Costs and pharmacoeconomics of cancer therapy

Summary

The pharmacoeconomics of cancer therapy opens a wide field of research regarding the description and analysis of its costs, and the consequences and results of cancer treatment for patients, healthcare systems and society. The way in which a patent system interacts with the drug approval process is a clear example of how investment decisions regarding the execution of clinical trials aimed at fighting cancer can be distorted. If the basic objective of a medicine policy is to guarantee the availability of safe, effective and quality treatments, it is important to be able to assume the costs that these originate from the health system beyond the opportunity cost that they represent. When the benefits are not significant,but the prices are excessive, the medicine policy goes into crisis. What happens in the field of cancer therapy shows that we are not so far from it.

Abstract

Pharmacoeconomics of cancer therapy opens a wide field of investigation in the description and analysis of costs, and the consequences and outcomes of cancer treatment for patients, healthcare systems and society. The way the patent system interacts with the drug approval process is a clear example of how they can distort investment decisions regarding the execution of clinical trials to fight cancer. If the basic goal of a drug policy is to safeguard the availability of safe, effective, quality treatment, it is important to bear the costs that these originate from the health system beyond the cost of opportunity they represent. When benefits are not significant, but prices are excessive, drug policy became in crisis. What happens in the field of cancer therapy shows that we are not that far from it.

Introduction

Cancer is the second leading cause of death in the US after heart disease, with about 580,000 new cases a year and an average of about 1,600 deaths per day. Globally, 60 percent of all cancer deaths occur in developing countries, where experts argue that the incidence of the disease is growing rapidly. This has added urgency to an active and necessary debate on whether the efforts to combat it are sufficient, and whether it is not strategic to rethink the low dedication to prevention research. It is also common for articles and stories to appear in scientific journals and newspapers with columns on health regarding the behavior of the pharmaceutical industry against cancer diseases.Some news items have a positive impact, the result of new therapeutic discoveries or better healthcare achievements in the face of complex resolution problems. For example, better control or obtaining remission in certain cancers. The other side is made up of news of negative bias, generally economic, linked to the weight that the price escalation of new oncological drugs, especially biological drugs, exerts on health funders and on patients themselves.especially the biological ones, it exerts on the health funders and the patients themselves.especially the biological ones, it exerts on the health funders and the patients themselves.

The innovative drug industry, known as "Big Pharma" and made up of large transnational companies, is in a frantic race to gain primacy on the strategic fronts of production and development of both oncological and "orphan" biotech drugs, in better business opportunities through a stream of acquisitions with market concentration, and mainly in obtaining financial and equity benefits from third-party funds not related to the sector. The main drawback that this competition offers is the price with which each of the new drugs enters the health market. That price is no longer being paid for innovation, nor for fewer side effects or better health.You are being paid based on a business model based on obtaining highly profitable benefits.

There are nearly a dozen cancer drugs priced in excess of $ 100,000 a year and administered to patients with advanced-grade disease. Paying that amount of money may not make much sense, given the little therapeutic benefit they offer, valued in quantity or quality of life. The astronomical price of new drugs represents the worst excesses of the industry on health systems, which are limited to exercising weak controls over the power of pricing and prioritizing small gains in health over the reality of higher costs. Citizens would certainly agree that it would be better to prevent cancer, if this were possible, rather than continuing to take on increasingly complex and expensive treatments. However,Economic incentives and regulatory issues encourage industry researchers and their managers to focus primarily on treatment improvements rather than therapeutic developments to improve prevention.

Finding a balance between costs and consequences is crucial to any economic scheme. One way to maximize the health of the population is to strike a certain balance between investment and profit, cost and quality, and between the needs and desires of patients and society, recognizing the impossibility of satisfying them in a different or indistinct way. There is more money for investment in R&D on drugs that allow extending the life of patients in late stages of the disease for a couple of weeks or months, than in treatments that prevent the disease from developing. And there is little research in search of drugs that have any significant clinical merit to treat the disease in its early stages, or vaccines that prevent it.

The alternative between curative, palliative or prevention treatment and QALY. The great dilemma

A few days ago I finished reading very interesting data regarding a study carried out by researchers from the Massachusetts Institute of Technology (MIT) and the University of Chicago, published in the New York Times (NYT) under the title Why Preventing Cancer Is Not the Priority in Drug Development?. An immediate question arose: Why in an almost 50-year war against cancer was there no result in finding a drug or new therapies that favor its prevention, or at least a highly effective therapeutic response? Paraphrasing Hamlet: Here is the dilemma.

A first conclusion of the article, based on research carried out by two economics professors, Heidi Williams, professor at the MacArthur Foundation and Eric Budish of the University of Chicago, together with Ben Roin, assistant of technological innovation, is that there are a series of Reasons why the pharmaceutical industry has not prioritized research applied to cancer prevention significantly, as it has done with other novel drugs. The authors comment that accelerating the availability of drugs to treat serious illnesses is of interest to all actors in the health system, be they patients, doctors, healthcare institutions and pharmaceutical companies.Especially when these drugs are the first possible therapeutic alternative and have obvious advantages over pre-existing treatments. In order to have more speed on the approval of new compounds, the Food and Drug Administration of the USA (FDA) has generated four strategies that aim to favor it:

Fast Track Breakthrough Accelerated approval Priority review

By Fast Track is known a process designed to facilitate the development of certain medications, starting with accelerating their review to allow the treatment of serious diseases with high risk of life. It must be requested by the pharmaceutical company, and can be started at any time during the drug development phases. The FDA reviews the request and makes a decision within sixty (60) days based on whether the drug meets an unmet medical need for critically ill patients. Every time a drug receives the Fast Track designation, frequent communication between the FDA and the innovative pharmaceutical company is necessary throughout the drug development process and during stage IV pharmacovigilance. The frequency of communication ensures that all questions,inconvenience or vital problem is resolved quickly.

