A large number of targeted anticancer drugs are currently under development and most of them will have a companion diagnostic linked to their use. If a diagnostic assay is developed in conjunction with a targeted anticancer drug, such an assay will later end up determining the conditions for the use of the drug after its approval. The assay then becomes a kind of ‘gatekeeper' in relation to which patients should be treated with the drug in question. This ‘gatekeeper' role implies that companion diagnostic assays must live up to the same regulatory standards and requirements known from drug development. The assays must have proven to be analytically robust and reliable and to have demonstrated clinical utility before they are routinely used in the clinic. In the drug-diagnostic codevelopment model, several ‘traditional' study designs have been used to demonstrate clinical utility. However, if we are to benefit from the increasing knowledge provided by molecular oncology, new ways should be developed to demonstrate the clinical utility of drug-diagnostic combinations. The development of such an approach will require a rethinking at different levels and is likely to include a number of ethical, regulatory and practical challenges.

Jørgensen JT: A changing drug development process in the era of personalized medicine. Drug Discov Today 2011;16:891-897.
No authors listed: Where will new drugs come from? Lancet 2011;377:97.
Jørgensen JT: Companion diagnostics and the drug-diagnostic co-development model. Drug Dev Res 2012;73:390-397.
Lerner HJ, Band PR, Israel L, Leung BS: Phase II study of tamoxifen: report of 74 patients with stage IV breast cancer. Cancer Treat Rep 1976;60:1431-1435.
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783-792.
Jørgensen JT, Winther H (eds): The development of the HercepTest - from bench to bedside; in: Molecular Diagnostics - The Key Driver of Personalized Cancer Medicine. Singapore, Pan Stanford, 2010, pp 43-60.
FDA 2012: In Vitro Companion Diagnostic Devices. http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm (accessed 21 November 2012).
Thomas J, Stratton E, Keppens M: Companion diagnostics: emerging strategies and issues in pharmaceutical development. Expert Rev Mol Diagn 2012;12:561-563.
Chustecka Z: Slew of Targeted Cancer Drugs on the Way. Medscape Medical News, 1 March 2012 http://www.medscape.com/viewarticle/759523 (accessed November 2012).
FDA 2011: In Vitro Companion Diagnostic Devices. Draft Guidance. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM262327.pdf (accessed November 2012).
EMA: Reflection paper on co-development of pharmacogenomic biomarkers and assays in the context of drug development. Draft. 24 June 2010. EMA/CHMP/641298/2008. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/07/WC500094445.pdf (accessed November 2012).
EMA: Reflection paper on methodological issues associated with pharmacogenomic biomarkers in relation to clinical development and patient selection. Draft. 9 June 2011. EMA/CHMP/917570/2011. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/07/WC500108672.pdf (accessed November 2012).
FDA: Drug-Diagnostic Co-Development Concept Paper. Draft. April 2005. http://www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/UCM116689.pdf (accessed November 2012).
Simon R, Maitournam A: Evaluating the efficiency of targeted designs for randomized clinical trials. Clin Cancer Res 2004;10:6759-6763.
Trusheim MR, Berndt ER, Douglas FL: Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers. Nature Rev Drug Discov 2007;6:287-293.
Duda DG, Ancukiewicz M, Jain RK: Biomarkers of antiangiogenic therapy: how do we move from candidate biomarkers to valid biomarkers? J Clin Oncol 2010;28:183-185.
Duda DG: Molecular biomarkers of response to antiangiogenic therapy for cancer. ISRN Cell Biol 2012;2012:1-11.
Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM, CLEOPATRA Study Group: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109-119.
Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K, EMILIA Study Group: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367:1783-1791.
FDA Approves Two Dako Assays as Companion Diagnostics for Genentech's New Breast Cancer Medicine Kadcyla. Agilent Technologies. http://www.agilent.com/about/newsroom/presrel/2013/05mar-dk13004.html (accessed 5 March 2013).
Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719-726.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD, Herceptin Adjuvant (HERA) Trial Study Team: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659-1672.
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673-1684.
Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group: Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011;365:1273-1283.
Andersson M, Lidbrink E, Bjerre K, Wist E, Enevoldsen K, Jensen AB, Karlsson P, Tange UB, Sørensen PG, Møller S, Bergh J, Langkjer ST: Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol 2011;29:264-271.
Winther H, Jørgensen JT: Drug-diagnostic co-development in cancer. Pharm Med 2010;24:363-375.
Burris H 3rd, Yardley D, Jones S, Houston G, Broome C, Thompson D, Greco FA, White M, Hainsworth J: Phase II trial of trastuzumab followed by weekly paclitaxel/carboplatin as first-line treatment for patients with metastatic breast cancer. J Clin Oncol 2004;22:1621-1629.
Baselga J, Carbonell X, Castañeda-Soto NJ, Clemens M, Green M, Harvey V, Morales S, Barton C, Ghahramani P: Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. J Clin Oncol 2005;23:2162-2171.
Nishimura R, Okumura Y, Arima N: Trastuzumab monotherapy versus combination therapy for treating recurrent breast cancer: time to progression and survival. Breast Cancer 2008;15:57-64.
Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A, Kennedy J, O'Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM: Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 2005;23:4265-4274.
Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D: Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2006;24:2786-2792.
Shojaei S, Gardaneh M, Rahimi Shamabadi A: Target points in trastuzumab resistance. Int J Breast Cancer 2012;2012:761917.
Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L: Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol 2011;9:16-32.
Mittendorf EA, Wu Y, Scaltriti M, Meric-Bernstam F, Hunt KK, Dawood S, Esteva FJ, Buzdar AU, Chen H, Eksambi S, Hortobagyi GN, Baselga J, Gonzalez-Angulo AM: Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes. Clin Cancer Re 2009;15:7381-7388.
Niikura N, Liu J, Hayashi N, Mittendorf EA, Gong Y, Palla SL, Tokuda Y, Gonzalez-Angulo AM, Hortobagyi GN, Ueno NT: Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors. J Clin Oncol 2012;30:593-599.
Lindström LS, Karlsson E, Wilking UM, Johansson U, Hartman J, Lidbrink EK, Hatschek T, Skoog L, Bergh J: Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression. J Clin Oncol 2012;30:2601-2608.
FDA: Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products. Draft Guidance. December 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM332181.pdf (accessed March 2013).
Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007;25:118-145.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-2516.
Ou SH: Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond. Drug Des Devel Ther 2011;5:471-485.
Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Jänne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693-1703.
CEDR, FDA: Medical Review. August 2011. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202570Orig1s000MedR.pdf (accessed December 2012).
FDA: Approval Order for Vysis ALK Break Apart FISH Probe Kit. August 2011. http://www.accessdata.fda.gov/cdrh_docs/pdf11/P110012a.pdf (accessed December 2012).
Mansfield E: Companion Diagnostics - FDA's Perspectives. Presentation at the FDA Seminar arranged by the Danish Embassy in Washington. Copenhagen, 15-16 November 2011.
Schilsky RL: Drug Approval Challenges in the Age of Personalized Cancer Treatment. Per Med 2011;8:633-640.
Weinstein IB: Cancer. Addiction to oncogenes - the Achilles heal of cancer. Science 2002;297:63-64.
Weinstein IB, Joe A: Oncogene addiction. Cancer Res 2008;68:3077-3080.
Garber K: New insights into oncogene addiction found. J Natl Cancer Inst 2007;99:264-265.
Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366:883-892.
Kreso A, O'Brien CA, van Galen P, Gan OI, Notta F, Brown AM, Ng K, Ma J, Wienholds E, Dunant C, Pollett A, Gallinger S, McPherson J, Mullighan CG, Shibata D, Dick JE: Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science 2013;339:543-548.
Lesko LJ, Zineh I, Huang SM: What is clinical utility and why should we care? Clin Pharmacol Ther 2010;88:729-733.
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