Novel thalidomide analogues, “me too” drugs and the Brazilian law / Novos análogos da talidomida, medicamentos “me too” e a lei brasileira

In Brazil, thalidomide has been used virtually without interruption since it was launched as a new and revolutionary sedative drug in 1956. After 1965, when its effi cacy to treat erythema nodosum leprosum (ENL) was discovered, it was regarded as an essential drug because the prevalence of Hansen’s disease is high in the country. In the 1990s and thereafter myriad novel therapeutic uses for thalidomide (autoimmmune diseases, multiple myeloma, aphthous ulcers in AIDS, and others) have emerged owing to its immunomodulatory and antiangiogenic activities. Owing to a marked teratogenicity, however, the prescription and dispensing of thalidomide to patients is strictly controlled in Brazil and elsewhere. Notwithstanding the stringent regulations, a number of post-1965 cases of thalidomide embryopathy have occurred in Brazil. In 2003, a federal law (Law 10.651/2003) prohibited the sale and dispensing of thalidomide in commercial pharmacies. The law, however, made no provision for teratogenic drug analogues such as lenalidomide and pomalidomide, which have been cleared for marketing in the USA, Europe and other countries. Although they are much more expensive than thalidomide, the clinical superiority of novel ana-logues over thalidomide in multiple myeloma and other conditions remains unproven. Therefore, so far novel analogues can be considered as thalidomide “me too” drugs. This author strongly recommends that an amendment to the current law prohibiting the sale and dispensing of thalid-omide in commercial pharmacies be extended to thalidomide analogues. Moreover, we consider that a demonstration of clinical superiority over thalidomide (through gold-standard comparative effi cacy trials) should be an essential requirement for registration of any teratogenic analogue. ---------------------------No Brasil, a talidomida tem sido usada praticamente sem interrupção desde o seu lançamento como novo e revolucionário medicamento sedativo em 1956. Depois de 1965, quando a sua efi cácia para tratar o eritema nodoso (ENL) foi descoberta ela tem sido considerada como medi-camento essencial porque a prevalência da hanseníase é alta no país. Nos anos 1990 e depois, surgiu uma diversidade de novos usos terapêuticos para a talidomida (doenças auto-imunes, mieloma múltiplo, ulcerações aftosas na AIDS, e outras) em virtude das suas atividades anti-infl ammatórias e anti-angiogênicas. Por causa da teratogenicidade, a prescrição e dispensação da talidomida são rigorosamente controladas no Brasil e outros países. Em que pese o rigor da regulamentação, muitos casos de embriopatia pela talidomida ocorreram no Brasil após 1965. Em 2003, uma lei federal (Lei 10.651/2003) proibiu a venda e a dispensação de talidomida em farmácias comerciais. A lei, entretanto, não faz referência aos análogos teratogênicos tais como lenalidomida e pomalidomida cuja comercialização foi autorizada nos EUA, Europa e outros países. Embora sendo muito mais caros que a talidomida, a superioridade clínica dos novos análogos em relação à talidomida no mieloma múltiplo e outras doenças não foi demonstrada. Portanto, até agora os novos análogos podem ser considerados como medicamentos “me too”. Recomenda-se enfaticamente uma emenda à lei atual que estenda a proibição da venda e dispensação em farmácias comerciais aos análogos da talidomida. Deve-se exigir também a demonstração de superioridade clínica em comparação com a talidomida (por meio de ensaios clínicos comparativos de padrão ouro) para registro de qualquer análogo teratogênico

Pharmaceutical lobbying in Brazil: a missing topic in the public health research agenda

In the US, where registration of lobbyists is mandatory, the pharmaceutical industry and private health-care providers spend huge amounts of money seeking to influence health policies and government decisions. In Brazil, where lobbying lacks transparency, there is virtually no data on drug industry expenditure to persuade legislators and government officials of their viewpoints and to influence decision-making according to commercial interests. Since 1990, however, the Associação da Indústria Farmacêutica de Pesquisa (Interfarma – Pharmaceutical Research Industry Association), Brazilian counterpart of the Pharmaceutical Research and Manufacturers of America (PhRMA), main lobbying organization of the US pharmaceutical industry, has played a major role in the advocacy of interests of major drug companies. The main goals of Interfarma lobbying activities are: shortening the average time taken by the Brazilian regulatory agency (ANVISA) to approve marketing authorization for a new drug; making the criteria for incorporation of new drugs into SUS (Brazilian Unified Health System) more flexible and speeding up technology incorporation; changing the Country’s ethical clearance system and the ethical requirements for clinical trials to meet the need of the innovative drug industry, and establishing a National Policy for Rare Diseases that allows a prompt incorporation of orphan drugs into SUS. Although lobbying affects community health and well-being, this topic is not in the public health research agenda. The impacts of pharmaceutical lobbying on health policies and health-care costs are of great importance for SUS and deserve to be investigated

