Substantial clinical benefit and patient acceptable symptom states of the Forgotten Joint Score 12 after primary knee arthroplasty

Background and purpose — Knowing how to interpret values obtained with patient reported outcome measures (PROMs) is essential. We estimated the substantial clinical benefit (SCB) and patient acceptable symptom state (PASS) for Forgotten Joint Score 12 (FJS) and explored differences depending on methods used for the estimates. Patients and methods — The study was based on 195 knee arthroplasties (KA) performed at a university hospital. We used 1 item from the Knee injury and Osteoarthritis Outcome Score domain quality of life and satisfaction with surgery, obtained 1-year postoperatively, to assess SCB and PASS thresholds of the FJS with anchor-based methods. We used different combinations of anchor questions for SCB and PASS (satisfied, satisfied with no or mild knee difficulties, and satisfied with no knee difficulties). A novel predictive approach and receiver-operating characteristics curve were applied for the estimates. Results — 70 and 113 KAs were available for the SCB and PASS estimates, respectively. Depending on method, SCB of the FJS (range 0–100) was 28 (95% CI 21–35) and 22 (12–45) respectively. PASS was 31 (2–39) and 20 (10–29) for satisfied patients, 40 (31–47) and 38 (32–43) for satisfied patients with no/mild difficulties, and 76 (39–80) and 64 (55–74) for satisfied patients with no difficulties. The areas under the curve ranged from 0.82 to 0.88. Interpretation — Both the SCB and PASS thresholds varied depending on methodology. This may indicate a problem using meaningful values from other studies defining outcomes after KA. This study supports the premise of the FJS as a PROM with good discriminatory ability in patients undergoing KA.

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

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.

The substantial clinical benefit of comprehensively considering low back pain and radiating pain caused by lumbar intervertebral disc herniation

BACKGROUND: Patients with lumbar disc herniation (LDH) may experience low back pain (LBP) and radiating pain (RP). Currently, there is no substantial clinical benefit (SCB) of assessing both LBP and RP due to LDH. OBJECTIVE: To determine enhanced SCB values by simultaneously assessing LBP and RP. METHODS: We retrospectively evaluated hospitalized LDH patients with concomitant LBP and RP between June 1, 2012, and May 31, 2013, and determined the numeric rating scale (NRS) and Oswestry Disability Index (ODI) scores at admission and discharge. Furthermore, the area under the receiver operating characteristic curve (AUC) was computed to assess diagnostic accuracy. RESULTS: SCB as per NRS for both LBP and RP was -2.50 in the 186 enrolled patients (AUC: 0.699 and 0.704, respectively). SCB as per ODI was -18.78 (AUC: 0.771). SCB for the mean of the two NRS scores for LBP and RP was -2.75 (AUC: 0.757). SCB for NRS score with a smaller change in LBP and RP was -3.50 (AUC: 0.767). CONCLUSIONS: SCB may be determined by comprehensively considering LBP and RP and choosing the mean NRS or NRS score with a small change.

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

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.

Cancer, Clinical Trials, and Canada: Our Contribution to Worldwide Randomized Controlled Trials

Canada has a long tradition of leading practice-changing clinical trials in oncology. Here, we describe methodology, results, and interpretation of oncology RCTs with Canadian involvement compared to RCTs from other high-income countries (HICs). A literature search identified all RCTs evaluating anti-cancer therapies published 2014–2017. RCTs were classified based on the country affiliation of first authors. The study cohort included 636 HIC-led RCTs; 155 (24%) had Canadian authors. Three-quarters (112/155, 72%) of Canadian RCTs were conducted in the palliative setting, compared to two thirds (299/481, 62%) of RCTs from other HICs (p = 0.022). Canadian RCTs were more likely than those from other HICs to be supported by industry (85% vs. 69%, p < 0.001). The proportion of positive Canadian trials that met the ESMO-MCBS threshold for substantial clinical benefit was comparable to RCTs without Canadian authors (29% vs. 32%, p = 0.137). Thirteen percent (20/155) of all Canadian trials were affiliated with the Canadian Cancer Trials Group (CCTG). Canada plays a meaningful role in the global cancer research ecosystem but is overly reliant on industry support. The very low proportion of trials that identify a new treatment with substantial clinical benefit is worrisome. A renewed investment in cancer clinical trials is needed in Canada.

The Emerging Circadian Phenotype of Borderline Personality Disorder: Mechanisms, Opportunities and Future Directions

Purpose of Review We review the recent evidence suggesting that circadian rhythm disturbance is a common unaddressed feature of borderline personality disorder (BPD); amelioration of which may confer substantial clinical benefit. We assess chronobiological BPD studies from a mechanistic and translational perspective and highlight opportunities for the future development of this hypothesis. Recent Findings The emerging circadian phenotype of BPD is characterised by a preponderance of comorbid circadian rhythm sleep-wake disorders, phase delayed and misaligned rest-activity patterns and attenuated amplitudes of usually well-characterised circadian rhythms. Such disturbances may exacerbate symptom severity, and specific maladaptive personality dimensions may produce a liability towards extremes in chronotype. Pilot studies suggest intervention may be beneficial, but development is limited. Summary Endogenous and exogenous circadian rhythm disturbances appear to be common in BPD. The interface between psychiatry and chronobiology has led previously to novel efficacious strategies for the treatment of psychiatric disorders. We believe that better characterisation of the circadian phenotype in BPD will lead to a directed biological target for treatment in a condition where there is a regrettable paucity of accessible therapies.