4:24 PM
 | 
Feb 16, 2018
 |  BioCentury  |  Product Development

This year’s model

How tumor kinetics modeling is informing dose and candidate selection

Companies are answering FDA’s push for model-informed dose optimization in cancer by modeling how tumors grow and how tumor kinetics relate to outcomes. The models can support dosing decisions and help companies make faster, better decisions about which products and combinations to take forward.

On Feb 1. the agency convened a joint workshop with the International Society of Pharmacometrics to discuss model-informed drug development (MIDD) for oncology products. FDA is committed to a series of workshops to enhance the use of MIDD under PDUFA VI.

At the workshop, FDA officials championed MIDD as a means to determine the optimal use of new products when scant clinical data leave unanswered questions. A key focus was how to choose a recommended dose regimen when the clinical program has not fully defined exposure-response or exposure-toxicity relationships.

“Model-informed drug development offers us a pathway to answers -- perhaps less conventionally than we have answered questions through empirical clinical trials -- but to give us answers that are quite convincing, and that can guide therapy in ways we have not utilized before,” said CDER Director Janet Woodcock.

“Model-informed drug development offers us a pathway to answers.”

Janet Woodcock, FDA

One way companies and FDA are using MIDD is to model the phenomena that explain how tumor sizes and rates of growth change over time. This modeling of tumor kinetics gives more information about how tumors respond to treatments than simple RECIST (Response Evaluation Criteria In Solid Tumors) criteria. As a result, these models can allow companies and regulators to draw more conclusions from their data.

The models have been used to justify proposed dosing regimens, design clinical trials and make go/no-go decisions in the clinic earlier or with more confidence.

Precompetitive collaborations are now developing standards and best practices that could permit the use of tumor kinetic modeling to develop new surrogate endpoints that predict survival better than surrogates based on RECIST criteria such as progression-free survival (PFS).

FDA’s ideal is to use MIDD to optimize dosing based on a complete characterization of dose-response that examines both efficacy and safety. However, that will likely require more sophisticated systems pharmacology models, which describe the underlying biology more in depth than tumor kinetic models and have the potential to answer a broader range of questions about how products affect disease.

Defining a trajectory

FDA has already started to accept tumor kinetic models to support its efficacy evaluations.

Akintunde Bello, head of clinical pharmacology and pharmacometrics at Bristol-Myers Squibb Co., told BioCentury the agency “ignited the field” of tumor kinetic modeling in 2009 with a paper in Clinical Pharmacology and Therapeutics.

In the paper, a group led by Yaning Wang, deputy director in FDA’s Division of Pharmacometrics, described the use of modeling to link changes in tumor size to survival outcomes for non-small cell lung cancer (NSCLC) chemotherapies.

“Clearly they have a deep interest in looking at tumor dynamics, as one of their senior people has written the seminal paper,” Bello said.

Wang and colleagues described tumor kinetics according to two related models, both of which rely on longitudinal clinical observations of tumor size. One is a treatment effect model that described how different drugs affected tumor size; the other a treatment-agnostic survival model that described how changes in tumor size predicted outcomes such...

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