Cost studies in clinical trials

Editorial

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Cost studies in clinical trials ‘Clinical trials are designed to answer specific scientific questions in order to find better ways to prevent, detect or treat disease.’ Expert Rev. Pharmacoeconomics Outcomes Res. 4(6), 591–594 (2004) Fadia T Shaya†, PhD, MPH Navendu Samant †Author for correspondence Center on Drugs and Public Policy, University of Maryland School of Pharmacy, 515 West Lombard Street, Baltimore, MD 21201, USA Tel.: +1 410 706 5392 Fax: +1 410 706 5394 [email protected]

10.1586/14737167.4.6.591

Clinical trials are the gold standard

Clinical trials are designed primarily to For as long as clinical trials have been the gold establish the safety and efficacy of a treatstandard in establishing, validating and ment. They yield valuable clinical data, approving new therapies, there have been which are essential for the acceptance of that questions surrounding them, ranging from treatment. In order to approve a new drug, validity issues to clinical concerns. More the US Food and Drug Administration recently, concerns have been voiced about (FDA) requires that well-designed clinical triselective dissemination of results, specifically als be conducted. While patients are the priwithholding negative results [1]. Conversely, mary stakeholders in clinical trials, physicians there are also questions regarding instances and other members of the healthcare team are where negative findings, even if perhaps some- closely involved in the development and times nonstatistically significant, have been implementation of these trials. Other major stakeholders repreoverlooked. The first issue has been brought ‘...it is always important to keep sent a wide cross-secto the forefront after a economic data in perspective, tion of the healthcare delivery system: clinistudy was released and give priority to safety cal trials are sponshowing evidence of and efficacy.’ sored or funded by a selective reporting [2]. The latter issue has surfaced after the pullout variety of organizations or individuals such as of rofecoxib from the market, following evi- physicians, medical institutions, foundadence of increased cardiovascular risk, post tions, voluntary groups and pharmaceutical companies, in addition to federal agencies marketing [101]. While it is important that the process of such as the National Institutes of Health, the disseminating results be transparent, the Department of Defense and the Department design of the randomized clinical trial is of Veteran’s Affairs. These stakeholders still considered to be best suited for estab- increasingly recognize the need not only for lishing internal validity. Clinical trials are proving safety and efficacy, but also for designed to answer specific scientific ques- demonstrating cost effectiveness. tions in order to find better ways to prevent, detect or treat disease. A clinical trial Value argument is the bridge between testing new drugs or From the standpoint of the drug sponsor, the treatments in animals, and the final prospect of a US$6 billion investment, at the approval to be used in humans. It is a pow- very least, to bring a drug to market, needs to erful tool to test new treatment approaches be justified by a matching prospect for a reasuch as a new drug, new surgical procedure sonable return on investment [3]. However, or new radiation techniques, or even combi- the parameters dictating the uptake of a drug nations of treatments. It could also be an in given markets are a function of clinical approach to prevent or screen disease, or efficacy as well as coverage and policy factors. improve quality of life. Thus, there has been a growing interest in

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looking at cost-effectiveness propositions, earlier and earlier quality of life (e.g., relief of pain and disability) and the in the drug lifecycle, even as early as during Phases I or II of probable effects on mortality. It also considers estimates of the associated costs [102]. In the UK, the NICE has developed clinical trials [4]. Currently, most of the literature supporting the valuation a ‘horizon scanning unit whose aim is to identify health techof treatments, widely known as outcomes research, has niques that might require urgent evaluation, consideration of focused on evidence from real-world practice, assessing the clinical and cost impact early in the product development clinical and economic impact of a given treatment in given cycle’ [4]. They have standardized a framework for presenting populations. The tools and methods have been designed and population-specific data and do include a cost component in implemented to mostly apply to postmarketing studies. Out- the decision-making process. comes research has developed as a way of understanding the end results of particular healthcare practices and interven- Case for cost studies in clinical trials tions or treatments. Concurently, pharmacoeconomic assess- Controlled clinical trials are recognized as the source of data ments have provided critical assessments of the monetary on the safety and efficacy of healthcare interventions and value of observed results, as they applied. For example, in technology [9]. Since economic evaluation is dependent upon addition to clinical improvements, the extent to which the the quality of the evidence, clinical trials form an efficient quality of life, including ability to function, emotional or platform for economic analyses. The population in a clinical cognitive status was to be affected by the choice of a given trial is very well defined and the design of the trial permits a drug, would play a major role in the evaluation of that drug. systematic and organized follow-up. That very design affords Chronic conditions in which cure is not always possible spe- cost studies conducted concurrently with clinical trials, the cifically underscore the importance of measuring quality of statistical rigor, better control of bias, well-established, life or functional status. accepted methodology and easier to interpret results [103]. Pharmacoeconomic studies have historically been incorpo- From a manufacturer’s perspective, economic data are instrurated mostly in Phase IV studies. The increased emphasis on mental to making crucial product launch decisions. Economic premarketing clinical trial-based economic evaluation reflects data collected in the early part of the product approval process a growing recognition that both will help the manufacturer better ‘For as long as clinical trials have sides, supply and demand, need analyze the economic benefits and evidence of cost effectiveness at an costs associated with the product. been the gold standard in early stage in the lifecycle of the The drug development process establishing, validating and drug [4]. In two treatments with would then allow for the timely similar clinical effectiveness, pat- approving new therapies, there have collection of data that can be utitern and side-effect profiles, for been questions surrounding them, lized to evaluate the cost and effects of a product. Given their example, outcomes research, can ranging from validity issues to large investment in research and bring to bear the decisive factors clinical concerns.’ development, drug manufacturers that determine the comparative advantage of one treamtent over the other. For clinicians and would also see an advantage to evidence that backs claims of patients, outcomes research provides evidence about the ben- economic, as well as clinical and quality of life advantages. efits, risks and results of treatments so they can make more This is of special significance given the movement toward informed decisions. The main purpose of economic studies is direct-to-consumer advertising. Including economic variables to help those making decisions regarding the allocation of in controlled studies, during the earlier part of the drug healthcare resources [5]. Pharmacoeconomic studies are approval process, will benefit the overall cost assessment of designed to meet the different needs of healthcare purchasers the new intervention. and regulatory authorities. Moreover, economic data from Phase III studies are used to support initial pricing of new Limitations of cost studies in clinical trials therapies and are used in professional educational activities Relying solely on randomized clinical studies may limit the by pharmaceutical firms [6]. In addition, Phases I and II are generalization of the economic impact of a treatment in used to develop pilot economic data, such as the estimates of real-world practice [103]. The extent to which clinical trials the mean and variance of the cost [6]. Although the US FDA generalize as proxies for cost effectiveness in naturalistic does not mandate inclusion of pharmacoeconomic data for clinical practice settings is limited. Clinical trials are condrug approval, such studies are often conducted [7]. Other ducted in controlled settings and the compliance of subjects countries such as Australia, UK and Canada, however, do is maximized, such that it overstates what it would be in require pharmacoeconomic information within the submis- actual practice. End points captured by clinical trials are most commonly sion package to allow the marketing of drugs [8]. As per the National Institute for Clinical Excellence (NICE), technol- intermediate, reflecting a duration shorter than what is necesogy appraisal considers the evidence of both health benefits sary for assessing longer term outcomes or final end points. and costs of health technologies. This includes the impact on Therefore, clinical trials provide limited evidence on the