To be or not to be a carcinogen; delving into the glyphosate classification controversy

The International Agency for Research on Cancer (IARC) placed the most widely used herbicide glyphosate (GLY) into the category 2A (probably carcinogenic to humans), a classification questioned by experts from academia and industry. This article critically appraised the epidemiological and experimental data that led the IARC working group (WG) to consider GLY a probable human carcinogen and the ensuing controversy. An association of GLY with non-Hodgkin lymphoma was suggested by some observational studies. A non-causal explanation for this weak association, however, cannot be excluded. Contrary to WG’s view, long-term rodent assays yielded no convincing evidence that GLY is carcinogenic. The mechanistic evidence remains elusive as well. Bacterial reverse mutation tests (including tester strains sensitive to oxidative mutagens) were clearly negative, and so were rodent genotoxicity assays by oral route. Tests with mammalian cells in vitro yielded conflicting results at high (cytotoxic) concentrations of GLY-based formulations. Conflicting results were also obtained when high doses of GLY-based herbicides were administered to rodents by the intraperitoneal route. Such high doses are unlikely to be attained in realistic scenarios of exposure. Finally, the IARC classification is based on a conjectural hazard, and rational public health interventions must be based on estimated risks

Beneficios de los inhibidores de apetito en la salud a largo plazo permanecen sin comprobación

El aumento de la prevalencia de la obesidad ha convertido la prevención y tratamiento del sobrepeso importante desafío para la Salud Pública. Aunado a la dieta y ejercicio, los medicamentos son necesarios para pacientes que no logran perder peso con los cambios de comportamiento. El objetivo del artículo fue englobar las preocupaciones actuales con la seguridad y la efectividad de medicamentos inhibidores del apetito. Varios anorexígenos fueron eliminados por razones de seguridad. En 2010, la sibutramina fue retirada del mercado porque un estudio de larga duración demostró que ésta aumentaba el riesgo de eventos cardiovasculares. Hasta ahora ningún estudio con número considerable de pacientes demostró que anorexígenos reducen la morbi-mortalidad asociada al sobrepeso. La retirada de sibutramina del mercado muestra que directrices para evaluación de medicamentos anorexígenos deben ser más rigurosas, y que estudios de larga duración sobre los beneficios para la salud deben ser realizados antes de la comercialización.O aumento da prevalência da obesidade tornou a prevenção e tratamento do sobrepeso importante desafio para a Saúde Pública. Além da dieta e exercício, os medicamentos são necessários para pacientes que não conseguem perder peso com as mudanças comportamentais. O objetivo do artigo foi sumarizar as preocupações atuais com a segurança e efetividade de medicamentos inibidores do apetite. Vários anorexígenos foram banidos por razões de segurança. Em 2010, a sibutramina foi retirada do mercado porque um estudo de longa duração mostrou que ela aumentava o risco de eventos cardiovasculares. Até agora nenhum estudo com número expressivo de pacientes demonstrou que anorexígenos reduzem a morbi-mortalidade associada ao sobrepeso. A retirada da sibutramina do mercado mostra que diretrizes para avaliação de medicamentos anorexígenos devem ser mais rigorosas, e que estudos de longa duração sobre os benefícios para a saúde devem ser realizados antes da comercialização.Because of the increasing prevalence of obesity, prevention and treatment of overweight has become a major public health concern. In addition to diet and exercise, drugs are needed for patients who failed to lose weight with behavioral treatment. The current article aimed to summarize recent concerns on the safety and efficacy of appetite suppressants. Several appetite suppressants have been banned for safety reasons. In 2010, sibutramine was withdrawn from the market because a long-term study showed it increased the risks of cardiovascular events. So far no study with a sufficiently large sample size has demonstrated that appetite suppressants can reduce morbidity and mortality associated with overweight. The withdrawal of sibutramine highlights that guidelines for the evaluation of weight control drugs must be more stringent, and studies on their long-term health benefits are needed prior to their marketing

