This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ratain, M. J. Search for Related Content PubMed Articles by Ratain, M. J. Related Articles Related Correspondence Social Bookmarking                            What's this?

In Reply

University of Chicago, Chicago, IL

The letter by Sonpavde et al provides an additional opportunity to clarify some of the advantages and disadvantages of the randomized discontinuation design, relative to other choices for phase II trials.¹ These include single-arm trials with historical controls (the most commonly used option in oncology) and the randomized controlled trial (the most commonly used option outside of oncology). They suggest that a single-arm trial with "a distribution of patients with characteristics similar to those in a phase III trial" would be "more cost-effective." It is difficult to discuss the cost effectiveness of the trial design proposed by Sonpavde et al without further details, although it is unlikely that a small uncontrolled trial would have been able to provide convincing evidence of activity comparable to that observed in our study,² resulting in a false-negative phase II trial, certainly not a cost-effective outcome.

Sonpavde et al also suggest that a standard randomized controlled trial would be preferable because of simplicity and ethical concerns with the randomized discontinuation. Although a standard randomized controlled trial may be simpler, a better criterion for choice of designs is efficiency (ie, power). From a statistical perspective, the randomized discontinuation design can be more or less efficient than a randomized controlled trial, depending on the specific details of the study.³ However, if optimally designed, the randomized discontinuation trial can be substantially more efficient.

It is particularly surprising that Sonpavde et al raise concerns regarding the ethics of the design (relative to a randomized controlled trial with upfront randomization to drug or placebo) because it was specifically proposed by Amery and Dony⁴ as a means to minimize exposure of patients to placebo. Although a randomized clinical trial certainly has some scientific advantages, this design requires a greater exposure to placebo for many patients, and is most likely less acceptable to most patients and oncologists, as compared with a randomized discontinuation trial.

Sonpavde et al have also suggested a potential modification to the randomized discontinuation design, the incorporation of stratification by tumor size (relative to baseline). This suggestion certainly could be considered in future trials using this design.

It is important to emphasize that the randomized discontinuation design is best used in a phase II setting. It is difficult to argue with success, as our results were confirmed by Escudier et al⁵ in a placebo-controlled phase III trial, resulting in US Food and Drug Administration approval. In contrast, single-arm phase II trials have had unsatisfactory positive predictive value (particularly in renal cancer),^6,7 with the recent exception of sunitinib.⁸

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Michaelis LC, Ratain MJ: Measuring response in a post-RECIST world: From black and white to shades of grey. Nat Rev Cancer 6:409-414, 2006[CrossRef][Medline]

2. Ratain MJ, Eisen T, Stadler WM, et al: Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24:2505-2512, 2006[Abstract/Free Full Text]

3. Kopec JA, Abrahamowicz M, Esdaile JM: Randomized discontinuation trials: Utility and efficiency. J Clin Epidemiol 46:959-971, 1993[CrossRef][Medline]

4. Amery W, Dony J: A clinical trial design avoiding undue placebo treatment. J Clin Pharmacol 15:674-679, 1975[Abstract]

5. Escudier B, Szczylik C, Eisen T, et al: Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol 23:16S, 4510, 2005 (suppl)

6. Ratain MJ: Phase II oncology trials: Let's be positive. Clin Cancer Res 11:5661-5662, 2005[Free Full Text]

7. Goffin J, Baral S, Tu D, et al: Objective responses in patients with malignant melanoma or renal cell cancer in early clinical studies do not predict regulatory approval. Clin Cancer Res 11:5928-5934, 2005[Abstract/Free Full Text]

8. Motzer RJ, Michaelson MD, Redman BG, et al: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16-24, 2006[Abstract/Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Correspondence

• Problems With the Randomized Discontinuation Design
  Guru Sonpavde, Thomas E. Hutson, Matthew D. Galsky, and William R. Berry
  JCO 2006 24: 4669-4670 [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ratain, M. J. Search for Related Content PubMed Articles by Ratain, M. J. Related Articles Related Correspondence Social Bookmarking                            What's this?