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Originally published as JCO Early Release 10.1200/JCO.2007.14.8874 on February 19 2008 © 2008 American Society of Clinical Oncology. Analysis of Phase II Studies on Targeted Agents and Subsequent Phase III Trials: What Are the Predictors for Success?
From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco; Department of Radiation Therapy, Division of Medical Oncology; Lane Medical Library & Knowledge Management Center, Stanford Cancer Center, Stanford University School of Medicine, Stanford; and the Chao Family Comprehensive Cancer Center, University of California, Irvine, Medical Center, Orange, CA Corresponding author: John K. Chan, MD, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero St, Room A747, Box 1702, San Francisco, CA 94143-1702; e-mail: chanjohn{at}obgyn.ucsf.edu
Purpose To identify the characteristics of phase II studies that predict for subsequent "positive" phase III trials (those that reached the proposed primary end points of study or those wherein the study drug was superior to the standard regimen investigating targeted agents in advanced tumors.
Methods We identified all phase III clinical trials of targeted therapies against advanced cancers published from 1985 to 2005. Characteristics of the preceding phase II studies were reviewed to identify predictive factors for success of the subsequent phase III trial. Data were analyzed using the Results Of 351 phase II studies, 167 (47.6%) subsequent phase III trials were positive and 184 (52.4%) negative. Phase II studies from multiple rather than single institutions were more likely to precede a successful trial (60.4% v 39.4%; P < .001). Positive phase II results were more likely to lead to a successful phase III trial (50.8% v 22.5%; P = .003). The percentage of successful trials from pharmaceutical companies was significantly higher compared with academic, cooperative groups, and research institutes (89.5% v 44.2%, 45.2%, and 46.3%, respectively; P = .002). On multivariate analysis, these factors and shorter time interval between publication of phase II results and III study publication were independent predictive factors for a positive phase III trial. Conclusion In phase II studies of targeted agents, multiple- versus single-institution participation, positive phase II trial, pharmaceutical company-based trials, and shorter time period between publication of phase II to phase III trial were independent predictive factors of success in a phase III trial. Investigators should be cognizant of these factors in phase II studies before designing phase III trials.
Targeted therapies have become an important modality in cancer treatment. The development of novel cancer therapies after preclinical evaluation follows a continuum from phase I to phase II to phase III studies. After analyzing the safety and dose from phase I studies, phase II studies are employed to show antitumor activity in patients.1-4 Phase III randomized clinical trials compare the new therapeutic regimen with standard treatment to determine the efficacy of cancer therapies and form the foundation for evidence-based medicine. Phase III trials are typically required for US Food and Drug Administration (FDA) approval of novel treatment regimens that may become new standards of care. Clearly, it is not possible to evaluate all novel agents in randomized trials because of ethical and cost considerations. These phase III studies are laborious, time consuming, and costly.5 The average time spent by clinical personnel per patient is 200 hours and duration per trial is approximately 4.5 years, with an estimated cost of more than $10 million per trial.6,7 Despite the extensive resources utilized, only 2% to 24% of these randomized clinical trials have demonstrated significant survival advantages associated with the experimental therapy.8-10 Given the poor success rates of these phase III trials, it is important to identify factors of phase II studies that can predict success in randomized clinical trials (or "positive" trials). Such factors can ultimately be used to prioritize various novel agents for rapid testing in phase III trials. Moreover, in life-threatening cancers where there is an unmet medical need, these predictive factors can be implemented to form a basis for accelerated drug approval by the FDA. Limited reports have evaluated the characteristics of phase II studies of chemotherapy that may predict for a subsequent success in phase III clinical trial. A prior study compared the outcomes of phase II studies and subsequent randomized controlled trials testing chemotherapeutic regimens and found that the sample size of phase II studies demonstrated a trend toward being predictive for positive phase III studies (P = 0.083).11 However, there are no studies that have analyzed the characteristics of phase II studies on targeted therapies to prioritize these novel compounds for phase III testing. In this current report, we proposed to identify the characteristics of phase II studies that predict for subsequent positive phase III trials on targeted therapies for cancer.
We identified phase III trials and their precedent phase II studies on targeted therapies in advanced cancers published in the English language between 1985 and 2005 (Appendix, online only). To retrieve all phase III clinical trials, systematic searches were made of PubMed, Cochrane Central Register of Controlled Trials, and BIOSIS. Search terms included: "biologics," "biologic therapy," "targeted therapy," "gene therapy," "immunotherapy," "oncolytic virotherapy," "monoclonal antibodies," "angiogenesis inhibitors," and "biologic response modifiers." We included studies that used targeted therapies alone or in combination with chemotherapy. Trials involving radiation therapy and neoadjuvant chemotherapy were excluded from our study.