Novel thalidomide analogues, “me too” drugs and the Brazilian law

In Brazil, thalidomide has been used virtually without interruption since it was launched as a new and revolutionary sedative drug in 1956. After 1965, when its efficacy to treat erythema nodosum leprosum (ENL) was discovered, it was regarded as an essential drug because the prevalence of Hansen’s disease is high in the country. In the 1990s and thereafter myriad novel therapeutic uses for thalidomide (autoimmmune diseases, multiple myeloma, aphthous ulcers in AIDS, and others) have emerged owing to its immunomodulatory and antiangiogenic activities. Owing to a marked teratogenicity, however, the prescription and dispensing of thalidomide to patients is strictly controlled in Brazil and elsewhere. Notwithstanding the stringent regulations, a number of post-1965 cases of thalidomide embryopathy have occurred in Brazil. In 2003, a federal law (Law 10.651/2003) prohibited the sale and dispensing of thalidomide in commercial pharmacies. The law, however, made no provision for teratogenic drug analogues such as lenalidomide and pomalidomide, which have been cleared for marketing in the USA, Europe and other countries. Although they are much more expensive than thalidomide, the clinical superiority of novel ana-logues over thalidomide in multiple myeloma and other conditions remains unproven. Therefore, so far novel analogues can be considered as thalidomide “me too” drugs. This author strongly recommends that an amendment to the current law prohibiting the sale and dispensing of thalid-omide in commercial pharmacies be extended to thalidomide analogues. Moreover, we consider that a demonstration of clinical superiority over thalidomide (through gold-standard comparative efficacy trials) should be an essential requirement for registration of any teratogenic analogue.In Brazil, thalidomide has been used virtually without interruption since it was launched as a new and revolutionary sedative drug in 1956. After 1965, when its efficacy to treat erythema nodosum leprosum (ENL) was discovered, it was regarded as an essential drug because the prevalence of Hansen’s disease is high in the country. In the 1990s and thereafter myriad novel therapeutic uses for thalidomide (autoimmmune diseases, multiple myeloma, aphthous ulcers in AIDS, and others) have emerged owing to its immunomodulatory and antiangiogenic activities. Owing to a marked teratogenicity, however, the prescription and dispensing of thalidomide to patients is strictly controlled in Brazil and elsewhere. Notwithstanding the stringent regulations, a number of post-1965 cases of thalidomide embryopathy have occurred in Brazil. In 2003, a federal law (Law 10.651/2003) prohibited the sale and dispensing of thalidomide in commercial pharmacies. The law, however, made no provision for teratogenic drug analogues such as lenalidomide and pomalidomide, which have been cleared for marketing in the USA, Europe and other countries. Although they are much more expensive than thalidomide, the clinical superiority of novel ana-logues over thalidomide in multiple myeloma and other conditions remains unproven. Therefore, so far novel analogues can be considered as thalidomide “me too” drugs. This author strongly recommends that an amendment to the current law prohibiting the sale and dispensing of thalid-omide in commercial pharmacies be extended to thalidomide analogues. Moreover, we consider that a demonstration of clinical superiority over thalidomide (through gold-standard comparative efficacy trials) should be an essential requirement for registration of any teratogenic analogue

Epidemiologia, toxicologia e causalidade ambiental de doenças

This article discusses the methodological limitations of epidemiological and experimental studies when these studies are utilized to establish the causality between environmental and occupational exposures and diseases. The high probability of non-causal explanations for weak associations revealed by observational studies is emphasized; additionally, the consequences are revealed when weak associations are taken to guide public health interventions, to support diagnosis in occupational medicine and expert reports addressed to the court, and to communicate risks. Shortcomings of risk estimations based only on the evidence from experimental toxicology studies are discussed. Uncertainties involved in extrapolating toxicological findings between species and the relevance of taking into account the dose–response relationships and exposure levels experimented on human populations are also commented upon.O artigo analisa o estabelecimento de nexos causais entre exposições ambientais e ocupacionais e doenças a partir das evidências epidemiológicas e experimentais. A alta probabilidade de explicações não causais para associações fracas encontradas por estudos observacionais é enfatizada, assim como as suas implicações para nortear intervenções em Saúde Pública, subsidiar diagnósticos de causalidade em Medicina do trabalho e perícias legais, e comunicação do risco. As limitações da estimativa do risco a partir unicamente das evidencias toxicológicas são comentadas, com destaque para a incerteza que cerca a extrapolação entre espécies, e a necessidade de levar em conta a relação dose-resposta e os níveis de exposição experimentados pelas populações humanas

