Food and Drug Administration Rockville Maryland USA

The science of contemporary drug development is a tremendously complex and costly process but it has successfully advanced our understanding of modern diseases and has improved public health significantly by providing society with many valuable drug treatments. A crucial step in the drug development process is the submission of nonclinical and clinical data and information in a New Drug Application (NDA) to the Food and Drug Administration (FDA) by a sponsor seeking marketing authorization. A typical new molecular entity (NME) that is the subject of a NDA has most likely been studied preclinically for 5-7 years and has been in clinical trials for 6-7 years. The average cost of bringing an NME to market is somewhere between 500 and 800 million dollars including the costs of lost opportunities and lead-compound failures [1]. With this investment of time and money, many scientists involved in drug development have explored various ways to make drug development as efficient, and yet informative, as possible [2].

Despite its successes, the drug development process, including regulatory decision-making based on benefit/risk assessments, can be improved in three areas.

1. Provide a greater understanding of human health and the causes of diseases at a genomic or molecular level. This would address the well-known heterogeneity of disease states that underlies the wide interindividual variation in efficacy observed with many common treatments. For example, incomplete or absence of response occurs in 30-50% of eligible patients with hypercholesteremia who are treated with "statins." With greater insights into health and disease, sponsors would be more likely to identify a target protein or receptor and to find the best NME to provide preventive, curative, or palliative treatment for patients.

2. Improve the safety of medicines. Adverse drug reactions (ADRs) have had a major impact on morbidity, mortality, and health economics. In studies going back to 1974, up to the present time, approximately 15-20% of hospitalized children and 25-30% of hospitalized adults have experienced drug-related adverse events [3, 4]. The overall incidence of drug-induced adverse events in nonhospitalized patients is thought to be around 7% [5]. The economic cost of drug-related morbidity and mortality to society has been estimated to be almost 200 billion dollars [6]. While there are many reasons, some of them unknown, for the relatively high incidence of ADRs (e.g., medication errors, drug interactions), it is thought that the majority of the risks associated with drug therapy are known and most drug-related adverse events are preventable [7].

3. Optimize drug doses and dosing schedules. Approximately 70% of drug-related adverse events are due to extended pharmacological actions. Thus, there is growing evidence to suggest that drug doses approved for marketing may be higher than is necessary and may be contributing to the high frequency of serious drug side effects. A recent study that examined the doses of 354 prescription drugs recommended in the label and released between 1980 and 1999 found that approximately 17% of these drugs had a reduction in dose or a new restriction for use in special populations such as patients with renal or hepatic disease [8]. Furthermore, it has been reported that prescribers in their practice frequently use doses which are lower than the FDA-approved label dose [9]. In an informal survey, it was also found that doses approved in other countries, e.g., Japan, are lower than those approved in the United States and most often there are no apparent scientific rationale for these differences.

These three areas of improvement should be viewed as a challenge to the scientific community in industry, academia, and the regulatory agencies to engage in dialogue and scientific collaboration to optimize the drug development process. This is especially important in light of the emergence of new genetic technologies and our understanding of the human genome that provides us new ways to ask important questions during the drug development process. Indeed, the promise of personalized or predictive medicine that stems from pharmacogenetics and pharmacogenomics means that the benefit/risk ratio of drugs is systematically optimized by identifying and selecting the right drug target, developing the right drug, and delivering the right dose to the right patient.

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