All phase III studies were retrieved by a medical research librarian (C.S.). Each study was reviewed by the other investigators. On the basis of the information from the phase III trial, the preceding phase II study that led to the randomized clinical trial was retrieved. The biologic regimens from both the phase II and III studies were then compared to ensure similar administration schedule and dose. We defined a trial as positive if the proposed primary end points of the study were reached based on the original trial design. If these primary objectives were not stated, a phase III clinical trial was considered positive if the study drug was superior to the standard regimen or best supportive care. A positive phase II trial is determined by what the author defined as positive in the publication of the phase II trial. All data were analyzed using SPSS 15.0 (SPSS Inc, Chicago, IL) and SAS (version 6.12; SAS Inc, Cary, NC). Statistical analyses were conducted using Pearson
Characteristics of Phase II Studies A total of 351 phase III clinical trials using biologic agents and their preceding phase II studies were identified from 1985 to 2005. The characteristics of these phase II studies are shown in Table 1. Two hundred three trials (57.8%) used targeted therapy alone, and 148 (42.2%) used a combination of targeted therapy and chemotherapy. Solid tumors were studied in 270 trials (77%) and the remaining 81 studies (23%) treated hematologic malignancies. The most common primary sites of cancer were genitourinary (17.9%), skin (17.9%), GI (14%), and breast (12.5%). More than half (53.8%) of the studies were performed in the United States, 32.8% in Europe, and 3.4% in Asia. The majority (56.4%) of these studies were reported from single rather than multiple institutions. Academic centers, research institutes, cooperative groups, pharmaceutical companies, and others were involved in 58.7%, 19.1%, 12.0%, 5.4%, and 4.8% of the phase II studies, respectively. Fifty-seven percent of the phase II studies had 50 patients or fewer. Other detailed characteristics of the phase II studies including type of study, number of patients, median age, performance status, attrition rate, and median follow-up are summarized in Table 2. The outcomes of the phase II studies including response rate, journal impact factor, time interval between phase II to III trials, year, and result of the subsequent phase III study are also presented. Response rates varied from 0% (1.1% of the phase II trials) to 100% (24% of the trials). For 27% of the trials, the response rates ranged between 21% and 40%. "Positive" outcomes were reported in 167 (47.6%) phase III trials and 184 (52.4%) were "negative" (ie, they did not meet the criteria for positive).
Correlation With Phase III Studies We identified factors involving study design, patient characteristics, and outcomes of phase II studies that may predict for subsequent positive (successful) phase III trials. A higher number of assessable patients in the phase II trial correlated with a higher percentage of positive phase III studies compared with a lower number of subjects, though the difference was not statistically significant (P = .081; Table 3). Phase II studies from multiple rather than single institutions were more likely to have a successful trial (60.4% v 39.4%; P < .001; Table 4). The percent of successful trials from pharmaceutical companies was significantly higher compared to academic, cooperative groups, and research institutes (89.5% v 44.2% v 45.2% v 46.3%; P = .002). Over the study periods of 1985 to 1990, 1991 to 1995, 1996 to 2000, 2001 to 2005, the percentage of phase II studies that led to positive phase III trials increased from 37.7% to 33.3% to 56.0% to 76.8% (P < .001). Similarly, more successful phase III studies were associated with a higher response rate in the phase II report (P = .093). There was agreement between the mean response rates of the phase II and the subsequent phase III trials (41.5% v 40.8%; P = .80). The publication of the phase II studies in journals with an impact factor greater than 10 showed a trend toward greater positivity in phase III clinical trials compared with journals with an impact factor of 10 or lower (52.6% v 43.6%; P = .098). The shorter interval between the publication of phase II and III studies (0.5 to 5, 6 to 10, 11 to 15, and 16 to 20 years), was also correlated with the success of phase III trials (55.6%, 42.2%, 32.6%, and 10.0%, respectively; P < .001). Positive phase II results were more likely to lead to a successful phase III trial (50.8% v 22.5%; P = .003; Fig 1A-1C). Of the targeted agents–only trials (n = 168), 66.7% of studies that used "disease progression" as an end point predicted for a positive phase III trial compared with 43.5% of phase II studies using "response" as an end point (P = .086; Table 4). However, factors of phase II trials such as the testing of a targeted therapy alone versus targeted therapy with chemotherapy, hematologic versus solid tumors, randomized versus nonrandomized phase II studies, median age of study participants, performance status, length of accrual, and median follow-up were not predictive for a successful phase III study (Tables 3-4). On multivariate analysis, multiple versus single institutional studies, phase II result, pharmaceutical company-sponsored trials, and shorter time interval between phase II to III study publication were independent predictive factors for a positive phase III trial (Table 5).
