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From Silos to a Critical Path of New Agent Development: A Paradigm to Revolutionize Clinical Research

Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL

Allegorically, American healthcare and research landscapes are fields of silos, often failing to cultivate products which adequately serve patients or fulfill the potential to advance human biologic science. Interactions, or lack thereof, among the component entities have not resulted in a whole greater than the sum of their parts. Yet, perturbations within one component can reverberate across systems with unintended consequences, or, perhaps more typically, with ignorance of consequences. Indeed, the American health care enterprise is an astounding array of disunited factors and forces including diverse populations, geography, economics, government, the private sector, healthcare providers, researchers, hospital and outpatient systems, and universities, often forced into unequal and haphazard partnerships. Clinical research is a particularly fragile network of silos. It is becoming increasingly more vulnerable because of mounting pressures within the healthcare industry and research community, including reimbursement, regulatory policies, stagnation (or worse) of the federal budget, allocation of physician time and resources, and impending shortage of healthcare personnel.

The historic undervaluation of clinical research is exemplified by the sizeable voluntary effort required by physicians to enroll patients, the philanthropic support that must supplement many clinical research programs, and the second-tier status allocated to clinical investigators by university leadership. There are also conflicting policies within government, such as the recent discussions within Centers for Medicare and Medicaid Services to change its coverage policy for Medicare patients on clinical trials (Decision Memo for Clinical Trial Policy). ¹ Ironically, the turmoil affecting clinical research within the American healthcare system comes at a time when the potential to unmask some of the complexities of human tumor biology has never been greater. The growing national emphasis supporting evidence-based medicine, quality initiatives, and cost containment mandates the discovery of more links between biology and treatment efficacy.

In this issue of the Journal of Clinical Oncology, Kopetz et al² evaluate lost opportunities and obstacles hindering the development of new agents for metastatic colorectal cancer—an analysis that can apply to cancer clinical research in general. In their systematic review of active clinical trials in advanced or metastatic colorectal cancer, the authors report that the majority of the trials recruited previously-untreated metastatic colorectal cancer patients. Investigated agents that were approved by the US Food and Drug Administration (FDA) for colorectal cancer were used in 53% of trials (representing 81% of the 21,409 patients planned for enrollment). The majority were phase I/II trials (79% representing 33% of the total patients), most trials were initiated since 2005 (66%), and only 13% of trials employed an enrichment trial design, accounting for just 2.9% of the patients planned for enrollment. It appeared that only 8% included tumor biomarkers in an enrichment trial design, representing just 1.7% of the planned trial population of patients. The primary sponsors of the trials included the US Government or cooperative groups, industry, academia, or non-US government (19%, 23%, 42%, and 17% of the trials, respectively, and 17%, 36%, 15%, and 32%, respectively, of the planned patient enrollment).

The authors emphasize the persistence of the empiric trial design to investigate antineoplastic agents; a methodology in contradistinction to the FDA Critical Path Initiative.^3,4 This FDA report emphasizes that for new biomedical science to advance, it will take a united effort on the part of patients, industry, academia, and government. The development of a host of integrated approaches will be essential, including predictive tools to identify candidate agents for additional investigation, animal models of human disease, statistical methodology, scientific instruments and tests, and new biomarkers and diagnostic devices to better establish treatment efficacy for individual patients. To reverse the alarming trend of the massive investment in biomedical research resulting in progressively fewer new medical therapies entering the market, the FDA's Critical Path must be implemented with the cooperation of all stakeholders. As emphasized by the FDA, the initiation of the National Critical Path will require appropriate infrastructure that can succeed in modernizing product regulation; development of genomic, proteomic, and metabolomic technologies that can lead to individualized or personalized medicine; promotion of innovative trial design; development of bioinformatics to create new models to analyze biologic data; and integration of new imaging. New models need to be developed for training the next generation of clinical trialists equipped to embrace the component stakeholders and to harmonize the laboratory and clinical sciences to more fully distinguish the human tumor biology that can promote highly specific product development.

