Uso racional de medicamentos antineoplásicos e ações judiciais no Estado de São Paulo Rational use of anticancer drugs and patient lawsuits in the state of São Paulo , Southeastern Brazil

MÉTODOS: Estudo descritivo, transversal, baseado em informações da Secretaria de Saúde sobre os medicamentos antineoplásicos solicitados por via judicial, com maior impacto fi nanceiro para o Sistema Único de Saúde em 2006 e 2007. Os fármacos foram avaliados quanto às evidências clínicas de efi cácia e segurança, com base na classifi cação do Micromedex®, em metanálises e revisões sistemáticas. As indicações foram confrontadas com aquelas aprovadas em agências reguladoras.

The Sistema Único de Saúde (SUS -Brazilian National Healthcare System) provides full and comprehensive healthcare to Brazilian citizens, including pharmaceutical services.a However, regardless of the fact that full and comprehensive mean high, mid, and low complexity medical assistance, many different interpretations of the term insist in understanding comprehensiveness as any and all kinds of known therapies, available or not under SUS.This results in distortions in terms of the strategies of access to technologies, among which access to medication. 13 Brazil, management problems concerning pharmaceutical services are common in the three branches of government.This combined with the constant pressure infl icted by the incorporation of new technologies under SUS, have resulted in an increase of court decisions ordering the supply of certain medicines.These lawsuits fi led against the State have become an alternative means of having access to medication within SUS. 9 On the other hand, the cost of complying with these court decisions is not budgeted for, thus consuming considerable resources from other areas of the budget and making it diffi cult to ensure the purchase of other medicines which are provided for under statute and agreed to by Inter-management Commissions.b,c On many occasions the medicines under the scope of these lawsuits are not considered essential according to the National Medicines Policy, nor have they had their safety and effi cacy proven.d Across the country, according to information from the Ministry of Health, the amounts spent with lawsuits in 2007 were over 500 million Brazilian reais in the federal, state and local administrations.e In the Ministry of Health alone the amount spent yearly went from R$ 188 thousand in 2003, a to R$ 52 million in 2008.f In the state of Paraná, southern region, between 2002 and 2007, the amount spent with lawsuits increased from R$ 200 thousand to R$ 14 million.g

INTRODUCTION
These lawsuits have been on the media, above all in terms of the amount spent by the State and Local Health Departments and the Ministry of Health with the acquisition of medication.The unrestricted supply of medication through legal suits privileges segments of health service users with more fi nancial resources to pay for attorney's fees, or that have more access to information, in detriment of the needy segment of the population. 4In this context, the public health management has required consistent information on the benefi ts of new technologies and the fi nancial repercussions on the public arena, with the goal of fostering new health policies and effective decision-making. 3e fi eld of oncology has a large demand for this, due to its high cost and use of sophisticated technology.h In the city of São Paulo, Southeastern Brazil, in 2005, the number of lawsuits to obtain anticancer medicines accounted for 7.2% of the total number of items sought after through legal suits, resulting in expenses of R$ 661 thousand, representing 75% of the total expenses with medication obtained through court orders. 12erefore, the objective of this study was to assess the rationality of lawsuits aimed at obtaining anticancer drugs, considering the scientifi c evidence based on effi cacy and safety of these medicines.In addition, the cost of supplying these drugs in cases not grounded on the scientifi c literature was also estimated in order to contribute to a pharmaceutical services model for oncology in SUS.

