General characteristics and reasons for the discontinuation of drug clinical trials in mainland China

Background Although discontinuation is common in clinical trials, no study has been conducted to analyse the current situation and reasons for the suspension or discontinuation of drug clinical trials in China. This study aims to analyse the general characteristics and reasons for the discontinuation of registered clinical trials in mainland China and to identify the associated factors. Methods We conducted a cross-sectional observational study of discontinued trials registered in the Drug Trial Registration and Information Publication Platform before March 31, 2020. All trials with a status of terminated or stopped recorded in the platform were classified as discontinued trials and included in the analysis. The basic characteristics of the discontinued trials were recorded, reasons for trial discontinuation were recorded and divided into 4 categories as drug development strategy, trial planning, trial conduct and studied drug. Pearson’s chi-square test and fisher’s exact test were used to compare the differences in reasons for discontinuation between neoplasm trials and non-neoplasm trials, and to examine the associations of trial characteristics with different reasons related to trials discontinuation. Results Three hundred twelve discontinued trials were included in this study. The studied drugs were mainly chemical drugs [229 (73.4%)], and indications of the studied drugs were mainly neoplasms [77 (24.7%)]. Geographical location of the discontinued trials were mostly in northern [114 (36.5%)] and eastern [96 (30.8%)] China. Study type of the included trials was mainly bioequivalence studies [97 (31.1%)]. The most common reason for trial discontinuation was commercial or strategic decision [84 (26.9%)], followed by futility/lack of efficacy [70 (22.4%)]. The number of trial centers, sample size and whether participants had been enrolled were significantly associated with trial discontinuation (P < 0.05). Multiple center trials showed a higher rate of trial discontinuation due to trial conduct related reasons than single center trials (P < 0.05), trials with sample size > 500 showed a higher rate of trial discontinuation due to studied drug related reasons (P < 0.05), and trials enrolled participants showed a lower rate of trial discontinuation due to commercial or strategic decision and a higher rate of trial discontinuation due to studied drug related reasons than trials without enrolled participants (P < 0.05). Besides, neoplasm trials showed a higher rate of trial discontinuation due to poor recruitment and safety comparing with non-neoplasm trials (P < 0.05). Conclusions Trial discontinuation in China mainly occurred because of commercial or strategic decision and futility/lack of efficacy of the studied drug. Clinical trials with multiple centers and a large sample size may more likely be discontinued due to trial conduct related reasons such as good clinical practice. Discontinuation due to drug safety and lack of efficacy in multiple center trials with a large sample size deserves more attention to avoid resources wastes. Full communication with regulatory authorities such as Center for Drug Evaluation and research institutes to develop a feasible protocol is important for sponsors to avoid trial discontinuation due to protocol issues.

Lessons Learned From Implementing a Novel Bayesian Adaptive Dose-Finding Design in Advanced Pancreatic Cancer

PURPOSE Novel Bayesian adaptive designs provide an effective way to improve clinical trial efficiency. These designs are superior to conventional methods, but implementing them can be challenging. The aim of this article was to describe what we learned while applying a novel Bayesian phase I-II design in a recent trial. METHODS The primary goal of the trial was to optimize radiation therapy (RT) dose among three levels (low, standard, and high), given either with placebo (P) or an investigational agent (A), for treating locally advanced, radiation-naive pancreatic cancer, deemed appropriate for RT rather than surgery. Up to 48 patients were randomly assigned fairly between RT plus P and RT plus A, with RT dose-finding done within each arm using the late-onset efficacy-toxicity design on the basis of two coprimary end points, tumor response and dose-limiting toxicity, both evaluated at up to 90 days. The random assignment was blinded, but within each arm, unblinded RT doses were chosen adaptively using software developed within the institution. RESULTS Implementing the design involved double-blind balance-restricted random assignment, real-time assessment of patient outcomes to evaluate the efficacy-toxicity trade-off for each RT dose in each arm to optimize each patient's RT dose adaptively, and transition from a single-center trial to a multicenter trial. We present lessons learned and illustrative documentation. CONCLUSION Implementing novel Bayesian adaptive trial designs requires close collaborations between physicians, pharmacists, statisticians, data managers, and sponsors. The process is difficult but manageable and essential for efficient trial conduct. Close collaboration during trial conduct is a key component of any trial that includes real-time adaptive decision rules.