Because of the low success rates of costly randomized phase III clinical trials, it is important to identify potential factors of the preceding phase II clinical trials that can predict for success in the phase III trial. Such factors can ultimately be used to design better phase II trials and to prioritize various novel agents for rapid testing in phase III trials. In this current study, our results showed that multi-institutional trials, positive phase II results, pharmaceutical company-sponsored trials, and shorter time interval between phase II to III study publication were independent predictive factors for a positive phase III trial. One prior study has compared the characteristics of phase II studies and the subsequent outcomes of randomized controlled studies for chemotherapeutic regimens.11 In the 43 phase III studies identified, only 12 phase III studies (28%) were positive. These authors did find that the sample size of phase II studies demonstrated a trend toward being predictive for positive phase III studies (P = .083). Nonetheless, other characteristics of the phase II study such as multicentricity, randomization, response rate, and journal impact factor were not found to be predictive for success in phase III study. However, analyses have not been performed to evaluate novel targeted agents using a large number of studies. In this current report of 351 studies, we identified several characteristics of the phase II studies on cancer targeted agents that predicted for subsequent positive phase III clinical trials. Studies involving cytotoxic chemotherapeutic agents typically evaluate the efficacy of these drugs based on response rates from the Response Evaluation Criteria in Solid Tumors (RECIST) as a surrogate for clinical benefit.1-4 Response rates characterized by tumor shrinkage may translate to increased survival and/or improved quality of life.12 However, response rates alone may not apply in the setting of novel cytostatic targeted agents. Prior phase III studies on targeted therapy have failed to demonstrate a correlation between response rates and improved survival.13-16 As such, other surrogate end points such as time to progression may be a more applicable end point for these targeted agents. This current study found that 67% of trials on targeted agents that used "disease progression" as an end point predicted for a successful phase III trial compared to only 43.5% of studies employing "response" as an end point. However, this difference was not statistically significant (P = .086). In addition, our data did not identify an independent association between a higher response rate in phase II study and the likelihood of success in a phase III trial. Our results suggest that newer approaches in clinical trial design may be warranted in the evaluation of cytostatic agents. Clearly, the ability to predict success in phase III trial on the basis of response rates reported in the phase II trial is complex; for, it not only depends on the type of cancer but also the percentage of overall response, number of complete responses, duration of responses, and reproducibility of response rate in multiple clinical trials.17 In addition, given the limited studies on evaluating end points for targeted therapies, future correlative studies are warranted to investigate novel tests involving molecular diagnostics and/or pharmacogenomics to identify more accurate biologic end points even if it is only in a subgroup of target-enriched patients. In this manner, translational investigations from phase II studies can potentially select novel biologic agents for development in smaller and less costly phase III studies. Single-institution studies may be fraught with significant selection bias. These biases may lead to overly promising results by including patients with favorable prognostic factors such as younger age, better performance, and socioeconomic status.18-20 Furthermore, there may exist other undetermined factors that may also influence the results of smaller phase II studies. For example, in a recent phase III study on head and neck cancer, there was an improved survival correlated with the distance that the patient lived from the treatment center.21 In this current study, we found that the results of phase II studies from multiple rather than single institutions more frequently predicted a positive result in the subsequent phase III clinical trial, suggesting that the enrollment of patients from multiple centers may decrease potential selection biases and lead to more accurate results in future trials. In this current analysis, our data showed that pharmaceutical company-sponsored phase II trials resulted in a significantly higher percentage of successful phase III clinical trials compared to other institutions. These results suggest that there may exist a selection bias toward publishing positive outcomes of pharmaceutical company-sponsored trials. Alternatively, the pharmaceutical companies may be better able to design and support clinical trials. The interval between the publication of phase II and III studies was also associated with the success of phase III trial. This finding supports the well-known publication bias in clinical trials.22 A prior study by Ioannidis23 demonstrated that the median time from the beginning of enrollment to publication was significantly shorter for positive compared to negative studies (4.3 v 6.5 years, respectively). Likewise, Stern