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Cost studies in clinical trials

long-term costs. Limiting pharmacoeconomic data to that most appropriate way. Use of active or existing therapies, for derived from randomized clinical studies would result in example, rather than placebo, would be more naturalistic decisions based primarily on price and not value. Moreover, and representative. It is also important to design randomized controlled clinical studies include comparator therapies that clinical studies to capture more resource utilization data, as may not be realistic choices in real practice. On the other it will help minimize bias to the economic component of the hand, by virtue of close monitoring, adverse events are detected study. Multicenter trials are being conducted more often to earlier in clinical trials than they would be in real-world set- handle issues related to location and small area variation, tings, and therefore are likely to engender relatively lower costs. and render the economic results more generalizable. Sample For all purposes, there is a concern that it is difficult to separate size, which is a concern, can be addressed with economic protocol-driven costs (or savings) from actual costs of care, analyses earlier in the drug approval process. It will help to and that the choice of outcome measures may not be relevant have a better estimate of the sample size required for clinical to standard or usual care [103]. With respect to the compara- and economic significance. In addition, there would be a tor therapy, the selection of the comparator should be an plan for postmarketing, surveillance and observational studalternative at best or an existing therapy in the market rather ies. These would allow for comparisons between products in than a placebo. Collecting economic information on a drug, more realistic settings and provide a platform for evaluating which is being compared with a placebo, is therefore of cost, as well as effectiveness. With the steady increase in healthcare costs, economic anallimited benefit. The actual location of a trial could also play a major role yses are gaining ground in earlier stages of product developin influencing the economic evaluation, to the extent that ment. An increase in the out-of-pocket costs and patient some difficult to measure practice variations occur across awareness programs leads to an increased demand for cost areas. Thus, generalizability must be ‘Since economic evaluation is information earlier in the approval cycle [10]. As long as progress in carefully addressed. Finally, one of the concerns for clinical trial-based dependent upon the quality of research and development continues economic evaluations would be the the evidence, clinical trials form in the quest of health improvement, estimation of the sample size. Samthere will be a need to assess relative an efficient platform for ple size is based on the minimum values of a number of therapies. Given economic analyses.’ number of observations required to the stakes in a drug launch decision, detect a clinically important difference for a given power there is a pressing need to incorporate cost information into (usually at least 80%) and level of significance that decision. It is important that clinical trials readjust to (usually 0.05). More observations are required for economic cater to the needs of the changing healthcare delivery system, evaluation at a given power. Clinical trials are powered by incorporating cost variables as early in the approval process toward detecting clinical significance. without hurting the outcome. Finally, it is always important to keep economic data in perspective, and give priority to safety Future directions and efficacy. In fact, it is the ethical thing to do, to ensure that As discussions continue to surround clinical trials, a consen- only safe and efficacious drugs are launched and made availasus is yet to be achieved on how to maximize the yield of ble to patients. It is as important to also ensure that no drug these studies. For example, to increase the integration which is safe and efficacious be withheld from launch. As presbetween randomized clinical studies and relevant health eco- sures of cost control mount, the stakes get higher, and it is nomic assessments, there should be increased collaborations important to ponder the ethics of a system that allows a decibetween clinical scientists and economic experts to design a sion not to launch, based on a negative cost-effectiveness clinical study incorporating the economic component in the proposition alone. References 1

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Fadia T Shaya, PhD, MPH Assistant Professor, Associate Director, Center on Drugs and Public Policy, University of Maryland School of Pharmacy, 515 West Lombard Street, Baltimore, MD 21201, USA Tel.: +1 410 706 5392 Fax: +1 410 706 5394 [email protected] Navendu Samant, PhD candidate University of Maryland School of Pharmacy, 515 West Lombard Street, Baltimore, MD 21201, USA

Expert Rev. Pharmacoeconomics Outcomes Res. 4(6), (2004)