The brazilian hazard-based cut-off criteria for pesticide registration: a critical appraisal

Brazil, world’s top consumer of agricultural pesticides, adopts a unique hazard based cut-off approach to pesticide registration. Cut-off criteria for mutagenicity, carcinogenicity, teratogenicity, hormonal disturbances and damage to reproductive organs were introduced by the Pesticide Law enacted in 1989. As far as health is concerned, law enforcement is additionally regulated by rules issued by the federal health authority (National Agency for Health Surveillance – ANVISA). Contrasting to European Union hazard-based cut-off criteria for pesticides, Brazilian rules do not make an exception for “negligible” exposures. Moreover, Brazilian regulations have shortcomings (e.g. no reference to relevance of Mode of Action to humans) that make cut-off criteria difficult to be put into effect. The deficiencies of regulations and difficulties to consistently apply the hazard-based cut-off criteria are appraised in this article. Adoption of a risk assessment approach or cut-off criteria based on classification in Globally Harmonized System hazard categories 1A and 1B is suggested

On the alleged anticancer efficacy of phosphoethanolamine pill, weakness of the scientific evidence and ethical concerns

Anecdotal reports say that cancer patients improved after taking “synthetic phosphoethanolamine” (syn-PEA), anticancer pills produced and distributed by chemists from a Brazilian university. Notwithstanding the fact that syn-PEA pill inventors disseminated in the lay press the information that their drug is effective against different types of malignant tumors, they showed no clinical documentation or case reports to corroborate this statement. Moreover, syn-PEA failed to exhibit a consistent anticancer response in in vitro assays with human and murine cancer cell lines, and in in vivo xenograft tumor rodent assays. Despite the lack of nonclinical and clinical evidence of drug efficacy and safety, a bill authorizing production, prescription and consumption of syn-PEA pill passed the Congress and the president signed it into law (Law 13269/2016) on April 13, 2016. Astonishingly, the National Committee for Ethics in Research approved (April 19, 2016) syn-PEA trials in cancer patients in the absence of scientifically valid indications of a probable efficacy and without an adequate preclinical safety evaluation. It is unlikely that syn-PEA will eventually play a role in cancer therapy. Nonetheless, syn-PEA sad story unavoidably damaged country’s reputation as far as drug regulation and human research ethical standards are concerned.TÍTULO PT: Sobre a alegada eficácia anti-câncer da pílula de fosfoetanolamina, fragilidade da evidência científica e preocupações éticasTem sido informalmente relatado que pacientes com câncer melhoraram após tomar pílulas de fosfoetanolamina sintética (sin-FEA) produzidas e distribuídas por químicos de uma universidade brasileira. Embora os inventores da sin-FEA divulguem na imprensa leiga que o seu medicamento é eficaz contra diferentes tipos de tumores malignos, eles não apresentaram documentação clínica e relatos de caso que corroborem esta afirmação. Além disso, a sin-FEA não mostrou uma resposta anticarcinogênica consistente em ensaios in vitro com células neoplásicas humanas e murinas, e em testes in vivo em roedores com tumores transplantados. Apesar da falta de evidência não clínica e clínica de eficácia e segurança deste medicamento, uma lei autorizando a produção, prescrição e consumo da sin-FEA foi aprovada pelo Congresso e sancionada sem vetos pela presidente (Lei no 13.269/2016) em 13 de abril de 2016. Surpreendentemente, a Comissão Nacional de Ética em Pesquisa aprovou (em 19 de abril de 2016) testes da sin-FEA em pacientes apesar da ausência de indícios cientificamente válidos de provável eficácia e de adequada avaliação pré-clínica de segurança. É improvável que a sin-FEA seja útil no tratamento do câncer. Entretanto, a triste história da sin-FEA inevitavelmente maculou a reputação do país com respeito à regulação de medicamentos e padrões éticos de pesquisa clínica

The Brazilian hazard-based cut-off criteria for pesticide registration: a critical appraisal