For its part, the Breakthrough allows to accelerate the development and review of medications that can demonstrate a substantial improvement over an already available therapy. To determine if the improvement with respect to this is substantial, the criterion depends on both the magnitude of the therapeutic effect and its duration and the importance of the clinical evolution observed. In general, preliminary clinical evidence should show a clear advantage over the available treatment.

The Expedited Approval dates from 2012. Through the approval by the US Congress of the Food and Drug Safety Innovation Act (FDASIA), the FDA is allowed to authorize the entry into the health market of certain drugs intended to treat serious diseases and that they fill an unmet medical need through indirect assessment criteria. An indirect criterion used for expedited approval is a marker - a laboratory measurement, radiographic / tomographic / MRI or PET image, a physical sign, or any other measure that may predict clinical benefit, even if it is not an accurate measure of clinical benefit, such as a positive effect on morbidity and irreversible mortality (IMM).

Finally, Priority Review means that the FDA can make a decision on an approval request within 6 months of filing, compared to 10 months for the standard review. A priority review will direct attention and human resources to the evaluation of drug requests, which, if approved, will bring significant improvements in the safety or efficacy of treatment, diagnosis or prevention of serious diseases, compared to standard therapies. The designation of a medicine as "priority" does not in any way alter the medical or scientific standard necessary for its approval or the quality of the evidence required.

These procedures define the reason for Big Pharma's eligibility to innovate in drugs that comprise a certain therapeutic band, for example the field of oncology. It is economically more profitable to focus on the rapid development and entry into the market of drugs that prolong survival time - albeit limited - rather than on improving quality of life, for example by helping to prevent disease.

The second conclusion is that while it is often held that R&D in cancer prevention and treatment in early stages is a socially very valuable fact, the same society provides private companies - perhaps inadvertently - with few incentives to carry out this type of investigations. Is it preferable to treat the disease than to anticipate that it appears? Where is the knot of the problem? It is that certain issues such as the delay in the approval and marketing authorization of a certain drug, or the time that elapses between the receipt of the patent application and the FDA approval, encourage the development of drugs that may be quickly approved, although paradoxically they have comparatively limited survival benefits.With a large enough sample size, a statistically significant prolongation of overall survival can be demonstrated even if the drug improves life span by only a few days or weeks. Drugs may also be approved on the basis of indirect criteria, for example reduction in tumor mass or decrease in biomarkers, with no evident evidence that patients benefit from improved survival.with no clear evidence that patients benefit from improved survival.with no clear evidence that patients benefit from improved survival.

The third conclusion is that the way the patent system interacts with the FDA's drug approval process distorts decisions about different types of clinical trials specifically aimed at solving the cancer problem. There are more economic resources to invest in the development of drugs that extend the life of cancer patients for a couple of months and recover the investment of their discovery, than in drugs that effectively prevent or block their appearance.

The fourth is based on the hope that the monoclonal ones incorporate, many still in the effectiveness research phase. They argue that "The industry wants to continue to hope in the long term to find something that will revolutionize cancer treatment, while patients die by the thousands in the short and medium term." Thus they go on to demonstrate that to secure FDA approval of a future superstar drug, "pharmaceutical companies are running against time to demonstrate in Phases II and III that the product is safer and more effective." The question is what alternative drug do they do, or is it only against placebo.

The patent system offers, perhaps inadvertently, very little incentive to private companies engaged in long-term research. In the case of oncological drugs, the faster it is possible to complete the studies, the longer the patent protection time on the molecule will be until it expires, a period during which the margins of economic benefit due to a monopoly position will be more elevated.

Continuing with the same study. Also notable is the number of oncology drug trials conducted before the advent of monoclonal biotechnology. Between 1973 and 2011 there were around 12,000 investigations in Phase II and III for patients at relatively late stages of disease evolution, with a 90% probability of dying in five years. Another 6,000 focused on patients whose chance was only 30% to die. And more than 17,000 trials included patients with the lowest probability of survival (recurrent or multimetastatic cancer). What is unique is that only 500 investigations were linked to cancer prevention, a factor that would provide the longest survival benefits.This bias towards studies focused on patients with fewer chances of survival has been frequent with medications whose R&D comes from private rather than public funding.

Generally, the clinical trials required for the FDA to approve a drug take several years. According to data provided by the innovative pharmaceutical industry, 58% of the cost of developing a drug is consumed in phase III clinical trials. The average approval time of an oncological drug from the beginning of clinical testing is approximately 8 years. Although the virtual patent can reach 20 years (or more if it is passed to evergreen), a standard drug reaches the market with about 12.5 real years of life remaining under protection. President Obama's Affordable Care Act includes a provision that grants 12 years of market exclusivity upon approval by the FDA - half a year less than the typical 12,5 years remaining on a patent - but only on biotech drugs.

Those who seek the most control over the time between receiving a patent and its approval for marketing by the FDA are precisely the innovative BigPharma. By studying patients in whom guaranteeing safety and efficacy can be done quickly, they manage to reduce this delay. The FDA has long begun to approve drugs based on evidence of clinical benefit and safety, with no clear Phase III requirement threshold for the necessary benefit achieved to justify such approval.

The peculiarity is that the development of drugs to treat cancer in an advanced stage is usually much faster than for an early or preventive stage, because the disease in the late phase turns out to be very aggressive and rapidly progressive and what is needed is to offer both safety as a certain efficiency. This allows companies to access clinical trial results more quickly. Even if they only consist of a small quantitative and non-qualitative clinical improvement in survival, even compared to other drugs already on the market. It also happens that some compounds do not complete the studies, simply because the available protection time granted by the patent to recover the cost of developing the molecule is too short.

Hence, increasingly, large pharmaceutical companies are betting on finding new cancer molecules that cost billions of dollars to develop and sell for thousands of dollars per dose. For example, in 2010 ten licensed cancer drugs became blockbusters, having reached - according to the Campbell Alliance Consultant - one trillion dollars in sales. In the previous ten years, only two products had been able to achieve this.

But the price is one thing and the benefit is quite another. In general, the newest and most expensive cancer drugs do not provide results that dramatically prolong life for patients. This is especially the case with some biotech companies that display statistically significant but clinically low relevant data. These health benefits are represented as a function of Quality-Adjusted Life Years (QALYs or QALYs) and not by amount of time, obtained from the moment treatment is started. The QALY measure expresses the number of years of life that would be added due to a certain therapeutic intervention, adjusted for quality of life. It is a key indicator that is commonly used in evaluating the value for money of a medicine or device,and it reflects the qualitative improvement of life in a more specific and less subjective way than the quantity of life that can be offered under certain conditions.

A QALY with a value of 1 is the equivalent of a year of life lived without any form of disease. On the other hand, a value of 0.5 indicates a quality of life 50% of normal. Therefore, a gain of 1 full year at a Q of 0.5 equals a gain of half a year in perfect health (QALY = 1 × 0.5 = 0.5 years). Zero is equivalent to being dead, since it is not possible to accumulate QALY after dying.

The benefits of a new drug are defined as the number of additional QALYs experienced by patients who were administered the drug, compared to a pre-existing or placebo treatment option. Once QALY is determined, the next step is to calculate the incremental cost-effectiveness ratio (ICER). Suppose that for a serious life-threatening condition, standard treatment costs $ 3,000 and offers 1 year of life with an expected quality of 0.4. The QALY associated with this treatment is, therefore, 0.4 years. Now suppose that a new treatment that costs $ 50,000 offers 2 years of life with a Q of 0.7. The QALY in this state is 2 × 0.7 = 1.4 years. The ICER is calculated by taking the cost difference between the 2 treatments, divided by the difference in QALYs between the two treatments:

ICER = (U $ 50,000- U $ 3000) / (1.4 - 0.4) = $ 47,000 per QALY gained.

The biggest drawback to calculating cost / effectiveness in oncology is for drugs that do not seem to make much sense to administer, given the high cost and the small benefits they add. For example, some biotech novelties may cost more than $ 10,000 per month, but provide an additional median survival that ranges from a few weeks to less than a month, associated with high substantial toxicity and adverse effects.

Chambers and collaborators (2014) reviewed effectiveness (in terms of QUALY / QALY) and cost-effectiveness ratio of a series of drugs intended to treat different diseases considered serious, including oncological ones, which were approved by the FDA between 1999 and 2011. They showed that the vast majority achieved modest benefits in the health of patients compared to what was achieved with other drugs already existing in the health market. Estimates of additional health benefits (measured in QALYs) and increased costs were made on fifty-eight new drugs and forty-four traditional drugs. Of the new drugs tested, 32% offered no additional benefit. Of those that did, a third contributed less than 0,1 incremental QALY (equivalent to 5 weeks of quality-adjusted survival) while the remaining two thirds gave less than 0.3 QALY (15 weeks). (See Table 1)

In the same study, fourteen state-of-the-art and two traditional drugs showed little more than 0.5 QALYs of benefit (25 weeks of quality-adjusted survival), and the cost / effectiveness estimate was high. Two drugs registered ratios of up to U $

50,000 / QALY, three between U $ 50,000 and 100,000 / QALY and in six they were higher than U $ 250,000 / QALY. An example was imatinib (Gleevec®), orally administrable to treat chronic myeloid leukemia with high efficacy. Chambers noted that it has the third highest incremental cost ($ 151,476) and the second as a QALY gain (4.1 QALY), with an incremental cost-effectiveness ratio of $ 36,921 per QALY. For reference, a threshold between $ 50,000 to $ 100,000 per QALY is justified in the US as a definition of cost-effective healthcare intervention, based on dialysis. For the United Kingdom and Canada, the desired ICER threshold for approval of cancer treatments is generally less than $ 50,000 per QALY.

Source: Taken from Chambers, J; Health Affairs, 33, no.10 (2014): 1751-1760

Therefore, although they may offer greater welfare gains in incremental terms compared to QALYs (0.183 versus 0.002 QALYs), many drugs have higher incremental additional costs (US $ 12,238 versus US $ 784). 26% of the drugs under analysis presented incremental cost / effectiveness ratios well above U $ 150,000 per QALY. This data indicates the need to raise an urgent debate regarding what should be the cost-effectiveness threshold that as a society is being prepared to pay in the face of escalating prices of new drugs.

Although in the last twenty years researchers have discovered a greater number of secrets regarding mutagenesis, tumorigenesis, gene and protein expression, messaging systems, angiogenesis and resistance to treatment, therapeutics are still insufficient to avoid a fatal outcome. According to a publication by Siddiqui & col in Mayo Clinic Proceedings, since the duration of the therapeutic effect of most oncological drugs is limited, when a treatment ceases to be effective, it is common for the patient to be administered another new drug until that all possible options fail. For example, if there are four drugs approved to treat a particular incurable cancer, there is no possibility of obtaining low prices, since all of them will be applied at some stage of the evolution of the disease,regardless of the answer. Typically, the therapeutic benefits last for a short time if measured in weeks or months, after which the tumor begins not to respond to the medication. Faced with this situation, doctors do not usually choose the most cost-effective option, but only decide the opportune moment to use each therapeutic option. For this reason, there is no competition for significant effectiveness between oncological drugs - many of them experimental - that allows reducing their prices, quite the opposite. Contrary to what happens with less complex and curable pathologies, where pharmaceutical companies have been successful in developing effective products with fewer adverse effects and better prices.The therapeutic benefits last for a short time if measured in weeks or months, after which the tumor begins not to respond to medication. Faced with this situation, doctors do not usually choose the most cost-effective option, but only decide the opportune moment to use each therapeutic option. For this reason, there is no competition for significant effectiveness between oncological drugs - many of them experimental - that allows reducing their prices, quite the opposite. Contrary to what happens with less complex and curable pathologies, where pharmaceutical companies have been successful in developing effective products with fewer adverse effects and better prices.The therapeutic benefits last for a short time if measured in weeks or months, after which the tumor begins not to respond to medication. Faced with this situation, doctors do not usually choose the most cost-effective option, but only decide the opportune moment to use each therapeutic option. For this reason, there is no competition for significant effectiveness between oncological drugs - many of them experimental - that allows reducing their prices, quite the opposite. Contrary to what happens with less complex and curable pathologies, where pharmaceutical companies have been successful in developing effective products with fewer adverse effects and better prices.Doctors do not usually choose the most cost-effective option, but only decide the appropriate time to use each therapeutic option. For this reason, there is no competition for significant effectiveness between oncological drugs - many of them experimental - that allows reducing their prices, quite the opposite. Contrary to what happens with less complex and curable pathologies, where pharmaceutical companies have been successful in developing effective products with fewer adverse effects and better prices.Doctors do not usually choose the most cost-effective option, but only decide the appropriate time to use each therapeutic option. For this reason, there is no competition for significant effectiveness between oncological drugs - many of them experimental - that allows reducing their prices, quite the opposite. Contrary to what happens with less complex and curable pathologies, where pharmaceutical companies have been successful in developing effective products with fewer adverse effects and better prices.Contrary to what happens with less complex and curable pathologies, where pharmaceutical companies have been successful in developing effective products with fewer adverse effects and better prices.Contrary to what happens with less complex and curable pathologies, where pharmaceutical companies have been successful in developing effective products with fewer adverse effects and better prices.

Something similar occurs with other incurable or highly disabling chronic diseases with each therapeutic innovation that is approved, as with many of the rare ones. The economic magnitude of the problem is more complex in oncology. The social impact of the disease and the severity of its diagnosis place patients and doctors in front of the urgent need to assume the high costs of treatment without over-measuring the results. For example in terms of QALYs earned.

Cancer therapy and prices. A path where science, economics and bioethics intersect

Oncology, a specialty that was considered a niche market a few years ago, managed to reach a turnover of U $ 41 billion in 2008, when compared to U $ 24 in 2004. Based on this data, market analysts of US drugs have been holding what they define as «financial toxicity«. Many of the new cancer drugs enter the market at a price of more than $ 100,000 a year in the United States. They do not replace others already existing in the market, but are added to the list, although without adding significantly more quality or quantity of life. The problem is that if the cost of a drug is calculated at $ 120,000, and the next innovation will not cost less than that, the need for financing will be a minimum of a quarter of a million dollars higher.This skyrocketing price far exceeds the supposed therapeutic benefits of these drugs and points to a huge gap between their final price and the actual cost of production. British researchers argue that the price of five cancer drugs turns out to be 600 times higher than it costs to produce them. For example, the analysis of the real cost of production figures for a one-year supply of the aforementioned imatinib (Gleevec®) is US $ 159. But its market price is US $ 106,322 / year in the US and of U $ 31,867 / year in the United Kingdom, while in Argentina it oscillates between U $ 39,434 and U $ 25,442 / year. Speechless.British researchers argue that the price of five cancer drugs turns out to be 600 times higher than it costs to produce them. For example, the analysis of the real cost of production figures for a one-year supply of the aforementioned imatinib (Gleevec®) is US $ 159. But its market price is US $ 106,322 / year in the US and of U $ 31,867 / year in the United Kingdom, while in Argentina it oscillates between U $ 39,434 and U $ 25,442 / year. Speechless.British researchers argue that the price of five cancer drugs turns out to be 600 times higher than it costs to produce them. For example, the analysis of the real cost of production figures for a one-year supply of the aforementioned imatinib (Gleevec®) is US $ 159. But its market price is US $ 106,322 / year in the US and of U $ 31,867 / year in the United Kingdom, while in Argentina it oscillates between U $ 39,434 and U $ 25,442 / year. Speechless.434 and U $ 25,442 / year. Speechless.434 and U $ 25,442 / year. Speechless.

Any final price of a medicine is also considered a function of the population to which it is addressed, the half-life of the patent and the return on investment projected. But the unusual sale value that certain oncological innovations have is not directly related to any of these variables. The argument most widely used by the industry relates to the costs of moving the laboratory findings to the development of all the regulatory studies (the three phases of clinical trial) that are required to achieve marketing approval by the FDA or the AEM. The truth and proven is that these costs do not always come from the private industry itself, but from the public sector and the public health institutes that support the research.

There is a variable that is binding, and it has to do with the incurability of many cancers. Patients are incorporated by doctors into treatment protocols for each new authorized product (sequentially or in combination) with the aim of investigating clinical results and at the same time trying to prolong their life time. This creates, in fact, a condition of virtual monopoly, since although there is no automatic elimination of the drugs present in the market, they come to be seen as a substandard of less therapeutic value and without the capacity to generate price competition. As occurs under this monopoly condition, drugs that effectively prolong the survival of incurable patients - even for a few weeks - can bear any price that the market or funders can bear.The evidence for this is represented by the inelasticity / price (the percentage change in the associated use of a medicine linked to a percentage increase in its price) that these highly specific drugs possess.

Whether due to the nature of the disease and the severity of its diagnosis, patients and doctors condition funders to bear the high price of new treatments. Even in the face of very small marginal improvements in the incremental cost / effectiveness of therapeutic alternatives. In addition, every new drug, regardless of its cost and alleged innovative function, will always have the alternative of being prosecuted in its provision (via recourse of amparo or tutela) in the event that its financing by an insurance agency is not accepted or is delayed. temporarily. Therefore, oncology drugs, like those used for certain rare diseases, represent a monopoly condition of use and price.Good for the biological complexity of cancer and its level of response to chemical or biotechnological treatment. Or based on its relationship with the health system, with medical autonomy and with the lack of regulation of use based on guidelines and protocols, situations that provide incentives to administer more chemotherapy without often taking into account considerations of efficiency and effectiveness. economic and clinical and adverse effects.

The transition from chemical to biological pharmacology represents a Copernican turn in the way of treating cancer. And the relationship between the clinical value of an oncological drug and its price is different depending on its type and the therapeutic area in which it is used. The BMJ published in 2015 an article by Allen Shaughnessy under the title "Monoclonal antibodies: magic bullets with a hefty price tag" in which the author makes an accurate analysis of the current situation of these pharmaceutical products. It anticipates that sales of monoclonal antibodies will reach more than $ 160 billion in the US in the coming years.How much does a person's life cost then? And reach six months of life? Can the survival of a sick person have an unpayable price? This series of key questions constitutes the dilemma of the main health regulators in the 21st century, be it the FDA or the EMA, regarding drugs with such high prices.

While there are new therapeutic developments that impact survival significantly, remarkably expensive products provide just a few weeks or months to live. Many of them entered the healthcare market very quickly, and should be withdrawn months after studies were published about their effectiveness but also about their adverse effects. Certain monoclonal drugs that were positioned with a certain therapeutic indication later, when another one was found, were opportunistically withdrawn from the healthcare market by the laboratory itself. This is the case of Sanofi - Genzyme, which changed the commercial name of one of its products with the same composition and re-entered it again with a very high price to compete against other rivals in a different therapeutic band. This happened with alemtuzumab,primarily indicated for chronic lymphocytic leukemia and more recently for multiple sclerosis. In the first case it is known commercially as Campath®, administrable for 12 weeks at a price of U $ 1,930 per dose. The total cost of treatment reaches U $ 60. 000 / year.

MS patients need a fraction of the dose used in Leukemia (two applications per year), so under that pricing scheme, the second variant of alemtuzumab under the brand name Lemtrada® would only cost $ 6,000 per year. But Sanofi has confirmed that a full course of treatment will cost approximately $ 95,000 in Germany, where the product was initially launched. The cost per bottle of Lemtrada® is close to $ 11,700, and patients typically receive eight applications over a two-year period. Its competitors in this therapeutic band are Biogen Idec's Natalizumab (Tysabri®) and Novartis' fingolimod (Gilenya®). The paradox is that this last drug, which is administered orally, has much higher prices (US2,940 / 28 tablets) than Campath®,at least in the dose used by the patients, but not that the Lemtrada® that is for intravenous use. For its part, Tysabri® for oral use costs $ 55,000 per year, closer to the price of Campath® but also below that of Lemtrada®.

Sanofi - Genentech has withdrawn Campath® from most of Europe and the USA, and only maintains it in 50 countries. The question is how this laboratory can distance Lemtrada® from Campath® - if it is the same drug - in order to obtain a higher dose price for MS, while avoiding the use of Campath® more. cheap removing it from the health market. And how can you justify going from $ 2,000 to $ 12,000 in the price of the same dose of alemtuzumab, with an increase of 600%. What then is the boundary between the economic, the scientific, and the bioethical?

Examples of absence of limits are too many. Breast cancer has multiple treatment options that have allowed survival to be extended for years, for example in tumors with HER2. In this case, the height of the price stick may be higher than in pancreatic cancer, where the average survival is only six months. Let's see some cases. Roche's bevacizumab (Avastin®) was first approved for the treatment of colorectal cancer in 2004 and subsequently for metastatic breast cancer in 2008. The results of two subsequent randomized trials of the latter disease, conducted in 2009, showed that while patients experience a statistically significant gain in "progression-free survival" (which measures the length of time the cancer is under control),they present small differences regarding survival, not statistically significant. But the disparity between added value and price is very strong, which is not sustainable. A study by the BMJ estimates that based on the current price of administering bevacizumab (£ 1,848.80 / month for patients weighing 70 kg) and the average treatment time required (approximately 10 months), the total cost of treatment is close to £ 18,500 / patient. Another study, published by the New England Journal of Medicine, showed that the drug extended life by 4.7 months (20.3 months versus 15.6 months) but at a cost of $ 42,800 to $ 55,000. A third, carried out by Goldstein & col, indicates that said drug, used as first-line treatment, provides an additional of only 0.10 QALY (5 weeks of survival) at a cost of $ 59,361.This implies an incremental cost / effectiveness of US $ 571,240 per QALY. For this reason, the National Institute for Health and Care Excellence (NICE) of the United Kingdom ruled out funding bevacizumab, estimating that at that cost it only added minimal clinical benefits. In the same vein, the FDA revoked the authorization for its use in breast cancer in 2011. However, a panel of experts subsequently convened by the National Comprehensive Cancer Network (2010) - a consortium of major US cancer centers - voted against the elimination of bevacizumab from the list of drugs indicated as for advanced breast cancer.estimating that at that cost it only added minimal clinical benefits. In the same vein, the FDA revoked the authorization for its use in breast cancer in 2011. However, a panel of experts subsequently convened by the National Comprehensive Cancer Network (2010) - a consortium of major US cancer centers - voted against the elimination of bevacizumab from the list of drugs indicated as for advanced breast cancer.estimating that at that cost it only added minimal clinical benefits. In the same vein, the FDA revoked the authorization for its use in breast cancer in 2011. However, a panel of experts subsequently convened by the National Comprehensive Cancer Network (2010) - a consortium of major US cancer centers - voted against the elimination of bevacizumab from the list of drugs indicated as for advanced breast cancer.A panel of experts subsequently convened by the National Comprehensive Cancer Network (2010) - a consortium of leading US cancer centers - voted against removing Bevacizumab from the list of drugs indicated as for advanced breast cancer.A panel of experts subsequently convened by the National Comprehensive Cancer Network (2010) - a consortium of leading US cancer centers - voted against removing Bevacizumab from the list of drugs indicated as for advanced breast cancer.

Other comparative examples of multiple use and varying effectiveness can be found in Eli Lilly's analysis of ramicirumab (Cyramza®), which was approved by the FDA in April 2014. It has a similar action as other angiogenesis inhibitors such as the aforementioned bevacizumab (Avastin) and the ziv-aflibercept (Zaltrap®) from Sanofi in combination treatment with FOLFIRI (folinic acid, fluorouracil and irinotecan). Cyramza® was commercially presented as a novel strategy for the treatment of advanced gastric cancer, where Avastin® was not effective. It gave 37% median overall survival, of 5.2 versus 3.8 months for placebo (1.4 difference). It also improved progression-free survival (SFP) from 1.3 to 2.1 months (0.8 difference). Later it was indicated to treat metastatic colon cancer,where it competed against good results of bevacizumab, although it doubled the price. In this case, the median overall survival of those treated with ramicirumab was 13.3 months, compared to 11.7 months (1.6 months apart) for patients treated with placebo plus FOLFIRI. Subsequently, the FDA authorized its use in metastatic non-small cell lung cancer in combination with docetaxel. Its effect was to increase the median overall survival to 10.5 months, versus 9.1 months (0.6 months) of placebo plus docetaxel, with a delay in disease progression of 4.5 to 3.0 months (0.5 difference). The example of a very high-priced drug with a remarkably small comparative therapeutic effect is clear.In this case, the median overall survival of those treated with ramicirumab was 13.3 months, compared to 11.7 months (1.6 months apart) for patients treated with placebo plus FOLFIRI. Subsequently, the FDA authorized its use in metastatic non-small cell lung cancer in combination with docetaxel. Its effect was to increase the median overall survival to 10.5 months, versus 9.1 months (0.6 months) of placebo plus docetaxel, with a delay in disease progression of 4.5 to 3.0 months (0.5 difference). The example of a very high-priced drug with a remarkably small comparative therapeutic effect is clear.In this case, the median overall survival of those treated with ramicirumab was 13.3 months, compared to 11.7 months (1.6 months apart) for patients treated with placebo plus FOLFIRI. Subsequently, the FDA authorized its use in metastatic non-small cell lung cancer in combination with docetaxel. Its effect was to increase the median overall survival to 10.5 months, versus 9.1 months (0.6 months) of placebo plus docetaxel, with a delay in disease progression of 4.5 to 3.0 months (0.5 difference). The example of a very high-priced drug with a remarkably small comparative therapeutic effect is clear.The FDA authorized its use in metastatic non-small cell lung cancer in combination with docetaxel. Its effect was to increase the median overall survival to 10.5 months, versus 9.1 months (0.6 months) of placebo plus docetaxel, with a delay in disease progression of 4.5 to 3.0 months (0.5 difference). The example of a very high-priced drug with a remarkably small comparative therapeutic effect is clear.The FDA authorized its use in metastatic non-small cell lung cancer in combination with docetaxel. Its effect was to increase the median overall survival to 10.5 months, versus 9.1 months (0.6 months) of placebo plus docetaxel, with a delay in disease progression of 4.5 to 3.0 months (0.5 difference). The example of a very high-priced drug with a remarkably small comparative therapeutic effect is clear.

Another is Bayer's regorafenib (Stivarga®), an orally administrable multi-kinase inhibitor for the treatment of metastatic colon cancer. Its use prolongs life by 1.4 months. It has a value in Mexico of U $ 9,350 for a 28-day treatment cycle and in the United States of between U $ 12,000 to 14,000 (U $ 167 / tablet). An editorial taken from The Lancet points out that it is unlikely to calculate its future profitability, given its modest efficacy and high toxicity.

The biggest problem occurs with the competition of monoclonal or their combination in search of greater effectiveness against the usual chemicals and market values. Although in the clinical phases they may have statistically significant data on disease progression-free survival (SSP), their cost alone or in combination can result in astronomical figures.

In 2009, the FDA approved the use of Astra Zeneca gefitinib (Iressa®) orally daily as a first-line treatment for metastatic non-small cell lung carcinoma with an epidermal growth factor receptor (EGFR) mutation that causes an antiapoptotic event. Its action consists in inhibiting the activity of the intracellular pathways involved in the growth and survival of neoplastic cells, at the level of the binding pocket of the receptor's intracellular catalytic domain. The IPASS (IRESSA Pan-Asia Study) was the first of four phase III trials on 1,207 patients aimed at showing confirmed superiority. Subsequently, the IFUS study carried out on 106 naive treatment patients showed an average survival of 10.9 months against 7,4 months for the control group treated with carboplatin / paclitaxel (3.5 months apart).

Astra Zeneca had already developed in 2003 a first study on 1,700 unelected patients. Those treated with Iressa® lived an average of 5.6 months against 5.1 months of the placebo group, with which the survival was limited to two weeks. For this reason, in 2005 it was withdrawn from commercialization in western countries. However, in Asians the response was better, since while the group treated with Iressa® lived on average 9.5 months, those under placebo only did so for 5.5 months. The difference in disease progression-free survival (PFS) was thus 4 months average .

Gefitinib is a generic made by 12 companies at an average price of between $ 319-400 / month and an average treatment duration of 9.8 months. As of its new indication, under the trade name of Iressa®, it will cost 30 tablets about $ 7,695 in the US and $ 3,000 in Canada. Its competition is nivolumab (Opdivo®) from BMS. Originally indicated to reduce the size and extend the life of patients with advanced melanoma, it is a monoclonal inhibitor against PD-1, a protein that prevents T cells from recognizing and attacking inflamed tissues and cancer cells. PD-1 can trick the system and make melanoma cells appear normal. The AEM has also authorized its use in the European Union for the treatment of advanced lung carcinoma previously treated with chemotherapy.Nivolumab improves median survival 9.2 months compared to doxetacel (6.0 months). After 12 months of treatment, 42 of the patients are alive, compared to 24% of the series with docetaxe l. The problem is again the price. Nivolumab costs $ 28.78 per mg of the drug, so a complete treatment implies a total cost of U $ 103,220 (to obtain a PFS of 6.9 months).

If used in the treatment of metastatic or unresectable melanoma, the cost of nivolumab can be extremely high per patient, if it is combined with another monoclonal named ipilimumab (Yervoy®) also from BMS and whose price is U $ 157.46 per mg. A trial carried out to demonstrate the effectiveness of this combination established that the cost of using ipilimumab was only US $ 158,282 (for a median progression-free survival of 2.9 months), that of nivolumab was US $ 103,220 (for a PFS of 6.9 months) and the combined form of $ 295,566 (PFS of 11.4 months), almost four times that seen with ipilimumab alone, which is currently the standard of care. The main drawback of the combination is that it produces serious side effects, such as inflammation of the colon, diarrhea and problems with the endocrine glands.

Another drug combination for recently metastatic breast cancer without prior treatment or with relapse after receiving adjuvant or neoadjuvant treatment, and in which tumor cells overexpress HER2 protein (HER2 positive), includes pertuzumab (Perjeta®) from Roche - Genentech. Its price is U $ 5,900 per month, and it is frequently used together with trastuzumab (Herceptin®) from the same company. Both drugs added have a cost of U $ 10,400 / month, with an average treatment extension of 18.5 months, which shows how future drug associations will continue to increase costs as more protocols can enter the healthcare market.

Pharmaceutical companies run a fine line between the poor survival effectiveness of new cancer drugs, the continuous increase in their prices and the level of moral outrage in society. The value that they add in terms of benefits becomes the new mantra of the industry, which it tries to define through different indicators: benefits regarding survival, tumor progression, improvement of quality of life, reduction of associated toxicity and concomitant medication and shorter hospital stays. But as more cancer innovations hit the market and more high-cost combinations become common, the value of cancer medicine becomes an increasingly challenging subject.One fact in favor of the industry is that one of the reasons why the global cost of cancer treatment is increasing is because patients are being treated for a longer time than they were years ago. And if the therapy is lasting longer, it means that the patients are surviving longer. But this in no way justifies the price spike.

If prevention comes before attention. Why in oncology is a term almost absent?

Are we losing the war against cancer? A necessary question. At the beginning of the 20th century, one person in twenty could have cancer. In the 1940s the ratio was one in sixteen. For the 1970s it dropped to one in ten. Today it is one in three people who will suffer it in the course of their lives. For 2014, a total of 1,665,540 new diagnosed cancer cases and 585,720 deaths were estimated in the US alone. The National Cancer Institute (NCI) admitted that medical expenses for cancer care had reached $ 125 billion in 2013, with an incremental projection to 2020 of 39% (U $ 173 billion).

Perhaps this is one of the reasons for the phrase of Dr. Linus Pauling, Nobel Prize in 1986, who suggested that "everyone should know that cancer research is largely a fraud." He did so with the incipient knowledge that the oncology industry was becoming a profitable business in the United States, but without knowing that the average survival provided by the approved drugs between 2002 and 2014 would be only 2.1 months.

According to the IMS Institute for Healthcare Informatics, a new cancer treatment entered the healthcare market in 2002 had an average cost of U $ 4,500 / month. Currently, the average price is around $ 10,000, and two of the new drugs approved in 2014 have already exceeded $ 35,000 per month of treatment. Meanwhile, the list of innovations, especially biotechnology, and the Research Phases continues to grow. Fifty of the new drugs approved in 2013 include seventeen for cancer treatment, with sales growth of $ 53 billion. For example, the monoclonal rituximab (Rituxan®), bevacizumab (Avastin®) and trastuzumab (Herceptin®), all from Roche Genentech laboratory, had combined sales gains of close to $ 21 billion,40% of the value of the 20 best-selling products in the healthcare market. Along with its other drugs erlotinib (Tarceva®) for Pancreatic Cancer and Capecitabine (Xeloda®) for Metastatic, Gastric and Breast Cancer, Roche generated by total sales in the therapeutic cancer band in 2013 about U $ 24 billion. In 2010, Novartis raised, only for sales with imatinib (Gleevec®), $ 4.3 billion.

If the dynamics of the innovative pharmaceutical industry is the rapid search for treatments for increasingly advanced stages of the disease, where has research in specific cancer prevention been? Certain studies have shown that regular and prolonged use of acetylsalicylic acid (Aspirin®) has been shown to be useful in reducing the risk of adenomas, colorectal cancer and its recurrent form in humans, although this utility has been inconsistent in other tumors. Both Aspirin® and Non-Steroidal Analgesics (NSAIDs) and rofecoxib may reduce the risk of cancer. It is not yet clear, but it appears to be linked to its ability to block the enzyme cyclooxygenase (COX). Also tamoxifen,FDA-approved as the first chemoprotective agent for women at high risk for breast cancer shows statistically significant data.

Recently, the Cancer Prevention Division of the National Cancer Institute (NCI) has identified two priority areas within the PREVENT Program of interventions and biomarkers for preclinical drug development. These two key areas can promote a high return on investment for companies through specific tests for a relatively short period of time. The first involves the development of anti-inflammatory drugs specifically aimed at cancer prevention. Defining potential biomarkers related to blocking inflammation pathways would be an avenue of investigation. This approach appears as particularly promising given expressed regarding the efficacy observed with NSAIDs and coxibs in preclinical and clinical studies. The second focuses on immune prevention.

