The Application of Systematic Analysis for Identifying and Addressing the Needs of the Pharmacometric Process
Thaddeus Grasela, PharmD, PhD
Cognigen Corporation
The current implementation of a pharmacometric process has, in most cases, grown from the ad hoc application of modeling and simulation activities to the drug-development process. This ad hoc implementation gives rise to a number of serious deficiencies that currently obstruct the optimal performance and application of pharmacometrics. The accelerating shift from empirical to model-based development strategies - and the growing reliance on modeling and simulation in decision-making will require the successful transformation of the pharmacometrics enterprise to a critical path service sufficiently provisioned to operate at the requisite level of efficiency, effectiveness, and reliability. We propose to use enterprise engineering methods and techniques to perform a systematic analysis of the current pharmacometrics operating environment in order to address critical unmet systematic, informatic and processual needs of the pharmacometric process.
Objectives: To describe a process for performing forensic analyses of the challenges arising during modeling and simulation activities
To formalize the pharmacometric process so that it can function at the requisite level of efficiency, effectiveness and reliability to support model-based development
Methods: Ongoing forensic analyses of pharmacometric project team communications and work products during the performance of modeling and simulation activities will be performed. Specific programming instructions, such as the requirements for a NONMEM® analysis-ready dataset or instructions for a graphical display, coupled with team communications to resolve uncertainties and unanticipated complexities, along with subsequent deliverables will be used to develop a catalogue of the problems that arise. The nature of the gap between what was intended in the initial instructions and what was eventually defined via team communications to resolve uncertainties will be characterized and documented. The underlying entities and relationships that must be invoked for rigorous requirements definitions will be identified.
Results:
Requirements definitions will serve as a basis for a series of interrelated enterprise definition efforts, including:
- Refining the informatic elements required to fully inform programming efforts,
- Providing feedback to upstream processes to improve deliverable effectiveness,
- Informing subsequent pharmacometric enterprise design efforts,
- Defining content and direction for training needs, and
- Developing productivity tools.
Conclusions: By identifying and addressing the specific needs of the pharmacometrics process the systematic analyses, and accompanying training programs, will directly impact the pharmacometric enterprise in three ways. First, they will improve the productivity, quality, and cost attributes of the existing pharmacometric process. Second, these initiatives lay the groundwork for developing improved governance and operational management strategies for the pharmacometrics enterprise. Third, they will point the way for the development of an idealized blueprint for a model-based drug devleopment enterprise.
References:
[1] Grasela TH, Fiedler-Kelly J, Cirincione BB, Hitchcock D, Reitz KE, Sardella S et al. Informatics and the future of pharmacometric analysis. AAPS J . 2007. http://www.aapsj.org/view.asp?art=aapsj0901008
[2] Grasela TH, Dement CW. Engineering a Pharmacometrics Enterprise. In: Ette EI, Williams P, editors. The Science of Quantitative Pharmacology. Hoboken, NJ: John Wiley & Sons, Inc., 2007: 903-924.
