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Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp. 2000-2005 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.2407 Systematic Survey of Therapeutic Trials for Metastatic Colorectal Cancer: Room for Improvement in the Critical Pathway
From the Departments of Gastrointestinal Medical Oncology and Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX Corresponding author: Scott Kopetz, MD, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 426, Houston, TX 77030; e-mail: skopetz{at}mdanderson.org
Purpose The current strategy of drug development has been criticized as being highly inefficient. In 2004, the US Food and Drug Administration (FDA) released recommendations to improve this process, including a push for increased use of enrichment trials. It is unclear to what extent aspects of this "Critical Path Initiative" have been adopted in trial designs in metastatic colorectal cancer. Methods A systematic review was conducted of actively enrolling treatment trials in metastatic colorectal cancer. Trials were identified from the National Cancer Institute's clinicaltrials.gov and Investigative Drug Branch databases. Trials were categorized based on the number of prior treatments allowed, phase of the trial, agent mechanism of action, and FDA approval status of agents under investigation. Results One hundred two trials are enrolling, with a combined enrollment goal of more than 20,000 patients. Thirteen percent of trials investigated an agent not yet FDA-approved for any oncology indication. The most common study design was a phase II study limited to previously untreated patients; compared with the remaining trials, these phase II trials were more than 10 times more likely to only use agents FDA-approved for colorectal cancer. Three percent of patients were enrolled onto trials enriched for tumor characteristics that were hypothesized to improve clinical benefit. Conclusion Current clinical trials for metastatic colorectal cancer are deficient in the investigation of agents directed at a novel therapeutic target, overuse phase II studies of FDA-approved agents, and fail to incorporate enrichment trial designs as encouraged by the FDA initiative.
Oncologic drug development is an expensive and risky undertaking, with an estimated research and development cost of $800 million dollars per new drug approved.1 Because of an increase in knowledge about the molecular underpinnings of tumorigenesis, almost half of the compounds in development are now directed against novel mechanisms. The result has been a four-fold increase in the number of oncology drugs in development between 1991 and 2001.2 Despite this promising trend, there has been a concomitant decline in the number of oncology drugs submitted to the US Food and Drug Administration (FDA) for approval.3 For example, it is estimated that only 8% of the compounds entering phase I clinical trials in 2006 will make it to the market, a 40% decline since the 1990s.4,5 The majority of the agents that undergo testing fail to reach phase II trials.5 Those that do proceed to phase II trials are explored in a limited number of tumor types and settings based on a combination of preclinical and early clinical data. Many factors contribute to the limited scope of phase II and later testing, but a lack of financial resources is the one most commonly cited. The traditional approach to drug development has been criticized as highly inefficient.6-12 Because of this decline in innovative therapeutics obtaining approval, the FDA has established the Critical Path Initiative,13 which seeks to modernize the medical product development process and revamp the tools used to conduct and evaluate clinical trials. The FDA released this initiative in early 2004 and has since offered specific recommendations to improve the drug development process.14 As part of this initiative, there is an increased emphasis on the use of innovative and efficient trial designs to reduce trial size and shorten patient follow-up. One specific design recommendation applicable to oncology studies is the so-called enrichment trial. This type of trial enrolls a group of patients believed to have a higher likelihood of response because of the presence of a tumor biomarker.15 Because the patient population is enriched to include select patients with potentially responsive disease, this design can demonstrate activity with fewer patients than traditional phase II studies, potentially improving the efficiency of drug development. Other recommendations of the Critical Path Initiative include incorporating novel statistical techniques into trial design and using imaging techniques to predict efficacy or demonstrate mechanistic activity. Over the past decade, metastatic colorectal cancer has been an attractive field for drug development, as demonstrated by the approval of six new agents. Thus it is reasonable to expect that the characteristics of clinical trials in metastatic colorectal cancer reflect recent advances in clinical trial design and the broader trends in oncologic drug development. This article reports a systematic review of ongoing clinical trials in metastatic colorectal cancer. In particular, we describe the characteristics of such trials, with emphasis on those testing unapproved agents and novel therapeutic targets. Finally, we describe the use of enrichment trials in metastatic colorectal cancer to gauge the extent to which the FDA Critical Path Initiative has been incorporated into drug development strategies.
