Analysis of Impact of Post-Treatment Biopsies in Phase I Clinical Trials

Abstract

Despite their increased use, the impact of biopsy-derived pharmacodynamic biomarkers in phase I oncology studies on subsequent drug development remains uncertain. No impact on subsequent dose or schedule was demonstrated. This issue requires further evaluation, given the risk and cost of such studies.

Underreporting of Research Biopsies from Clinical Trials in Oncology

“…Prior studies evaluating the reporting of pharmacodynamics biomarkers in oncology trials have found wide variability in reporting both within and across studies. (41–43) In addition, a number of these trials examining pharmacodynamic analysis from phase I trials have suggested a limited impact on subsequent dose or schedule. Such work lends strength to the need for transparent reporting of all biopsy conducted analyses in order to better assess the impact of biopsy-derived pharmacodynamic biomarkers in phase I oncology trials.…”

Pharmacodynamic endpoints as clinical trial objectives to answer important questions in oncology drug development

“…Thus, it is ethically imperative that the value and utility of the acquired MOA knowledge justify the increased risk to the patient from the research biopsies. The crux of the matter is that this knowledge is valuable and useful only when it answers key questions and correctly informs the development of an investigational agent [4], so the only ethical PD studies are those conducted with methodology of sufficient quality to provide reliable and relevant measurements. The primary ethical responsibility for the clinical PD study lies with the team that will collect and analyze the research biopsy samples to obtain this knowledge.…”

“…Although it is tempting to use whatever R&D reagents are already available to measure some signal from a tumor biopsy sample, the need for specific MOA information to accelerate development of new drugs and drug combinations should motivate us to design rigorous assays of the most important drug effects and to interpret the resulting data within the limits of the assay measurement. As described recently [4], the study of clinical PD in oncology must be distinct from academic exercises aiming to generate data about “laboratory correlates” that one's colleagues just happen to be able to measure. The latter is exemplified by a physician PI combing the laboratories of the local institution to locate a scientist colleague who can measure something ( anything ) relevant to their clinical protocol.…”

Burdensome Research Procedures in Trials: Why Less Is More

“…Many drug developers are turning to enrichment designs (which select patients on the basis of a biomarker) to boost their success rate. Invasive procedures have also been used to assess drug response at a molecular level, although the scientific value of this approach is controversial (3).…”

“…Finally, some studies suggest findings are not used often to plan subsequent investigations. For example, one study found that only a third of biopsy-derived pharmacodynamic studies in phase I cancer studies were cited in subsequent publications; fewer than half of "positive" analyses were cited in subsequent publications (3).…”