Abstract
The role of noninvasive imaging in clinical trials has evolved, thanks both to improvements in conventional morphologic imaging and also to innovation in molecular and functional imaging techniques. In this chapter, some basic principles of clinical trials are explained, and the role of imaging biomarkers is discussed with examples. The main emphasis is on the application of imaging biomarkers as outcome measures in therapeutic drug trials, as inclusion criteria (patient selection and stratification), and as safety monitoring tools (measure harm or lack of harm). Despite the obvious value of imaging, the integration of imaging biomarkers into trials faces various challenges, such as the complexity of imaging techniques, lack of standardization across multivendor platforms, and paucity of optimized trial design and operational support. Some common pitfalls of imaging biomarker implementation in trials are listed and accompanied by proposed solutions. Finally, perspectives are given on how to increase imaging biomarker value in drug development and clinical practice.
Keywords
- Positron Emission Tomography
- Leave Ventricular Ejection Fraction
- Surrogate Endpoint
- Accelerator Mass Spectrometry
- Renal Papillary Necrosis
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Food and Drug Administration. FDA official web. http://www.fda.gov/.
European Medicines Agency. EMA offical web. http://www.ema.europa.eu/ema/.
China Food and Drug Administration. CFDA official web. http://eng.cfda.gov.cn/WS03/CL0755/.
Ministry of Health Labour Welfare. MHLW official web. http://www.mhlw.go.jp/english/.
International Conference on Harmonization. ICH official web. http://www.ich.org/home.html.
WMA. WMA declaration of Helsinki – ethical principles for medical research involving human subjects. 2013. http://www.wma.net/en/30publications/10policies/b3/.
Scannell JW, Blanckley A, Boldon H, Warrington B. Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov. 2012;11:191–200. doi:10.1038/nrd3681.
PWC. From vision to decision pharma 2020. 2013. https://www.pwc.com/jp/ja/japan-knowledge/archive/assets/pdf/pharma-2020-vision-to-decision.pdf.
https://report.nih.gov/investigators_and_trainees/acd_bwf/pdf/Phrma_Industry_Profile_2011.pdf
Bria E, Di Maio M, Carlini P, et al. Targeting targeted agents: open issues for clinical trial design. J Exp Clin Cancer Res. 2009;28:66. doi:10.1186/1756-9966-28-66.
Atkinson AJ, Colburn WA, DeGruttola VG, et al. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89–95. doi:10.1067/mcp.2001.113989.
FDA. Novel drugs approved using surrogate endpoints. 2015. http://www.fda.gov/downloads/NewsEvents/Testimony/UCM445375.pdf.
Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324(12):781–8. doi:10.1056/NEJM199103213241201.
Wilson WH, Schenkein DP, Jernigan CL, Woodcock J, Schilsky RL. Reevaluating the accelerated approval process for oncology drugs. Clin Cancer Res. 2013;19:2804–9. doi:10.1158/1078-0432.CCR-13-0315.
FDA. Guidance for industry clinical trial endpoints for the approval of cancer drugs and biologics. 2007. http://www.fda.gov/downloads/Drugs/…/Guidances/ucm071590.pdf.
Lancellotti P, Nkomo VT, Badano LP, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy. J Am Soc Echocardiogr. 2013;26:1013–32. doi:10.1016/j.echo.2013.07.005.
Adebahr S, Collette S, Shash E, et al. LungTech, an EORTC phase II trial of stereotactic body radiotherapy for centrally located lung tumours – a clinical perspective. Br J Radiol. 2015;88:20150036. doi:10.1259/bjr.20150036.
Von Pawel J, Von Roemeling R, Gatzemeier U, et al. Tirapazamine plus cisplatin versus cisplatin in advanced non-small-cell lung cancer: a report of the international CATAPULT I study group. J Clin Oncol. 2000;18:1351–9. http://www.ncbi.nlm.nih.gov/pubmed/10715308
Rischin D, Hicks RJ, Fisher R, et al. Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group Study. J Clin Oncol. 2006;24(13):2098–104. doi:10.1200/JCO.2005.05.2878.
Morris RT, Joyrich RN, Naumann RW, et al. Phase II study of treatment of advanced ovarian cancer with folate-receptor-targeted therapeutic (vintafolide) and companion SPECT-based imaging agent (99mTc-etarfolatide). Ann Oncol. 2014;25(4):852–8. doi:10.1093/annonc/mdu024.
Na II, Byun BH, Kang HJ, et al. 18F-fluoro-2-deoxy-glucose uptake predicts clinical outcome in patients with gefitinib-treated non-small cell lung cancer. Clin Cancer Res. 2008;14:2036–41. doi:10.1158/1078-0432.CCR-07-4074.
Dijkers EC, Oude Munnink TH, Kosterink JG, et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther. 2010;87:586–92. doi:10.1038/clpt.2010.12.
Chang AJ, DeSilva R, Jain S, Lears K, Rogers B, Lapi S. 89Zr-radiolabeled trastuzumab imaging in orthotopic and metastatic breast tumors. Pharmaceuticals. 2012;5:79–93. doi:10.3390/ph5010079.
