Cardiac Monitoring Guidelines in Clinical Trials and Post-Approval Surveillance for Patients Exposed to Anticancer Treatments: Do the Data Support the Recommendations?

Concerns regarding cardiac adverse events during and after cancer care include contractile dysfunction, dysrhythmia, and inflammation. Clinical trials and practice guidelines may require or recommend sequential ejection fraction determinations for early recognition of contractile dysfunction, bio-marker screening where inflammation or contractile dysfunction could be anticipated, and multiple electrocardiograms with timings of cardiac intervals. In some instances, surveillance schedules used in clinical trial protocols have been incorporated in recommendations without revision or critical scrutiny. When adverse events are rare and interpretative parameters imperfect, false positive results may lead to delay or interruption of vital cancer treatment, may suggest that further cardiac testing be undertaken, and may add to patient anxiety. The risks of excessive monitoring also include inconvenience and increased cost. This paper looks at areas where surveillance recommendations may be problematic, specifically, ejection fractions, cardiac biomarkers, and electrocardiographic monitoring are considered. Changes reported following surveillance monitoring of cancer patients using these parameters may reflect true adverse events or clinically relevant future risk, but interpretative uncertainty or true physiologic change that is unrelated to the drug in question should be considered. Clinicians may not be sufficiently aware of the degree to which reported changes may reflect surveillance artifacts. A balance that incorporates both the likelihood of an event that could be prevented along with clinical implications is suggested. The authors recognize that differentiating among these variables is not always possible yet advocate for modifying surveillance schedules to balance the frequency and severity of events that can be mitigated, based on reliable data. SIGNIFICANCE STATEMENT: The authors' concerns regarding the predictive value of surveillance initiatives are explored. Confounding factors and false-positive results may add to the expense of cancer care and/or compromise optimal therapeutic initiatives.

Final overall survival analysis of the phase 3 HERITAGE study demonstrates equivalence of trastuzumab-dkst to trastuzumab in HER2-positive metastatic breast cancer.

PURPOSE: The phase 3 HERITAGE trial demonstrated that the biosimilar trastuzumab-dkst is well tolerated with similar efficacy (measured by overall response rate [ORR] and progression-free survival [PFS]) compared with originator trastuzumab combined with taxane followed by monotherapy in patients with HER2-positive metastatic breast cancer (MBC). Herein, we present final overall survival (OS) from HERITAGE. METHODS: HERITAGE is a multicenter, double-blind, randomized, parallel-group study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab plus taxane followed by continued monotherapy until disease progression. Overall survival was to be assessed at 36 months or after 240 deaths, whichever occurred first, as observed from time of randomization of last patient. RESULTS: At the final analysis (36 months), 242 patients in the intention-to-treat population had died during the study: 116 and 124 in the trastuzumab-dkst and trastuzumab groups, respectively, and 1 untreated patient from each treatment group. Median OS by Kaplan-Meier analysis was 35.0 months with trastuzumab-dkst and 30.2 months with trastuzumab. Evaluation of PFS showed a median of 11.1 months in both treatment groups. No new safety concerns were reported from week 48 until the end of the survival follow-up. CONCLUSION: This is the first phase 3 trial of a trastuzumab biosimilar to report long-term survival data similar to originator trastuzumab in patients with MBC. The comparable long-term OS between the trastuzumab-dkst and originator trastuzumab groups further supports the similarity of trastuzumab-dkst with originator trastuzumab and establishes trastuzumab-dkst as a safe and effective treatment option for patients with HER2-positive MBC. ClinicalTrials.gov NCT02472964; 6/16/2015.

False Positive Cardiotoxicity Events in Cancer-Related Clinical Trials: Risks Related to Imperfect Noninvasive Parameters.

PURPOSE: Cardiac ultrasound provides important structural and functional information that makes identification of cardiac abnormalities possible. Left ventricular ejection fraction (LVEF) provides the most commonly used parameter for recognition of treatment-related cardiac dysfunction. Random reading variance and physiologic factors influence LVEF and make the reported value imperfect. We attempt to quantitate the likelihood of false positive events by computer simulation. METHODS: We simulated four visits on hypothetical trials. We assumed a baseline LVEF of 55% and normal distribution with regard to reading error and physiologic variation. 1,000 trials of sample size 1,500 were simulated. In a separate simulation, 1,000 patients entered with LVEFs of 45, 43, and 41% to estimate true positive incidence. RESULTS: At each examination, less than 1.0% of false positives were noted. The cumulative false positive rate over four visits was 3.60%. True cardiotoxicity identification is satisfactory only when LVEF declines substantially. CONCLUSION: A 3.60% false positive rate in trials where the expected level of toxicity is low suggests that false positives are troubling and may exceed true positive results. Strategies to reduce the number of false positive results include making confirmatory studies mandatory. Evaluating increases along with decreases obtains some estimation of variance.