METHODS
A cross-sectional study was carried out.The unit of analysis was the State of São Paulo, Southeastern Brazil, and the object lawsuits aimed at obtaining anticancer drugs.The Secretaria Estadual de Saúde de São Paulo (SES-SP -State Health Department of the State of São Paulo) was asked to point out the seven anticancer drugs most sought after through legal suits with the highest fi nancial impact on SUS.The sample of lawsuits was built based on the drugs on the SES-SP list.These drugs are indicated for the treatment of several types of cancer and are part of the anticancer therapy aimed at specifi c molecular targets, thus representing a new approach to the treatment of cancer. 5In addition to the lawsuits, administrative requests -formal requests of medications patients were not able to obtain at SUS units to the government entity -containing the drugs scope of this study, according to the entries in the Sistema de Controle Jurídico (Court Control System) of the SES-SP.The study variables were: clinical indication, prescribing physician, attorney and origin of case.
To estimate the cost of acquiring these medications, the amount purchased during the period of study and the price paid were calculated based on the Banco das Atas de Registro de Preços (Price Registration Minutes Database) of the SES/SP.Therapeutic indications expressed in the legal claims were compared to the evidence supplied by the medical literature in PubMed, LILACS, SciELO, and Cochrane BVS, in the form of systematic reviews and metaanalyses.Papers were selected if they assessed at least one of the seven drugs studied, for any therapeutic indication, in which the intervention was compared to another treatment or to placebo.Forty meta-analyses and 38 systematic reviews, published until July 2008, were selected.The fi ndings of these studies coincide with the evidence described in Thomson Micromedex ® .
The data on the approval of the drugs were obtained with regulatory agencies, such as the Agência Nacional de Vigilância Sanitária (Anvisa -National Sanitary Surveillance Agency), the Food and Drug Administration (FDA), and the European Medicines Agency (EMEA), thus enabling the clinical indication expressed on the legal claims to be compared to the ones approved by the regulatory agencies.
The data on the lawsuits were obtained from an SES-SP software called Court Control System.Data confidentiality was ensured concerning the identity of all the individuals identifi ed during the study.This study was approved by the Ethics in Research Committee of the Universidade de Sorocaba on December 20, 2007 (Document 052/2007).
Table 1 shows the number of lawsuits fi led against the SES-SP between 2006 and 2007, the total cost and the average cost per lawsuit.The total amount spent by the Department with these seven drugs was 120% higher in 2007 than in 2006.This increase is explained by the one in the number of requests.In some cases, despite the increase in the number of requests, the average amount spent decreased (capecitabine, cetuximab, rituximab).On the other hand, the average amount spent per imatinib request almost increased fi ve-fold.
Table 2 shows the characteristics of the administrative requests and legal suits.With some exceptions resulting from the incorporation of medications by the SES-SP, the requests are mostly made via the courts.A share of the lawsuits originated from prescriptions made by SUS professionals not complying with the protocols in force.The origin of the requests was concentrated in nine prescribing physician and seven lawyers.One single physician was responsible for almost 40% of erlotinib prescriptions and one single lawyer was responsible for 70% of the lawsuits requesting cetuximab.
Prescriptions written by fi ve physicians cost R$ 7 million in two years.Five attorneys responsible for most of the lawsuits fi led against the SES-SP cost almost R$ 16 million.Table 3 shows the itemized amounts per prescribing physician and attorneys.
Each of the drugs studied has been employed in several therapeutic indications, some of which have not been approved by the consulted regulatory agencies.Out of the 16 indications for bevacizumab, two met the criteria of evidence and degree of recommendation considered acceptable.About 30% of the requests were related to other kinds of cancer, for which there is no evidence that support its indication.capecitabine was used for treating colorectal cancer in 30% (in 2006) and 40% (in 2007) according to the lawsuits and the administrative requests fi led against the SES/SP.Requests for capecitabine to treat breast cancer dropped from 46.2% (2006) to 28.1% (2007), whereas off-label indications (indications not approved by regulatory agencies) have been increasing (23.0% of the requests in 2006 and 31.2% in 2007 contained other indications, such as, pancreatic cancer, for which there is not a single registration in any of the consulted regulatory agencies).
More than 80% of the legal suits and administrative requests for cetuximab required the drug for colorectal cancer treatment.Despite metastatic colorectal cancer treatment benefi ting from the EGFR-receptor inhibitors, and the indication having been approved by the FDA and by EMEA, 7 in Brazil the indication still has not been approved.Cetuximab indication for treating head and neck cancer, squamous cells, locally or regionally advanced cancer, in combination with radiotherapy is the only indication for the product in Brazil with evidence for use.However, less than 5% of the administrative requests and lawsuits requesting the drug were related to types of head and/or neck cancer.On the other hand, the use of the drug in unapproved indications by the regulatory agencies consulted was around 14% in 2006 and 10% in 2007.
Erlotinib indication for pancreatic cancer, although not approved by Anvisa, has been approved by the FDA and the EMEA, in addition to there being defi ned benefi t for locally advanced or metastatic pancreatic cancer, as fi rst-line therapy, in combination with gencitabine.About 12% in 2006 and 6% in 2007 of the administrative requests and legal suits were related to some kind of pancreatic cancer.The use of erlotinib in indications not yet approved by the consulted regulatory agencies was under 5% in 2006 and 2007.
Approximately 86% of the administrative requests and lawsuits seeking imatinib were related to chronic myeloid leukemia (CML).There is defi ned benefi t for the use in Philadelphia chromosome-positive CML recently diagnosed or after failed therapy using alpha interferon, which is one of the indications approved by Anvisa, the FDA, and the EMEA. 7Imatinib indications not supported by evidence of effi cacy or safety increased from 10.4% (2006) to 14.4% (2007).
In 2006, rituximab was the aim of about 90%of the court and administrative requests and, in 2007, 75% corresponded to indications for non-Hodgkin's treatment.Although Rituximab has been approved by the three regulatory agencies for the treatment of rheumatoid arthritis (moderate to severe, in combination with methotrexate in patients responding inadequately to other therapies with TNF antagonists), the indication is not grounded on evidence in the literature in order for it to be incorporated to class IIb (recommended for some cases, but not for the majority of cases).There was an increase in the number of administrative requests and lawsuits aimed at obtaining this drug for this indication, from 1 The fi ndings show that part of the lawsuits and administrative requests lack scientifi c grounds supporting the effective and, above all, safe use of anticancer drugs on patients.
Table 4 shows the clinical indication of the seven anticancer drugs object of this study with levels of evidence (A and B) and degree of recommendation (classes I and IIa) and their respective approvals by the Anvisa, the FDA, and the EMEA.Some indications approved by other regulatory agencies have not been approved in Brazil and, nevertheless, there are lawsuits and administrative requests for such uses.
The assessment of the rates of lawsuits and administrative requests fi led by patients to obtain anticancer drugs for indications that lack clinical evidence account for the inappropriate amount of R$ 6,870,926.83 in expenses to the SES-SP.Bevacizumab (59.5%) and rituximab (31%) were the drugs with use not based on clinical evidence with the highest request rate during the period of study (Table 5).

