Conventional cancer clinical trials can be slow and costly, often produce results with limited external validity, and are difficult for patients to participate in. Recent technological advances and a dynamic policy landscape in the United States have created a fertile ground for the use of real-world data (RWD) to improve current methods of clinical evidence generation. Sources of RWD include electronic health records, insurance claims, patient registries, and digital health solutions outside of conventional clinical trials. A definition focused on the original intent of data collected at the point of care can distinguish RWD from conventional clinical trial data. When the intent of data collection at the point of care is research, RWD can be generated using experimental designs similar to those employed in conventional clinical trials, but with several advantages that include gains in efficient execution of studies with an appropriate balance between internal and external validity. RWD can support active pharmacovigilance, insights into the natural history of disease, and the development of external control arms. Prospective collection of RWD can enable evidence generation based on pragmatic clinical trials (PCTs) that support randomized study designs and expand clinical research to the point of care. PCTs may help address the growing demands for access to experimental therapies while increasing patient participation in cancer clinical trials. Conducting valid real-world studies requires data quality assurance through auditable data abstraction methods and new incentives to drive electronic capture of clinically relevant data at the point of care.
On a trial level, there is a strong association between ORR and PFS. An association between ORR and OS and between PFS and OS was not established, possibly because of cross-over and longer survival after progression in the targeted therapy and first-line trials. The patient-level analysis showed that responders have a better PFS and OS compared with nonresponders. A therapy in advanced NSCLC with a large magnitude of effect on ORR may have a large PFS effect.
On April 29, 2014, the FDA granted accelerated approval to ceritinib (ZYKADIA; Novartis Pharmaceuticals Corporation), a breakthrough therapy-designated drug, for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The approval was based on a single-arm multicenter trial enrolling 163 patients with metastatic ALK-positive NSCLC who had disease progression on (91%) or intolerance to crizotinib. Patients received ceritinib at a starting dose of 750 mg orally once daily. The objective response rate (ORR) by a blinded independent review committee was 44% (95% CI, 36-52), and the median duration of response (DOR) was 7.1 months. The ORR by investigator assessment was similar. Safety was evaluated in 255 patients. The most common adverse reactions and laboratory abnormalities included diarrhea (86%), nausea (80%), increased alanine transaminase (80%), increased aspartate transaminase (75%), vomiting (60%), increased glucose (49%), and increased lipase (28%). Although 74% of patients required at least one dose reduction or interruption due to adverse reactions, the discontinuation rate due to adverse reactions was low (10%). With this safety profile, the benefit-risk analysis was considered favorable because of the clinically meaningful ORR and DOR.
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