Effect of a Proposed Trastuzumab Biosimilar Compared With Trastuzumab on Overall Response Rate in Patients With ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Randomized Clinical Trial.

Importance: Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves outcome in patients with ERBB2 (HER2)-positive metastatic breast cancer; a clinically effective biosimilar may help increase access to this therapy. Objective: To compare the overall response rate and assess the safety of a proposed trastuzumab biosimilar plus a taxane or trastuzumab plus a taxane in patients without prior treatment for ERBB2-positive metastatic breast cancer. Design, Setting, and Participants: Multicenter, double-blind, randomized, parallel-group, phase 3 equivalence study in patients with metastatic breast cancer. From December 2012 to August 2015, 500 patients were randomized 1:1 to receive a proposed biosimilar or trastuzumab plus a taxane. Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred. Interventions: Proposed biosimilar (n = 230) or trastuzumab (n = 228) with a taxane. Main Outcomes and Measures: The primary outcome was week 24 overall response rate (ORR) defined as complete or partial response. Equivalence boundaries were 0.81 to 1.24 with a 90% CI for ORR ratio (proposed biosimilar/trastuzumab) and -15% to 15% with a 95% CI for ORR difference. Secondary outcome measures included time to tumor progression, progression-free and overall survival at week 48, and adverse events. Results: Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The ORR was 69.6% (95% CI, 63.62%-75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%-70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974-1.211) and ORR difference (5.53; 95% CI, -3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; -1.7%; 95% CI, -11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; -0.4%; 95% CI, -9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, -2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%). Conclusions and Relevance: Among women with ERBB2-positive metastatic breast cancer receiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumab resulted in an equivalent overall response rate at 24 weeks. Further study is needed to assess safety and long-term clinical outcome. Trial Registration: clinicaltrials.gov Identifier: NCT02472964; EudraCT Identifier: 2011-001965-42.

Strategies for dealing with fraud in clinical trials.

Research misconduct and fraud in clinical research is an increasing problem facing the scientific community. This problem is expected to increase due to discoveries in central statistical monitoring and with the increase in first-time clinical trial investigators in the increasingly global reach of oncology clinical trials. This paper explores the most common forms of fraud in clinical trials in order to develop offensive and defensive strategies to deal with fraud. The offensive strategies are used when fraud is detected during a trial and the defensive strategies are those design strategies that seek to minimize or eliminate the effect of fraud. This leads to a proposed fraud recovery plan (FRP) that would be specified before the start of a clinical trial and would indicate actions to be taken upon detecting fraud of different types. Statistical/regulatory issues related to fraud include: dropping all patients from a site that committed fraud, or just the fraudulent data (perhaps replacing the latter through imputation); the role of intent-to-treat analysis; effect on a planned interim analysis; effect on stratified analyses and model adjustment when fraud is detected in covariates; effect on trial-wide randomization, etc. The details of a typical defensive strategy are also presented. It is concluded that it is best to follow a defensive strategy and to have an FRP in place to follow if fraud is detected during the trial.

Aggregate IND Safety Reporting for Smaller Companies and Programs.

The United States (US) Food and Drug Administration (FDA) Investigational New Drug (IND) Final Rule (US FDA, Final rule: Investigational new drug safety reporting requirements for human drug and biological products and safety reporting requirements for bioavailability and bioequivalence studies in humans, 2010) applies to all human drugs and biological products being studied under an IND. The Final Rule specifies that a sponsor must file an IND safety report for any Suspected Unexpected Serious Adverse Reaction (SUSAR) of a medicinal product being investigated. To make a proper SUSAR classification, sponsors need to go beyond conventional Data Monitoring Committees (DMCs) with an interdisciplinary effort, using all relevant data (including data outside clinical trials), to make judgments on the possibility of serious adverse events being caused by the study drug-rather than the underlying condition of the patient or a concomitant therapy. Ball et al. (Ball et al. in Ther Innov Regul Sci 55:705-716, 2021) have reported on how the Final Rule has been implemented by large pharmaceutical companies. This paper explores the experiences of small sponsor companies regarding the Final Rule, to understand the current challenges that they have been facing to meet aggregate IND safety reporting requirements.

Cardiovascular adverse events in oncology trials: understanding and appreciating the differences between clinical trial data and real-world reports.

Reports of cardiac adverse events from oncology clinical trials often are at variance with reports derived from clinical observations or data-base reviews. These differences may lead to confusion, as different levels of risks abound in the literature, and the true cardiac risk of using some agents is uncertain. Additionally, such discrepancies may lead to the creation of over-cautious surveillance algorithms. Reasons for these reported differences are complex and often reflect subtleties in the criteria for individual patient evaluation. Both clinical trial data and real-world data have potential flaws that make reconciliation problematic. Importantly, however, both provide crucial information regarding the risk of adverse events. Major factors contribute to these differences including different tools used to diagnose events, and how those tools are interpreted. Additionally, differences in the populations of clinical trial participants and real-world populations play a crucial role. This paper looks at these differences and provides a perspective intended to help clinicians interpret reported variations in event rates derived from highly scrutinized clinical trials and broader real-world data.

