Adaptive Clinical Trial Designs with Surrogates: When Should We Bother?

The success of a new drug is assessed within a clinical trial using a primary endpoint, which is typically the true outcome of interest—for example, overall survival. However, regulators sometimes approve drugs using a surrogate outcome—an intermediate indicator that is faster or easier to measure than the true outcome of interest—for example, progression-free survival—as the primary endpoint when there is demonstrable medical need. Although using a surrogate outcome (instead of the true outcome) as the primary endpoint can substantially speed up clinical trials and lower costs, it can also result in poor drug-approval decisions because the surrogate is not a perfect predictor of the true outcome. In this paper, we propose combining data from both surrogate and true outcomes to improve decision making within a late-phase clinical trial. In contrast to broadly used clinical trial designs that rely on a single primary endpoint, we propose a Bayesian adaptive clinical trial design that simultaneously leverages both observed outcomes to inform trial decisions. We perform comparative statics on the relative benefit of our approach, illustrating the types of diseases and surrogates for which our proposed design is particularly advantageous. Finally, we illustrate our proposed design on metastatic breast cancer. We use a large-scale clinical trial database to construct a Bayesian prior and simulate our design on a subset of clinical trials. We estimate that our design would yield a 16% decrease in trial costs relative to existing clinical trial designs, while maintaining the same Type I/II error rates. This paper was accepted by J. George Shanthikumar for the Special Issue on Data-Driven Prescriptive Analytics.

Genetically Targeted Clinical Trials in Parkinson’s Disease: Learning from the Successes Made in Oncology

Clinical trials in neurodegenerative disorders have been associated with high rate of failures, while in oncology, the implementation of precision medicine and focus on genetically defined subtypes of disease and targets for drug development have seen an unprecedented success. With more than 20 genes associated with Parkinson’s disease (PD), most of which are highly penetrant and often cause early onset or atypical signs and symptoms, and an increasing understanding of the associated pathophysiology culminating in dopaminergic neurodegeneration, applying the technologies and designs into the field of neurodegeneration seems a logical step. This review describes some of the methods used in oncology clinical trials and some attempts in Parkinson’s disease and the potential of further implementing genetics, biomarkers and smart clinical trial designs in this disease area.

Role of Radiotherapy in the Management of Pancreatic Adenocarcinoma: Debate and Discordance in Clinical Trials

Pancreatic adenocarcinoma (PAC) is an extremely fatal malignancy with dismal outcome with standard treatment till date. Investigators are constantly in search of optimal treatment approach and radiation therapy (RT) remains in the centre of debate. Human pancreatic cancer cell lines have shown both intrinsic and hypoxia induced radio resistance, and RT has produced conflicting results as well in the various clinical trials. However, most of the American studies continued the use of RT as a potential treatment modality but the European school of thought is widely criticized for their ‘therapeutic nihilism’ towards radiation and faulty clinical trial designs. This article has reviewed the available literature on the evolving role of RT for the management of resectable and borderline resectable PAC and has highlighted the increasing trend towards the use of radiotherapy for both adjuvant and neo adjuvant treatment. With the advent of modern RT techniques, the acute and late toxicities are much less than the earlier time, and therefore augmented RT is expected to produce better clinical outcomes for the patients with pancreatic carcinoma.

Integrating Cancer Vaccines in the Standard-of-Care of Ovarian Cancer: Translating Preclinical Models to Human

As the majority of ovarian cancer (OC) patients are diagnosed with metastatic disease, less than 40% will survive past 5 years after diagnosis. OC is characterized by a succession of remissions and recurrences. The most promising time point for immunotherapeutic interventions in OC is following debulking surgery. Accumulating evidence shows that T cells are important in OC; thus, cancer vaccines capable of eliciting antitumor T cells will be effective in OC treatment. In this review, we discuss different cancer vaccines and propose strategies for their incorporation into the OC standard-of-care regimens. Using the murine ID8 ovarian tumor model, we provide evidence that a cancer vaccine can be effectively combined with OC standard-of-care to achieve greater overall efficacy. We demonstrate several important similarities between the ID8 model and OC patients, in terms of response to immunotherapies, and the ID8 model can be an important tool for evaluating combinatorial regimens and clinical trial designs in OC. Other emerging models, including patient-derived xenograft and genetically engineered mouse models, are continuing to improve and can be useful for evaluating cancer vaccination therapies in the near future. Here, we provide a comprehensive review of the completed and current clinical trials evaluating cancer vaccines in OC.

Osteoporosis-Related Randomized Clinical Trials With Middle-Aged and Older Adults Registered on the International Clinical Trials Registry Platform

BackgroundA better understanding of the current features of osteoporosis-related randomized clinical trials (RCTs) is important for improving clinical trial designs and promoting the translatability of results into benefits for patients. However, there is a lack of thorough evaluation of osteoporosis-related RCTs in middle-aged and older populations. Therefore, this study aimed to investigate the characteristics of registered RCTs on osteoporosis among middle-aged and older adults on the International Clinical Trials Registry Platform (ICTRP).MethodsOsteoporosis-related RCTs registered on the ICTRP were searched on December 31, 2020. The main features of eligible RCTs were assessed. We searched PubMed, Google scholar, Medline, and Embase databases for the publication status of completed RCTs.ResultsA total of 537 osteoporosis-related RCTs were identified for analysis. The number of registered RCTs increased rapidly in 2005 (N = 47). Of these, 346 (64.4%) RCTs involved only women and 275 (51.2%) were retrospectively registered. Most RCTs were of open-label design (61.3%). The most common primary purpose of osteoporosis-related RCTs was treatment (72.3%). Intervention investigated was mainly focused on medication (62.8%), followed by lifestyle or education (19.0%), and dietary supplement (10.4%). After trial completion, the results of only 140 (35.5%) RCTs were available on the ICTRP, and the publication rate after trial completion was 30.5%.ConclusionsRCTs on osteoporosis among middle-aged and older adults were dominated by retrospectively registered and open-label trials. Most trials lacked available results and associated publications. More awareness of prospective registration and blinding design in osteoporosis-related RCTs is needed. Further, publication and dissemination of RCTs results should be promoted.