Annals of Oncology Advance Access originally published online on November 29, 2005
Annals of Oncology 2006 17(5):877-878; doi:10.1093/annonc/mdj088
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© 2005 European Society for Medical Oncology
letter to the editor |
Reply to the Letter to the Editor on ‘Cost-opportunity analysis in clinical oncology: from the "wild far-west" to a correct integration of the disciplines, avoiding the "war of the worlds"’, by D. Tassinari et al. (Ann Oncol 2006; 17: 876)
We thank Dr Tassinari and colleagues for their interest in our study and their useful comments. Tassinari and co-workers raise several relevant questions regarding pharmacoeconomic studies in general, and with respect to phase II trials in particular. A detailed discussion concerning the issues that we have raised is both important and welcome and should help to generate accurate pharmacoeconomic evaluations on available clinical studies. Economic analyses, including those of phase II and phase III trials, are based on the principle that society's resources are finite and those used in the support of one service cannot be used for another, thus necessitating difficult choices among competing goals [1
]. Thus it is essential to: (i) measure costs accurately, (ii) perform appropriate analyses and (iii) understand the perspectives from which an analysis is performed. As we stated in many sections of our article [2], comparative pharmacoeconomic analyses should be viewed with caution when they are based on phase II clinical trials because they present both important opportunities and difficult challenges for health care managers or companies. As pointed out by Mark and Simmons [1], economic measures in phase II trials have both potential uses and limitations. Such measures can anticipate what might be found in a phase III trial. In principle, such economic data could be used to decide whether to go forward with a particular study (i.e. organizing and funding a randomized phase III trial). A therapy that was found to be effective but not economically attractive with respect to profitability might reasonably be judged not to be commercially viable by a pharmaceutical company. On the contrary, it could be highly desirable, for example, for certain public health care systems, especially in developing countries, due to its low cost. Indeed, several economic evaluations are being conducted during early phase II stage of drug development, also in the oncology field [3, 4]. They serve, for example, to inform decision-makers within the pharmaceutical industry about relevant cost drivers and potential ways to optimize phase III clinical trial design [5]. We agree with Tassinari and colleagues that there is an increasing, although questionable, number of registrations of new drugs based on data available from phase II clinical trials only. This situation underlines the necessity to have, at least, some preliminary economic data, and to identify appropriate economic comparators. In this regard, Hughes and Walley [5] state that ‘as many countries require evidence of cost effectiveness for market entry and reimbursement, early pharmacoeconomic analyses should be an integral part of a company’s strategic action plan during the drug development process'. Our paper was meant to serve as an additional stimulus for investigators and institutions, including companies, to consider undertaking phase III trials of metronomic chemotherapy regimens. There are potential advantages of the metronomic chemotherapy concept and one of these, obviously, is cost, depending on the drugs/drug combinations used. Our analysis provides an indication that reduced cost may indeed be a benefit and our results strengthen the rationale, and need, for undertaking well-designed phase III clinical trials on metronomic chemotherapy. The limitations of traditional phase II studies affect economic outcomes at least as much as they affect clinical issues [1]. Small sample sizes that target a selected patient population and the short follow-up period create problems when researchers attempt to establish whether the results are statistically significant and clinically relevant. Moreover, prior to phase III studies (perhaps it would be more correct to say prior to post-marketing experience), there is no definitive evidence available about comparative efficacy. Therefore many assumptions are required when generalizing from the results of phase II/III clinical trials [5]. In order to maintain the credibility of early economic analyses, these assumptions must be justified and based on scientific reasoning. However, when dealing with a high degree of uncertainty, these limitations could be minimized by strictly applying sensitivity analyses to test the robustness of the results. Thus, although an economic analysis of a phase II trial can provide valuable information, clinicians, researchers, trial planners and administrators should be aware that important limitations characterize economic data derived from small size studies. Planners should thus be advised that such data must be carefully evaluated and interpreted [1] as we clearly stated in our paper. Despite these limitations, our findings are likely to assist researchers who design subsequent economic analyses alongside phase III trials in metastatic breast cancer patient populations. The necessity for pharmacoeconomic evaluation is evident from the high incidence of the disease, and the personal as well as social costs associated with metastatic breast cancer. The statement by Dr Tassinari and colleagues about the need for ‘correct integration among physicians, economists, industry researchers and public administrators’ is welcome and highly desirable, but would be helped significantly by economic analyses of the kind we undertook on phase II clinical trials, which could provide preliminary but nevertheless critical insights.
1 Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Via Roma, 55, 56126 Pisa, Italy; 2 Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Department of Medical Biophysics, University of Toronto, S-217, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5; 3 SAS®, Pisa, Italy; 4 U.O. Oncologia Medica, Ospedale Civile, Livorno, Italy
* (E-mail: g.bocci{at}med.unipi.it)
References
1. Mark DB, Simons TA. Economic end points in phase II trials. Am Heart J 2000; 139: S155–S157.[CrossRef][ISI][Medline]
2. Bocci G, Tuccori M, Emmenegger U et al. Cyclophosphamide–methotrexate ‘metronomic’ chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann Oncol 2005; 16: 1243–1252.
3. Lees M, Aristides M, Maniadakis N et al. Economic evaluation of gemcitabine alone and in combination with cisplatin in the treatment of nonsmall cell lung cancer. Pharmacoeconomics 2002; 20: 325–337.[CrossRef][ISI][Medline]
4. Evans WK, Dahrouge S, Stapleton J et al. An estimate of the cost of conducting phase II trials in lung cancer. Lung Cancer 2000; 28: 85–95.[CrossRef][ISI][Medline]
5. Hughes DA, Walley T. Economic evaluations during early (phase II) drug development: a role for clinical trial simulations? Pharmacoeconomics 2001; 19: 1069–1077.[CrossRef][ISI][Medline]
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