DISCUSSION
The seven drugs addressed in this study were selected by the SES-SP, according to the following criteria: cost    Findings show that patient lawsuits to obtain the anticancer drugs examined in this study are prescribed by a small number of physicians and fi led by a small number of lawyers.This fi nding suffi ces to justify auditing the prescriptions, prescribing physicians and lawyers, so as to identify their direct and indirect relations with the pharmaceutical industry.
Several studies point out the infl uences prescribing physicians suffer in order to decide on possible therapeutic alternatives: concepts on the health-disease process; quality of education, sociocultural and economical conditions of the population they treat; availability of the drugs in the service for which they work; access to information, requirements by the pharmaceutical industry, among others 1,2,10 In addition, a number of Brazilian organizations defending the rights of healthcare service users are funded by the pharmaceutical industry aiming at having the drugs they manufactured included under the SUS list.An entity representing lymphoma and leukemia patients headquartered in São Paulo, received R$ 1,5 million from eight multinational companies in 2007.k The pharmaceutical industry is widely known for providing funding for scientifi c research across all areas of Medicine.This is a necessary and invaluable alliance.However, studies funded by pharmaceutical companies have a higher probability of reporting fi ndings that favor their products when compared to independent studies.Friedberg et al 6 (1999) found unfavorable results in 5% of the studies funded by pharmaceutical companies manufacturing drugs for oncology; whereas, in independent studies this rate was 38%.The clinical use of a drug in different indications from those to which the literature has provided evidence of effi cacy and safety is not recommended.Among the consequences is the possibility of employing a therapy of uncertain effi cacy, with signifi cant adverse effects, and the burdening of SUS.Moreover, to register a new indication with the regulatory agencies, the pharmaceutical company must provide evidence, through strict clinical trials, of effi cacy and safety of the drug in regard to a certain condition.Supplying medication for nonformulary indication by means of court orders means placing an undue burden on SUS to fund studies that should be funded by the innovating manufacturer.
The fi nding that approximately 17% of the lawsuits and administrative requests were not based on evidence of the indications informed in the proceedings amounts to inappropriate spending of at least R$ 6.8 million during the study period.The limitations of this study in terms of the imprecise diagnosis provided in the prescription -instead of supplying the International Classifi cation of Diseases -underestimates the rate of requested non-evidence based clinical indications, because the strength of the recommendation of use is specifi c to each condition.Therefore, the amount spent by the SES-SP in supplying medication for which there is no scientifi c evidence of effi cacy and safety may be much higher than the amount estimated in this study.
Well-planned health policies result in effective actions to promote health and prevent health conditions, thus being translated as preventive medicine.In contrast, in curative medicine, medicines play an overly important role in healthcare. 8,11Moreover, considering an equitable distribution of resources, which is one of the most complex dilemmas faced by SUS, there is an obvious need of technical expertise to deal with patient lawsuits.Therefore, this requires capacity building to enable appropriately selecting the drugs used in therapies and choosing the best therapeutic action for a certain clinical condition.m Providing sound information on the use of medication and clinical data on the actual condition of the patient are essential to assessing the request and orders determining SUS to provide certain medicines to patients.Establishing clinical protocols for the use of immunobiologicals, that have limited indications and pose high risks, could rationalize the use of these drugs, thus contributing to improved pharmaceutical services for oncology in SUS.

