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Originally published as JCO Early Release 10.1200/JCO.2004.06.918 on July 26 2004 © 2004 American Society of Clinical Oncology.
Cancer Drug Development: For Populations or for Individuals?Division of Oncology Drug Products, Center for Drug Evaluation, United States Food and Drug Administration, Rockville, MD Drug approval always involves a degree of extrapolation. We approve drugs for indicated populations based on results from a sample of patients who were willing and able to participate in clinical trials. This process of extrapolation becomes more challenging when drug development becomes a global process. Drug approval in the United States and many other countries is often based, at least in part, on evidence from foreign studies. Multinational studies commonly support cancer drug approval in the United States, and questions frequently arise whether evidence from one region of the world will support use in a different region. The use of foreign data has been addressed in a guidance document from the International Conference on Harmonization—Ethnic Factors in the Acceptability of Foreign Clinical Data (ICH E5).1 This document acknowledges potential differences between the uses of medicines in different regions of the world. These ethnic differences are categorized as intrinsic (based on genetic or physiologic differences) or extrinsic (based on cultural or environmental characteristics). ICH E5 assumes that the entire drug development program need not be repeated in each region of the world. When the regulatory authority or drug sponsor is concerned that differences in ethnic factors could alter the efficacy or safety of the medicine in the new region, ICH E5 describes the generation of "bridging" data that allow extrapolation to a new region. Drugs of particular concern would include drugs cleared by enzymes showing genetic polymorphism and with steep dose-response curves. Such medicines are termed "ethnically sensitive." On the other hand, often conditions exist where bridging data are not needed, and the medicine is said to be "ethnically insensitive," when medical practice and trial conduct in the regions are generally similar. In this issue of the Journal of Clinical Oncology, Shirao et al2 report results of a bridging study. They describe a comparison of uracil/tegafur (UFT) plus oral leucovorin (LV) in Japanese and American patients with advanced colorectal cancer. The purpose of this comparison was to determine whether the results of phase III studies performed in the West could be extrapolated to Japanese patients. The authors assumed that if the study "showed equality of efficacy, safety, and pharmacokinetics in both Japanese patients and American patients, then the results of the Western phase III trials could be extrapolated to Japanese patients." Presumably, regulatory authorities in Japan will determine whether concerns exist regarding ethnic differences between the Japanese and American study populations, and whether bridging data satisfy those concerns. The UFT studies described by Shirao et al2 are two identical phase II and pharmacokinetic (PK) studies in advanced colon cancer patients, one performed in the United States and one in Japan. Patients received identical 300 mg/m2 UFT daily doses plus LV. PK parameters (sampled up to 8 hours), response rates, and toxicities were compared. This study design has limitations because it compares two groups sampled from different populations. Even though identical entry criteria were applied, the samples may reflect different patterns of patient selection; therefore, a statistically significant difference between these samples does not necessarily reflect a statistically significant or clinically relevant difference between the Japanese and US cancer populations. The PK results are not definitive. First, the study as originally designed had only limited statistical power to evaluate similarity of PK parameters between the Japanese and American patients. Second, even for this limited goal, only a subgroup of patients received comparable doses for the PK study. PK parameters are best compared in the 18 American patients and 26 Japanese patients with similar body surface area (1.5 to 1.83 m2). No formal test for similarity between these groups is provided, but the authors note that the Japanese patients' data are distributed within the range of the American patients' data. The striking finding (shown in Figure 3 of the Shirao et al article) is the large variation in the degree of exposure among patients from each country. With such large variation in individual exposure for each population, it would be difficult to detect significant differences in exposure between the populations. The comparisons of UFT activity and toxicity between the Japanese and American populations lead to more uncertainties than answers. The response rate comparison provides as much reassurance as one could expect in a cross-study comparison. The response rates were 36% (95% CI, 22% to 52%) and 34% (95% CI, 21% to 50%) for the Japanese