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Originally published as JCO Early Release 10.1200/JCO.2008.21.5798 on April 13 2009 © 2009 American Society of Clinical Oncology.
Phase 0 Clinical Trials: An Answer to Drug Development Stagnation?Department of Internal Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI Despite important recent advances in biomedical research, such as the sequencing of the human genome, the arrival of the new millennium marked the beginning of a downturn in the submission of major drug and biologic product applications to the US Food and Drug Administration (FDA). Instead of an expected acceleration in innovative FDA-approved medical therapies for commercial use, a slowdown actually occurred. Recognizing this unfortunate trend, the FDA published an Executive Summary Statement in 2004, detailing its analysis of the critical pipeline problem of new medical products.1 In the statement, titled "Innovation or Stagnation: Challenges and Opportunity on the Critical Path to New Medical Products," the agency stated that spending for new development of novel therapies had disproportionately increased relative to major drug and biologic product submissions. Despite improvements in preclinical drug discovery tools, a novel agent entering development had only an 8% chance of making it to commercial use in 2000, down from the historical success rate of 14% in 1985. The investment required for one successful therapeutic launch increased more than 55% in less than a decade, due in large part to the monies required to take a drug from the laboratory and carry it through the clinical phase I to III trials required for filing and drug launch—the steps between discovery and approval known as the critical path. As a result of the significant escalation in investment required to navigate the critical path, there was great concern about a new health care crisis: a few commercially available products would be required to carry the financial burden for many product failures. The FDA concluded that something was significantly wrong with the critical path. The tools of development had not kept pace with the tools of discovery. To overcome stagnation in the critical path, they recognized that new and practical tools needed to be developed. The only way to meet this challenge was to create innovations in the drug development network to make the process more efficient, effective, and more likely to result in safe products that benefit patients. Out of this statement came the concept of exploratory investigational new drug (IND) studies. Exploratory IND studies are clinical trials conducted early in phase I (hence, the term phase 0) that involve limited human exposure and have no therapeutic or diagnostic intent.2 The purpose of the phase 0 study is to assist in the go versus no-go decision-making process of a drug's fate earlier in the development process, using relevant human models instead of relying on sometimes inconsistent animal data, thus helping to confirm end points such as mechanism of action, pharmacology, bioavailability, pharmacodynamics, and metabolic microdose assessments. These studies of novel agents expose a small number of patients (perhaps 10 or fewer) to a limited duration (eg, 7 days or less) and dose (in the range of one 100th of the dose required to yield a pharmacologic effect of the test substance with a maximum dose of < 100 µg).3 They are conducted before the traditional phase I dose-escalation safety and tolerance studies. By not having the traditional phase I objectives of toxicity and dose finding, phase 0 studies can be conducted early in the development process and are actually considered more of a discovery, rather than development, tool. In early 2006, the FDA published "A Guidance for Industry, Investigators, and Reviewers for Exploratory IND Studies" as part of the agency's critical path initiative to streamline drug development and improve the understanding of drugs early in the clinical process.3 There must be several considerations before initiating a phase 0 trial, given that not all novel agents will be appropriate for pre–phase I analysis. For example, if researchers are to evaluate a specific pharmacodynamic target, they must be certain that the drug's mechanism of action is defined by that target to avoid misleading or even meaningless data. Sorafenib (BAY 43-9006), for instance, was originally tested in clinical trials as a B-Raf kinase inhibitor, but may actually have positive inhibitory effects due to other off-target effects.4,5 If the clinical investigators of sorafenib had focused solely on B-Raf as its target, the antitumor profile of this drug may have gone undefined. To evaluate target effect, a biomarker must be known and an assay to measure it must be developed and validated before study initiation.6 It is imperative that proper sample handling be acknowledged, and if a surrogate is being used, that it gives meaningful results relative to the tissue/organ target of attack. The ethics of doing phase 0 trials must also be considered carefully.7 These trials have no therapeutic intent and often will require significant invasive procedures. They have a finite treatment duration and, theoretically, are not in the range of efficacious dosing. Fewer toxicology data are necessary, so there is some concern that this limited toxicology will be insufficient and not well defined in every drug scenario to maximize patient safety. The patient must be made aware of the investigational nature of these studies, the lack of therapeutic intent, and the limited toxicology and safety testing. There is a responsibility on the part of the investigator to advocate for the patient's ability to be treated after his or her phase 0 experience, either with conventional treatment or on another clinical trial, in as timely a fashion as possible. Thus, during the design of a phase 0 study, additional patient treatment strategies must be taken into account and possibly incorporated into the actual trial. The necessary end points of the phase 0 trial must be defined in real time so that there is minimal delay for subsequent treatment intervention. Therefore, significant multidisciplinary input from biostatisticians, clinicians, and basic and translational scientists in the design process is required to best protect the patient. Who benefits from the use of phase 0 trials? By incorporating this innovative tool to potentially expedite a new drug to clinic, the hope is that the main beneficiary will eventually be the patient population at large. Even if the phase 0 trial identifies the drug as not being of therapeutic worth, the patient population may benefit through the minimization of study participants recruited to subsequent trials on the critical path. The sponsor of the compound may realize the benefits of a phase 0 trial the most. Currently, the pharmaceutical community has many redundancies—multiple similar compounds are being developed concurrently. Theoretically, phase 0 trials can enable companies to reduce costs by identifying the most promising of similar agents in their pipeline. The true question is, "Do phase 0 trials represent a paradigm