Are investigators’ access to trial data and rights to publish restricted and are potential trial participants informed about this? A comparison of trial protocols and informed consent materials

Objectives To determine to which degree industry partners in randomised clinical trials own the data and can constrain publication rights of academic investigators. Methods Cohort study of trial protocols, publication agreements and other documents obtained through Freedom of Information requests, for a sample of 42 trials with industry involvement approved by ethics committees in Denmark. The main outcome measures used were: proportion of trials where data was owned by the industry partner, where the investigators right to publish were constrained and if this was mentioned in informed consent documents, and where the industry partner could review data while the trial was ongoing and stop the trial early. Results The industry partner owned all data in 20 trials (48%) and in 16 trials (38%) it was unclear. Publication constraints were described for 30 trials (71%) and this was not communicated to trial participants in informed consent documents in any of the trials. In eight trials (19%) the industry partner could review data during the trial, for 20 trials (48%) it was unclear. The industry partner could stop the trial early without any specific reason in 23 trials (55%). Conclusions Publication constraints are common, and data is often owned by industry partners. This is rarely communicated to trial participants. Such constraints might contribute to problems with selective outcome reporting. Patients should be fully informed about these aspects of trial conduct.

Ancillary-Care Obligations

Medical researchers’ ancillary-care obligations have, until recently, been ignored by the authoritative guidelines on the ethics of medical research. Ancillary care is medical care, often unrelated to what is under study, that is not required by sound science, safe trial conduct, morally optional promises, or redressing research injuries. The question is when medical researchers have moral responsibilities to provide such care if their study participants need it. This question shows up insistently in studies done in resource-poor areas and—as the question of whether to return incidental findings—in genomic and imaging studies. After laying out six desiderata for a fully adequate account of medical researchers’ ancillary-care obligations, this chapter critically evaluates six potential grounds for such obligations—the duty of rescue, human rights, rectificatory justice, professional-role obligations, the researcher–participant relationship, and partial entrustment. It closes by suggesting the possibility of combining two or more of these grounds.

How the COVID-19 pandemic is changing clinical trial conduct and driving innovation in bioanalysis

Thousands of clinical trials all over the world were stopped, disrupted or delayed while countries grappled to contain the pandemic and research resources were redeployed. The long-term effects of the turbulence caused by the pandemic have yet to be fully understood, but it should already be clear that the increased focus on participant needs and on the logistical challenges of current models are not likely to fade away quickly. This disruption is opening doors for rethinking traditional approaches to clinical trial conduct – including decentralizing site visits, introducing new methods of sample collection, rethinking matrix selection, reducing sample volumes and collaborating on device development. These approaches reduce participant burden while improving critical trial data.

Responding to COVID-19 threats to trial conduct: lessons learned from a feasibility trial of a psychological intervention for South African adolescents

The COVID-19 pandemic has posed challenges to the conduct of clinical trials. Strategies for overcoming common challenges to non-COVID-19 trial continuation have been reported, but this literature is limited to pharmacological intervention trials from high-income settings. The purpose of this paper is to expand the literature to include a low- and middle-income country perspective. We describe the challenges posed by COVID-19 for a randomised feasibility trial of a psychological intervention for adolescents in Cape Town, South Africa, and lessons learned when implementing strategies to facilitate trial continuation in this context. We used a Plan-Do-Study-Act cycle method to explore whether our adaptations were having the desired effect on trial accrual and retention. We found that stakeholder engagement, trial coordination and team communication need to be intensified while testing these procedural changes. We learned that strategies found to be effective in high-income countries required significant adaptation to our resource-constrained setting. The detailed documentation of extraneous influences, procedural changes and trial process information was essential to guiding decisions about which adaptations to retain. This information will be used to examine the potential impact of these changes on study outcomes. We hope that these reflections will be helpful to other trialists from low- and middle-income countries grappling with how to minimise the impact of public health emergencies on their research. Trial registration The trial is registered with the Pan African Clinical Trials Registry (PACTR20200352214510). Registered 28 February 2020. https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=9795.

Adjuvant versus Neoadjuvant Immunotherapy for Hepatocellular Carcinoma: Clinical and Immunologic Perspectives

Advancement in systemic therapy, particularly immune checkpoint inhibitor (ICI)-based combination regimens, has transformed the treatment landscape for patients with advanced hepatocellular carcinoma (HCC). The advancement in systemic therapy also provides new opportunities of reducing recurrence after curative therapy through adjuvant therapy or improving resectability through neoadjuvant therapy. Improved recurrence-free survival by adjuvant or neoadjuvant ICI-based therapy has been reported in other cancer types. In this article, developments of systemic therapy in adjuvant and neoadjuvant settings for HCC were reviewed. The design of adjuvant and neoadjuvant therapy using ICI-based regimens and potential challenges of trial conduct and result analysis was discussed. Results from these trials may extend the therapeutic benefit of ICI-based systemic therapy beyond the advanced-stage disease and lead to a new era of multidisciplinary management for HCC.