Cost-effectiveness of Cancer Nanotechnology - deel 1

Abstract

Cancer is a class of diseases in which abnormal cells divide without control and are able to invade other tissues and organs through the blood stream and lymphatic system, which is called metastasis. Cancer belongs to the top three causes of death worldwide. It affects people at all ages with the risk for most types increasing with age. On the one hand, malignant phenotypes can be caused by internal factors, such as inherited mutations, hormones, immune conditions, and mutations from the metabolism. These cancers are, thus, due to genetics. On the other hand, the disease can be induced by environmental factors or a bad lifestyle, for instance, chemicals, radiation, and infectious organisms, the use of tobacco, alcohol, and lack of physical activity. Environmental factors can cause abnormalities in the genetic material of cells. While some cancers can be prevented through an adapted lifestyle, others can not be prevented. Since the 1950s great strides have been made in cancer treatment. This is particularly true for early detected, localized malignancies. Nevertheless, still more than half of cancer patients do not respond to therapy or progress to the metastatic stage. The low effectiveness of current chemotherapeutic treatments is, however, not due to the efficacy of the drug itself, but to the ineffective delivery of those agents to the cancerous regions. After the intravenous administration, drugs encounter some biological barriers that have a negative impact on the particles’ ability to reach the target cells at desired concentrations. Striking is the declaration that only 1-10 out of 100.000 drug molecules are able to reach their parenchymal targets. Consequently, many healthy cells will be irreversibly damaged causing patient suffering and this at the expense of therapeutic action. This, in turn, causes a decreased therapeutic index. There is, thus, an urgent need to find an effective and safe cure for cancer. To that end, thousands of nanodevices are currently being studied. By combining nanodevices with different drugs and targeting moieties, scientists hope to find novel therapies. The promise of nanotechnology is to find a way to combat cancer with novel, personalized treatments. The National Cancer Institute (NCI) defines nanotechnology as: “the field of research that deals with the engineering and creation of things from materials that are less than 100 nanometers (one-billionth of a meter) in size, especially single atoms or molecules. It is being studied in the detection, diagnosis, and treatment of cancer.” The promise of nanotechnology is to find the right combination of therapeutics and targeting moieties to attack diseased cells without or with minimal side-effects. Nanotechnology can be used in different fields: prevention and control, early detection and proteomics, imaging, multifunctional and targeted therapeutics, pain management, therapeutic monitors, and finally, tissue engineering. Spiraling costs are a major concern for health administrators allocating limited resources. Rising health care costs are, on the one hand, due to a growing and ageing population. On the other hand, new therapies, like nanotherapeutics, typically entail high acquisition costs that may be offset and justified, however, by increased effectiveness, reduced toxicities and a better quality of life. The increasing demand – and costs – for health care services coupled with constant or even decreasing national resources, led to an increased interest in the economic analyses of medical interventions. The challenge is to adopt new therapeutics and medical technologies while maintaining the standard quality of care and staying within the constraints of a predetermined health care budget. The available cost-effectiveness studies of nanotechnological cancer therapies have some serious methodological flaws. Typically, the results are not qualityadjusted. Since therapies affect both the length and quality of life, this might lead to ineffective choices. Moreover, only direct medical costs are taken into account, neglecting indirect costs that impose a significant economic burden on patients and society. This might lead to wrong policy conclusions at the expense of patients and society. It is, thus, crucial to develop a cost-effectiveness taxonomy comprising all direct and indirect costs and adjusting effectiveness outcomes with quality of life estimates. Only then, cost-effectiveness analysis is helpful to making efficient choices in healthcare. Developing a framework for cost calculation starts with the identification of all possible relevant costs in function of a given perspective, preferably that of society, i.e. all relevant costs are considered regardless of who they incur. Cost analysis comprises the costs related to treatment itself, but also resource uses associated with the therapies’ downstream events. Identifying, measuring, and valuing resources is, however, not easy. A new drug may cause fewer or less severe adverse events, require less monitoring efforts, or may not require hospitalizations. Consequently, savings may offset the higher acquisition cost. A cost framework should include all relevant costs, direct and indirect, of treatment, the management of adverse events, and recurrent disease. Relevant direct costs are drug (study drug and pre-treatment), administration (in- and outpatient visits), expected administration (e.g. drug administration at home), and monitoring (diagnosis and follow-up) costs, and expected costs of after care (psychological assistance, rehabilitation, palliation, additional therapies). Lost production of patients and relatives, transportation costs, expected costs related to caregivers, visiting costs, interests forgone on funeral expenses due to a premature death, and administration costs of health insurances can not be directly attributed to a specific treatment. These are the tangible indirect costs of cancer. Moreover, intangible indirect costs, which are the emotional costs of pain, suffering and reduced quality of life, are conceptualized into quality-of-life estimates. As more CEAs are pursued, it will become a lot easier to compare different treatments in terms of their cost-effectiveness. The taxonomy is used to calculate the cost-effectiveness of conventional and nanotechnology-based treatments for recurrent or progressive ovarian cancer. Ovarian cancer is the most prevalent cause of death due to gynecological malignancy. Second-line chemotherapeutic agents not only show limited tumor activity, but may also result in adverse events of increasing severity. Costs to manage adverse events tend to be high. A comprehensive cost-effectiveness analysis (CEA) was pursued, taking into account all direct and indirect costs of cancer. Effectiveness outcomes were taken from a recent phase III clinical trial carried out in Italy comparing gemcitabine (GEM) versus PEGylated liposomal doxorubicin (PLD) for recurrent or progressive ovarian cancer. A hundred fifty three patients were, therefore, enrolled and randomly assigned to PLD (n = 76) and GEM (n = 77). The robustness of the model was tested by Monte Carlo resampling. Total average direct costs per patient were estimated at €4.723,83 in the PLD treatment group, compared to €6.517,08 for patients treated with GEM. The higher acquisition cost of PLD was, thus, significantly offset by other direct costs related to conventional therapy (GEM). Moreover, tangible indirect costs were also higher in the GEM patients group, namely €2.233,43 per patient compared to €2.083,84 for patients treated with PLD. The intangible indirect costs monetizing pain and suffering were also included by using quality of life estimates. Liposome therapy saved 2.017,065 quality-adjusted weeks compared with only 1.453,945 for conventional treatment. The CEA shows that PLD is more cost-effective than GEM. The cost-effectiveness ratio of PLD is €247,60 per quality-adjusted week (€12.875,20/QALY) compared to €439,33 (€22.845,16/QALY) for GEM. The CEA, thus, suggests that the nanotechnologybased cancer agent PLD is more cost-effective than GEM, and thus helps saving scarce health resources. Although its acquisition cost is significantly higher, this cost difference is more than offset by other direct and indirect costs. However, most drug candidates fail in the drug development cycle. High attrition rates are mainly due to three obstacles: safety, efficacy, and economics. Because the cost of failure rises with duration, unsuccessful drugs have to be abandoned as early as possible in the development process. An important venue to avoid waste of scarce resources is cost-effectiveness analysis, which should be pursued in the early stages of the drug development cycle. To that end, an algorithm estimating the sales revenues required to recover costs and earn a reasonable profit to be successful is developed. For 2010, sales revenues should be at least US$9.902 million. To break even, 247.550 quality-adjusted life years should, therefore, be saved. Clinical researchers have to demonstrate that it is possible to save this number of quality-adjusted life years. If not, the new medicine is not cost-effective and further development should be abandoned. Pursuing cost-effectiveness analysis in an early stage is crucial when investing scarce health care resources. However, this could be particularly important for nanotherapeutics as well as target-based agents. Since these therapies will probably be very effective but also have very high acquisition costs, it will be crucial to demonstrate their cost-effectiveness. If not, these new therapeutics could be considered as not cost-effective due to their high acquisition cost. Consequently, cures to treat life-threatening diseases could be lost. Over the next 10 to 20 years, new nanotechnologies may revolutionize science, technology and society. But if medical nanotechnology wants to realize its full potential, some major legal and economic impediments blocking a genuine breakthrough have to be removed. The future of nanomedicines is undermined by lack of financial profitability, consumer distrust, ineffective regulation of new and generic products, weak patent protection and insurance market failure. Its success, in turn, requires a whole set of countervailing measures and actions. Success requires more investments induced by cost-effectiveness analyses and business plans based on clinical data, public education based on nanotoxicology studies, smart regulatory reform in the areas of testing, market entry and liability, effective and strategic patenting, patent dispute prevention and resolution, and innovative insurance policies.