Skip to main content

Thank you for visiting nature.com. 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.

  • Review Article
  • Published:

Role of randomized phase III trials in an era of effective targeted therapies

Nature Reviews Clinical Oncology volume 9, pages 208–214 (2012)Cite this article

Subjects

Abstract

In the era of cytotoxic therapies, tumor regression has rarely been observed in phase I trials and randomized controlled trials have usually been required to demonstrate modest improvements over prevailing standards of care. In the era of effective targeted therapies, drugs such as vemurafenib and crizotinib have demonstrated convincing efficacy in early clinical testing, raising the question of whether randomized phase III trials are necessary and feasible before drug approval. Since 1992, the FDA has approved a number of drugs without data from confirmatory clinical trials as part of the accelerated approval process. While this initiative has largely been successful in bringing effective drugs to the market more quickly, there is much to be learned from case studies of drugs, such as gefitinib, which subsequently failed to gain full approval. In this Review, we use a number of historical examples to make the case that it may be reasonable to consider foregoing randomized phase III trials for certain drugs before drug approval. We explore the consequences (both good and bad) of foregoing randomized phase III trials and propose criteria that might be used to select drugs for consideration of such an approach.

Key Points

  • There have been significant advances in the development of targeted anticancer therapies that are evident even in early-phase clinical trials

  • It may be reasonable to forego randomized phase III trials for those drugs that demonstrate substantial activity before phase III, particularly for diseases with a high unmet medical need

  • The consequences of foregoing randomized phase III trials must be recognized, most notably the risk of approving drugs without definitive evidence of efficacy and a limited knowledge of safety

  • Additional research and/or expert discussion is needed, along with guidance from regulatory agencies, to better define the criteria for selecting drugs to forego randomized phase III trials before approval

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. US National Library of Medicine. ClinicalTrials.gov [online].

  2. Flaherty, K. et al. Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer [abstract]. J. Clin. Oncol. 27 (Suppl. 15), 9000 (2009).

    Google Scholar 

  3. Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).

    Article  CAS  Google Scholar 

  4. US National Library of Medicine. ClinicalTrials.gov [online].

  5. Roche. Roche personalized investigational medicine shows survival benefit in advanced skin cancer [online], (2011).

  6. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

    Article  CAS  Google Scholar 

  7. FDA. Highlights of prescribing information for Zelboraf (vemurafenib) [online], (2011).

  8. Harmon, A. New drugs stir debate on rules of clinical trials. The New York Times (New York) A1 (19 Sept 2010).

    Google Scholar 

  9. Miller, F. G. & Joffe, S. Equipoise and the dilemma of randomized clinical trials. N. Engl. J. Med. 364, 476–480 (2011).

    Article  CAS  Google Scholar 

  10. Miller, F. G. & Joffe, S. Balancing access and evaluation in the approval of new cancer drugs. JAMA 305, 2345–2346 (2011).

    Article  CAS  Google Scholar 

  11. Joffe, S. & Miller, F. G. Equipoise: Asking the right questions for clinical trial design. Nat. Rev. Clin. Oncol. (in press)

  12. PhRMA. More than 800 medicines and vaccines in testing offer hope in the fight against cancer [online], (2009).

  13. Huang, M. E. et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72, 567–572 (1988).

    CAS  Google Scholar 

  14. Soignet, S. L. et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N. Engl. J. Med. 339, 1341–1348 (1998).

    Article  CAS  Google Scholar 

  15. Maloney, D. G. et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 90, 2188–2195 (1997).

    CAS  PubMed  Google Scholar 

  16. Kantarjian, H. et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N. Engl. J. Med. 346, 645–652 (2002).

    Article  CAS  Google Scholar 

  17. Demetri, G. D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002).

    Article  CAS  Google Scholar 

  18. Von Hoff, D. D. et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N. Engl. J. Med. 361, 1164–1172 (2009).

    Article  CAS  Google Scholar 

  19. Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010).

    Article  CAS  Google Scholar 

  20. Fukuoka, M. et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial). J. Clin. Oncol. 21, 2237–2246 (2003).

    Article  CAS  Google Scholar 

  21. Kris, M. G. et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290, 2149–2158 (2003).

    Article  CAS  Google Scholar 

  22. Giaccone, G. et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1. J. Clin. Oncol. 22, 777–784 (2004).

    Article  CAS  Google Scholar 

  23. Herbst, R. S. et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J. Clin. Oncol. 22, 785–794 (2004).

    Article  CAS  Google Scholar 

  24. Thatcher, N. et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366, 1527–1537 (2005).

    Article  CAS  Google Scholar 

  25. Tamura, K. & Fukuoka, M. Gefitinib in non-small cell lung cancer. Expert Opin. Pharmacother. 6, 985–993 (2005).

    Article  CAS  Google Scholar 

  26. Sanford, M. & Scott, L. J. Gefitinib: a review of its use in the treatment of locally advanced/metastatic non-small cell lung cancer. Drugs 69, 2303–2328 (2009).

