Japan's valsartan clinical trials shambles; time for fundamental changes.

Japan's Diovan® /valsartan 'scandal' has received sensational coverage in the nation's media since 2012. Publication of fraudulent research and their subsequent retraction boosted and then curtailed the use of what was a useful therapeutic drug. Some authors of the papers resigned, others disputed the retractions and resorted to legal counsel to protect themselves. One individual, an undeclared Novartis employee involved in the research, was arrested. A complex and virtually unwinnable case was brought against him and Novartis, claiming that data alteration amounted to false advertising, but lengthy criminal court cases resulted in the case failing. Unfortunately, key elements, including conflicts of interest, pharmaceutical company interference in trials of its product, and the role of the institutions involved, have been effectively ignored. The incident also emphasised the fact that Japan's unique society and approach to science does not conform well to international standards. Although the supposed impropriety caused the appearance of a new Clinical Trials Act in 2018, the law has been criticized for being ineffectual and simply increasing clinical trial bureaucracy. This article examines the 'scandal' and identifies where changes must be made to clinical research and the roles of the various stakeholders in Japan to increase public trust in clinical trials and biomedical publications.

Opioids: A 'crisis' of too much or not enough - or simply how rich you are and where you live?

The 'Opioid Crisis', which originated in Western countries, has been misrepresented and is misinforming the global public. For 20 years, since the advent of the synthetic opioids, 25,000 Americans, on average, have died annually from opioid-related overdoses. The United States produces and consumes by far the greatest amounts of opioids. National regulations introduced to curb overdoses and restrict opioid availability have condemned many Americans, such as cancer patients or those in need of palliative care, to a life of extreme pain due to lack of access to adequate pain management. As is often the case, US-driven laws have informed and guided international regulations. Worldwide, 83% of countries have low or non-existent access to opioids for pain relief. Over 25 million people are at the end-of-life stage, with eight million people dying annually in unnecessary pain and distress. Ineffectively controlled pain is a global public health issue blighting the lives of billions of people worldwide with immeasurable human and socioeconomic costs. International conventions regulate the trade and use of controlled medications, including many opioids. The goal is to balance widespread access to optimal forms of pain management with restrictions to govern the use and prevent the misuse of controlled substances. Those conventions are failing to meet their goals. International guidelines to inform national legislation have been compromised and withdrawn, thanks to undue interference from US-based opioid manufacturers. The new goal must be to ensure equitable access, for all, to opioids and ensure that optimal pain management becomes a central component of Universal Health Coverage. SIGNIFICANCE: The opioid crisis is, more accurately, a multicomponent global crisis and one that is not fully apparent or well understood. Regulations of the wealthy and powerful to control a surfeit of opioids, which encourages misuse, cannot be allowed to govern legislation in the majority of countries worldwide where citizens have little or no access to opioids to reduce pain and suffering. International conventions must be revised to ensure an optimal balance that allows access to opioids for all those who need them.

Community-directed distributors-The "foot soldiers" in the fight to control and eliminate neglected tropical diseases.

The neglected tropical diseases (NTDs) affect hundreds of millions of people, predominantly in rural, often difficult-to-access areas, poorly served by national health services. Here, we review the contributions of 4.8 million community-directed distributors (CDDs) of medicines over 2 decades in 146,000 communities in 27 sub-Saharan African countries to control or eliminate onchocerciasis and lymphatic filariasis (LF). We examine their role in the control of other NTDs, malaria, HIV/AIDS interventions, immunisation campaigns, and support to overstretched health service personnel. We are of the opinion that CDDs as community selected, trained, and experienced "foot soldiers," some of whom were involved in the Ebola outbreak responses at the community level in Liberia, if retrained, can assist community leaders and support health workers (HWs) in the ongoing Coronavirus Disease 2019 (COVID-19) crisis. The review highlights the improved treatment coverage where there are women CDDs, the benefits and lessons from the work of CDDs, their long-term engagement, and the challenges they face in healthcare delivery. It underscores the value of utilising the CDD model for strong community engagement and recommends the model, with some review, to hasten the achievement of the NTD 2030 goal and assist the health system cope with evolving epidemics and other challenges. We propose that, based on the unprecedented progress made in the control of NTDs directly linked to community engagement and contributions of CDDs "foot soldiers," they deserve regional and global recognition. We also suggest that the World Health Organization (WHO) and other international stakeholders promote policy and guidance for countries to adapt this model for the elimination of NTDs and to strengthen national health services. This will enhance the accomplishment of some Sustainable Development Goals (SDGs) by 2030 in sub-Saharan Africa.

Pharmaceutical good manufacturing practice: Leuplin® production in Japan identifies major international shortcomings.

In Japan, the production of Leuplin®, a key drug for the treatment of prostate cancer and breast cancer, was temporarily suspended in 2020 by the manufacturer. The incident illustrated several significant failings, namely the lack of uniformity in international GMP (Good Manufacturing Practice) regulations, the lack of mechanisms to resolve disputes between PIC/S (Pharmaceutical Inspection Co-operation Scheme) member countries, and the importance of maintaining a stable supply of safe GMP-compliant essential medicines.

Legionellosis in Japan: A Self-inflicted Wound?

