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With several candidate dengue vaccines under development, this is an important time to help stakeholders (e.g., policy makers, scientists, clinicians, and manufacturers) better understand the potential economic value (cost-effectiveness) of a dengue vaccine, especially while vaccine characteristics and strategies might be readily altered. We developed a decision analytic Markov simulation model to evaluate the potential health and economic value of administering a dengue vaccine to an individual (≤ 1 year of age) in Thailand from the societal perspective. Sensitivity analyses evaluated the effects of ranging various vaccine (e.g., cost, efficacy, side effect), epidemiological (dengue risk), and disease (treatment-seeking behavior) characteristics. A ≥ 50% efficacious vaccine was highly cost-effective [< 1× per capita gross domestic product (GDP) ($4,289)] up to a total vaccination cost of $60 and cost-effective [< 3× per capita GDP ($12,868)] up to a total vaccination cost of $200. When the total vaccine series was $1.50, many scenarios were cost saving.

This review highlights strategies to integrate dose optimization into premarketing drug development and discusses the underlying statistical principles. Poor dose optimization can have negative consequences for patients, most commonly because of toxicity, including poor quality of life, reduced effectiveness because of inability of patients to stay on current therapy or receive subsequent therapy because of toxicities, and difficulty in developing combination regimens. We reviewed US Food and Drug Administration initial approvals (2019-2021) of small molecules and antibody-drug conjugates for oncologic indications to determine the proportion with a recommended dosage at the maximum tolerated dose or the maximal administered dose, to characterize the use of randomized evaluations of multiple dosages in dose selection, to describe the frequency of dose modifications at the recommended dosage, and to identify case examples that highlight key principles for premarket dose optimization during drug development. Herein, we highlight major principles for dose optimization and review examples of recent US Food and Drug Administration approvals that illustrate how investigation of dose- and exposure-response relationships and use of randomized dose trials can support dose optimization. Although there has been some progress, dose optimization through randomized dose evaluation in oncology trials is not routinely conducted. Dose optimization is essential to ensure that patients receive therapies which maximize efficacy while minimizing toxicity.

Abstract. Visceral leishmaniasis (VL) is responsible for substantial morbidity and mortality and current available treatments have many limitations. The ability of VL infection to generate life-long immunity offers promise for the development of a VL vaccine. A VL vaccine candidate has recently completed phase I clinical trials. We constructed a computer simulation model to determine the potential economic value of a VL vaccine in the endemic region of Bihar state, India. Results found a potential vaccine to be cost-effective (and in many cases economically dominant, i.e., saving costs and providing health benefits) throughout a wide range of vaccination costs, vaccine efficacies, and VL risks. Overall, our study strongly supports the continued development of a VL vaccine.

On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. This was the first new molecular entity evaluated under Project Orbis, an FDA Oncology Center of Excellence initiative, which supports concurrent review of oncology drugs by multiple global health authorities. Approval was based on the HER2CLIMB trial, which randomized patients to receive tucatinib or placebo with trastuzumab and capecitabine. Tucatinib demonstrated efficacy compared with placebo in progres-sion-free survival [PFS; HR: 0.54; 95% confidence interval (CI): 0.42-0.71; P < 0.00001] and overall survival (OS; HR: 0.66; 95% CI, 0.50-0.87; P ¼ 0.00480). Patients with either treated and stable or active brain metastases made up 48% of the study population. PFS in patients with brain metastases confirmed benefit (HR: 0.48; 95% CI, 0.34-0.69; P < 0.00001). The benefit in patients with brain metastases allowed for inclusion of this specific population in the indication. Important safety signals included diarrhea and hepatotoxicity which are listed under Warnings and Precautions. This article summarizes the FDA thought process and data supporting the favorable benefit-risk profile and approval of tucatinib.

Over the last decade, the treatment of patients with breast cancer has been greatly impacted by the approval of multiple drugs and indications. This summary describes 30 FDA approvals of treatments for breast cancer from 2010 to 2020. The trial design endpoints, results, and regulatory considerations are described for each approved indication. Of the 30 indications, 23 (76.6%) received regular and 7 (23.3%) received accelerated approval. Twenty-six approvals were granted in metastatic breast cancer (MBC) and four in early breast cancer. Approval decisions for the 26 MBC indications were initially supported by progression-free survival (PFS) in 21 (80.8%), overall survival (OS) or a combination of OS and PFS in two (7.7%), and objective response rate (ORR) in three (11.5%). The four approvals in early breast cancer utilized pathologic complete response (pCR) in one (25%) and invasive disease-free survival (iDFS) in three (75%) trials. Among the 30 indications, 22 received priority review, seven were granted Breakthrough Therapy Designation, and 10 applications participated in one or more pilot Oncology Center of Excellence regulatory review initiatives, including Real Time Oncology Review, Assessment Aid, and Project Orbis. FDA initiatives to advance breast cancer drug development are also described.

On July 26, 2021, the Food and Drug Administration granted approval to pembrolizumab in combination with chemotherapy for neoadjuvant treatment and then continued as a single agent for adjuvant treatment following surgery for patients with high-risk, early-stage triple negative breast cancer (TNBC). Approval was based on results from KEYNOTE-522, an ongoing randomized (2:1) trial evaluating pembrolizumab or placebo in combination with chemotherapy for neoadjuvant treatment and then as a single agent for adjuvant treatment. The co-primary endpoints were pathological complete response (pCR) rate and event free survival (EFS). The trial demonstrated an improvement in pCR and EFS in the pembrolizumab arm compared to the control arm. The number of patients who experienced an EFS event was 123 (16%) and 93 (24%), respectively (HR: 0.63, 95% CI: 0.48-0.82, p=0.00031). Patients on the pembrolizumab arm experienced EFS benefit regardless of tumor PD-L1 status. The absolute pCR rate improvement with the addition of pembrolizumab was 7.5% (95% CI: 1.6%, 13.4%). Among patients receiving pembrolizumab, 44% experienced an immune-related adverse reaction. This article summarizes FDA’s review of pembrolizumab and the data supporting the favorable benefit-risk assessment.

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? ✔ Ras signaling and the PI3K/AKT pathway are known to be commonly aberrant in pancreatic tumors. Preclinical studies showed that inhibiting these pathways with cyclin dependent kinase (CDK) and AKT inhibitors reduce cell proliferation and apoptosis. WHAT QUESTION DID THIS STUDY ADDRESS? ✔ This study combined dinaciclib (CDK inhibitor) and MK-2206 (Akt inhibitor) together in a phase I study for patients with previously treated advanced pancreatic cancer. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? ✔ This study showed that combining these agents can be done safely but that it was not possible to achieve biologically effective doses. HOW MIGHT THIS CHANGE CLINICAL PHARMACOL-OGY OR TRANSLATIONAL SCIENCE? ✔ Due to the clear preclinical rationale of combined CDK and Akt inhibition, targeting these pathways is still worth pursuing. However, alternative agents or combinations are required in future studies. Clinical and Translational Science Dinaciclib and MK-2206 in Pancreatic Cancer Murphy et al.