Editorial
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`Phase II Oncology Trials: Let's Be Positive
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`Mark J. Ratain
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`indication, it is not possible to calculate the sensitivity).
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`The critical decision in drug development is often at the end of
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`phase II, as phase III trials are an expensive undertaking, with
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`Specificity, or true negative rate, is defined as the percentage
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`the potential for significant corporate and public consequences
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`of drugs not approved for an indication for which the phase II
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`in the event of a negative phase III trial. Thus, retrospective
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`trial did not exceed the threshold response rate. Positive
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`analyses of the usefulness of phase II trials are welcomed and
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`predictive value is the likelihood of approval (for a disease)
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`valued, as illustrated by the study of Coffin et al. (1). In this
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`given a positive phase II trial (i.e., exceeding threshold response
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`analysis of 58 cytotoxic drugs, 46 studied in phase II, the
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`rate). Negative predictive value is the likelihood of not being
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`authors show a statistical relationship between objective
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`approved for a disease ( regardless of whether a phase III trial
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`response rate and probability of approval of the drug, with
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`was conducted) given a negative phase II trial (i.e., not
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`the important exception of responses in metastatic melanoma
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`exceeding threshold response rate).
`and renal cell carcinoma.
`When the data of Coffin et al. ( 1) were reanalyzed in this way
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`Most readers will not be surprised by the authors' findings of
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`(Table 1 ), it is clear that phase II oncology trials have a high
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`a relationship between phase II response rate and subsequent
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`negative predictive value but a low positive predictive value.
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`marketing of the drug. A drug may show activity in a specific
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`Sensitivity was high at a threshold response rate of 10%, as this
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`disease in phase I or II, however, but may not be developed
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`would be expected to exclude few active agents. At a higher
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`further in that disease because of business concerns. Thus, one
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`threshold response rate of 20%, there was greater specificity but
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`would expect a bias towards phase III trials in diseases with
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`with some tradeoff on sensitivity.
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`larger markets, generally considered to be breast, colorectal,
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`Is response rate the right end point for phase II oncology
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`lung, and prostate cancers. Therefore, a lower approval rate in
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`trials? This paradigm has recently been questioned in
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`melanoma and renal cell cancer could potentially be affected by
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`the context of the development of noncytotoxic agents (3).
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`a lower number of phase III trials in these indications with
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`The data of Coffin et al. suggest that we should consider
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`smaller markets. In fact, Coffin et al. ( 1) did not address
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`rejecting our current paradigm for cytotoxic agents as well,
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`whether or not phase III trials were conducted with those
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`particularly if the goal of phase II studies is to predict for
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`agents that had phase II response rates of 10% or more. One
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`phase III success. Oncology has been recently singled out as a
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`cannot firmly conclude, therefore, that the phase II results were
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`therapeutic area for which positive phase II trials have not
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`not predictive for phase III results in melanoma and renal cell
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`been predictive of phase III success (4). As noted in Table 1,
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`cancer, as opposed to an alternative explanation that there was
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`the best positive predictive value was for non -small-cell lung
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`relatively little interest in seeking approval for these indications.
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`cancer, in which 75% of agents whose phase II response rate
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`What have we learned from this analysis? It is important to
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`exceeded 20% were subsequently approved. Unfortunately,
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`emphasize that a correlation, albeit significant, does not
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`this threshold would have excluded two of our currently
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`necessarily result in usefulness. A more important issue is the
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`approved cytotoxic agents for non -small-cell lung cancer as
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`usefulness of phase II oncology trials, particularly in the context
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`only three of the five approved agents in this study met this
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`of predicting marketing approval for the indication studied in
`criterion.
