomy: analysis of 140 patients

2015 ◽  
Vol 23 (3) ◽  
pp. 340-348 ◽  
Author(s):  
Shayan Fakurnejad ◽  
Justin K. Scheer ◽  
Virginie Lafage ◽  
Justin S. Smith ◽  
Vedat Deviren ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Minimum Clinically Important Difference ◽  
Thoracic Region ◽  
Self Image ◽  
Clinically Important Difference ◽  
Substantial Clinical Benefit ◽  
Thoracolumbar Region ◽  
Upper Thoracic ◽  
The Impact

OBJECT Three-column osteotomies (3COs) are technically challenging techniques for correcting severe rigid spinal deformities. The impact of these interventions on outcomes reaching minimum clinically important difference (MCID) or substantial clinical benefit (SCB) is unclear. The objective of this study was to determine the rates of MCID and SCB in standard health-related quality of life (HRQOL) measures after 3COs in patients with adult spinal deformity (ASD). The impacts of location of the uppermost instrumented vertebra (UIV) on clinical outcomes and of maintenance on sagittal correction at 2 years postoperatively were also examined. METHODS The authors conducted a retrospective multicenter analysis of the records from adult patients who underwent 3CO with complete 2-year radiographic and clinical follow-ups. Cases were categorized according to established radiographic thresholds for pelvic tilt (> 22°), sagittal vertical axis (> 4.7 cm), and the mismatch between pelvic incidence and lumbar lordosis (> 11°). The cases were also analyzed on the basis of a UIV in the upper thoracic (T1–6) or thoracolumbar (T9–L1) region. Patient-reported outcome measures evaluated preoperatively and 2 years postoperatively included Oswestry Disability Index (ODI) scores, the Physical Component Summary and Mental Component Summary (MCS) scores of the 36-Item Short Form Health Survey, and Scoliosis Research Society-22 questionnaire (SRS-22) scores. The percentages of patients whose outcomes for these measures met MCID and SCB were compared among the groups. RESULTS Data from 140 patients (101 women and 39 men) were included in the analysis; the average patient age was 57.3 ± 12.4 years (range 20–82 years). Of these patients, 94 had undergone only pedicle subtraction osteotomy (PSO) and 42 only vertebral column resection (VCR); 113 patients had a UIV in the upper thoracic (n = 63) orthoracolumbar region (n = 50). On average, 2 years postoperatively the patients had significantly improved in all HRQOL measures except the MCS score. For the entire patient cohort, the improvements ranged from 57.6% for the SRS-22 pain score MCID to 24.4% for the ODI score SCB. For patients undergoing PSO or VCR, the likelihood of their outcomes reaching MCID or SCB ranged from 24.3% to 62.3% and from 16.2% to 47.8%, respectively. The SRS-22 self-image score of patients who had a UIV in the upper thoracic region reached MCID significantly more than that of patients who had a UIV in the thoracolumbar region (70.6% vs 41.9%, p = 0.0281). All other outcomes were similar for UIVs of upper thoracic and thoracolumbar regions. Comparison of patients whose spines were above or below the radiographic thresholds associated with disability indicated similar rates of meeting MCID and SCB for HRQOL at the 2-year follow-up. CONCLUSIONS Outcomes for patients having UIVs in the upper thoracic region were no more likely to meet MCID or SCB than for those having UIVs in the thoracolumbar region, except for the MCID in the SRS-22 self-image measure. The HRQOL outcomes in patients who had optimal sagittal correction according to radiographic thresholds determined preoperatively were not significantly more likely to reach MCID or SCB at the 2-year follow-up. Future work needs to determine whether the Schwab preoperative radiographic thresholds for severe disability apply in postoperative settings.

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