Technical Infrastructure Supporting a Model-Driven Future
by Daniel Weiner, PhD, Mark Hovde, and Adam Rutkin
The move to model-based drug development presupposes the ready availability of PK/PD data to support model building. When data are not readily available, the time needed to locate, clean, and prepare the data for analysis may cause delay in overall project execution and effective decision-making. The problem is growing as increases in the number of trials per development compound, the number of patients per trial, and the number of samples per patient are causing rapid escalation in PK data volumes.
The FDA acknowledges these trends and has proposed utilization of model-based approaches to improve drug development knowledge management and decision-making. Several historical Guidances, a more recent focus to incorporate model-based drug development into its review process with voluntary End of Phase IIa meetings, and newly published FDA-led applied research on pharmacometric analysis provide substantial evidence that FDA is moving in a direction of increasing reliance on quantitative modeling and simulation. As FDA moves in this direction, a critical question must be asked: how will FDA cope with the increasing data management challenges it will face as it takes a more active role in the evaluation and creation of drug and disease models?
Dr. Robert Powell, director of FDA’s Division of Pharmacometrics, recently presented on the topic of FDA’s possible plans for a modern PK/PD data management architecture at the Pharsight PKS™ User Group meeting in October, 2005. In his speech delivered to PKS user companies representing 15 top pharmaceutical and biotech organizations, Dr. Powell discussed FDA’s need for a centralized clinical pharmacology data repository, for which PKS is currently being evaluated. Such a repository can be used to create a productive and validated workflow collecting all inputs and supporting all analyses.
Slide presented by Bob Powell, Pharm.D., Director of Pharmacometrics, FDA, at 2005 Pharsight PKS User Group Meeting. Slide courtesy Bob Powell.
A fully integrated PK/PD data management repository can improve compliance with 21 CFR Part 11 with regard to pharmacokinetic data stored for internal and regulatory review as well as electronic submission. A repository also addresses the problem of a lack of central management of the wealth of PK related knowledge generated in discovery, lead optimization and development, and how that knowledge can be optimized through modeling and simulation of clinical trial designs and clinical development programs. A repository also facilitates productivity improvements by reducing quality assurance overhead to uncover unavoidable data mismatches caused by manual data transformation steps. Finally, a repository can reduce long data preparation cycles for PK analysis, interpretation and presentation, due to fragmented source data from multiple heterogeneous systems with incompatible formats, and can reduce extensive lead-out time due to cumbersome manual data transcription and transfer steps for the preparation of report tables and graphs.
Several important challenges must be met to move forward with an integrated PK/ PD data repository. The first is a profound adoption of standards. Without standards the value of a central data repository is severely limited. Standards must be adopted for data definitions, workflow, analysis, and reporting. The second principle is the use of automation wherever possible. Pharsight clients have estimated that they spend, on average, 40 hours of quality control for each clinical pharmacology report. Because automation imposes a need for discipline across the organization, it requires a management mandate. However, once committed to, automation frees up quality assurance staff and increases the productivity of the pharmacokineticists who actually perform the work.
FDA’s move to increased reliance on proactive modeling and simulation has begun to drive trial designs and involve FDA and sponsors in more intensive communication about modeling assumptions and conclusions. Effective communication is a key component of a successful modeling and simulation effort, particularly for team members who approach key development questions from their own functional and disciplinary vantage points (e.g., PK/PD, clinical medicine, biostatistics, clinical pharmacology). For these and other project team members, who are often separated by geography in today’s global pharmaceutical environment, there is often a lack of familiarity with models or modeling techniques that makes it challenging to develop confidence in model-based results.
Products like Pharsight’s Drug Model Explorer™ (DMX®) can play a role in facilitating communication and use of modeling results. DMX allows all project team members to easily view and query the modeled efficacy, safety, and other performance attributes of a new drug versus competing therapies. It also provides a uniform visual framework for presentation of modeling and simulation results, and serves as a database of current knowledge for a compound and its competitors that can be updated when new information becomes available.
The full potential of modeling and simulation will be realized when sponsor R&D management fully commits to implementation of data, workflow, and reporting standards, and builds state-of-the-art technical infrastructure for managing and communicating the growing volume of PK/PD data and modeling results. Continued commitment to technical PK/PD infrastructure will enhance the productivity and capabilities of modeling and simulation practitioners, and will also support further adoption of software tools that make modeling results more accessible to drug development teams and organizational decision-makers.