patients and the American patients, respectively. However, the wide confidence intervals demonstrate the limitations of such studies. Observed differences in toxicity included mild thrombocytopenia (American, 31%; Japanese, 7%) and diarrhea (American, 69%; Japanese, 39%), including grade 3/4 diarrhea (American, 22%; Japanese, 9%). What does one make of these apparent differences? Is the apparent increased rate of diarrhea in US patients due to chance, different patient selection, different reporting patterns, different drug exposure, different chronobiologic schedules, or extrinsic ethnic differences? Further data evaluation might provide additional clues, but definitive answers are unlikely. United States cancer drug development includes a growing number of multinational and numerous multicenter, multiethnic US studies. After demonstration of safety and efficacy in the overall population, analyses are performed in ethnic subgroups. These subgroups, however, are usually small and the analyses often have inadequate statistical power. Drug approval is usually granted for treatment of the entire study population, and drug labeling describes important ethnic subgroup findings. When should bridging studies be recommended? To address this question, we need more detailed knowledge than is usually available with oncology drugs. ICH E5 lists factors suggesting that drugs may be sensitive to ethnic factors, such as nonlinear PK, steep pharmacodynamic curves for safety and efficacy, a narrow therapeutic dose range, metabolism through a single pathway (thereby increasing the potential for drug-drug interaction), and administration as a prodrug. Unfortunately, current oncology drug development programs often do not provide sufficient data to construct detailed dose-response and dose-toxicity curves. Bridging studies, however, will not address the most important differences among cancer patients. As the UFT pharmacokinetics data from Shirao et al2 suggest, fluorouracil exposure varies widely, even within regions. As outlined in ICH E5, we need to define PK and dose-response relationships early in drug development programs. We need to develop pharmacodynamic surrogate end points that can be incorporated into early dose-finding studies to develop reliable dose-response curves. For drugs with steep dose-response curves or with narrow therapeutic indices, we need to design phase III studies that use individualized dosing. For drugs metabolized by polymorphic enzymes, we need to determine correct doses for each genetic patient cohort and, preferably, use these doses prospectively in phase III studies, or at least develop retrospective models that predict optimal dosing. Cancer patients are individuals who serve as unwilling hosts to individual tumors. Both the hosts and the tumors have unique DNA that may hold the key to predicting optimal drug dose, tumor responsiveness, and drug toxicity. In the future, instead of bridging studies to guide treatment of ethnic groups, we may use pharmacogenomic data to guide treatment of individuals.3 To allay fears regarding pharmacogenomic data collection, the US Food and Drug Administration recently published a draft guidance document clarifying that they will not use exploratory genomic data for regulatory decision-making.4 Sponsors that are overly cautious about collecting genomic data may be missing important opportunities. As knowledge increases, educated patients will likely request analysis of their DNA so they and their tumors can be treated individually. Physicians, rather than choosing one-size-fits-all, poorly-evaluated drugs, will choose DNA-directed drugs given at individualized doses. We will move away from the treatment of groups and toward the treatment of individuals. In oncology, with access to tumor DNA and drugs with steep dose-response and dose-toxicity curves, we are well positioned to lead the way to this goal. Our challenge is to provide leadership, infrastructure, funding, and a regulatory environment that will encourage correlative studies during early drug development and facilitate optimal treatment of individuals with cancer. Note: The views expressed herein do not necessarily represent the views or findings of the US Food and Drug Administration or the United States Government. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use: ICH Harmonised Tripartite Guideline: Ethnic Factors in the Acceptability of Foreign Clinical Data, E5, 1998. http://www.ich.org
2. Shirao K, Hoff P, Ohtsu A, et al: Comparison of the efficacy, toxicity, and pharmacokinetics of a uracil/tegafur (UFT) plus oral leucovorin (LV) regimen between Japanese and American patients with advanced colorectal cancer: Joint United States and Japan Study of UFT/LV. J Clin Oncol 22:3466–3474, 2004
3. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139, 2004 4. Food and Drug Administration Guidance for Industry: Genomic Data Submission, November, 2003. http://www.fda.gov/cder/guidance/5900dft.pdf
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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