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`the specific phase II trial. To address this question, the data of
`Moving forward, it is critical to consider the purpose of phase
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`Coffin et al. ( 1) have been reanalyzed using standard
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`II trials. In essentially all other therapeutic areas, such studies
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`approaches to studying diagnostic tests. In this context, one
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`are usually randomized, dose-ranging controlled trials, often
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`normally uses metrics such as sensitivity, specificity, and
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`including a placebo group, but enable determination of the
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`predictive value (2). To assess this, one can consider various
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`relationship between dose and an end point of clinical interest,
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`objective response rate cutoffs, as illustrated in Table 1, such as
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`and, by extension, provide evidence of activity (5). Most
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`cutoffs of 10% and 20%. Sensitivity, or true positive rate, is
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`importantly, phase III trials are expected to confirm findings of
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`defined as the percentage of drugs approved for an indication
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`phase II studies, and, outside of oncology, are generally
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`for which the phase II trial exceeded the threshold response
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`positive; consequently, phase II trials in other therapeutic areas
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`rate. (It should be noted that if no drugs were approved for an
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`have a high positive predictive value ( 4, 6). In contrast,
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`oncology trials have a high negative predictive value but a
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`relatively low positive predictive value (Table 1 ). These features
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`may be due to the nature of cancer and anticancer agents. On
`Section of Hematology/Oncology, Department of Medicine,
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`Author's Affiliation:
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`the other hand, these may be due to the differences in the
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`Committees on Clinical Pharmacology and Pharmacogenomics and Molecular
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`designs used for phase II trials in oncology, in which the classic
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`Medicine, and Cancer Research Center, University of Chicago, Chicago, Illinois
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`designs are formally aimed at proving that the drug does not
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`Received 5/11/05; accepted 5/25/05.
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`have activity (7). In fact, a trial that is not negative is not
`Mark J. Ratain, Department of Medicine, University of
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`Requests for reprints:
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`Chicago, MC2115, 5841 South Maryland Street, Chicago, IL 60637. Phone: 773-
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`necessarily "positive," as borne out by the low positive
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`702-4400; Fax: 773-702-3969; E-mail: mratain@medicine.bsd.uchicago.edu.
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`predictive value for marketing approval, presumably due in a
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`© 2005 American Association for Cancer Research.
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`large part to the low phase III success rate.
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`doi:10.1158/1078-0432.CCR-05-1046
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`www.aacrjournals.org
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`5661
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`Clin Cancer Res 2005;11 (16) August 15, 2005
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`AVENTIS EXHIBIT 2145
`Mylan v. Aventis, IPR2016-00712
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`

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`Editorial
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`Table 1. Analysis of usefulness of phase II results to predict drug approval within disease category by threshold
`response rate (using data from Goffin et al.)
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`Melanoma
`(n = 29)
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`Renal
`(n = 15)
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`Breast
`(n = 26)
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`NSCLC
`(n = 25)
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`Ovarian
`(n = 22)
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`Colorectal
`(n = 28)
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`ORR > 10%
`SE (%)
`SP (%)
`PPV (%)
`NPV (%)
`ORR > 20%
`SE (%)
`SP (%)
`PPV (%)
`NPV (%)
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`84
`0
`100
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`95
`0
`100
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`93
`0
`100
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`?
`93
`0
`100
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`100
`50
`25
`100
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`100
`77
`44
`100
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`80
`70
`40
`93
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`60
`95
`75
`90
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`100
`85
`33
`100
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`67
`80
`33
`80
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`100
`88
`57
`100
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`50
`96
`67
`92
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`Abbreviations: NSCLC, non ^ small-cell lung cancer; ORR, objective response rate; SE, sensitivity; SP, specificity; PPV, positive predictive value; NPV, negative predictive
`value.
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`In addition, classic phase II designs may not identify a highly
`active agent, as exemplified by the recent studies of sorafenib.
`A randomized discontinuation trial of this kinase inhibitor was
`conducted in 202 patients with metastatic renal cell cancer (8).