et al24 found that clinical trials with negative results had a significantly longer time to publications: 8.0 versus 4.8 years, respectively. Thus, the results of this current study support that of other studies showing a time lag in publication is associated with negative findings and less promising results in subsequent phase III trials. In this retrospective review of the literature, our analyses were limited by a potential bias in the search criteria. For example, we may not have covered a comprehensive review of all clinical trials and only selected those that were published in English language. In addition, no attempt was made to validate the quality of the reported results or obtain any updated unpublished analyses from the authors of the publication. Furthermore, because negative trials are less likely to be published, this publication bias can lead to an overestimation of the number of positive phase III trials and treatment effect of targeted therapies.25 Krzyzanowska et al26 evaluated 510 abstracts from large phase III, randomized controlled trials presented at the Annual Meetings of the American Society of Clinical Oncology and found that 81% of studies with significant results had been published within a 5-year period compared with only 68% of the studies with results that were not statistically significant. In addition, these authors showed that studies with pharmaceutical sponsorship were published sooner than those with cooperative group involvement. Thus, publication bias may also be confounded by the potential influence of pharmaceutical company-sponsored trials, which are more likely to publish positive trials.27-32 Furthermore, the nondissemination of negative results can significantly impact on clinical practice. To minimize the problem of publication bias, there needs to be registration of all clinical trials and support for publishing those with nonsignificant results.22,24,25,33 In addition, there are multiple factors that our study was not able to analyze that may contribute to the success of a phase III study. Other critical factors for advancing drugs to phase III study include the novelty and unique target of the drug, favorable pharmacokinetic profile, biologic activity in phase I and II trials, clinical demand for new therapies in specific diseases, market demand, and financial return on investment.34 With respect to the financial implications of drug development, it is estimated that more than 30% of the drugs entering clinical trials are abandoned because of economic concerns.35 Nevertheless, it is important to identify factors predictive of success in phase III trials that should be considered in the prioritization of various novel agents for rapid development into phase III trials. Moreover, in life-threatening cancers where there is an unmet medical need, these predictive factors may be of use to form a foundation for accelerated FDA approval. In summary, our review of the reported clinical trials showed that, for phase II studies on targeted agents, multiple versus single institution participation, positive phase II trials, pharmaceutical company-sponsored trials, and shorter time period between publication of phase II to phase III trial were independent predictive factors of success in a phase III trial on targeted agents. These factors should be studied prospectively to confirm their potential value in predicting positive phase III trials. These findings also suggest the need to increase the quality of phase II studies of targeted agents to obtain the critical information required for better planning of phase III clinical trials. On the basis of our results, we need to encourage multi-institutional testing to minimize selection bias. Furthermore, additional studies are warranted to improve our understanding of the reasons for the higher yield of positive phase III trials by pharmaceutical companies. Investigators need to be cognizant of these factors in phase II studies before designing future phase III trials.
The author(s) indicated no potential conflicts of interest.
Conception and design: John K. Chan, Stefanie M. Ueda, Valerie E. Sugiyama, Christopher D. Stave, Jacob Y. Shin, Bradley J. Monk, Branimir I. Sikic, Kathryn Osann, Daniel S. Kapp Administrative support: John K. Chan, Jacob Y. Shin Provision of study materials or patients: John K. Chan, Stefanie M. Ueda, Valerie E. Sugiyama, Christopher D. Stave, Jacob Y. Shin, Bradley J. Monk, Branimir I. Sikic, Kathryn Osann, Daniel S. Kapp Collection and assembly of data: John K. Chan, Stefanie M. Ueda, Valerie E. Sugiyama, Christopher D. Stave, Jacob Y. Shin, Bradley J. Monk, Kathryn Osann, Daniel S. Kapp Data analysis and interpretation: John K. Chan, Stefanie M. Ueda, Valerie E. Sugiyama, Christopher D. Stave, Jacob Y. Shin, Bradley J. Monk, Branimir I. Sikic, Kathryn Osann, Daniel S. Kapp Manuscript writing: John K. Chan, Stefanie M. Ueda, Valerie E. Sugiyama, Christopher D. Stave, Jacob Y. Shin, Bradley J. Monk, Branimir I. Sikic, Kathryn Osann, Daniel S. Kapp Final approval of manuscript: John K. Chan, Stefanie M. Ueda, Valerie E. Sugiyama, Christopher D. Stave, Jacob Y. Shin, Bradley J. Monk, Branimir I. Sikic, Kathryn Osann, Daniel S. Kapp
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published online ahead of print at www.jco.org on February 19, 2008. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test and logistic regression models. 