Barriers to optimal clinical research productivity have been outlined over the years, often focusing on the physician as a consistent barrier, as well as regulatory and funding limitations. More recently, the focus of discussion has transcended important issues such as barriers to patient accrual and diminished federal funding to explore structural, infrastructural, and procedural barriers to creating relevant timely oncology clinical trials.^5,6 Dilts et al^5,6 have outlined the laborious labyrinth of clinical trial development that has created significant barriers to the success of the oncology clinical trials enterprise, reflecting processes endemic across research organizations, including cooperative groups, industry, and institutions. Biostatisticians and other investigators are currently exploring new design models, especially to reduce the high failure rate of phase II trials. These include predictive marker validation designs such as a marker-by-treatment interaction design and a marker-based strategy design as championed by Sargent et al.^7,8 Adaptive trial designs including use of Bayesian methodology are other examples.

Kopetz et al emphasize that the heterogeneity inherent to colorectal cancers could stimulate expanded use of phase II enrichment trials to develop molecular-directed therapies to "reduce the high rate of late-phase drug development failures." They also articulate some of the obstacles to this approach, including the need to validate biomarkers linking diagnostic and therapeutic strategies, and develop better preclinical models to correlate with human tumor interactions. The authors also describe the cost of conducting laboratory-based clinical trials, including obtaining biopsies from patients to complete laboratory experiments, encouraging the regulatory system to recognize individualized patient strategies, and increasing incentives for the pharmaceutical industry to develop agents that may benefit only subsets of the cancer population. In addition, funding agencies and academic departments must be compelled to expand their definitions of science beyond individual laboratory-based research to encompass translational clinical research embracing extensive collaborations among clinicians, laboratory scientists, and others, such as imaging investigators.

The analysis by Kopetz and colleagues clearly articulates the continuation of an imperfect—if not failed—clinical trials methodology for the development of new colorectal cancer treatments based on empiric design. The isolation—or at least, ineffective interactions—among the silos within industry, government, academia, and the practice and research communities perpetuates the undervalue of clinical research while at the same time, wastes billions of dollars without producing adequate new agents to benefit a highly diverse population. Colorectal cancer patients have indeed benefited from the introduction of new biologic agents, including bevacizumab, cetuximab, and panitumumab. However, the availability of these agents is confounded by the inability to select appropriately the patients most likely to achieve tumor control based on individual patient tumor analysis. The recent observations linking colon tumor KRAS mutation status and response to cetuximab and panitumumab are encouraging, and are being integrated in current clinical trials designs. The FDA Critical Path Initiative provides an outline from which new paradigms of clinical research could emerge. Adhering to this path could revolutionize our understanding of human tumor biology, resulting in appropriately targeted drug development. This revolution is only possible if the silos collectively integrate, so that the whole becomes greater than the sum of the parts.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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: Al B. Benson III, Sanofi-aventis (C), ImClone (C), Bristol-Meyers Squibb (C), Pfizer (C), Roche (C), Genentech (C), Amgen (C) Stock Ownership: None Honoraria: None Research Funding: Al B. Benson III, Sanofi-aventis, Roche, Genentech, Pfizer, ImClone, Bristol-Meyers Squibb, Amgen Expert Testimony: None Other Remuneration: None

REFERENCES

1. US Department of Health and Human Services Decision Memo for Clinical Trial Policy (CAG-00071R2). http://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=210

2. Kopetz S, Overman M, Chang D, et al: Systematic survey of therapeutic trials for metastatic colorectal cancer: Room for improvement in the critical pathway. J Clin Oncol 26:2000-2005, 2008[Abstract/Free Full Text]

3. Food and Drug Administration: Challenge and opportunity on the critical path to new medical products. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf

4. Food and Drug Administration: Critical path opportunities report, 2006. http://www.fda.gov/oc/initiatives/criticalpath/report/opp_report.pdf

5. Dilts DM, Sandler AB: Invisible barriers to clinical trials: The impact of structural, infrastructural, and procedural barriers to opening oncology clinical trials. J Clin Oncol 24:4545-4552, 2006[Abstract/Free Full Text]

6. Dilts DM, Sandler AB, Baker M, et al: Processes to activate phase III clinical trials in a cooperative oncology group: The case of Cancer and Leukemia Group B. J Clin Oncol 24:4553-4557, 2006[Abstract/Free Full Text]

7. Sargent DJ, Conely BA, Allegra C, et al: Clinical trial designs for predictive marker validation in cancer treatment trials. J Clin Oncol 23:2020-2027, 2005[Abstract/Free Full Text]

8. Mandrekar SJ, Grothey A, Goetz MP, et al: Clinical trial designs for prospective validation of biomarkers. Am J Pharmacogenomics 5:317-325, 2005[CrossRef][Medline]

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