Originally published as JCO Early Release 10.1200/JCO.2008.21.1938 on January 26 2009

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The Transition From Phase II To Phase III Studies

Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

Aliya Gulamhusein

Princess Margaret Hospital and University of Toronto, Toronto; Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada

John I. Jackson, Ian F. Tannock

Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada

To the Editor:

New treatments for cancer are derived through a series of clinical trials. Phase I and phase II trials are undertaken to evaluate tolerance and to seek evidence of antitumor activity, respectively. Promising new agents or treatment strategies should then be evaluated in phase III randomized controlled trials (RCTs). During the past several years, the number of phase II trials has been increasing steadily, whereas the number of RCTs has not increased significantly,¹ implying that many phase II trials do not lead to subsequent phase III trials. This is appropriate when the phase II trial does not suggest the desired level of efficacy of a treatment or intervention; it is not appropriate if phase II trials with encouraging results do not lead to phase III RCTs. The aim of this study was to determine how often phase II trials with positive results have led to phase III trials, and how often phase II trials are designed with the potential to lead to phase III trials.

The research is composed of two parts. The first analysis included assessment of abstracts presented at the annual American Society for Clinical Oncology (ASCO) meetings in 1995 and 1996, in each of five major cancer sites (breast, lung, gastrointestinal, genitourinary, and gynecologic). From these, 20 abstracts from each site where the author's conclusion indicated "encouraging" or "promising" results were selected randomly with the aid of the computer program Excel (Microsoft, Redmond, WA). The decision to base this analysis on abstracts rather than peer-reviewed articles was motivated by the desire to minimize publication bias, as better-quality studies are more likely to be published.² A systematic review was then performed using the Medline database to detect subsequent published large RCTs evaluating the same regimen as explored in the 100 phase II trials. Considering the relatively short time of 10 years for organizing, running, and publishing phase III trials, we also accessed recent abstracts in proceedings of ASCO meetings, as well as the ClinicalTrials.gov database.³

The second data set is based on abstracts presented in 2006 at the annual ASCO meeting. Abstracts describing phase II trials for the same five cancer sites were assessed, and 20 abstracts from each site that described "encouraging" or "promising results" were selected randomly using Excel. A questionnaire was sent to the principal investigator of each study that asked whether his or her phase II study had met its primary end point, about plans to investigate the regimen further, and about the potential resources to do so.

At 10 years after presentation of 100 phase II trials with positive results, our search strategy identified only 13 regimens that had been evaluated in phase III trials.

For the 100 phase II trials with encouraging results selected from the 2006 ASCO meeting proceedings, 44 investigators responded and 42 returned a completed questionnaire. Thirty-six investigators (85%) confirmed that the desired outcome for the primary end point had been met; six investigators (15%) disagreed with the interpretation of "positive results." Twenty-five investigators (59%) stated that it would be worthwhile to explore the tested regimen in an RCT. Among these were 10 investigators (23%) who planned to undertake an RCT and eight (19%) who stated that they had the necessary resources (Fig 1). Eleven investigators indicated potential support from academia (five), the pharmaceutical industry (seven), and/or cooperative groups in planning a phase III trial (five); these investigators intended to proceed with an RCT. There was no obvious difference in intention to proceed to a phase III trial on the basis of sponsorship.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Results of the survey of authors of abstracts published in 2006. RCT, randomized controlled trial.

A possible limitation of our research is that we selected abstracts where authors used their own words to indicate that the results of their studies were positive, rather than using a uniform post hoc definition of what we might consider to be a truly positive phase II study. Concluding statements might be inappropriately enthusiastic or influenced by a commercial sponsor, although in the recent series, 85% of the authors who responded to our questionnaire confirmed that their study had met preset criteria for the primary end point.

Some investigators might assign value to phase II trials even if they do not proceed to phase III studies. Thus, phase II trials might be undertaken to define better a safety profile after completing phase I evaluation, to investigate a modified schedule, or to determine whether promising agents warrant additional research in other patient populations; but all of these would require phase III evaluation if results were promising. The rare phase II trial with a translational component may contribute to understanding of biology even if it does not lead to the next-generation trial.

DiMasi et al⁵ addressed recently the approval of new drugs and found that the transition rate for new molecules was 59%. This high transition rate might be explained by the fact that these are single drugs pushed through the developmental pipeline by powerful pharmaceutical companies, and many of them may be approved after evaluation in an RCT for a single type of cancer. For other phase II trials, investigators often run short of money, drugs, patients, or time; many of these factors are known at the time that a phase II trial is designed.

Many phase II trials address the efficacy of drug combinations that are already registered. We suspect that some phase II trials are designed to legitimize treatments where there is no intention of studying them in RCTs. Furthermore, there is substantial pressure on young investigators to undertake research and publish results. Young investigators are usually not in a position to design controlled, randomized trials, but many have access to smaller projects such as single-arm phase II trials. This will only be resolved if investigators are given more academic and other credit for supporting practice-changing phase III trials.

In conclusion, few encouraging phase II trials are followed by phase III trials. We suggest that more resources should be invested in well-conducted phase III trials that have potential to change clinical practice, with fewer resources spent on phase II trials that are not planned to lead to additional studies.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

ACKNOWLEDGMENT

We thank all investigators for participating in the survey.

REFERENCES

1. Hillner BE: Trends in clinical trials reports in common cancers between 1989 and 2000. J Clin Oncol 21:1850–1858, 2003.[Abstract/Free Full Text]

2. De Bellefeuille C, Morrison CA, Tannock IF: The fate of abstracts submitted to a cancer meeting: Factors which influence presentation and subsequent publication. Ann Oncol 3:187–191, 1992.[Abstract/Free Full Text]

3. National Institutes of Health. ClinicalTrials.gov. http://www.clinicaltrials.gov.

4. Emanuel EJ, Schnipper LE, Kamin DY, et al: The costs of conducting clinical research. J Clin Oncol 21:4145–4150, 2003.[Abstract/Free Full Text]

5. DiMasi JA, Grabowski HG: Economics of new oncology drug development. J Clin Oncol 25:209–216, 2007.[Abstract/Free Full Text]

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