Shaking up the drug pipeline means rethinking the way drugs are currently moving through the pipeline. “Confident, data-based decision making in early development of novel medicines is a critical capability in the pharmaceutical industry,” says Hans Winkler, Ph.D., senior director and global head, oncology biomarkers at Ortho Biotech Oncology Research and Development, a division of Janssen Pharmaceutica.
“The way we are looking at handling early clinical trials now is that we have to study safety first and do those escalations as rapidly as possible in early cohorts where we are working on low doses and will collect only peripheral, noninvasive biomarker samples and not have mandatory tumor collection. Traditionally, we used to escalate dose until we established a maximal tolerated dose (MTD).”
However, Dr. Winkler notes, with new targeted therapies, “we may not ever see a MTD, but we might actually have to rely on biological activity and we’re thinking it might be a biologically effective dose that will be the Phase II dose.”
Once his group figures out a biologically effective dose, it will go into an expansion phase that will focus on specific tumor types, where the researchers believe that the target plays a controlling role. “We will test predictive markers to identify some populations, and in that focused population we will examine antitumor activity, looking at tumor cells pre- and post-treatment to make sure that we are giving the optimal dose.”
The biggest challenge is getting tumor samples in early trials. “It’s not feasible to collect serial tumor biopsies, and the quality of biopsies is always an issue,” explains Dr. Winkler. “Logistics are still difficult, especially when it comes to larger trials. If you collect samples, you sometimes lose half of the samples in some way. We need to collect more like 80 to 90 percent usable samples.”
For pharmacodynamic analysis, Dr. Winkler reports, “we need an early start and enough support to actually develop the assays to the degree that they are acceptable for clinical applications ahead of time. For predictive markers, we need to work up the assays to a point where we can actually test them in Phase II, we need to sort out the regulatory process, we need to have a strong hypothesis to be tested when we get into Phase II, and we need more predictive models to allow us to discover these predictive markers ahead of time, rather than in the clinic.”