shift in clinical drug development?"8 Until the agents under study in the initial phase 0 trials reach the end of their development, particularly if that end results in regulatory approval, the answer will likely remain unknown. However, the reality is that there have been similar but limited phase 0–like trials done in the past, before the nomenclature of phase 0 was recognized. Schellens elegantly presented prior examples of such types of trials at the 20th European Organization for Research and Treatment of Cancer symposium in 2008, discussing scenarios that led to go (eg, capecitabine) and no-go (eg, SPI-779) decisions based on early, pre–phase I trials.10 Studies using microdoses of imaging agents have been successfully conducted, including 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl) uracil as an example of a drug that has progressed from subtherapeutic dosing into a currently ongoing phase I clinical trial.11 These examples indicate that although the specific terminology of phase 0 studies is new, the idea behind them is not. Although the value gained from a phase 0 study may be significant, and includes important information such as an optimal clinical candidate, elimination of uncertainty as to whether the drug reaches the target, and time and money savings by possibly preventing a full phase I trial, it cannot replace the later stages of clinical drug development process or overcome the lack of proof-of-concept in the preclinical and clinical arena. For example, if there is no biomarker, or the kinetics of the agent is nonlinear, a phase 0 trial of a novel agent may be of limited use. Investigators must be careful not to miss potentially valuable anticancer agents due to disparities in character between its microdose and full-dose kinetics. Thus, not every drug may benefit from a phase 0 trial. In addition, not every institution is capable of conducting these studies in a timely and efficient manner. If the proper resources and committed expertise are not available, a phase 0 trial may take too long to conduct and result in possible delays in the development of the drug, leading to meaningless data with significant patient and financial resources wasted. Kummar et al12 should be commended for the outstanding job they did in executing the phase 0 trial of the novel oral poly (ADP-ribose) polymerase inhibitor, ABT-888, reported in this issue of Journal of Clinical Oncology. An excellent team of preclinical and clinical investigators was brought together to maximize the translational worth of this initial phase 0 trial, and the primary objectives were met within 5 months. Using information gained from the phase 0 study, ABT-888 was able to move quickly into combination studies, bypassing the traditional monotherapy phase I clinical trial.13 The agent under study fit the profile of an ideal phase 0 agent: the target could be monitored, the biomarker could be assayed with validity and reproducibility, and the kinetics of ABT-888 appeared linear. There was support by governing agencies, and a team of several investigators was recruited to establish a core biomarker laboratory at the National Cancer Institute. The team demonstrated that, given adequate resources and dedication, an exceptional phase 0 trial can be carried out, with the potential to serve as an example of innovation to the rest of the drug development community. The oncology drug development world is watching the outcome of this pioneering study with great interest. Will it ultimately expedite the development of ABT-888? Will it lead to an FDA new drug application? It will take the next several years of additional vigorous, well-executed clinical trials to help find the answers. Whatever the final development fate of ABT-888, this phase 0 trial has been instrumental in bringing to the forefront the need and acceptance of newer clinical development tools in an era in which treatments are being discovered rationally. With more than 500 oncology drugs expected to enter clinical development within this decade, those of us involved in clinical research recognize the need for smarter development plans. Although such an influx of new agents is an extreme financial burden to the cancer drug development community, we must never lose focus that the most limited and valuable resource remains the patients themselves. It is not only the responsibility of the FDA, but also our individual professional responsibility as clinical investigators, to make sure that we develop these agents in an intelligent, efficient, and ethical manner. Historically, we have typically developed compounds that give an incremental improvement in response or a minimal survival advantage. It is becoming increasingly apparent that a true paradigm shift in cancer drug development will be necessary to reach the twin goals of significant response and survival increase. Only time will tell whether phase 0 studies will be one of the discovery tools that will eventually assist us in reaching these goals. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES 1. US Department of Health and Human Services Food and Drug Administration. Innovation or stagnation: Challenges and opportunity on the critical path to new medical products. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html. 2. Kinders R, Parchment RE, Ji J, et al: Phase 0 clinical trials in cancer drug development: From FDA guidance to clinical practice. Mol Interv 7:325–334, 2007. 3. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies. http://www.fda.gov/cder/guidance/7086fnl.htm. 4. Wilhelm S, Carter C, Lynch M, et al: Discovery and development of sorafenib: A multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5:835–844, 2006.[CrossRef][Medline] 5. Madhunapantula SV, Robertson GP: Is B-Raf a good therapeutic target for melanoma and other malignancies? Cancer Res 68:5–8, 2008. 6. Murgo AJ, Kummar S, Rubinstein L, et al: Designing phase 0 cancer clinical trials. Clin Cancer Res 14:3675–3682, 2008. 7. Abdoler E, Taylor H, Wendler D: The ethics of phase 0 oncology trials. Clin Cancer Res 14:3692–3697, 2008. 8. Takimoto CH: Phase 0 clinical trials in oncology: A paradigm shift for early drug development? Cancer Chemother Pharmacol 63:703–709, 2009.[CrossRef][Medline] 9. Meerum Terwogt JM, Groenewegen G, Pluim D, et al: Phase I and pharmacokinetic study of SPI-77, a liposomal encapsulated dosage form of cisplatin. Cancer Chemother Pharmacol 49:201–210, 2002.[CrossRef][Medline] 10. Schellens JHM. Implementation of phase 0 trials Presented at the 20th EORTC-NCI-AACR symposium on Molecular Targets and Cancer Therapeutics, Geneva, Switzerland, October 21-24, 2008. 11. Sun H, Collins JM, Mangner TJ, et al: Imaging the pharmacokinetics of [F-18]FAU in patients with tumors: PET studies. Cancer Chemother Pharmacol 57:343–348, 2006.[CrossRef][Medline] 12. Kummar S, Kinders R, Gutierrez ME, et al: Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol 27:2705–2711, 2009. 13. Eliopoulos H, Giranda V, Carr R, et al: Phase 0 trials: An industry perspective. Clin Cancer Res 14:3683–3688, 2008.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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