Pharmacometric Enterprise

Current pharmacometrics practices and available techniques for model-based development are heavily constrained by a vision of model-based development as a subsidiary development process in an empirical development paradigm. Many of the symptoms of the less than optimal functioning of pharmacometrics in this setting are the result of a failure to appreciate the true needs and requirements of the pharmacometrics group. In this chapter, we use the term pharmacometrics enterprise to denote the need to transform the current pharmacometrics analysis process to an interdependent enterprise capable of managing the growing complexity of the critical upstream and downstream implications of a fully functional and accountable service. The design of a pharmacometrics enterprise that embodies the required elements is a novel and complex endeavor that can overtax the experience and... 

The preceding is meant to emphasize that the capability of a pharmacometrics enterprise is directly determined by the scope, effectiveness, and efficiencies of the processes that the enterprise executes and the infrastructure that supports those... 

Solution. The output of an enterprise is generically referred to as a solution and it can be a product, a service, or, in the case of a pharmacometrics enterprise, information about the determinants of drug safety and efficacy. Solution realization is a general term for processes that dehne and dehver solutions to the needs and requirements that stem from stakeholder purposes. The pharmacometric analysis process would be an example of a pharmacometric solution realization and it is described in detail in Section 36.3. 

A pharmacometrics enterprise is, intrinsically and by definition, a needs-driven solution-oriented enterprise. Therefore, establishing a pharmacometrics service consists of designing and implementing specific variants of the nine processes enumerated above and the infrastructure required to execute and sustain them. The core process of a pharmacometrics service enterprise is pharmacometric analysis, conceived of and visualized in Figure 36.2 as a specific variant of solution... 

Three of the supervening enterprise processes highlighted in Figure 36.2 are particularly important in the context of engineering or reengineering a pharmacometrics enterprise in an industry undergoing a profound transformation. These three key processes include Intent Formalization, Enterprise Definition, and Enterprise Programming. 

Integrating both pharmacokinetic and pharmacodynamic analyses, a life-cycle complete pharmacometric analysis process comprises seven major subprocesses, as depicted in Figure 36.3. That is, any comprehensive pharmacometrics enterprise will be capable of executing and governing the complete process—all seven major subprocesses—from invocation to termination. Of course, not every performance of the service will necessarily require the comprehensive and complete pharmacometrics enterprise. 

Rigorous techniques for technical effectiveness and performance measurement exist and have been used for years and must be mined for applicable lessons and directions for the pharmacometrics enterprise. The development of an integrated solution to these strategic and technical challenges is a particularly difficult, but nonetheless crucial, effort that will define the level of performance achievable by a pharmacometrics service in model-based development. 

There are four key requirements that, programmatically speaking, constitute critical success factors for the desired level of effectiveness of the pharmacometrics enterprise. These requirements stem from the shift in roles of the pharmacometrics enterprise that mandates a clear formalization of intents from the larger drug realization enterprise and provide answers to several key questions What are the actual requirements for the hosting organization What are the implications of deploying a solution to those requirements What resources are available and would be required to pursue such an initiative ... 

Definitive Characterizations of Stakeholder Aims. The purposes of a pharmacometrics enterprise must be explicitly defined to enable action programs, with their upstream and downstream implications for the drug realization process, to be devised and executed. Purposes typically exemplify tremendous variations in several dimensions. They range from the abstract to concrete from the unattainable to the trivial from the short-term to the long-term. Some purposes are identical, some are congruent, and some are diametrically opposed. Some purposes depend on the successful attainment of others in order for them to be accomplished. 

The capabilities and resources of even the most well funded pharmacometrics enterprise are finite, and it is almost always impossible to achieve all of the aims of its stakeholders to the degrees they desire. An achievable and acceptable balance must be struck. Requirements antecedent to the purposes of the pharmacometrics enterprise must be identified to enable the synthesis, development, and use of specific solutions for implementing the analysis process. QuaUfication criteria must be explicitly defined to enable governance of the actions of pharmacometricians and to enable determination of the value of the solution. 

Demonstrable Traceability. Proposed pharmacometric enterprise capabilities and assets must constitute demonstrable solutions to the strategic, technical, and infrastructure requirements entailed by stakeholder aims. This in turn mandates an enterprise design, or architecture, that is provably traceable to the mission requirements. This enterprise architecture requires the identification of the needs and requirements stemming from mission definitions, synthesis of system element designs entailed by the needs and requirements, and an evaluation process based on measures of acceptability. 

Actionable Assurance Process. The results of analyses performed by the pharmacometrics enterprise will not always align with stakeholder expectations. In fact, expectations may themselves be invalidated by changes in the environment, includ-... 

The challenges of designing a pharmacometrics enterprise that can achieve requisite levels of efficiency, effectiveness, and capability stem from the unmet, and in some cases poorly recognized, needs of the pharmacometrics analysis process. Many of these needs can be addressed by using the following criteria to guide enterprise engineering efforts. 

There are two fundamental ways an enterprise can execute a process. The first is unilaterally—the enterprise acts alone or at least is the dominant execution and governance agency in the process. The second is multilaterally—the enterprise acts in concert with others. Unilateral action is efficient but requires total command of all the resources and capabilities to execute and govern a process. Multilateral action is less efficient because it requires consensus building and coordination. However, multilateral action does not require total command of all the resources and capabilities to execute a process it is a strategy to accomplish stakeholder purposes with less. The intensely competitive and global pharmaceutical business environment places severe constraints on the resources available to a pharmacometrics enterprise to achieve and sustain success. The capability to act in multilateral partnerships with various stakeholders is a very effective means to achieve this success. Thus, the design of an effective pharmacometrics service should be assessed in terms of how... 

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