Fig. 2.24. Factors in R&D Decisions (Example @ Phase 2/3) (Copyright 2006 from Encyclopedia of Pharmaceutical Technology, 3rd Ed by Swarbrick. Reproduced by permission of Routledge/Taylor & Francis Group, LLC) (Reprinted with permission from Pharmaceutical Executive, Vol 24, No. 2, 2004, page 58. Pharmaceutical Executive is a copyrighted publication of Advanstar Communication Inc. All rights reserved.)

Source: CenterWatch 2004

drug examples in many pharmacologic classes and subsets of patients exist where individual patients experience adversity, but finding those patients in a practical, cost-effective, clinically useful manner remains a major challenge to health care. These diagnostic tests are not routinely done today in clinical practice, which could change especially in oncology.

Figure 2.25 presents the pros and cons in incorporating pharmacogenomic approaches in product development plans. Drug developers suggest that many of the 20 drug withdrawals from the market after approval over the past 20 years was due to unexpected serious adverse experiences potentially related to pharmacogenomic variation in the population. Pharmacogenomic variation is starting to be used in drug development in cancer area. In efficacy, Herceptin® (monoclonal antibody) is only effective in breast cancer patients with her2neu oncogene present. Gleevec® is tyrosine kinase inhibitor and highly effective in chronic myelogenous

Pros (Proposed):

o More Safety in phase 1 o Identify best responders o More efficient trials o Identify outliers with SAE e Explain unusual AEs o Fewer late stage failures o Avoid PI restrictions c Less cost of drug development

Cons (Costs & Challenges):

o Cost of genotyping c Patient consent x 2 needed c SNP diagnostic tests not done c Clinical significance?

o SNPs polygenic, utility?

c SNPs predict disease?

o Insurance Impact c Ethics & Access to data o FDA regulation of PIs & trials c Market of drug reduced

Fig. 2.25. Pharmacogenomic Issues in Development leukemia patients with the c-abl oncogene fused to the bcr cluster protein region. For toxicity, the hepatic enzyme system cytochrome p-450 is involved in metabolism of many drug categories (e.g., beta-blockers, tricyclic antidepressants), with numerous different mutations common often in ethnic groups; they alter drug clearance and lead to toxic effects. However, identification of these patients is not done routinely in clinical practice, they add cost to health care system, the tests are not readily available, and education of professionals is lacking. Furthermore, FDA has only recently written (end of 2004) proposed optional guidelines for use of pharmacogenomics in drug development. This discipline could help identify the best responders or patients more likely to experience adverse effects. However, added cost to drug development without proven diagnostic capability, with high variability, unsure ethics, unsure insurance issues, and negative impact on the market, are some of the current challenges [13, 49, 50].

Administration of products to patients depends on the properties of drug or biological products, disease characteristics, human physiology, and health care system variables, which will impact the formulation options desirable for a new product (Fig. 2.26). Products must cross several biologic membranes from their site of administration and encounter endogenous enzymes that could alter their activity. Goals of formulation development include mechanical and physical stability that is compatible with how product will be used, long shelf-life, maximum patient acceptance, provider utility, bioavailability, lowest cost of goods to manufacture, competitive advantage, and less local adverse effects with use. Most products are intended for oral use as tablets, capsules, or liquids, which is preferred by patients, but the disease or drug metabolism may not permit this route of administration.


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