    Article  CAS  Google Scholar 

  27. Sequist, L. V., Bell, D. W., Lynch, T. J. & Haber, D. A. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J. Clin. Oncol. 25, 587–595 (2007).

    Article  CAS  Google Scholar 

  28. Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009).

    Article  CAS  Google Scholar 

  29. Maemondo, M. et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380–2388 (2010).

    Article  CAS  Google Scholar 

  30. Keedy, V. L. et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J. Clin. Oncol. 29, 2121–2127 (2011).

    Article  Google Scholar 

  31. Department of Health and Human Services. New drug, antibiotic, and biological drug product regulations; accelerated approval—FDA. Final rule. Fed. Regist. 57, 58942–58960 (1992).

  32. Johnson, J. R. et al. Accelerated approval of oncology products: the food and drug administration experience. J. Natl. Cancer Inst. 103, 636–644 (2011).

    Article  Google Scholar 

  33. Food and Drug Administration Oncologic Drugs Advisory Committee. Transcript of the 8 February meeting, [online] (2011).

  34. Tsimberidou, A. M., Braiteh, F., Stewart, D. J. & Kurzrock, R. Ultimate fate of oncology drugs approved by the US Food and Drug Administration without a randomized trial. J. Clin. Oncol. 27, 6243–6250 (2009).

    Article  CAS  Google Scholar 

  35. Sievers, E. L. et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J. Clin. Oncol. 19, 3244–3254 (2001).

    Article  CAS  Google Scholar 

  36. FDA. Pfizer voluntarily withdraws cancer treatment Mylotarg from U. S. market [online], (2010).

  37. Sharma, M. R., Stadler, W. M. & Ratain, M. J. Randomized phase II trials: a long-term investment with promising returns. J. Natl. Cancer Inst. 103, 1093–1100 (2011).

    Article  CAS  Google Scholar 

  38. FDA. Guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics [online], (2007).

  39. Escudier, B. et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356, 125–134 (2007).

    Article  CAS  Google Scholar 

  40. Motzer, R. J. et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 356, 115–124 (2007).

    Article  CAS  Google Scholar 

  41. Motzer, R. J. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372, 449–456 (2008).

    Article  CAS  Google Scholar 

  42. Escudier, B. et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370, 2103–2111 (2007).

    Article  Google Scholar 

  43. Rini, B. I. et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J. Clin. Oncol. 26, 5422–5428 (2008).

    Article  CAS  Google Scholar 

  44. Sternberg, C. N. et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J. Clin. Oncol. 28, 1061–1068 (2010).

    Article  CAS  Google Scholar 

  45. Cunningham, D. et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med. 351, 337–345 (2004).

    Article  CAS  Google Scholar 

  46. Van Cutsem, E. et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J. Clin. Oncol. 25, 1658–1664 (2007).

    Article  CAS  Google Scholar 

  47. Tang, P. A., Bentzen, S. M., Chen, E. X. & Siu, L. L. Surrogate end points for median overall survival in metastatic colorectal cancer: literature-based analysis from 39 randomized controlled trials of first-line chemotherapy. J. Clin. Oncol. 25, 4562–4568 (2007).

    Article  Google Scholar 

  48. Buyse, M. et al. Progression-free survival is a surrogate for survival in advanced colorectal cancer. J. Clin. Oncol. 25, 5218–5224 (2007).

    Article  CAS  Google Scholar 

  49. Lara, P. N. Jr. et al. Disease control rate at 8 weeks predicts clinical benefit in advanced non-small-cell lung cancer: results from Southwest Oncology Group randomized trials. J. Clin. Oncol. 26, 463–467 (2008).

    Article  Google Scholar 

  50. Halabi, S. et al. Progression-free survival as a predictor of overall survival in men with castrate-resistant prostate cancer. J. Clin. Oncol. 27, 2766–2771 (2009).

    Article  Google Scholar 

  51. Heng, D. Y. et al. Progression-free survival as a predictor of overall survival in metastatic renal cell carcinoma treated with contemporary targeted therapy. Cancer 117, 2637–2642 (2011).