Brazil, the world’s top consumer of agricultural pesticides, adopts a unique hazard-based cut-off approach to pesticide registration. Cut-off criteria for mutagenicity, carcinogenicity, teratogenicity, hormonal disturbances and damage to reproductive organs were introduced by the Pesticide Law enacted in 1989. As far as health is concerned, law enforcement is additionally regulated by rules issued by the federal health authority (National Agency for Health Surveillance – ANVISA). Contrasting to the European Union’s hazard-based cut-off criteria for pesticides, Brazilian rules do not make an exception for “negligible” exposures. Moreover, Brazilian regulations have shortcomings (e.g. no reference to relevance of Mode of Action to humans) that make cut-off criteria difficult to be put into effect. The deficiencies of regulations and difficulties to consistently apply the hazard-based cut-off criteria are appraised in this article. Adoption of a risk assessment approach or cut-off criteria based on classification into the Globally Harmonized System’s hazard categories 1A and 1B is suggested.Título em português: Critérios de exclusão baseados em perigo adotados no Brasil para registro  de pesticidas: Uma avalição críticaO Brasil, líder mundial do consumo de agro-químicos, adota uma singular abordagem para registro de agrotóxicos que é baseada em critérios de exclusão quanto à periculosidade. Critérios de exclusão para mutagenicidade, carcinogenicidade, teratogenicidade, distúrbios hormonais e dano a órgãos reprodutivos foram introduzidos pela Lei de Agrotóxicos promulgada em 1989. Em relação à saúde, a aplicação da lei é também regulada por portarias publicadas pela autoridade sanitária federal (Agência Nacional de Vigilância Sanitária – ANVISA). Em contraste com os critérios de exclusão baseados na periculosidade que a União Européia usa para agrotóxicos, a regulamentação brasileira não faz exceção para exposições insignificantes. Além disso, a regulamentação brasileira apresenta deficiências (e.g., não faz menção à relevância do modo de ação para seres humanos)que tornam difícil a aplicação dos critérios de exclusão. As falhas dos regulamentos e as dificuldades para aplicar consistentemente os critérios de exclusão baseados na periculosidade são examinados neste artigo. Sugere-se a adoção da avaliação de risco ou de critérios de exclusão baseados na classificação quanto a periculosidade (categorias 1A e 1B) do Sistema Harmonizado Globalmente

Current challenges in toxicological research: Evaluation of the developmental toxicity of manufactured nanomaterials

Nanomaterials are particles or fibers with at least one of the three dimensions in the size range between 1 and 100 nm. Owing to unique physical and chemical properties, nano-sized particles (NPs) have a variety of industrial uses and are more and more prevalent in everyday life. However, despite the growing number of nanotechnology products, health risk assessment of NPs is in its early infancy. The potential adverse effects of NPs on prenatal development are even less well investigated. This article summarizes the literature on the developmental toxicity of NPs. Generally, the studies are very recent and include ex vivo experiments using non-mammalian species, in vitro assays (mouse embryonic stem cell test) and in vivo investigations using rodents. Very little has been published on the effects of NPs on the development and function of the human placenta or on the transference of NPs into the human embryo and fetus. Some limitations of using ex vivo and in vitro assays to predict adverse effects of NPs on human prenatal development are discussed in this overview. The structural and functional differences between the rodent and human placenta in early pregnancy and their possible relevance to the transplacental passage of NPs are also commented upon.Título-PT:  Desafios atuais da pesquisa em toxicologia: Avaliação da toxicidade de  nanomateriais manufaturados para o desenvolvimentoNanomateriais são partículas ou fibras que possuem pelo menos uma das três dimensões na faixa de tamanho entre 1 e 100 nm. Em virtude das suas propriedades físico-químicas ímpares as nano partículas têm uma variedade de usos na indústria e cada vez mais fazem parte do nosso cotidiano. Entretanto, apesar do número crescente de produtos da nanotecnologia chegando ao mercado, a avaliação dos riscos das NPs para saúde está na sua infância. Os efeitos nocivos das NPs sobre o desenvolvimento pré-natal tem sido ainda menos investigados. Este artigo sumariza a literatura sobre os efeitos das NPs sobre o desenvolvimento. Os estudos são em geral muito recentes e incluem experimentos ex vivo empregando invertebrados e vertebrados não-mamíferos, ensaios in vitro (células tronco embrionárias de camundongos) e in vivo em roedores. Muito pouco tem sido publicado a respeito dos efeitos das NPs na placenta e sobre a passagem das NPs da mãe para o embrião e feto humanos. Algumas limitações dos ensaios ex vivo e in vitro para evidenciar potenciais perigos das NPs para o desenvolvimento prenatal humano são discutidas nesta revisão. As diferenças de estrutura e função entre a placenta de roedores e a placenta humana no período inicial da gravidez e a possível relevância delas para a transferencia transplacentária de NPs também são comentadas