A systematic review was conducted of actively enrolling clinical trials in colorectal cancer. Data was collected from the National Institutes of Health (NIH) online database (www.clinicaltrials.gov)16 and the National Cancer Institute's (NCI) Cancer Therapy Evaluation Program supported trial list. The NIH online database also includes trials submitted to the NCI's Physician Data Query database (www.cancer.gov/clinicaltrials/search).17 Under Section 113 of the FDA Modernization Act of 1997,18 all phase II and higher drug treatment trials are required to register with the NIH database. Additionally, the International Committee of Medical Journal Editors requires that all phase II and higher trials that use a prospective comparison group register in the database as a condition of subsequent publication.19 The databases were accessed on November 30, 2006. For the NIH online database, a database search was performed using the following search terms: colon (colorectal, colon, or rectal) and (cancer or carcinoma) and (metastatic or advanced) and (phase II or phase III). Data collected included the study start date, planned enrollment size, phase of the study, current recruitment status, end points, eligibility criteria, and therapeutic agents used. The name and type of group (US government or cooperative group, industry, academic, or non-US government) serving as the primary sponsor for the research was recorded. The definition of sponsorship did not necessarily reflect the source of funding for the trial; for example, investigator-initiated pharmaceutical industry trials were categorized as academic according to these criteria. The results were then filtered to exclude trials no longer recruiting or completed. Trials for which recruitment was scheduled to begin in 2006 were included. The database was limited to treatment trials, excluding supportive care and observational trials. The resulting trial list was further screened to exclude trials focusing on tumor types other than adenocarcinoma and trials of adjuvant and neoadjuvant therapies. Combined phase I and phase II trials were allowed if colorectal cancer patients were specifically included in both the phase I and phase II portions. Trials were considered to be specific to patients with colorectal cancer if the title of the trial explicitly mentioned colorectal cancer. Broader phase II trials that included a longer list of eligible tumor types without specific mention of colorectal cancer in the trial title were not included. Trials were considered to include an enriched population if they had tumor-specific inclusion criteria with the expectation that this enriched patient population would be more likely to derive therapeutic benefits from active agents than a nonenriched patient population. Agents were categorized by their FDA approval status into one of three groups: FDA approved for colorectal cancer, FDA approved for another indication, and not FDA approved. Agents were also classified based on the novelty of their mechanism of action. If a therapeutic agent targeted the same ligand/receptor complex or cellular mechanism as an existing FDA-approved agent, then it was not considered novel.
Three hundred eighty-three trials were identified from the NIH Physician Data Query database, and 49 trials were identified from the NCI Cancer Therapy Evaluation Program database. After limiting the results to active or newly activated treatment trials for metastatic colorectal cancer, we identified 102 unique trials (Fig 1). Twelve trials did not report the planned enrollment size. The remaining 90 trials reported a total of 21,409 patients planned for enrollment, with a median of 66 patients per trial.
Studies testing agents in patients previously untreated for metastatic cancer accounted for the majority of the trials and patients (Table 1). Trials of agents used in patients refractory to two or more regimens accounted for 8% of the trials and 2% of the planned patient enrollment. Academia-sponsored trials had a median enrollment of 50 patients and accounted for the largest number of trials. In contrast, the trials sponsored by the US government, industry, and non-US governments were less numerous but had larger median enrollment goals (at 67, 90, and 242 patients per trial, respectively).
Agents Studied Most trials used only agents that were FDA approved for colorectal cancer (Table 2). Twenty-one percent of the trials explored the utility of agents FDA approved for another tumor type, and 25% of the trials explored non–FDA-approved agents.
Of the trials that tested unapproved agents, approximately half, or 13% of the total trials, had a novel therapeutic target (Appendix Fig A1, online only). Approximately 9% of the trials used an investigational agent with the same therapeutic target as one of the seven FDA-approved colorectal cancer drugs. Most trials of novel agents limited their enrollment to previously treated patients. Trials of vaccine or dendritic cell therapy were categorized separately and accounted for 4% of the trials but only 1% of the planned enrollment.
Study Populations
Most patients enrolled onto the 102 trials reviewed were previously untreated for metastatic disease. Only a minority of this subset of patients were treated in trials of an agent unapproved by the FDA for any indication (Fig 3). Patients with refractory or relapsed disease who were enrolled onto trials limited to previously treated patients were only slightly more likely than previously untreated patients to be treated with an agent not yet approved by the FDA.
