Editorial
`
`Phase II Oncology Trials: Let’s Be Positive
`Mark J. Ratain
`
`The critical decision in drug development is often at the end of
`phase II, as phase III trials are an expensive undertaking, with
`the potential for significant corporate and public consequences
`in the event of a negative phase III trial. Thus, retrospective
`analyses of the usefulness of phase II trials are welcomed and
`valued, as illustrated by the study of Goffin et al. (1). In this
`analysis of 58 cytotoxic drugs, 46 studied in phase II, the
`authors show a statistical relationship between objective
`response rate and probability of approval of the drug, with
`the important exception of responses in metastatic melanoma
`and renal cell carcinoma.
`Most readers will not be surprised by the authors’ findings of
`a relationship between phase II response rate and subsequent
`marketing of the drug. A drug may show activity in a specific
`disease in phase I or II, however, but may not be developed
`further in that disease because of business concerns. Thus, one
`would expect a bias towards phase III trials in diseases with
`larger markets, generally considered to be breast, colorectal,
`lung, and prostate cancers. Therefore, a lower approval rate in
`melanoma and renal cell cancer could potentially be affected by
`a lower number of phase III trials in these indications with
`smaller markets. In fact, Goffin et al. (1) did not address
`whether or not phase III trials were conducted with those
`agents that had phase II response rates of 10% or more. One
`cannot firmly conclude, therefore, that the phase II results were
`not predictive for phase III results in melanoma and renal cell
`cancer, as opposed to an alternative explanation that there was
`relatively little interest in seeking approval for these indications.
`What have we learned from this analysis? It is important to
`emphasize that a correlation, albeit significant, does not
`necessarily result in usefulness. A more important issue is the
`usefulness of phase II oncology trials, particularly in the context
`of predicting marketing approval for the indication studied in
`the specific phase II trial. To address this question, the data of
`Goffin et al. (1) have been reanalyzed using standard
`approaches to studying diagnostic tests. In this context, one
`normally uses metrics such as sensitivity, specificity, and
`predictive value (2). To assess this, one can consider various
`objective response rate cutoffs, as illustrated in Table 1, such as
`cutoffs of 10% and 20%. Sensitivity, or true positive rate, is
`defined as the percentage of drugs approved for an indication
`for which the phase II trial exceeded the threshold response
`rate. (It should be noted that if no drugs were approved for an
`
`Author’s Affiliation: Section of Hematology/Oncology, Department of Medicine,
`Committees on Clinical Pharmacology and Pharmacogenomics and Molecular
`Medicine, and Cancer Research Center, University of Chicago, Chicago, Illinois
`Received 5/11/05; accepted 5/25/05.
`Requests for reprints: Mark J. Ratain, Department of Medicine, University of
`Chicago, MC2115, 5841 South Maryland Street, Chicago, IL 60637. Phone: 773-
`702-4400; Fax: 773-702-3969; E-mail: mratain@medicine.bsd.uchicago.edu.
`F 2005 American Association for Cancer Research.
`doi:10.1158/1078-0432.CCR-05-1046
`
`is not possible to calculate the sensitivity).
`it
`indication,
`Specificity, or true negative rate, is defined as the percentage
`of drugs not approved for an indication for which the phase II
`trial did not exceed the threshold response rate. Positive
`predictive value is the likelihood of approval (for a disease)
`given a positive phase II trial (i.e., exceeding threshold response
`rate). Negative predictive value is the likelihood of not being
`approved for a disease (regardless of whether a phase III trial
`was conducted) given a negative phase II
`trial (i.e., not
`exceeding threshold response rate).
`When the data of Goffin et al. (1) were reanalyzed in this way
`(Table 1), it is clear that phase II oncology trials have a high
`negative predictive value but a low positive predictive value.
`Sensitivity was high at a threshold response rate of 10%, as this
`would be expected to exclude few active agents. At a higher
`threshold response rate of 20%, there was greater specificity but
`with some tradeoff on sensitivity.
`Is response rate the right end point for phase II oncology
`trials? This paradigm has
`recently been questioned in
`the context of the development of noncytotoxic agents (3).
`The data of Goffin et al. suggest that we should consider
`rejecting our current paradigm for cytotoxic agents as well,
`particularly if the goal of phase II studies is to predict for
`phase III success. Oncology has been recently singled out as a
`therapeutic area for which positive phase II trials have not
`been predictive of phase III success (4). As noted in Table 1,
`the best positive predictive value was for non – small-cell lung
`cancer, in which 75% of agents whose phase II response rate
`exceeded 20% were subsequently approved. Unfortunately,
`this threshold would have excluded two of our currently
`approved cytotoxic agents for non – small-cell lung cancer as
`only three of the five approved agents in this study met this
`criterion.