FDA. Prescribing information (tositumomab and Iodine I 131 Tositumomab). 2003. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125011s102lbl.pdf.
Zweifel M, Padhani AR. Perfusion MRI in the early clinical development of antivascular drugs: decorations or decision making tools? Eur J Nucl Med Mol Imaging. 2010;37 Suppl 1:S164–82. doi:10.1007/s00259-010-1451-z.
Jonker DJ, Rosen LS, Sawyer MB, et al. A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors. Ann Oncol. 2011;22:1413–9. doi:10.1093/annonc/mdq599.
Thomas AL, Morgan B, Horsfield MA, et al. Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol. 2005;23(18):4162–71. doi:10.1200/JCO.2005.09.034.
Drevs J, Siegert P, Medinger M, et al. Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2007;25(21):3045–54. doi:10.1200/JCO.2006.07.2066.
Hahn OM, Yang C, Medved M, et al. Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma. J Clin Oncol. 2008;26:4572–8. doi:10.1200/JCO.2007.15.5655.
Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343:1586–93. doi:10.1056/nejm200011303432201.
Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum. 2002;46:1443–50. doi:10.1002/art.10308.
Stroobants S, Goeminne J, Seegers M, et al. 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec®). Eur J Cancer. 2003;39:2012–20. doi:10.1016/S0959-8049(03)00073-X.
Sinkus R, Van Beers BE, Vilgrain V, DeSouza N, Waterton JC. Apparent diffusion coefficient from magnetic resonance imaging as a biomarker in oncology drug development. Eur J Cancer. 2012;48:425–31. doi:10.1016/j.ejca.2011.11.034.
O’Connor JPB, Jackson A, Parker GJM, Jayson GC. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer. 2007;96:189–95. doi:10.1038/sj.bjc.6603515.
Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis. 2004;24:3–20. doi:10.1055/s-2004-823098.
FDA. Guidance for industry standards for clinical trial imaging endpoints guidance for industry standards for clinical trial imaging endpoints. 2015. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm268555.pdf.
FDA. Guidance for industry developing medical imaging drug and biological products part 2: clinical indications. 2004. http://www.gmp-compliance.org/guidemgr/files/MEDIMAGEIND.PDF.
FDA. Guidance for industry developing medical imaging drug and biological products part 1: conducting safety assessments. 2004. http://www.fda.gov/downloads/Drugs/…/Guidances/ucm071600.pdf.
FDA. Developing medical imaging drug and biological products part 3: design, analysis, and interpretation of clinical studies. 2004. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071604.pdf.
Waterton JC, Pylkkanen L. Qualification of imaging biomarkers for oncology drug development. Eur J Cancer. 2012;48:409–15. doi:10.1016/j.ejca.2011.11.037.
Boellaard R, O’Doherty MJ, Weber WA, et al. FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0. Eur J Nucl Med Mol Imaging. 2010;37(1):181–200. doi:10.1007/s00259-009-1297-4.
NCI. NCI-CQIE qualification materials. http://www.acrin.org/CORELABS/NCICQIEQUALIFICATIONPROGRAM/SITEQUALIFICATIONMATERIALS.aspx.
QIBA. https://www.rsna.org/QIBA_Protocols_and_Profiles.aspx.
Leach MO, Morgan B, Tofts PS, et al. Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging. Eur Radiol. 2012;22(7):1451–64. doi:10.1007/s00330-012-2446-x.
QuIC-ConCePT. http://www.quic-concept.eu/.
RECIST. RECIST web. http://www.eortc.org/recist/.
Achieve cancer imaging. Cancer imaging archive. http://www.cancerimagingarchive.net.
Alzheimer disease neuroimaging initiative. ADNI web. http://adni.loni.usc.edu/data-samples/access-data/.
Chu TF, Rupnick MA, Kerkela R, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007;370:2011–9. doi:10.1016/S0140-6736(07)61865-0.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. doi:10.1016/j.ejca.2008.10.026.
Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52–60. doi:10.1055/s-0030-1247132.
Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol. 2004;15:257–60. doi:10.1093/annonc/mdh059.
Salloway S, Sperling R, Gilman S, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73:2061–70. doi:10.1212/WNL.0b013e3181c67808.
Liu Y, Litière S, de Vries EG, et al. The role of response evaluation criteria in solid tumour in anticancer treatment evaluation: results of a survey in the oncology community. Eur J Cancer. 2014;50(2):260–6. doi:10.1016/j.ejca.2013.10.011.
Hunter DJ, Zhang W, Conaghan PG, et al. Systematic review of the concurrent and predictive validity of MRI biomarkers in OA. Osteoarthritis Cartilage. 2011;19:557–88. doi:10.1016/j.joca.2010.10.029.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Liu, Y., Waterton, J.C. (2017). Imaging Biomarkers in Clinical Trials. In: Martí-Bonmatí, L., Alberich-Bayarri, A. (eds) Imaging Biomarkers. Springer, Cham. https://doi.org/10.1007/978-3-319-43504-6_21
Download citation
DOI: https://doi.org/10.1007/978-3-319-43504-6_21
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-43502-2
Online ISBN: 978-3-319-43504-6
eBook Packages: MedicineMedicine (R0)