Enrichment Trial Design Of the trials available for review on the NCI and NIH databases, only 13 were determined to have an enrichment trial design (Table 2). These represented 3% of the total planned patient enrollment. Vaccine trials, all of which require that tumor tissues express carcinoembryonic antigen, accounted for five of the enrichment trials. Another five trials explored epidermal growth factor receptor (EGFR) antibodies and had specific requirements for EGFR expression levels in the tumors. Only three trials were enriched for novel tumor characteristics: two for thymidylate synthase overexpression and one for a mutation in the PI3K gene. These three trials accounted for less than 1% of the total planned patient enrollment.
Metastatic colorectal cancer is an active area of clinical research, with more than 20,000 patients planned for enrollment in more than 100 trials. This systematic survey demonstrates that the majority of clinical trials in metastatic colorectal cancer have not yet incorporated the recommendations of the FDA Critical Path Initiative. Novel agents against metastatic colorectal cancer account for only a small percentage of the trials, a deficiency particularly evident in the large numbers of phase II trials for untreated patients and in trials for previously treated patients. Furthermore, trials involving patients with metastatic colorectal cancer rarely use an enrichment strategy. This survey suggests areas in which improvements in drug development in colorectal cancer would likely allow for more efficient use of clinical trial resources. Specifically, we suggest decreasing the number of phase II studies that are limited to FDA-approved agents, redirecting resources to explore agents with novel mechanisms of action, and increasing utilization of enrichment trials. Most patients with metastatic colorectal cancer enrolled onto clinical trials are treated with drugs already FDA approved for colorectal cancer. Even in trials limited to refractory disease, 73% of the patients are treated only with FDA-approved agents. This represents a population with a poor prognosis for whom more innovative therapeutics are clearly needed. Some rare, phase III trials using only FDA-approved agents are designed to explore questions with important therapeutic and economic ramifications, such as the utility of continuing bevacizumab after tumor progression or the efficacy of combinations of targeted agents in the front-line setting. However, many of the front-line trials are small, single-arm, nonenrichment, phase II designs limited to approved colorectal cancer agents, which seem less likely to affect our treatment of metastatic colorectal cancer.20 A survey of published phase II studies demonstrated that reliance on uncontrolled, phase II studies is not unique to colorectal cancer research, but mirrors the broader field of oncology.21,22 Our study demonstrates that many of these trials are redundant or only explore alternative combinations or schedules of already FDA-approved therapies. Of the unapproved agents currently under study, only a minority address a novel mechanism or pathway. Most new agents are instead being developed to target a previously proven signal pathways or cellular mechanisms. Examples of this approach include agents targeting the EGFR or vascular endothelial growth factor pathway and new formulations of pyrimidines and camptothecins. Although preclinical evidence may suggest that these agents improve on those currently available, this effort should be complimented by increased investigation of high-risk/high-yield therapeutics that focus on novel pathways with a greater potential for significant clinical impact. An improved balance between the investigation of agents for existing and novel targets is needed. Because of its heterogeneity in carcinogenesis, colorectal cancer is amenable to the development of molecularly directed therapies and is suited to enrichment trial designs. Without enrichment strategies, the activity of many agents may not be recognized even in large phase III trials.23,24 Nevertheless, in this review, few trials were enriched for a novel biomarker associated with the drug's proposed mechanism of action. This may reflect a lack of understanding about the molecular biology of metastatic colorectal cancer and a hesitancy to narrow the patient population to those patients expressing a tumor profile of interest. Yet given the increasing number of molecular targets undergoing investigation in metastatic colorectal cancer, the opportunity for concurrent development of associated tumor biomarkers by using an enrichment trial design is appealing. The increased use of smaller, single-arm, phase II enrichment trials may