Drug Development Strategies

Penelope K. Manasco, M.D. and Teresa E.Apledge, D.V.M.


I. Introduction

Genetics will fundamentally change the practice of medicine and the process of drug development. The timing of this massive change is not certain; however, it is likely to occur in the next 5-10 years. The reasons for the change include the evolution of the science and technology in the fields of the human genome, single-nucleotide polymorphism (SNP) maps, genotyping, and bioinformatics. We are living through a momentous time when the convergence of scientific and technological developments has resulted in the possibility of new approaches to unraveling the mysteries of disease and health.

DNA was described less than 50 years ago. In 2000, the draft sequence of the entire human genome was released by the Human Genome Project (HGP), a publicly funded effort, and Celera, a privately held company. Through the discoveries enabled by the HGP, the SNP Consortium (a group of 11 pharmaceutical companies, 5 academic centers, 2 information technology companies, and the Wellcome Trust) expanded the map of the genome that had been used for the past 10 years from 400 markers to 1.7 million markers. The impact of this new map can be imagined in the following way. If you think of the distance from New York to California as the genome, the road signs would change from one every 7.5 miles to one every 9 feet. The markers (or road signs) are SNPs. The SNP Consortium released the map into the public domain so that anyone doing gene mapping experiments could use this new SNP map. The original 400 markers were difficult to measure and required significant laboratory personnel time. In contrast, SNPs are much easier to measure and high-throughput assays can be developed, decreasing the cost and time required to do whole genome scans. Advances in measurement of gene expression have also been phenomenal. In five years, the numbers of genes, sensitivity of the assays, and reproducibility of results have also increased significantly as has the ability to analyze the data. The measurement of gene expression has been used in several ways in cancer genetics and cancer pharmacogenomics. Gene expression has led to better ways to classify cancers and to select the appropriate therapy (Miyazato et al., 2001; Birner et al., 2001). Through a different avenue of technological development, the field of bioinformatics has also developed into a specialty in its own right. Computational experts take data from multiple sources (genetic data from different species, different tissues, and different types of studies, including the scientific literature) and make sense of it (Searls, 2001). Data exploration techniques that were developed through the study of vast amounts of biological data, data from space, and even data from the banking industry are now being focused on the problems of understanding the copious complex data from the genome.

The growth of the biotech industry has helped the field of genotyping technology development to bloom. Many companies with competing technologies are trying to meet the challenge of taking genotyping from a cost of $10.00 per genotype down to $.10 in a period of five years-with throughput increasing exponentially with the advent of high-throughput genotyping using SNPs.

The stage is now set to use all of these discoveries to improve the way we diagnose, treat, and even prevent disease. The changes in understanding disease will lead to new targets and better therapeutics, as well as changes in drug development. Although this chapter is designed to discuss the changes that the genetic and genomic revolution will make in drug discovery and development, the changes to the rest of the practice of medicine will be similarly astounding.


II. The Pharmaceutical Industry

The pharmaceutical industry faces many challenges today. Despite an increase in research and development (R&D) spending of more than $30 billion per year; there has actually been a decline in new drugs approved by the FDA on a yearly basis, with fewer than 30 new drugs approved in 2001. The attrition rate is still exceedingly high, and only one in 1000 compounds that are developed actually makes it to the market and only one in 10 of those compounds is a commercial success (as defined by sales of over $500 million per year). Each compound today costs approximately $800 million and over 10-15 years to develop and bring to the marketplace. When each compound fails, it is often not clear whether the failure can be attributed to the characteristics of the specific compound or the target. Most companies have taken the approach of bringing several compounds in different chemical classes forward for each biological target to try to minimize the risk that the toxicity of a single compound will derail the evaluation of a molecular target. Thus if the lead compound has unacceptable safety issues associated with early testing, a compound from another class of drugs is less likely to have the same safety concerns.

The costs of adverse events can be measured in many ways. Since 1997, 13 drugs were taken off the market because of unacceptable side effects (http://www.fda.gov/fdac/features/2002/chrtWithdrawals.html). The costs to the patients are significant, both to those who suffer the adverse events and to those who responded to the medicines and were unable to take them once they had been removed from the market. Lazarou et al. (1998) estimated that the deaths from adverse events from drugs was between the fourth and sixth leading cause of death in the United States. Johnson and Bootman (1995) estimated that in 1995, the cost of morbidity and mortality of drugs was approximately $76 billion. In 2001, Ernst and Grizzle (2001) updated the outputs from the Johnson and Bootman model and estimated the total annual cost of drug-related problems among ambulatory Americans at $177.4 billion. The FDA has made the issue of drug safety such a high priority that it has started a new Office of Postmarketing Surveillance (http://www.fda.gov/cder/present/dia-699/opdra2-dia/). Recent publications by the FDA have stressed that individualized therapy through pharmacogenetics and pharmacogenomics offers the hope of maximizing benefit and minimizing risk to patients (Lesko, 2002).

Not only is safety a key concern, better defining the responder population is also critical. Table 5.1 presents a review of the data from the Physicians Desk Reference (PDR) showing the variability in efficacy rates (as defined by the percent of responders) for every class of drugs. The percent of responders range from a low of 25% (oncology products) to a high of 80% (Cox2 inhibitors), with the majority of drugs having a responder rate of 50-60%. There are costs associated with lack of efficacy, including direct costs such as additional visits to the health care provider and loss of productivity for the patient as well as the indirect costs of continuing to suffer from the signs and symptoms of the illness while trying to find an efficacious drug.

Mark A. Rothstein. Pharmacogenomics: Social, Ethical, and Clinical Dimensions (2003).