Pharmacogenomics Space

In assessing the status of pharmacogenomics for drug discovery/development and clinical adaptation, a recent market analysis was completed by O'Dell and Doyle in 2004 (13). The market analysis was conducted by surveying 53 out of 200 person-contact databases. These individuals were representatives in pharmaceutical and diagnostic companies, regulatory and clinical colleagues, and others. The market was small, $800 million in 2002 as compared to the pharmaceutical market of $433 billion in 2003. Some of the key findings included the encouraging and engaging roles of the FDA and the need for physician education. It concluded that the pharmacogenomics approached a "tipping" point in 2003/2004. With the recent developments of several new FDA-approved pharmacogenomics testing/devices, pharmacogenomics "tipped" forward in the clinical pharmacogenomics/personalized medicine space, in part due to the proactive roles of the FDA in collaboration with other professional organizations for the past several years.

Another recent study funded by the European Commission examined the status of pharmacogenetics and the challenges for its applications (14). It reviewed the science and industry base in the United States, Europe, and Japan. Pharmacogenomics is regarded as interdisciplinary in 60 research institutions. The countries with more than 10 institutions are United States, 73; Germany, 35; UK, 27; Japan, 25; The Netherlands, 21; Sweden, 14; Italy and Switzerland, 13; and France, 12. The US institutions are usually better funded by National Institute of Health. European institutions received funding from the Government but not from the European Union. The major areas of research study are drug metabolism, disease mechanisms, and disease predisposition. These institutions collaborated more with other research groups than with companies, with the possible outcome of limiting the clinical applications. The commercial sector was comprised of about 47 companies, mostly small to medium sizes with a high turn-over rate of about 40%. However, the influx of new companies seemed to have maintained the total number. The business model may be divided into 12 options under the areas: drug discovery, drug safety in development, drug efficacy in development, marketed drug safety, and stratification of diseases and infectious agents. Furthermore, the top five areas are listed below.

1. Central nervous system.

2. Drug metabolism/toxicity.

3. Cardiovascular.

4. Cancer.

5. Infection.

Both FDA and the European Agency for the Evaluation of Medicinal Products (EMEA) are proactive but follow different paths. Whereas FDA provides guidance documents, EMEA conducts meetings with sponsors. The established clinical pharmacogenomics tests for the European countries would include HER2 testing for breast cancer and thiopurine methyltransferase (TPMT) for acute lymphoblastic leukemia. It concluded that many interdependent variables would contribute to clinical applications of pharmacogenomics.

By applying the genomic medicine for drug discovery and development, pharma-cogenomics has been regarded as a "new science." FDA has proactively outreached to the scientific colleagues in pharmaceutical companies, partially for the purpose of developing a rational approval process. A series of workshops were held in the Washington, D.C. area (Pharmacogenomics: first workshop, May, 2002, second workshop, November, 2003, and third workshop, April, 2005; Pharmacogenomic drug-diagnostic co-development workshop, July 2004; and Application and Validation of Genomic Markers, October 2005), followed by publications of guidance documents (first draft, November 2003 and final draft, March, 2005), and white/concept papers (Critical Path Initiative, March 2004 and Drug-diagnostic co-development, April, 2005) (15-26).

The topics included co-development of drug and diagnostics, sometimes regarded as "theranostics," and the voluntary genomics data submission (VGDS) process. More recently, VGDS was modified to VXDS—voluntary "X" data submission, with "X" representing diagnostic proteomic and other "omics" biomarkers in the future. In September

2006, the Center for Clinical Device and Radiological Health (FDA-CDRH) issued a draft of a guidance document "In Vitro Diagnostic Multivariate Index Assays" which addresses test system and data process, with implications to genetic testing. For practitioners of clinical pharmacogenomics, it would be important to follow the outcome of the final draft of this and other documents. Two recent chapters by the FDA-CDRH (27) and FDA-Center for Drug Evaluation and Research (28) provided guidance of the various regulatory issues related to use of pharmacogenomic biomarkers. In summary, the FDA workshops, the guidance documents, and publications of concept and white papers serve as enabling tools toward the practice of clinical pharmacogenomics.

As a result of the decreasing number of submissions as shown in Fig. 1, the critical path has been advocated by the FDA to facilitate the co-development of drugs along with genomic and proteomic diagnostic biomarkers (29). As an example and extension of that concept/practice, the Critical Path Institute (C-Path), founded by the University of Arizona as part of the Arizona Biosciences Roadmap in July 2005, is an independent, neutral, community-funded, non-profit/tax exempt organization. Other key members are SRI International and FDA. Funding sources included public sector, foundations, FDA, and Agency for Healthcare Research on Quality. It also has a partnership with universities such as George Washington University and professional organizations such as the Drug Information Association, the American College of Clinical Pharmacology, and others. It has a consortium of 13 pharmaceutical companies: Merck, Johnson & Johnson, Pfizer, Novartis, GlaxoSmithKline, Schering, Roche, AstraZeneca, Boehringer-Ingelheikm, Amge, Sanofi-Aventis, Bristol-Myers Squibb, and Abbott.

As shown by the model of collaboration in Fig. 2, the C-Path Institute would share methods, data, and strategies in order to ensure the safety of newly marketed drugs. Some of projects enlisted consortium of diagnostic and pharmaceutical companies to develop better treatment of lung cancer and to develop an approach for strokes treatment and to lower the incidence of death due to embolism via warfarin dosing therapy possibly by using pharmacogenomic biomarkers. According to the article by Feigal et al. (29), C-Path is currently undertaking 76 projects in six main categories.

1. Better evaluation tools.

2. Streamlining clinical trials.

3. Harnessing bioinformatics.

4. Modernizing manufacturing.

Submtoiloni to FDA by V«; for bocg -.1 and V-'L '- -■ .'>

80 70

SO 40 30 20 10

Fig. 1. Submissions to Food Drug Administration by year for biologics and New Molecular Entities (NME) drugs (29). Reprinted with permission.

Submtoiloni to FDA by V«; for bocg -.1 and V-'L '- -■ .'>

Fig. 1. Submissions to Food Drug Administration by year for biologics and New Molecular Entities (NME) drugs (29). Reprinted with permission.

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