Skip to main content
SpringerLink
Log in
Book cover

Omics for Personalized Medicine pp 123–145Cite as

Omics Approaches and Applications in Clinical Trials

  • Chapter
  • First Online:

  • 1896 Accesses

Abstract

Clinical trials are aimed at compiling evidence of efficacy and safety through the use of drugs in a large number of patients. Large numbers are required to overcome the issues such as disease heterogeneity, partial understanding of the underlying disease mechanisms, and variability in drug response adverse drug reactions. Due to poor efficacy and suboptimal safety, the failure rate of potential products in development is more than 90 %. This pipeline attrition has an enormous cost – both financially and time-wise.

Novel approaches and tools of omics, especially “pharmacogenomics,” have enabled exploration of the molecular mechanisms underlying differences in drug response and thereby reduce attrition. After the sequencing of human genome, genomic information has benefitted the mankind in a number of ways. The stratification of patients based on their genotype, thus prevents the occurrence of severe drug reactions and better clinical outcome in susceptible patients, is one of the few examples of use of genomics in the area of health care. Pharmacogenomics identifies safety biomarkers and provides an opportunity to rescue a compound that would otherwise fail to be commercialized due to safety concerns. Further the knowledge of pharmacogenomics along with bioinformatics during different phases of clinical trials will formulate the drugs with more therapeutic effectiveness and with minimum adverse effects. This will also reduce the cost of adverse drug reactions being experienced by the patients and chances of withdrawal of the drug molecule from the market.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Ahn C (2007) Pharmacogenomics in drug discovery and development. Genomics Inform 5(2):41–45

    Google Scholar 

  • Anon (2001) Tufts Centre for the Study of Drug Development pegs cost of a new prescription medicine at $802 million. Press Release, Tufts Centre for the Study of Drug Development, Tufts University. 30 November. http://www.tufts.edu/med/csdd/

  • Aronson JK (2004) What is a clinical trial? Br J Clin Pharmacol 58(1):1–3

    Article  CAS  PubMed  Google Scholar 

  • Beutler E, Gelbart T, Demina A (1998) Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A 95:8170–8174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhatt A (2010) Evolution of clinical research: a history before and beyond James Lind. Perspect Clin Res 1:6–10

    PubMed  PubMed Central  Google Scholar 

  • Boa AN (2003) Introduction to drug discovery. Department of Chemistry, University of Hull, Hull

    Google Scholar 

  • Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Oude Elferink RP et al (1995) The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 333:1171–1175

    Article  CAS  PubMed  Google Scholar 

  • Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, Wu JY, Chen YT (2004) Medical genetics: a marker for Stevens–Johnson syndrome. Nature 428:486

    Article  CAS  PubMed  Google Scholar 

  • Council for International Organizations of Medical Sciences (CIOMS) (2005) Pharmacogenetics: towards improving treatment with medicines. CIOMS, Geneva

    Google Scholar 

  • Daly AK (2003) Pharmacogenetics of the major polymorphic metabolizing enzymes. Fundam Clin Pharmacol 17:27–41

    Article  CAS  PubMed  Google Scholar 

  • DiMasi JA (2002) The value of improving the productivity of the drug development process: faster times and better decisions. Pharmacoeconomics 3:1–10

    Article  Google Scholar 

  • DiMasi JA, Hansen RW, Grabowski HG (2003) The price of innovation: new estimates of drug development costs. J Health Econ 22(2):151–185

    Article  PubMed  Google Scholar 

  • Evans WE, McLeod HL (2003) Pharmacogenomics – drug disposition, drug targets, and side effects. N Engl J Med 348(6):538–549

    Article  CAS  PubMed  Google Scholar 

  • Evans WE, Horner M, Chu YQ, Kalwinsky D, Roberts WM (1991) Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr 119:985–989

    Article  CAS  PubMed  Google Scholar 

  • FDA CDER/CBER/CDRH (2005) Guidance for industry: pharmacogenomic data submission. Posted on March 22, 2005: http://www.fda.gov/cder/guidance/6400fnl.pdf

  • FDA. Table of pharmacogenomic biomarkers in drug labels. http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics

  • Frank M (2008) Application of pharmacogenomics in clinical trials. In: Cohen N (ed) Pharmacogenomics and personalized medicine, Ith edn. Humana Press, Totowa