Clinical trial preparations for the next pandemic.

This paper describes the need to prepare for the development of antiviral therapeutics for the next pandemic. Preparation would consist of a stockpiling of best practices for clinical trial design, analysis and operations during the current SARS-CoV-2 pandemic as well as continuous development of treatments and methodology between pandemics. This development would be facilitated by a global clinical trial pandemic reserve similar to the military reserves consisting of medical and quantitative methods professionals who would remain engaged between pandemics. Continuous identification of potential antiviral drugs and diagnostic methods would also be needed. Specific methodology addressed includes the importance of large simple trials, follow up time, efficacy endpoint, appropriate estimands, non-inferiority trials, more sophisticated patient accrual models and procedures for data sharing between clinical trials.

Correlation between week 24 trastuzumab-dkst response and week 48 progression-free survival: the HERITAGE trial.

BACKGROUND: Trastuzumab-dkst is a biosimilar of trastuzumab. The phase 3 HERITAGE trial demonstrated equivalent overall response rate (ORR) with trastuzumab-dkst or originator trastuzumab at 24 weeks in patients with HER2-positive metastatic breast cancer receiving chemotherapy. We now present the correlation of ORR with progression-free survival (PFS) for maintenance monotherapy with trastuzumab-dkst vs trastuzumab at 48 weeks of treatment, and the safety, tolerability, and immunogenicity. METHODS: HERITAGE is a multicenter, double-blind, randomized, parallel-group, phase 3 study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab in combination with taxane followed by continued monotherapy until disease progression. The analysis included PFS at 48 weeks to support the primary efficacy endpoint of ORR and safety, tolerability, and immunogenicity of trastuzumab-dkst vs trastuzumab as maintenance monotherapy. RESULTS: Of 500 randomized patients, 342 entered the monotherapy phase; 214 patients received ≥48 weeks of treatment. There were no statistically significant differences between PFS, ORR, or interim overall survival at week 48 between trastuzumab-dkst and trastuzumab. Week 24 ORR was highly correlated with week 48 PFS (rb = 0.75). Cumulative treatment-emergent adverse events (TEAEs) and serious AEs were similar in both groups, with few grade ≥3 TEAEs. Immunogenicity was low and similar in both groups at 48 weeks. CONCLUSION: The correlation between ORR and PFS supports the design of first-line metastatic trials assessing biosimilar trastuzumab. Overall, trastuzumab-dkst and trastuzumab were well tolerated with similar efficacy, including ORR and PFS, in combination with a taxane followed by monotherapy.

National Depressive and Manic-Depressive Association consensus statement on the use of placebo in clinical trials of mood disorders.

A consensus conference on the use of placebo in mood disorder studies consisted of expert presentations on bioethics, biostatistics, unipolar depression, and bipolar disorder. Work groups considered evidence and presented statements to the group. Although it was not possible to write a document for which there was complete agreement on all issues, the final document incorporated input from all authors. There was consensus that placebo has a definite role in mood disorder studies. Findings of equivalence between a new drug and standard treatment in active control studies is not evidence of efficacy unless the new drug is also significantly more effective than placebo. Add-on studies in which patients are randomized to standard therapy plus the investigational drug or standard therapy plus placebo are especially indicated for high-risk patients. Mood disorders in elderly and pediatric patients are understudied, and properly designed trials are urgently needed. Research is needed on the ethical conduct of studies to limit risks of medication-free intervals and facilitate poststudy treatment. Patients must fully understand the risks and lack of individualized treatment involved in research.

Guidelines for data and safety monitoring for clinical trials not requiring traditional data monitoring committees.

This is a commissioned report by a writing committee formed by the Society for Clinical Trials. The committee was formed with the objectives of 1) reviewing data monitoring guidelines for confirmatory (phase III) trials published by the National Institutes of Health, US Food and Drug Administration, Veterans Administration, and the International Conference on Harmonisation and 2) proposing corresponding guidelines for exploratory clinical trials (ie, most phase I and phase II trials and others not requiring a fully independent data monitoring committee). These trials typically involve fewer subjects and are of shorter duration than phase III trials. Nevertheless there are safety concerns, especially because these are often the first human trials for a new intervention. Recommendations are given for appropriate elements of a data monitoring plan, decision criteria for institution of a data monitoring committee (DMC), and critical elements for a DMC to consider in exploratory trials. Review and approval of data monitoring plans are suggested to fall under Institutional Review Board purview. Forming a committee with all the characteristics of a traditional phase III trial monitoring committee may be warranted for a small fraction of exploratory trials. Such a panel could consist of both trial investigators and outside members. The paper concludes with examples of data and safety monitoring practice from the University of Wisconsin Comprehensive Cancer Center and the AIDS Clinical Trials Groups.