ACKNOWLEDGEMENT
To the State Health Department for supplying the data.

Table 1 .
Number of administrative requests and lawsuits fi led by patients to obtain anticancer drugs and corresponding cost to the State Health Secretariat.State of São Paulo, Southeastern Brazil, 2006-2007.

Table 2 .
Characterization of administrative requests and lawsuits according to type of claim, origin of request, main prescribing physicians and legal representatives.State of São Paulo, Southeastern Brazil, 2006-2007.Variable

Table 3 .
Expenditure with prescribed medication in relation to t o prescribing physician and lawsuit.State of São Paulo, Southeastern Brazil, 2006-2007.

Table 4 .
Clinical indication (classifi ed under levels of evidence A and B and degrees of recommendation I and IIa) and respective approval by regulatory agencies.State of São Paulo, Southeastern Brazil, 2006-2007.2006 and 2007.In another biennium the requested drugs will probably be different, because the process is dynamic and needs change, thus constantly requiring new assessments.The results do not enable an accurate assessment of the economic impact of the drugs on the SES-SP, because information was not provided on the amount spent with medication and with compliance to court orders in the State of São Paulo during 2006 and 2007.
Anvisa: National Sanitary Surveillance Agency; FDA: Food and Drug Administration; EMEA: European Medicines Agency.NA: Not available and demand in

Table 5 .
State expenditure with lawsuits and administrative requests without substantiated clinical evidence.State of São Paulo, Southeastern Brazil, 2006-2007.Critical assessment of the literature determines the quality, strength and boundaries of clinical evidence.In this way, public policies that actually contribute to the rationalization of the use of medical technologies could be drafted, based on good quality scientifi c data.