    Google Scholar 

  • Geisen C, Watzka M, Sittinger K, Steffens M, Daugela L, Seifried E, Muller CR, Wienker TF, Oldenburg J (2005) VKORC1haplotypes and their impact on the inter-individual and interethnical variability of oral anticoagulation. Thromb Haemost 94:773–779

    PubMed  Google Scholar 

  • Gilbert J (2003) Rebuilding big PhRMA’s business model. In Vivo 21:73–80

    Google Scholar 

  • Gupta E, Lestingi TM, Mick R, Ramirez J, Vokes EE, Ratain MJ (1994) Metabolic fate of ironectin in humans correlation of glucuronidation with diarrhea. Cancer Res 54:3723–3725

    CAS  PubMed  Google Scholar 

  • Guzey C, Norstrom A, Spigset O (2002) Change from the CYP2D6 extensive metabolizer to the poor metabolizer phenotype during treatment with bupropion. Ther Drug Monit 24:436–437

    Article  PubMed  Google Scholar 

  • Henry D, Lexchin J (2002) The pharmaceutical industry as a medicines provider. Lancet 360(9345):1590–1595

    Article  PubMed  Google Scholar 

  • Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD (2002) Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 359:1121–1122

    Article  CAS  PubMed  Google Scholar 

  • Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, Lin YL, Lan JL, Yang LC, Hong HS, Chen MJ, Lai PC, Wu MS, Chu CY, Wang KH, Chen CH, Fann CS, Wu JY, Chen YT (2005) HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 102:4134–4139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ingleman-Sundberg M (2004) Human drug metabolizing cytochrome P450 enzymes: properties and polymorphisms. Naunyn Schmiedebergs Arch Pharmacol 369:89–104

    Article  Google Scholar 

  • Innocenti F, Iyer L, Ratain MJ (2000) Pharmacogenetics: a tool for individualizing antineoplastic therapy. Clin Pharmacokinet 39:315–325

    Article  CAS  PubMed  Google Scholar 

  • Innocenti F, Grimsley C, Das S, Ramírez J, Cheng C, Kuttab-Boulos H, Ratain MJ, DiRienzo A (2002) Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 12:725–733

    Article  CAS  PubMed  Google Scholar 

  • Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramírez J, Rudin CM, Vokes EE, Ratain MJ (2004) Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22:1382–1388

    Article  CAS  PubMed  Google Scholar 

  • International HapMap Project (2007) HapMap homepage. Retrieved February 1, 2008 from http://www.hapmap.org

  • Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, Coffman BL, Ratain MJ (1998) Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 101:847–854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iyer L, Hall D, Das S, Mortell MA, Ramírez J, Kim S, Di Rienzo A, Ratain MJ (1999) Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin Pharmacol Ther 65:576–582

    Article  CAS  PubMed  Google Scholar 

  • Iyer L, Das S, Janisch L, Wen M, Ramírez J, Karrison T, Fleming GF, Vokes EE, Schilsky RL, Ratain MJ (2002) UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2:43–47

    Article  CAS  PubMed  Google Scholar 

  • Kalow W, Tang BK, Endrenyi I (1998) Hypothesis: comparisons of inter- and intra-individual variations can substitute for twin studies in drug research. Pharmacogenetics 8:283–289

    Article  CAS  PubMed  Google Scholar 

  • Kirk RJ, Hung JL, Horner SR, Perez JT (2008) Implications of pharmacogenomics for drug development. Exp Biol Med (Maywood) 233(12):1484–1497

    Article  CAS  Google Scholar 

  • Klein TE, Chang JT, Cho MK, Easton KL, Fergerson R, Hewett M, Lin Z, Liu Y, Liu S, Oliver DE, Rubin DL, Shafa F, Stuart JM, Altman RB (2001) Integrating genotype and phenotype information: an overview of the PharmGKB Project. Pharmacogenomics J 1:167–170

    Article  CAS  PubMed  Google Scholar 

  • Lazarou J, Pomeranz BH, Corey PN (1998) Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. J Am Med Assoc 279:1200–1205

    Article  CAS  Google Scholar 

  • Lee W, Lockhart AC, Kim RB, Rothenberg ML (2005) Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development. Oncologist 10(2):104–11

