Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Compressing drug development timelines in oncology using phase '0' trials


The optimal evaluation of molecularly targeted anticancer agents requires the integration of pharmacodynamic assays into early clinical investigations. Phase '0' trials conducted under the new Exploratory Investigational New Drug Guidance from the US Food and Drug Administration can provide a platform to establish the feasibility of assays for target modulation in human samples, evaluate biomarkers for drug effects and provide pharmacokinetic data. Phase 0 trials could facilitate rational drug selection, identify therapeutic failures early, and might compress timelines for anticancer drug development. We expect that such trials will become a routine part of early-phase oncological drug development in the future.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Stages of drug development.
Figure 2: Single-dose phase 0 trial of a drug with serial sampling of blood and tumour for pharmacokinetic and pharmacodynamic analysis.
Figure 3: Pharmacodynamic assay development before the initiation of phase 0 clinical trials.

Similar content being viewed by others


  1. US Food and Drug Administration. Guidance for Industry, Investigators, and Reviewers. US Food and Drug Administration, [online] (2006).

  2. Kola, I., Landis, J. Can the pharmaceutical industry reduce attrition rates? Nature Rev. Drug Discov. 3, 711–715 (2004).

    Article  CAS  Google Scholar 

  3. Johnson, J. I. et al. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br. J. Cancer 84, 1424–1431 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Olson, H., Betton, G., Robinson D . et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul. Toxicol. Pharmacol. 32, 56–67 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Tomaszewski, J. E., Smith, A. C., Covey, J. M., Donohue, S. J., Rhie, J. K. & Schweikart, K. M. in Anti-Cancer Drug Design (ed. Baguley, B. C.) Chpt 17, 301–328 (San Diego, Academic Press, 2001).

    Google Scholar 

  6. Tomaszewski, J. E., Doroshow, J. H. in Molecular Targets in Oncology (ed. Antman, K.) (Humana Press, Totowa, USA, in the press).

  7. Fox, E., Curt, G. A. & Balis, F. M. Clinical trial design for target-based therapy. Oncologist. 7, 401–409 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Millar, A. W., Lynch, K. P. Rethinking clinical trials for cytostatic drugs. Nature Rev. Cancer. 3, 540–545 (2003).

    Article  CAS  Google Scholar 

  9. Rothenberg, M. L., Carbone, D. P. & Johnson, D. H. Improving the evaluation of new cancer treatments: challenges and opportunities. Nature Rev. Cancer. 3, 303–309 (2003).

    Article  CAS  Google Scholar 

  10. Kummar, S., Gutierrez, M. E., Doroshow, J. H. & Murgo, A. J. Drug development in oncology: classical cytotoxics and molecularly targeted agents. Br. J. Clin. Pharmacol. 62, 15–26 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Workman, P. et al. Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. J. Natl Cancer Inst. 98, 580–598 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Parulekar, W. R., Eisenhauer, E. A. Phase I trial design for solid tumor studies of targeted, non-cytotoxic agents: theory and practice. J. Natl. Cancer Inst. 96, 990–997 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Bartlett, J. M. Pharmacodiagnostic testing in breast cancer: focus on HER2 and trastuzumab therapy. Am. J. Pharmacogenomics 5, 303–315 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Lehmann, F., Lacombe, D., Therasse, P., Eggermont A. M. M. Integration of translational research in the european organization for research and treatment of cancer research (EORTC) clinical trial cooperative group mechanisms. J. Transl. Med. 1, 2 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hidalgo, M., and Eckhardt, S. G. Matrix metalloproteinase inhibitors: how can we optimize their development? Ann. Oncol. 12, 285–287 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Moore, M. J. et al. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12–9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 21, 3296–3302 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Van Den Bossche, B., Van de Wiele, C. Receptor imaging in oncology by means of nuclear medicine: current status. J. Clin. Oncol. 22, 3593–3607 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Sun, H. et al. Imaging the pharmacokinetics of [F-18]FAU in patients with tumors: PET studies. Cancer Chemother. Pharmacol. 57, 343–348 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Liu, G. et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J. Clin. Oncol. 23, 5464–5473 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Collins, J. M. Imaging and other biomarkers in early clinical studies: one step at a time or re-engineering drug development? J. Clin. Oncol. 23, 5417–5419 (2005).

    Article  PubMed  Google Scholar 

  21. Collins, J. M., Grieshaber, C. K. & Chabner, B. A. Pharmacologically guided phase I clinical trials based upon preclinical drug development. J. Natl. Cancer Inst. 82, 1321–1326 (1990).

    Article  CAS  PubMed  Google Scholar 

Download references


This project has been funded in whole or in part with federal funds from the US National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does any mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was supported by the Division of Cancer Treatment and Diagnosis and the Center for Cancer Research of the National Cancer Institute.

Author information

Authors and Affiliations


Corresponding author

Correspondence to James H. Doroshow.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links


National Cancer Institute

Division of Cancer Treatment and Diagnosis

Center for Cancer Research, National Cancer Institute

Cancer Therapy and Evaluation Program, National Cancer Institute Guidelines for Correlative Studies in Clinical Trials

Office of Biorepositories and Biospecimen Research, National Cancer Institute

Steps for pharmacodynamic assay development

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kummar, S., Kinders, R., Rubinstein, L. et al. Compressing drug development timelines in oncology using phase '0' trials. Nat Rev Cancer 7, 131–139 (2007).

Download citation

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing