AML: a rare and expensive cancer
Acute myeloid leukemia (AML) arises in the bone marrow from the abnormal clonal expansion of myeloid blood cell precursors. Leukemic blast cells are found in circulating blood and also in bone marrow, where they disrupt normal blood cell production, leading to myelosuppression.1 The consequences of AML include anemia, with weakness and pallor, thrombocytopenia, resulting in bleeding and leukopenia, leading to fever and infection.
AML, which accounts for about 30% of all leukemia cases, is a relatively rare cancer, accounting for about 1.1% of all cancers in the United States, with about 20,000 new cases and 11,000 deaths each year.two The global incidence of AML in 2018 was estimated at around 130,000.3 AML tends to affect older individuals, with a median age at diagnosis of 68 years.two
Without treatment, acute leukemias can be quickly fatal, but with the immediate onset of intensive treatment, survival of several years or more is achievable.1 Conventional treatment for AML involves aggressive cytotoxic induction chemotherapy, with the aim of allogeneic hematopoietic stem cell (HSCT) transplantation in eligible patients. This intensive approach, although successful in some patients, was not feasible in many elderly patients due to poor performance and comorbidities.4 Thus, although long-term survival approaches 50% in patients under 65 years of age, it drops to around 10% in patients over 65 years of age.5 The overall 5-year survival rate in the USA from 2010 to 2016 was 28.7%.two
Based on the low overall survival rates in AML, as well as disparities in treatment outcomes for younger and older patients, there has been considerable research in recent years to develop treatment pathways for different subgroups of patients. At the same time, an evolving understanding of AML biology has triggered the development of targeted therapies that can be adapted for patients based on the genetic characteristics of their cancer cells.4 The current standard approach is to assess patients’ fitness for intensive chemotherapy (HF) and HSCT. If a patient is a candidate for IC, he usually receives an induction regimen, such as cytarabine plus daunorubicin, followed by HSCT, if possible. Patients can also undergo consolidation therapy with high-dose cytarabine. If a patient is a candidate for non-intensive chemotherapy (CIN), he may receive a low-dose hypomethylating agent (HMA), such as azacytidine or decitabine, or he may receive low-dose cytarabine (LDAC). Although these CIN options have relatively modest effectiveness, in recent years there has been a series of approvals of new targeted drugs that can be used with or without CIN, providing patients with a range of options in addition to conventional chemotherapy. Patients who achieve complete remission can receive maintenance therapy with recently approved oral options (oral azacitidine approved by the US Food and Drug Administration [FDA] and midostaurine approved by the European Medicines Agency [EMA]) Relapsing or refractory (R / R) patients may receive an IC or NIC re-induction regimen, with or without a targeted agent, or single-agent targeted therapy.1,4,6
Conventional AML therapies incur considerable costs and the use of healthcare resources (HCRU), with infusions of chemotherapy in hospitals, the need for frequent monitoring and the inevitable need to treat the serious adverse effects of treatment.7 HSCT, although potentially curative, is an expensive hospital procedure. Newer treatments, with more manageable safety profiles, can help limit medical and hospitalization costs, but in general these new drugs cost more than conventional chemotherapy. In addition, the increased tolerability of new treatments increases the number of patients who can start and stay on treatment, potentially expanding the overall budgetary impact of AML on health systems.
In conducting this review, we first sought to characterize the current AML cost and value landscape, identifying the main cost drivers and how they have evolved in recent years. Then, we seek to consider how the next advances in treatment and care can impact the economic impact of LMA, so that we could identify opportunities for manufacturers, treatment centers and others to add value to LMA in the coming years.
AML: A therapeutic scenario in transition
Historical cost drivers in AML
We conducted a systematic review of studies that report economic results in AML. The systematic review was carried out in accordance with the methodological principles of conduct for systematic reviews, as detailed in the “Guidance for Undertaking Reviews in Health Care” at the University of York CRD and in accordance with the methodology set out in the preferred report items for systematic reviews and meta-declaration of analysis (PRISMA).8,9 SLR searches (from the beginning of the database until December 2020) were carried out in the MEDLINE, Embase, EconLit and Cochrane databases. In addition to searches in databases, searches for keywords in the annual annals of scientific meetings (American Society for Clinical Oncology [ASCO], European Hematology Association [EHA], European Society for Medical Oncology [ESMO] and American Society for Hematology [ASH]) A total of 54 records were selected from 48 original studies reporting on the use of health resources or costs in AML. Among the selected studies, 31 included data from the USA and 14 included data from the EU.
One of the large retrospective database studies on the economic burden of LMA in the USA prior to the approval of target agents (2008 to 2016) examined HCRU and direct costs at the LMA in a database of commercial payers.10 The most expensive care episodes were R / R AML ($ 439,104), HSCT ($ 329,621), induction IC ($ 198,657), consolidation IC ($ 73,428) and NIC ($ 53,081). In all of these groups, the main cost factor was hospitalization, which represented about 70% of the costs. Symptoms of AML and treatment toxicity have been associated with higher costs, suggesting that less toxic alternatives to chemotherapy may help control healthcare costs in AML. Several other retrospective studies have confirmed these findings, noting very high costs associated with disease recurrence / progression; the biggest cost factor was the use of inpatients in public and private health settings.11-13
Outside the United States, the economic picture of AML is similar, as demonstrated in a study of the claims database (1997 to 2015) covering about 40,000 AML patients in Spain.14 With average annual direct costs of € 30,775 per patient, which increased 3.7 times from 1999 to 2011, the main factors were hospitalization and HSCT. A retrospective study in the Netherlands with the aim of calculating the cost of initial treatment in AML also concluded that hospitalization was the main cost driver.15 A large study based on a Swedish registry (N = 2954, 2007 to 2015) found that, of all stages of AML treatment, the total cost from the date of HSCT to death is the highest, totaling more than $ 160,000 , with hospitalization costs representing 60% of the total.16
These and other database studies that explore the costs of AML before the advent of new therapies describe a scenario that is likely to change as less toxic and more effective therapies increase absorption. The remainder of this review explores the likely transition of AML’s main cost drivers in the coming years.
Evolution of the clinical and economic condition of AML
After the development of the cytarabine + daunorubicin and HSCT regimen for AML in the 1970s, there were several decades without significant innovation in the treatment of AML.4,17 This situation changed in 2017, and in recent years, nine new products have been approved at AML. A growing understanding of the genetic characteristics of AML cells has enabled many of these new therapies to target the specific biological pathways involved in the development and progression of AML.18 Relevant for the HCRU associated with these treatments, seven of the nine newly approved drugs are administered orally.
Two are for patients with fms-like tyrosine kinase 3 positive (FLT3 +) cancer: oral midostaurin can be added to IC in newly diagnosed patients, and patients with AML R / R may receive oral gilteritinib.
Patients with isocitrate dehydrogenase (HDI) mutations may receive oral enasidenib for AMI IDH2 + RR, while elderly patients with IDH1 + AML may receive oral ivosidenib in the newly diagnosed or relapsing / refractory setting.
Patients with newly diagnosed AML eligible for IC who have CD33 expression may receive intravenous (IV) gemtuzumab ozogamycin in combination with IC.
A liposomal combination of cytarabine and IV administered daunorubicin, CPX-351, is available for AML related to recently diagnosed therapy or AML with changes related to myelodysplasia (AML-MRC).
Two targeted therapy options that can be added to the NIC for newly diagnosed patients are oral venetoclax and oral glasdegib.
Finally, oral azacitidine has been approved as maintenance therapy in patients who have achieved first complete remission (CR) or complete remission with incomplete blood count (CRi) recovery after intensive induction chemotherapy and who are unable to complete intensive curative therapy .
In addition to the rapid growth in treatment options for patients with AML, including those eligible for HF or NIC, there have been progressive improvements in supportive care for patients undergoing AML. Although IC remains an intensive treatment that can result in serious complications or even death, there have been substantial advances, such as the introduction of broad-spectrum oral antifungals and improvements in transfusion medicine. These changes, combined with the increased emphasis on patient and caregiver quality of life and cost management, have enabled many patients to receive a higher proportion of AML treatment on an outpatient basis. More recently, the COVID-19 pandemic has accelerated the push for the use of telehealth and outpatient care when appropriate, and these new approaches to care are likely to influence long-term treatment practices.7
The main cost drivers in AML include hospitalization and medical costs, stem cell transplantation for eligible patients and drug costs (conventional chemotherapy and new agents). From a broader health plan or from a social perspective, another cost driver is the proportion of AML patients who undergo treatment. Patients who previously were unable to tolerate chemotherapy are more likely to be treated with the range of NIC options now available. The effectiveness of the latest AML treatment options also suggests that, in general, there may be more patients alive and on treatment for longer than in the past.
Cost drivers in the transition: hospitalization and medical costs
Inpatient hospital care and medical costs more broadly have historically been the main cost drivers in AML. Several recent factors are likely to reduce these costs, which, in principle, could reduce the overall economic burden of LBC. This includes the advent of oral AML therapies and chemotherapy regimens that can be administered in an outpatient setting, as well as enhanced supportive care that can reduce the need for emergency care and prolonged hospitalizations.7
AML treatments that can be administered on an outpatient basis include the seven recently approved oral options. Some of the oral therapies are administered as single agents and others as complementary therapy; the choice of agent and regimen depends on the biological characteristics of the patient’s AML and the stage of treatment. In addition to oral options, which avoid administration costs, the new liposomal formulation of daunorubicin and cytarabine, CPX-351, has a simplified dosing schedule19 which allows it to be administered to suitable patients in the outpatient setting, potentially reducing hospitalization costs. In a pilot study, 14 patients were able to receive induction chemotherapy as outpatients, reducing the overall average hospital stay by more than 2 days compared to those who received the same inpatient regimen.20 Another pilot study found that patients were able to safely receive IC for AML and high-risk myelodysplastic syndromes (MDS) as outpatients.21 Fourteen of the 17 patients completed IC without the need for hospitalization, although most eventually required hospitalization for supportive treatment typical of patients after induction. The outpatient administration of induction regimens is not expected to prevent hospitalization altogether, but it can reduce costs by decreasing the total number of days of hospitalization.
Cost factors in the transition: HSCT and other cell therapies
In addition to hospitalization and medical costs, the other major historical cost generator at LMA has been HSCT. This intensive procedure requires specialized care, with patients frequently hospitalized for prolonged periods and requiring extensive follow-up. Although many AML patients have historically not been considered candidates for HSCT, improved methods for donor selection and relaxed requirements for patient fitness have expanded the population of eligible patients, potentially increasing the overall costs of HSCT in AML.
In recent years, the ability to identify patients likely to benefit from allogeneic HSCT has been enhanced by advances in AML cytogenetic and molecular risk stratification, as well as early assessments of measurable residual disease (MRD).22,23 Among patients considered suitable candidates for HSCT, there are growing options, even if they do not have a compatible donor sibling. More than 30 million adults are registered worldwide as potential voluntary donors, cryopreserved umbilical cord blood is growing in availability and there is growing evidence to support the safe transplantation of haploidenic (paired) stem cells.24 These factors have led to a sharp increase in the number of allogeneic HSCT procedures performed in AML in the last decade.
There are several new transplantation technologies that potentially expand the donor pool. Despite the promise of cord blood stem cells to increase the pool of potential compatible donors, a challenge in using this approach in adults has been the relatively low dose of available stem cells, which can lead to graft failure and recovery delayed bone marrow.25,26 One strategy that is being investigated to address this challenge is UM171, a hematopoietic stem cell self-renewing agonist, which expands stem cells from umbilical cord blood, thus allowing a higher dose of stem cells. The initial results in malignant hematological diseases demonstrate the viability of this approach, with a potential for low risk of graft versus chronic host disease and recurrence.27 An ongoing study (NCT03913026) is evaluating the use of UM171 expanded umbilical cord cells in patients with acute high-risk leukemia / myelodysplasia. In a UM171 pilot study (NCT02668315), among 22 patients who received a single UM171 cell bank transplant, the GVHD rate (10%) was low, without moderate to severe chronic GVHD.27 If methods such as UM171 enter clinical practice, there may be an increase in the number of patients who undergo transplants and, therefore, in the associated costs – both for new technology and for the transplant procedure and post-transplant care.
Another possible cell therapy on the horizon for AML is chimeric antigen receptor (CAR-T) T cell therapy. So far, approved CAR-T products are used in malignant B-cell diseases, which lend themselves to this approach because they express antigens that are unique to the B-cell lineage. Myeloid cancers, on the other hand, tend to to express tumor antigens that are also found in several healthy cells, including hematopoietic stem cells or progenitor cells, making it a challenge to design CAR-T therapy for AML.28 Depletion of stem cells by CAR-T cell therapy would cause prolonged myeloablation, with consequences such as infection and transfusion dependence. Despite these significant challenges, there are ongoing efforts to develop CAR-T treatments for AML RR, with ten clinical trials underway identified in a survey by clinictrials.gov on January 31, 2021 (table 1)
table 1 On-going trials of CAR-T therapies in AML
If experimental cell therapies, such as those described in table 1 show efficacy with acceptable safety profiles in the LMA, they would probably come at a very high cost. CAR-T therapies currently available range in the range of $ 375,000 to $ 475,000 for a single infusion, in addition to medical costs and treatment of complications.29 If a large number of AML patients were considered candidates for cell therapy, there could be a significant impact on the overall cost burden of AML. There are, however, substantial restrictions to the payer on the coverage of currently available CAR-T therapies. The real cost impact, therefore, may be less if only a small fraction of AML patients are able to access treatment.
The high cost of CAR-T therapies can be outweighed by their benefits if these approaches are considered to be economical over other options. Our systematic review of the literature did not identify any cost-effectiveness analysis for CAR-T treatments in AML. CAR-T therapy was considered cost-effective, with an incremental cost-effectiveness ratio (ICER) of $ 64,600 / year of life adjusted for quality (QALY), in a micro-simulation model of pediatric acute lymphoblastic leukemia (ALL) ).30 The authors of the pediatric ALL analysis note that long-term efficacy data for CAR-T may alter their findings, and it is not clear whether comparable findings would apply in adults with AML.
Cost drivers in the transition: drug costs
Conventional AML chemotherapy uses generic drugs extensively, so the primary costs are in the administration and management of toxicity, rather than the direct costs of the drugs. The large number of new AML therapies approved in recent years stems in large part from the explosion in the search for abnormal genetic pathways in cancer cells and how to interrupt these pathways.18 Adapting therapies to specific biological pathways helps to get the right treatment for the right patient, but it also requires the genetic profile of a patient’s cancer cells to inform treatment decisions. The increased demand for genetic testing is likely to contribute to the economic burden of AML.
The impact of new AML drugs on costs would be better assessed by looking at treatment patterns. Although the currently published treatment pattern studies are largely based on data prior to the availability of new drugs in 2017, the new therapies are now fully integrated with prominent treatment guidelines, such as the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines . NCCN guidelines include HF regimens that use brand new therapies, such as gemtuzumab ozogamycin, midostaurin, venetoclax and CPX-351, along with conventional chemotherapy options.6 For NIC induction therapy, the NCCN guidelines include a variety of brand new therapies, such as venetoclax, glasdegibe, gemtuzumab ozogamycin, ivosidenib and enasidenib. The guidelines also include most new agents as options for post-remission or maintenance therapy, as well as for R / R AML, with specific recommendations based on the patient’s fitness, biological factors and previous therapies.
These new targeted therapies, with more on the horizon, offer many potential benefits in terms of efficacy, safety, ease of administration and reduced hospital time, but like branded drugs and combinations, they tend to substantially increase spending on drugs in AML, for both patients and payers. In the United States, patients with private insurance may face substantial co-payments for self-administered medications, and those on Medicare may have access challenges, as they may be required to justify branded therapies rather than established generic options.
In the coming years, the costs of genetic testing and new therapies are likely to rise as more targeted therapies become available. In January 2021, there were 621 Phase 1 to Phase 3 AML intervention studies registered at ClinicalTrials.gov, more than 450 of which are Phase 2 or Phase 3. Among the ongoing studies, 99 evaluate biological treatments, 25 are transplant studies, and the remaining 496 are evaluating drug treatments and combinations. Although many of these studies involve new combinations of existing drugs, the innovative pipeline is strong. table 2 it presents studies of phase 2 or phase 3 in progress of treatments directed to subgroups of patients or specific biologically or genetically defined molecular pathways.
table 2 Phase 2 and Phase 3 trials underway for therapies targeting patient subgroups or biologically or genetically defined molecular pathways in AML
Cost drivers in the transition: Use of AML treatment
The three main cost drivers discussed in this review – hospitalization / medical costs, HSCT / cell therapies and drug costs – are related to how advances in AML treatment can impact the treatment costs of an AML patient. The final category refers to how the evolution of AML treatment can impact the general economic burden of AML, making high-cost treatment a possibility for a greater proportion of AML patients.
Despite the availability of CIN options, a recent literature review found that up to a third of patients in the US and Europe receive only the best supportive care for AML, with advanced age, comorbidities and poor performance as major factors in deciding not to to administer active treatment.31 There is, however, an increasing tendency to use broader criteria to assess suitability for treatment: NCCN guidelines refer to “physiological age” rather than chronological age, to avoid declining treatment for elderly patients who are likely to tolerate and benefit from treatment.32
New treatment options may increase the likelihood that doctors will offer anti-cancer treatment to older patients. Glasdegib and venetoclax, for example, are specifically approved for use in elderly or disabled patients, based on essential studies in these populations.33,34 CPX-351 was approved without age restriction after a fundamental study that demonstrated superior efficacy and safety comparable to conventional cytarabine + daunorubicin in patients aged 60 to 75 years.19 With increased awareness of physiology over chronological age, expanded options for targeted therapy with manageable safety profiles and improved strategies for managing adverse treatment effects, the proportion of patients treated is likely to increase, leading to costs higher overall rates in AML.
As noted above, the NCCN guidelines include a variety of options for maintenance therapy in AML. The increasing role of maintenance therapy in AML is likely to increase the overall number of patients receiving treatment, since patients would continue to be treated instead of waiting for relapse before starting treatment again. Cytarabine IV and daunorubicin regimens with or without gemtuzumab ozogamycin are recommended by the NCCN for patients under 60 years of age who are eligible for intensive chemotherapy.32 The EMA, but not the FDA, approved oral midostaurine as maintenance therapy based on its phase 3 study (RATIFY; NCT00651261), which included the use of midostaurine in the induction, consolidation and maintenance settings (with progressively fewer patients completing each treatment stage).35 Maintenance with hypomethylating agents, azacitidine IV or oral and decitabine IV, has also demonstrated efficacy and is recommended by NCCN guidelines.6,36,37 With increasingly effective treatments, maintenance therapy can be long-lasting: in the phase 3 oral azacitidine trial, 71% of patients remained on therapy for at least 6 months, while 49% were exposed for more than 1 year.37
Likewise, there has been an expansion in the number of options for R / R AML, with the NCCN guidelines for R / R AML including oral therapies such as gilteritinib, enasidenib, ivosidenib and venetoclax, and other treatments, such as gemtuzumab ozogamycin.6 These new therapies have generally controllable toxicity profiles, making treatment for R / R AML a viable option for a broader set of patients.
It is likely that there will be even more options for maintenance and R / R therapy at AML in the coming years. In January 2021, there were 14 ongoing studies registered with ClinicalTrials.gov investigating new therapies targeted as maintenance. In addition, among the 621 intervention studies underway in AML, 171 were specifically in the R / R population; of these, 46 were phase 2 or phase 3 studies with primary school completion dates ranging from 2020 to 2029. Table 3 presents a selection of studies on R / R AML that are expected to have primary results by 2023. With the number of existing and future treatment options for R / R disease and maintenance therapy, patients could probably stay on therapy for several years, effectively converting AML to a disease that can be treated chronically. Such a scenario would have important implications in terms of the typical patient journey and associated costs.
Table 3 Phase 2 and Phase 3 studies underway notable in LMA RR with primary results expected by 2023
Finally, with the increase in life expectancy, there was a modest increase in the incidence of AML, from 3.4 per 100,000 people in the U.S. in 1975 to 4.3 per 100,000 in 2017.two Thus, the general population of AML patients has grown, contributing to the cumulative economic impact.
Opportunities to add value in AML
The rapid evolution of treatment options for AML leaves patients and doctors with notably more decisions than in the past, while presenting payers with more costs and compensation to consider. Where the route of treatment for AML previously depended on age and fitness, it must now begin with the genetic profile followed by consideration of a variety of conventional and new regimens based on the patient’s factors and preferences. Patients may choose to undergo induction therapy followed by HSCT, or perhaps their initial therapy may induce a response sufficient to allow a direct transition to maintenance therapy. Those who undergo HSCT may need less time in the hospital for the procedure, as the methods have improved, or may, in the near future, undergo alternative forms of stem cell transplantation or cell therapies. Patients who eventually develop R / R disease may consider a variety of targeted options, many of which can be self-administered at home. As the number of drugs with different mechanisms increases, there may be an opportunity to sequence treatments in AML, as patients experience long-term survival, even in the absence of a cure. These potential survival gains and clinical benefits will require investment by payers, and it will be up to those who develop new treatments to demonstrate economic value with compelling evidence.
Historically, hospitalization has been a major driver of costs at LMA. While some evolving treatments, such as stem cell transplants and cell therapies, include substantial hospital or medical costs, the main driver of costs in AML over the next decade is likely to be the rapid acceptance of a variety of new targeted therapies. The use of these therapies at various stages of treatment – recent diagnosis, maintenance and R / R – will extend the time that patients can remain on treatment. With the survival gains, there will be increases in the general cost burden of the LMA. O panorama da LMA pode se desenvolver de maneira semelhante ao que tem sido observado nos últimos anos no mieloma múltiplo, onde um “deserto” de tratamento se transformou ao longo de duas décadas em uma oportunidade de sequenciar pacientes por meio de várias linhas de terapia, mantendo a qualidade de vida.
Uma oportunidade de agregar valor ao tratamento de LMA é o uso de terapias orais e outras terapias autoadministradas e manter os pacientes em regime de ambulatório, quando viável. Embora essas abordagens provavelmente reduzam os custos para os pagadores, elas podem transferir uma carga maior de custos para os pacientes, especialmente nos Estados Unidos, onde novos medicamentos orais incorrem em copagamentos substanciais. A idade avançada do paciente típico com LMA significa que é improvável que ele tenha um emprego e pode ser incapaz de cobrir esses custos.
Os pacientes que recebem terapia ambulatorial anticâncer ainda requerem recursos de saúde substanciais devido aos perfis de toxicidade da maioria dos tratamentos disponíveis. Os regimes ambulatoriais como glasdegib + LDAC ou venetoclax + azacitidina são mielossupressores e os pacientes podem necessitar de transfusões e outras medidas de suporte.33,34 Portanto, outra forma de agregar valor ao tratamento da LMA é desenvolver tratamentos e regimes com perfis de segurança aprimorados, com o objetivo de reduzir os gastos com monitoramento e tratamento de eventos adversos. O direcionamento de tratamentos com base em fatores biológicos, embora exija investimento em testes moleculares, pode ajudar a concentrar os gastos em tratamentos com maior probabilidade de serem eficazes.
Apesar das oportunidades para compensações de custos com terapias inovadoras, seria ingênuo sugerir que novas terapias para AML acabarão por reduzir os custos de saúde. O valor da maioria dos tratamentos contra o câncer reside na oportunidade de prolongar a sobrevida enquanto mantém a qualidade de vida. Ao realizar uma avaliação holística de custo-benefício dos tratamentos de LMA, deve-se considerar se os custos se traduzem em resultados mensuráveis, como aumento da sobrevida, diminuição da carga de sintomas, redução da necessidade de tratamento de emergência e internação e diminuição da pressão sobre os cuidadores. Tal avaliação de valor pode ser usada para determinar os custos apropriados de terapias inovadoras.
AML é um câncer relativamente raro, mas caro, atualmente caracterizado por tratamentos intensivos de alto custo que muitas vezes requerem hospitalização, ao lado de uma fração substancial de pacientes que recebem pouco ou nenhum tratamento anticâncer devido à idade ou desempenho. Nos últimos anos, assistimos a um aumento dramático no número de opções de tratamento e há pesquisas em andamento para expandir ainda mais o cenário terapêutico na LMA. Embora certos avanços, como o aumento do uso de terapias orais e ambulatoriais, possam reduzir os custos, o impacto econômico geral da LMA tende a aumentar à medida que mais pacientes são elegíveis para novas terapias em várias fases, desde a indução até a manutenção da doença R / R. Essas novas terapias têm o potencial de agregar valor na forma de maior eficácia, segurança e conveniência. Nos próximos anos, as avaliações de valor formarão a base para as negociações de preços, à medida que os pagadores determinam como cobrir uma via de tratamento mais longa e complexa na LMA.
KS e AF são funcionários da Purple Squirrel Economics, uma empresa da Cytel, que atua como consultora para vários clientes farmacêuticos. Os autores não relatam outros conflitos de interesse neste trabalho.
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