    Article  CAS  PubMed  Google Scholar 

  • Leeder JS, Kearns GL, Spielberg SP, van den Anker J (2010) Understanding the relative roles of pharmacogenetics and ontogeny in pediatric drug development and regulatory science. J Clin Pharmacol 50(12):1377–1387

    Article  PubMed  Google Scholar 

  • Lennard L, Gibson BE, Nicole T, Lilleyman JS (1993) Congenital thiopurinemethyltransferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia. Arch Dis Child 69:577–579

    Article  CAS  PubMed  Google Scholar 

  • Lesko LJ, Woodcock J (2004) Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective. Nat Rev Drug Discov 3:763–769

    Article  CAS  PubMed  Google Scholar 

  • Lesko LJ, Salerno RA, Spear BB, Anderson DC, Anderson T, Brazell C, Collins J, Dorner A, Essayan D, Gomez-Mancilla B, Hackett J, Huang SM, Ide S, Killinger J, Leighton J, Mansfield E, Meyer R, Ryan SG, Schmith V, Shaw P, Sistare F, Watson M, Worobec A (2003) Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: report of the first FDA-PWG-PhRMA-DruSafe Workshop. J Clin Pharmacol 43:342–358

    Article  CAS  PubMed  Google Scholar 

  • Lindpaintner K (2002) Pharmacogenetics and the future of medical practice. Br J Clin Pharmacol 54:221–230

    Article  PubMed  Google Scholar 

  • Lowe D (2006) What you need to know about adaptive trials. Pharm Exec Jul 1

    Google Scholar 

  • Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139

    Article  CAS  PubMed  Google Scholar 

  • Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT (2002) Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse transcriptase inhibitor abacavir. Lancet 359:727–732

    Article  CAS  PubMed  Google Scholar 

  • Mancinelli L, Cronin M, Sade’e W (2000) Pharma-cogenomics: the promise of personalized medicine. AAPS PharmSci 2(1):1–13. http://aapspharmsci.org/articles/ps0201/ps020104/ps020104.pdf

  • McCarthy AD, Kennedy JL, Middleton LT (2005) Pharmacogenetics in drug development. Philos Trans R Soc B 360:1579–1588

    Article  CAS  Google Scholar 

  • Motl S, Miller SJ, Burns P (2003) Programs established by FDA to expedite patient access. Am J Health Syst Pharm 60(4):339–345

    PubMed  Google Scholar 

  • Noble ME, Endicott JA, Johnson LN (2004) Protein kinase inhibitors: insights into drug design from structure. Science 303:1800–1805

    Article  CAS  PubMed  Google Scholar 

  • Papanikolaw J (1999) Bioinformatics emerges as key technology for developing new drugs. Chem Mark Report 255(21):ABI/INFORM 22

    Google Scholar 

  • Park BK, Pirmohamed M (2001) Toxicogenetics in drug development. Toxicol Lett 120(1–3):281–291

    Article  CAS  PubMed  Google Scholar 

  • Patent Prosecution in Pharmacogenomics. More information is available on http://www.iploft.com/

  • Pauli-Magnus C, Kroetz DL (2004) Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1). Pharm Res 21:904–913

    Article  CAS  PubMed  Google Scholar 

  • Pirmohmad M, Lewis G (2004) The implications of pharmacogenetics and pharmacogenomics for drug development and health care. In: Mossialos E, Mrazek M, Walley T (eds) Regulating pharmaceuticals in Europe: striving for efficiency, equity and quality. Open University Press, Maidenhead

    Google Scholar 

  • Public Citizen (2001) Rx R&D myths: the case against the drugs industry “scare card”. http://www.citizen.org/publications/release.cfm?ID=7065

  • Ratti E, Trist D (2001) Continuing evolution of the drug discovery process in the pharmaceutical industry. Pure Appl Chem 73(1):67–75

    Article  CAS  Google Scholar 

  • Rau T, Wohlleben G, Wuttke H, Thuerauf N, Lunkenheimer J, Lanczik M, Eschenhagen T (2004) CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants – a pilot study. Clin Pharmacol Ther 75:386–393

    Article  CAS  PubMed  Google Scholar 

  • Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, Pui CH, Evans WE (1999) Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91:2001–2008