The development of early-stage cancer vaccines also appears as a feasible alternative in preclinical studies. There is a substantial amount of recent data regarding the use of vaccines or activated T cells in a therapeutic setting. This second approach would offer an excellent strategy to combat the cancer process early with minimal toxicity. At a time when the increasing number of increasingly expensive drugs calls into question the sustainability of health systems, especially in lower-income countries, research in cancer prevention becomes essential. The United States Institutes of Health have admitted to the existence of more than 1,000 cancer drugs under development. About 123 are aimed at treating lung cancer, the leading cause of death.106 correspond to therapies for severe forms of leukemia, 92 for lymphomas including the non-Hodking form, 82 for breast cancer, 58 for brain tumors (including glioma that represents 80% of all malignant tumors) and 53 for skin cancer (including highly aggressive melanoma) But most of the research costs do not belong to the industry, but to governments and consumers that finance 84% of applied research, while only 12% correspond to laboratories. This data dispels the myth of the price of drugs tied to investment in R&D. A study carried out on 117 research protocols showed that the average private investment is only around US $ 80 million.The FDA admits that only 20% of the investment in research corresponds to products that provide significant therapeutic improvement and innovation compared to other drugs already on the market. It is the monopoly condition established by the patent that allows companies to arbitrarily set prices, far from production costs. Paradoxically, 75% of the financing of said regulatory agency comes from the industry itself, to which it must regulate.

Conclusions

The pharmaceutical industry is aiming for permanent innovation. And drug patents are their main incentive. Especially with biotechnology, an issue already specifically incorporated in the Asia Pacific Treaty. FDA approval of a new drug is a blank check regarding its safety and effectiveness. Subsequently, the pharmacovigilance phase allows adjusting the problems that have arisen during its use in the market.

During the first decade of the 21st century, important steps have been taken in understanding cancer biology in general and, therefore, specific therapy. An important step was the understanding of intratumoral cellular phenotype / genotype variation, which could explain the differences in drug efficacy in terms of clinical improvement and well-being gains. The same for the identification of a series of processes that occur in the interaction of tumor cells with their microenvironment, which govern the evolution of metastasis. Biotechnology confirms that, for each patient, there is gene sequencing, intracellular signaling patterns, groups of biomarkers and therapeutic targets that pave the way towards personalized medicine and target therapy for the patient. Precisely,The researchers are looking for biomarkers that express various disease states. They can be proteins whose levels are correlated with predicting the risk of disease, diagnosing it early or using them as outcome indicators of the course of treatment.

Researchers are exploring new high-tech methods to fight a more even battle against the disease, as well as new ways to maximize the use of existing drugs, either alone or in combination with other therapies. In fact, approximately 80% of oncology drugs in the pipeline are first-in-class drugs and 70% are profiled to be part of personalized medicine. Of the 836 drugs currently under development, the greatest drawback in the search for treatments for the prevention and / or care of certain forms of cancer lies in the distortion produced by the pharmaceutical industry by the type of incentives that condition the development of certain lines. of treatment.In the same way, the high market prices act with which they introduce their products and the response of the competition and also of the use that is given to certain drugs from the assistance point of view and the value that this means in terms of life gain. But fundamentally it is the elasticity / price the factor that the industry finds both at the time of the launch of a new product and in the subsequent price increases, which show no signs of stopping.

Many insurers worldwide, such as the case of Express Scripts Holding Co., A management of prescription drug benefits in the US, are beginning to consider the possibility of closing agreements with pharmaceutical companies to pay less when the drugs to be used, of very high price, they do not generate, against certain types of tumors and indications, the expected results. A mechanism called performance payment.

The case of erlotinib serves as a witness to the difference in effectiveness and price according to the indication, type of tumor and stage of progress. Administered orally in the case of unresectable or metastatic pancreatic cancer, the average survival obtained compared to placebo does not exceed two weeks. In lung cancer, its effectiveness is 6.7 months versus 4.7 months of a combination of traditional chemotherapy. Based on these wide differences, the price per tablet of the drug should be lower for the first case than for the second. The drawback is that the drug has a single price, for either of the two alternatives, of U $ 7,224 for the 30 150mg tablets.

Today there is a wide variety of treatments that prolong the life of patients with advanced or metastatic tumors. Also many of the new drugs have become common therapy for patients with disease in early stages, post surgery or radiotherapy, using them as adjuvants. Especially those with genetic markers. These targeted therapies are more likely to be successful throughout clinical trials. The dilemma arises between the scientific knowledge embodied by the new drugs, especially biotechnology, and progress in terms of available therapeutic alternatives, when it is not accompanied by proportional improvements in the results that patients obtain in terms of net benefits. Gains in Quality Adjusted Life Years, unfortunately,they are still measured in oncology in weeks or months, and not in years.

For this reason, drugs intended for patients with a short life expectancy can move more quickly throughout clinical trials than drugs intended for those with a longer life expectancy. But this does not lead to the extremely high prices of medicines changing downwards after their launch. Precisely because that is the turning point of the industry. How are cancer drug prices decided? Of the many complex factors that seem to be involved, a simple formula seems to be followed: putting the most recent price of a similar drug on the market and adding 10 to 20% as a base. Although oncologists do not face direct incentives to avoid more expensive drugs,they can resist the prescription of those medicines whose prices are above the reference price level. There is a "zone of indifference" around a reference price, which allows consumers to ignore deviations from the final price with respect to it, and manufacturers to grant them the possibility of setting excessively high prices for new medicines, without reducing it. the quantity demanded.

The structure of the drug market, in this case for cancer therapy, includes the protection of patents and does not offer other price control mechanisms that do not arise from the goodwill of funders and patients and the tolerance of companies for advertising. adverse regarding monopolistic and abusive behaviors and that the increases are not related to the magnitude of the expected health benefits. The process by which companies establish the "launch prices" of new drugs is quite opaque, and at the time of FDA marketing approval, most of these are already patent, therefore the industry constitutes monopolies temporary with broad freedom of action and unlimited power to set prices.

Cancer therapy is becoming increasingly complex and accelerates the development of new products. We are far from prevention. Drug prices are rising in the elevator and funders are shaking their economic structures. Regulators feel regulated and doctors escape protocols in the name of professional autonomy. And patients receive thousands of treatments, many experimental, with low evidence of benefits in quality or quantity of effective life. The crossroads becomes a dilemma. The problem, like Alice in the story, is which way to go. Pharmacoeconomics can help, but it needs health policy. As I wrote not long ago, paraphrasing the great Leonardo "Technique without politics is handicapped, but politics without technique is blind."

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