    Article  Google Scholar 

  52. Cheng, S. K., Dietrich, M. S. & Dilts, D. M. A sense of urgency: evaluating the link between clinical trial development time and the accrual performance of cancer therapy evaluation program (NCI-CTEP) sponsored studies. Clin. Cancer Res. 16, 5557–5563 (2010).

    Article  Google Scholar 

  53. Hamilton, E. P., Lyman, G. H. & Peppercorn, J. Availability of experimental therapy outside oncology randomized clinical trials in the United States. J. Clin. Oncol. 28, 5067–5073 (2010).

    Article  Google Scholar 

  54. Schilsky, R. L. Accrual to cancer clinical trials in the era of molecular medicine. Sci. Transl. Med. 3, 75cm9 (2011).

    Article  Google Scholar 

  55. Miller, K. et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med. 357, 2666–2676 (2007).

    Article  CAS  Google Scholar 

  56. D'Agostino, R. B. Sr . Changing end points in breast-cancer drug approval—the Avastin story. N. Engl. J. Med. 365, e2 (2011).

    Article  CAS  Google Scholar 

  57. Online reference. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/125085s091ltr.pdf (2008).

  58. Food and Drug Administration Oncologic Drugs Advisory Committee. Transcript of the 20 July meeting [online], (2010).

  59. O'Shaughnessy, J. et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N. Engl. J. Med. 364, 205–214 (2011).

    Article  CAS  Google Scholar 

  60. Anders, C. K. et al. Poly(ADP-Ribose) polymerase inhibition: “targeted” therapy for triple-negative breast cancer. Clin. Cancer Res. 16, 4702–4710 (2010).

    Article  CAS  Google Scholar 

  61. Pollack, A. Promising results in stomach and breast cancer drugs. The New York Times (New York) (1 June 2009).

    Google Scholar 

  62. O'Shaughnessy, J. et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC) [abstract]. J. Clin. Oncol. 29 (Suppl. 15), a1007 (2011).

    Article  Google Scholar 

  63. Richey, E. A. et al. Accelerated approval of cancer drugs: improved access to therapeutic breakthroughs or early release of unsafe and ineffective drugs? J. Clin. Oncol. 27, 4398–4405 (2009).

    Article  CAS  Google Scholar 

  64. Psaty, B. M. & Prentice, R. L. Minimizing bias in randomized trials: the importance of blinding. JAMA 304, 793–794 (2010).

    Article  CAS  Google Scholar 

  65. Burzykowski, T. et al. Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J. Clin. Oncol. 26, 1987–1992 (2008).

    Article  CAS  Google Scholar 

  66. Cohen, M. H. et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin. Cancer Res. 8, 935–942 (2002).

    CAS  PubMed  Google Scholar 

  67. Inoue, L. Y., Thall, P. F. & Berry, D. A. Seamlessly expanding a randomized phase II trial to phase III. Biometrics 58, 823–831 (2002).

    Article  Google Scholar 

  68. Korn, E. L. & Freidlin, B. Outcome—adaptive randomization: is it useful? J. Clin. Oncol. 29, 771–776 (2011).

    Article  Google Scholar 

  69. Berry, D. A. Adaptive clinical trials in oncology. Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2011.165 (2011).

Download references

Acknowledgements

This work was supported by a training grant from the National Institutes of Health for Clinical Therapeutics, T32GM007019. The funders did not have any involvement in the design of this Review; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.

Author information

Authors and Affiliations

  1. Department of Medicine, Section of Hematology/Oncology, and Comprehensive Cancer Center, University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, 60637–1470, IL, USA

    Manish R. Sharma & Richard L. Schilsky

Authors
  1. Manish R. Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard L. Schilsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M. R. Sharma completed the research of data for the article and wrote the manuscript. Both authors made a substantial contribution to discussion of the content and to editing and revising the manuscript before submission.

Corresponding author

Correspondence to Richard L. Schilsky.

Ethics declarations

Competing interests

R. L. Schilsky declares that he is a consultant for and owns shared from Foundation Medicine and that he is a consultant for Universal Oncology. M. R. Sharma declares no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sharma, M., Schilsky, R. Role of randomized phase III trials in an era of effective targeted therapies. Nat Rev Clin Oncol 9, 208–214 (2012). https://doi.org/10.1038/nrclinonc.2011.190

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2011.190

This article is cited by

Search

Advanced search

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