    Article  CAS  PubMed  Google Scholar 

  • Robertson JA, Brody B, Buchanan A, Kahn J, McPherson E (2002) Pharmacogenetic challenges for the health care system. Health Aff 21(4):155–167

    Article  Google Scholar 

  • Roses AD (2000) Pharmacogenetics and the practice of medicine. Nature 405:857–865

    Article  CAS  PubMed  Google Scholar 

  • Roses AD (2004) Pharmacogenetics and drug development: the path to safer and more effective drugs. Nat Rev Drug Discov 3:645–656

    Article  Google Scholar 

  • Rothenberg ML, Kuhn JG, Burris HA 3rd, Nelson J, Eckardt JR, Tristan-Morales M, Hilsenbeck SG, Weiss GR, Smith LS, Rodriguez GI et al (1993) Phase I and Pharmacokinetic trial of weekly CPT-11. J Clin Oncol 11:2194–2204

    CAS  PubMed  Google Scholar 

  • Shyh-Yoh L, Stringer F, Hirayama M (2012) The impact of pharmacogenomics research on drug development. Drug Metab Pharmacokinet 27(1):2–8

    Article  Google Scholar 

  • Stanford University (2007) PharmGKB: the pharmacogenetics and pharmacogenomics knowledge base. Retrieved January 31, 2008 from http://www.pharmgkb.org

  • Surendiran A, Pradhan SC, Adithan C (2008) Role of pharmacogenomics in drug discovery and development. Indian J Pharmacol 40(4):137–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sweeney BP (2005) Pharmacogenomics: the genetic basis for variability in drug response. In: Cashman JN, Grounds RM (eds) Recent advances in anaesthesia and intensive care, vol 23. Cambridge University Press, Cambridge, pp 1–34

    Google Scholar 

  • Turner SD, Crawford DC, Ritchie MD (2010) Methods for optimizing statistical analyses in pharmacogenomics research. Expert Rev Clin Pharmacol 2(5):559–570, Author manuscript; available in PMC

    Article  Google Scholar 

  • Usdin S (2008) Proof is in the pudding. Biocentury 16(14):A1–A6

    Google Scholar 

  • Vaidyanathan G (2012) Redefining clinical trials: the age of personalized medicine. Cell 148:1079–1080

    Article  CAS  PubMed  Google Scholar 

  • Vogel F (1959) Moderneprobleme der humangenetik. Ergeb Inn Med Kinderheilkd 12:52–125

    Article  Google Scholar 

  • Vogel CL, Franco SX (2003) Clinical experience with trastuzumab (herceptin). Breast J 9(6):452–462

    Article  CAS  PubMed  Google Scholar 

  • Weinshilboum R (2003) Inheritance and drug response. N Engl J Med 348:529–537

    Article  PubMed  Google Scholar 

  • Xie HG, Kim RB, Wood AJ, Stein CM (2001) Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol 41:815–850

    Article  CAS  PubMed  Google Scholar 

  • Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH, Relling MV, Evans WE (1997) Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 126(8):608–614

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Apollo Health City, Jubilee Hills, Hyderabad, Andhra Pradesh, India

    Sanjeev Sharma

  2. Department of Molecular Biology, Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad, 500016, Andhra Pradesh, India

    Anjana Munshi

Authors
  1. Sanjeev Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anjana Munshi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sanjeev Sharma .

Editor information

Editors and Affiliations

  1. Centre for Genomics & Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Purba Medinipur, West Bengal, India

    Debmalya Barh

  2. Institute of Life Sciences, B.V. Patel Pharmaceutical Education and Research Development Centre, Ahmedabad University, Ahmedabad, Gujarat, India

    Dipali Dhawan

  3. Policy Centre for Biomedical Research, Translational Health Science and Technology Institute (Department of Biotechnology Institute, Government of India), Office @ National Institute of Immunology, New Delhi, India

    Nirmal Kumar Ganguly

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer India

About this chapter

Cite this chapter

Sharma, S., Munshi, A. (2013). Omics Approaches and Applications in Clinical Trials. In: Barh, D., Dhawan, D., Ganguly, N. (eds) Omics for Personalized Medicine. Springer, New Delhi. https://doi.org/10.1007/978-81-322-1184-6_7

Download citation

Publish with us

Policies and ethics

Search

Navigation