Basic Premises Pipelines And Timelines

The pharmaceutical industry's goal of developing beneficial drugs is achieved through a well-organized process termed the pharmaceutical pipeline (Fig. 1). An outline of this process facilitates an understanding of both opportunities and challenges presented by pharmacogenomics. Compounds are selected (i.e., candidate selection, CS) based on promising chemical and biological properties that predict developability, a process that lasts anywhere from 12 months to several years. Following this, candidates are tested for toxicity in preclinical animal models, resulting in the filing of an IND (Investiga-tional New Drug application) with the regulatory agencies to obtain authorization to initiate the evaluation of the drug's safety and efficacy in man; this phase usually takes 12-18 months and follows well-defined regulatory guidelines. The next phase involves testing in humans, with "first time in human" (FTIH)/phase I studies aimed at evaluating

CS IND POC NDA

CS IND POC NDA

Preclinical FTtH Phase I Phase II Phase III

Fig. 1. The Pharmaceutical Pipeline. The different phases of drug development are outlined, starting with a lead compound and moving forward through preclinical and clinical testing towards market approval. (CS: candidate selection; IND: investigational new drug application; POC: proof of concept; NDA: new drug application; FTIH: first time in human).

Preclinical FTtH Phase I Phase II Phase III

Fig. 1. The Pharmaceutical Pipeline. The different phases of drug development are outlined, starting with a lead compound and moving forward through preclinical and clinical testing towards market approval. (CS: candidate selection; IND: investigational new drug application; POC: proof of concept; NDA: new drug application; FTIH: first time in human).

the safety of the new compound and selecting an appropriate dose, phase II studies geared at providing a "proof of concept" (POC) regarding the drug's efficacy, and, finally, phase III studies where the magnitude of clinical benefit over the standard care is defined and safety is assessed on a large number of patients. This latter part takes several years, as it depends on accumulating enough event rates, sufficient treatment duration, and length of follow up to ascertain efficacy and safety. Furthermore, in oncology the process of phase II—IV testing invariably continues in parallel in multiple types of cancer and in combination with other therapies even after achieving an initial marketing approval.

Given the overall time required to successfully develop a compound into a marketed drug, this uniform drug development approach has been successful at defining tangible milestones and providing a framework for assessing an overall return on investment. The return on investment then becomes a function of the value to the patient and society within the context of a limited drug patent life. As has been recognized, this process resides in its entirety only within the pharmaceutical industry (3), which has the resources and expertise required to accomplish these tasks and the metrics needed to make transition-point decisions on the potential progression of new compounds to market.

This assembly-line paradigm, even superimposed on a limited scientific understanding of disease etiology, has been remarkably successful in bringing new and effective drugs to market. The ever-increasing pace of scientific discovery and the deciphering of the human genome had been expected to yield a plethora of novel targets and means to realize their benefit (4,5); paradoxically however, the overall efficiency of the drug development process has been declining (6).

In so far as pharmacogenomics is the study of the relationship between the effects of a drug and the genomic makeup of the host (or tumor), new discoveries and technologies should enable a more productive discovery and development pipeline by maximizing the benefit-risk ratio of therapy—and doing so at earlier stages of drug discovery, thus reducing (expensive) attrition later in development. While this is a promising vision shared by the pharmaceutical industry, the regulatory agencies, and academia (7), many practical hurdles need to be overcome for this vision to be realized within acceptable costs, risks, and timeframes.

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