`Moving forward, it is critical to consider the purpose of phase
`II trials. In essentially all other therapeutic areas, such studies
`are usually randomized, dose-ranging controlled trials, often
`including a placebo group, but enable determination of the
`relationship between dose and an end point of clinical interest,
`and, by extension, provide evidence of activity (5). Most
`importantly, phase III trials are expected to confirm findings of
`phase II studies, and, outside of oncology, are generally
`positive; consequently, phase II trials in other therapeutic areas
`have a high positive predictive value (4, 6). In contrast,
`oncology trials have a high negative predictive value but a
`relatively low positive predictive value (Table 1). These features
`may be due to the nature of cancer and anticancer agents. On
`the other hand, these may be due to the differences in the
`designs used for phase II trials in oncology, in which the classic
`designs are formally aimed at proving that the drug does not
`have activity (7). In fact, a trial that is not negative is not
`necessarily ‘‘positive,’’ as borne out by the low positive
`predictive value for marketing approval, presumably due in a
`large part to the low phase III success rate.
`
`www.aacrjournals.org
`Downloaded from
`
`5661
`Clin Cancer Res 2005;11(16) August 15, 2005
`
`on April 4, 2016. © 2005 American Association for Cancerclincancerres.aacrjournals.org
`Research.
`
`NOVARTIS EXHIBIT 2221
`Par. v. Novartis, IPR 2016-00084
`Page 1 of 3
`
`

`
`Editorial
`
`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.)
`
`Melanoma
`(n = 29)
`
`Renal
`(n = 15)
`
`Breast
`(n = 26)
`
`NSCLC
`(n = 25)
`
`Ovarian
`(n = 22)
`
`Colorectal
`(n = 28)
`
`ORR > 10%
`SE (%)
`SP (%)
`PPV (%)
`NPV (%)
`ORR > 20%
`SE (%)
`SP (%)
`PPV (%)
`NPV (%)
`
`?
`84
`0
`100
`
`?
`95
`0
`100
`
`?
`93
`0
`100
`
`?
`93
`0
`100
`
`100
`50
`25
`100
`
`100
`77
`44
`100
`
`80
`70
`40
`93
`
`60
`95
`75
`90
`
`100
`85
`33
`100
`
`67
`80
`33
`80
`
`100
`88
`57
`100
`
`50
`96
`67
`92
`
`Abbreviations: NSCLC, non ^ small-cell lung cancer; ORR, objective response rate; SE, sensitivity; SP, specificity; PPV, positive predictive value; NPV, negative predictive
`value.
`
`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
`
`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.
`
`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
`
`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.
`
`5662
`www.aacrjournals.org
`Clin Cancer Res 2005;11(16) August 15, 2005
`on April 4, 2016. © 2005 American Association for Cancer
`clincancerres.aacrjournals.org Downloaded from
`
`Research.
`
`NOVARTIS EXHIBIT 2221
`Par. v. Novartis, IPR 2016-00084
`Page 2 of 3
`
`

`
`Phase II Oncology Trials: Let's Be Positive
`(cid:160)
`Mark J. Ratain
`Clin Cancer Res(cid:160)(cid:160)
`
`2005;11:5661-5662.
`
`(cid:160)
`(cid:160)
`(cid:160)
`(cid:160)
`
`(cid:160)
`(cid:160)
`
`Updated version
`(cid:160)
`
`
`
`Access the most recent version of this article at:
` http://clincancerres.aacrjournals.org/content/11/16/5661
`(cid:160)
`
`Cited articles
`(cid:160)
`Citing articles
`(cid:160)
`
`This article cites 7 articles, 3 of which you can access for free at:
`http://clincancerres.aacrjournals.org/content/11/16/5661.full.html#ref-list-1
`(cid:160)
`This article has been cited by 18 HighWire-hosted articles. Access the articles at:
`
`http://clincancerres.aacrjournals.org/content/11/16/5661.full.html#related-urls
`(cid:160)
`
`
`
`E-mail alerts
`(cid:160)
`Reprints and
`Subscriptions
`(cid:160)
`Permissions
`(cid:160)
`
`Sign up to receive free email-alerts
`
` related to this article or journal.
`
`To order reprints of this article or to subscribe to the journal, contact the AACR Publications
`.
`pubs@aacr.org
`Department at
`(cid:160)
`To request permission to re-use all or part of this article, contact the AACR Publications
`.
`permissions@aacr.org
`Department at
`(cid:160)
`
`Downloaded from
`
`on April 4, 2016. © 2005 American Association for Cancer
`clincancerres.aacrjournals.org
`Research.
`
`NOVARTIS EXHIBIT 2221
`Par. v. Novartis, IPR 2016-00084
`Page 3 of 3