provide an early indication of the efficacy of a new agent and reduce the high rate of late-phase drug development failures.5,7,25,26 However, there are limitations to the increased use of enrichment trials. Little precedence exists for linking therapeutics and diagnostics during the drug development process. Previous development strategies, such as those used in developing targeted agents for EGFR-expressing tumors, focused on an enriched population without subsequent validation of this biomarker, arguably resulting in inaccurate patient selection.27,28 Ultimately, improving the quality of preclinical models to interrogate the tumor-host-treatment interactions will be necessary to improve confidence in a proposed biomarker of efficacy. Optimal use of enrichment designs also requires that the assay be validated before inclusion in clinical trials, which can be a time-consuming and costly proposition. The enrichment approach is also limited by a regulatory system that does not encourage approval of so-called individualized therapies or combination treatments without previously established single-agent efficacy in broad patient populations. Incentives from or changes in drug-approval requirements of regulatory agencies may be needed for such studies to counter the economic forces that oppose limiting the size of the market for an approved drug.29 Acquisition of the appropriate patient sample may require the added complexity of a new tumor biopsy or the retrieval of prior tissue specimens, both of which need to be done in a timely manner to allow patient enrollment onto the trial. As a result of the costs associated with obtaining the tissue and performing the assay for the biomarker of enrichment, these trials require higher per-patient funding, which can be difficult to obtain from both the private and public sectors. Involvement of laboratory collaborators can be limited by a funding system that values so-called original laboratory research over involvement in translational clinical trials. These barriers can only be overcome with public, industry, and institutional support to foster collaborations among clinical, laboratory, and imaging scientists during the conceptual stage of trial design and will need to be addressed to increase the use of enrichment trials based on biomarkers of efficacy. Despite clinical trial registration requirements, it is certain that some trials were inadvertently excluded from this review. Indeed, recent reviews suggest that additional education is required to get full compliance with the registration standards.30,31 Nevertheless, a broad array of clinical trials was represented here, highlighting the majority of ongoing metastatic colorectal cancer research. Some changes recommended by the FDA Critical Path Initiative, such as novel statistical methods, were unable to be rigorously assessed in this analysis. These include methods such as Bayesian statistics, adaptive allocation designs, and selective dose escalation.32,33 In addition, this survey was unable to effectively identify trials that incorporated novel diagnostic imaging to predict the agents’ efficacy. Such approaches should also be incorporated into drug development. In conclusion, current clinical trials for metastatic colorectal cancer are deficient in the investigation of agents directed at a novel therapeutic target, commonly overuse phase II studies of existing FDA-approved agents, and largely fail to incorporate enrichment trial designs. Despite these findings, metastatic colorectal cancer is an ideal setting for innovative trial designs and the exploration of novel agents. We recommend several approaches to optimize drug development in metastatic colorectal cancer to embrace key portions of the paradigm laid out by the Critical Path Initiative—a paradigm that seeks to rapidly validate promising therapeutic targets and improve the efficiency of drug development.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: David Z. Chang, Amgen Expert Testimony: None Other Remuneration: None
Conception and design: Scott Kopetz Collection and assembly of data: Scott Kopetz Data analysis and interpretation: Scott Kopetz, Michael Overman, Katrina Y. Glover, Imad Shureiqi, Robert A. Wolff, James L. Abbruzzese, Cathy Eng Manuscript writing: Scott Kopetz, Michael Overman, David Z. Chang, Katrina Y. Glover, Imad Shureiqi, James L. Abbruzzese, Cathy Eng Final approval of manuscript: Scott Kopetz, Michael Overman, David Z. Chang, Katrina Y. Glover, Imad Shureiqi, Robert A. Wolff, James L. Abbruzzese, Cathy Eng
Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. DiMasi JA, Hansen RW, Grabowski HG: The price of innovation: New estimates of drug development costs. J Health Econ 22:151-185, 2003[CrossRef][Medline] 2. Booth B, Glassman R, Ma P: Oncology's trials. Nat Rev Drug Discov 2:609-610, 2003[CrossRef][Medline] 3. Rovin L: FDA's Critical Path Initiative: History, Objectives, Approach. http://www.fda.gov/oc/initiatives/criticalpath/presentations/bio200501_files/bio200501.html. 4. Dimasi JA: Risks in new drug development: Approval success rates for investigational drugs. Clin Pharmacol Ther 69:297-307, 2001[CrossRef][Medline] 5. Roberts TG Jr, Lynch TJ Jr, Chabner BA: The phase III trial in the era of targeted therapy: Unraveling the "go or no go" decision. J Clin Oncol 21:3683-3695, 2003 6. Rowinsky EK: Curtailing the high rate of late-stage attrition of investigational therapeutics against unprecedented targets in patients with lung and other malignancies. Clin Cancer Res 10:4220s-4226, 2004[CrossRef][Medline] 7. Von Hoff DD: There are no bad anticancer agents, only bad clinical trial designs: Twenty-first Richard and Hinda Rosenthal Foundation Award Lecture. Clin Cancer Res 4:1079-1086, 1998[Abstract] 8. Schein PS: The case for a new national program for the development of cancer therapeutics. J Clin Oncol 19:3142-3153, 2001 9. Bailar JC III, Gornik HL: Cancer undefeated. N Engl J Med 336:1569-1574, 1997 10. Wood AJJ: A proposal for radical changes in the drug approval process. N Engl J Med 355:618-623, 2006 11. Ratain MJ: Phase II oncology trials: Let's be positive. Clin Cancer Res 11:5661-5662, 2005 12. de Bono JS, Tolcher AW, Rowinsky EK: The future of cytotoxic therapy: Selective cytotoxicity based on biology is the key. Breast Cancer Res 5:154-159, 2003[CrossRef][Medline] 13. US Food and Drug Administration: Challenge and opportunity on the critical path to new medical products. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf 14. US Food and Drug Administration: Critical path opportunities report. http://www.fda.gov/oc/initiatives/criticalpath/reports/opp_report.pdf. 15. Temple RJ: Enrichment designs: Efficiency in development of cancer treatments. J Clin Oncol 23:4838-4839, 2005 16. ClinicalTrials.gov: http://www.clinicaltrials.gov/. 17. National Cancer Institute Physicians Query Database. http://www.cancer.gov/clinicaltrials/search. 18. US Food and Drug Administration: Food and Drug Administration Modernization Act (FDAMA) Section 113 and ClinicalTrials.gov. http://www.fda.gov/oashi/clinicaltrials/section113/default.htm 19. International Committee of Medical Journal Editors: Uniform requirements for manuscripts submitted to biomedical journals: Writing and editing for biomedical publication. http://www.icmje.org/ 20. Zia MI, Siu LL, Pond GR, et al: Comparison of outcomes of phase II studies and subsequent randomized control studies using identical chemotherapeutic regimens. J Clin Oncol 23:6982-6991, 2005 21. Chabner B: Phase II cancer trials: Out of control? Clin Cancer Res 13:2307-2308, 2007 22. Michaelis LC, Ratain MJ: Phase II trials published in 2002: A cross-specialty comparison showing significant design differences between oncology trials and other medical specialties. Clin Cancer Res 13:2400-2405, 2007 23. Betensky RA, Louis DN, Gregory Cairncross J: Influence of unrecognized molecular heterogeneity on randomized clinical trials. J Clin Oncol 20:2495-2499, 2002 24. Castro M: The simpleton's error in drug development. J Clin Oncol 20:4606-4607, 2002 25. Korn EL: Nontoxicity endpoints in phase I trial designs for targeted, non-cytotoxic agents. J Natl Cancer Inst 96:977-978, 2004 26. Marshall JL, Gehan EA: The development of novel agents for the treatment of colorectal cancer: A critical review of current practice and some suggestions for the future. Clin Adv Hematol Oncol 5:167-172, 2007[Medline] 27. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 28. Chung KY, Shia J, Kemeny NE, et al: Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23:1803-1810, 2005 29. Roberts TG Jr, Chabner BA: Beyond fast track for drug approvals. N Engl J Med 351:501-505, 2004 30. Zarin DA, Tse T, Ide NC: Trial registration at ClinicalTrials.gov between May and October 2005. N Engl J Med 353:2779-2787, 2005 31. De Angelis CD, Drazen JM, Frizelle FA, et al: Is this clinical trial fully registered? A statement from the International Committee of Medical Journal Editors. N Engl J Med 352:2436-2438, 2005 32. Thall PF, Simon RM, Estey EH: New statistical strategy for monitoring safety and efficacy in single-arm clinical trials. J Clin Oncol 14:296-303, 1996[Abstract] 33. Yao Q, Wei LJ: Play the winner for phase II/III clinical trials. Stat Med 15:2413-2423, 1996[CrossRef][Medline] Submitted July 10, 2007; accepted October 4, 2007.
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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