`Although the objective response rate (by independent review)
`was only 4%, there was an obvious and highly significant
`difference in failure-free survival after randomization, which
`was confirmed in a phase III trial of 800 patients (9). If this
`drug had been developed using classic criteria, it may never
`have entered phase III
`for this indication, given its low
`response rate.
`The solution for moving forward is to design trials for
`success, not for failure. This requires abandonment of current
`oncology paradigms for early clinical trials and adoption of
`generally accepted principles of drug development. These
`principles have been promulgated by the Food and Drug
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`Administration (10) and the U.S. Code of Federal Regulations
`Title 21 Section 312.21 (11), which states, ‘‘Phase 2 includes
`the controlled clinical studies conducted to evaluate the
`effectiveness of
`the drug for a particular
`indication or
`indications in patients with the disease or condition under
`study and to determine the common short-term side effects and
`risks associated with the drug. Phase 2 studies are typically well
`controlled, closely monitored, and conducted in a relatively
`small number of patients, usually involving no more than
`several hundred subjects.’’
`Implementation of such new
`paradigms will require greater attention to trial design issues
`in both phase I and II, but with the overriding principle that
`will require larger trials to prove activity. Such change will
`hopefully lead to a higher success rate in phase III, thereby
`allowing a more rapid translation of scientific advances into
`cost-effective therapy for cancer patients.
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`References
`1. Goffin J, Baral S, Dongsheng T, Nomikos D,
`Seymour L. Objective responses in patients with
`malignant melanoma or renal cell cancer in early clin-
`ical studies do not predict for regulatory approval.
`Clin Cancer Res 2005;11:5928 ^ 34.
`2. Chu K. An introduction to sensitivity, specificity, pre-
`dictive values and likelihood ratios [review]. Emerg
`Med 1999;11:175 ^ 81.
`3. Ratain MJ, Eckhardt SG. Phase II studies of modern
`drugs directed against new targets: if you are fazed,
`too, then resist RECIST. J Clin Oncol 2004;22:
`4442 ^ 5.
`4. Booth B, Glassman R, Ma P. Oncology’s trials. Nat
`Rev Drug Discov 2003;2:609 ^ 10.
`5. Shen L. An improved method of evaluating drug
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`effect in a multiple dose clinical trial. Stat Med 2001;
`20:1913 ^ 29.
`6. Sheiner LB. Learning versus confirming in clinical
`drug development. Clin Pharmacol Ther 1997;61:
`275 ^ 91.
`7. Ratain MJ, Mick R, Schilsky RL, Siegler M. Statistical
`and ethical issues in the design and conduct of phase I
`and II clinical trials of new anticancer agents. J Natl
`Cancer Inst 1993;85:1637 ^ 43.
`8. Ratain M, EisenT, Stadler W, et al. Final findings from
`a phase II, placebo-controlled, randomized discontin-
`uation trial (RDT) of sorafenib (BAY 43 ^ 9006) in
`patients with advanced renal cell carcinoma (RCC).
`Proc Am Soc Clin Oncol 2005;23:388s.
`9. Onyx Pharmaceuticals [homepage on the Internet].
`
`BAY 43 ^ 9006 shown to delay disease progression
`in phase III study in advanced kidney cancer patients.
`[cited 2005 Mar 21]. Available from: http://www.
`onyx-pharm.com/wt/page/pr_1111376865.
`10. Food and Drug Administration [homepage on the
`Internet]. General considerations for the clinical
`evaluation of drugs. [issued 1978]. Available from:
`www.fda.gov/cder/guidance/old034fn.pdf.
`11. US Government Printing Office-NARA[homepage
`on the Internet]. Food and Drug Administration,
`Dept. of Healthy and Human Services, Code of
`Federal Regulations. Investigational new drug
`application. Vol. 21, pp. 54, 2003. Available from:
`http://www.access.gpo.gov/cgi-bin/cfrassemble.
`cgi?title=200021.
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`Clin Cancer Res 2005;11(16) August 15, 2005
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`5662
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`www.aacrjournals.org