Legionellosis is a serious bacterial infection characterized by atypical pneumonia primarily due to infection with Legionella pneumophila, and bathing can be a potential cause of this infection. Legionellosis was first identified in 1977, and it is caused by Gram-negative bacteria belonging to the genus Legionella. Legionellosis remains an important public health threat, particularly in Japan, where the population is rapidly aging, thereby becoming more at risk of developing severe disease and accompanying life-threatening pneumonia. The bacteria are most commonly transmitted via the inhalation of contaminated aerosols produced and broadcast via water sprays, jets or mists. Infection can also occur via the aspiration of contaminated water or ice, or through inhalation of contaminated dust. Because the signs and symptoms of Legionnaires' disease (LD), as well as radiographic imaging are similar to pneumonia caused by other pathogens, a specific diagnostic test is required, such as a urine antigen detection test. Six clinical and laboratory parameters, a high body temperature, a non-productive cough, low serum sodium and platelet counts, and high lactate dehydrogenase (LDH) and c-reactive protein concentrations can be used to reliably predict the likelihood of LD. The first choices for chemotherapy are fluoroquinolone and macrolide antibiotic drugs. The main goals of LD prevention measures are 1) the prevention of microbial growth and biofilm formation, 2) the removal of all biofilm formed on equipment and in facilities, 3) minimizing aerosol splash and spread, and 4) minimizing bacterial contamination from external sources. It is apparent that, in Japan, where hot spring (onsen) bathing is common among aged people, strict regulations need to be in place - and enforced - to ensure that all Japanese onsens and spas provide a safe environment and undertake regular, effective infection control practices.

Severe Fever with Thrombocytopenia Syndrome: Japan under Threat from Life-threatening Emerging Tick-borne Disease.

Japan, like many other parts of the world, is under threat from newly emerging, potentially fatal diseases. Severe fever with thrombocytopenia syndrome (SFTS), first clinically identified in 2009, is an emerging tick-borne hemorrhagic viral disease, currently limited in distribution to East Asia. Relatively little is known about the disease with an initial Case Fatality Rate ranging from 5% to 40%. It primarily affects the elderly living in rural areas, which is particularly troublesome given Japan's rapidly aging population. Control efforts are severely hampered by lack of specific knowledge of the disease and its means of transmission, coupled with the absence of both a vaccine and an effective treatment regime, although some antiviral drugs and blood transfusions are successful in treating the disease. Despite both the causative virus and vector ticks being commonly found throughout Japan, the disease shows a very specific, limited geographical distribution for as yet unknown reasons.

Iron Deficiency Anaemia: Its Prevalence Among Women of Reproductive Age in Shanghai and Tokyo and Links to Body Mass Index.

In this study, we examined the prevalence of iron deficiency anaemia (IDA) among young women between the ages of 20-44 living in Shanghai, China, and Tokyo, Japan with a particular emphasis on investigating its possible links with body mass index (BMI). Shanghai data were obtained from annual health check-up records conducted between May and September 2016 (n=2,006). Tokyo data were from health examinations of employees working in dispensing pharmacies between July and February 2017 (n=877). Anaemia prevalence was found to be 14.8% and 11.4% in Shanghai and Tokyo, respectively. The proportion of women with a BMI of <18.5 was 9.9% in Shanghai and 25.7% in Tokyo. Anaemia prevalence tends to be high in women with a low BMI. Women with a BMI of <18.5 had the highest prevalence of anaemia (18.2%) in Shanghai. Yet, the prevalence of anaemia was low (9.3%) among Tokyo women with a BMI of <18.5, significantly lower than those with a BMI between 18.5-25.0 (12.5%). IDA is a significant problem among women in both Shanghai and Tokyo, where the 'desire for thinness" is commonplace among young women. The Tokyo participants with a low BMI, however, appear to have managed to avoid developing IDA.

Factors affecting the provision of analgesia during childbirth, Japan.

Japan's universal health-care system means that it is a very safe country in which to give birth. Perinatal outcomes in Japan are excellent, with low infant mortality and neonatal mortality. However, childbirth remains a challenge for many Japanese women, who are faced with a scarcity of places to give birth, limited availability of analgesia and social norms that favour natural birth. The number of birth facilities in Japan continues to decrease as fewer children are born. The numbers of qualified medical staff remain inadequate, with a continuing lack of female physicians, perpetuated by a pervasive negative gender bias. Recruitment efforts are underway, but few doctors want to specialize in obstetrics or gynaecology. Furthermore, around half of female obstetricians and gynaecologists in Japan's male-dominated medical system stop practising when they have their own children. The difficulty of obtaining analgesia during labour is another problem. Although low uptake of labour pain relief in Japan is said to be due to cultural influences, the root of the problem is a lack of qualified anaesthesiologists and the inflexibility of a system that will not allow other staff to be trained to administer labour analgesia. Problems with labour anaesthesia have been linked to 14 maternal deaths since 2010. Japanese policy-makers need to act to renovate the nation's obstetric facilities, reorganize regional perinatal care systems, train more obstetricians and anaesthesiologists, promote task-shifting and better integrate biomedical and traditional, non-medical care for pregnant women.

Le système de soins de santé universel du Japon en fait un pays très sûr pour les accouchements. Les résultats en matière de santé périnatale au Japon sont excellents, avec une mortalité infantile et une mortalité néonatale faibles. Néanmoins, l'accouchement reste problématique pour de nombreuses Japonaises, qui doivent faire face à un manque d'établissements adaptés pour les accouchements, à une disponibilité limitée de l'analgésie et à des normes sociales qui favorisent les accouchements naturels. Le nombre de maternités au Japon ne cesse de baisser, à mesure de la diminution du nombre de naissances. Les effectifs en personnel médical qualifié restent inappropriés, avec une pénurie persistante de femmes médecins, perpétuée par des préjugés négatifs généralisés liés au genre. Des efforts de recrutement sont en cours, mais peu de médecins souhaitent se spécialiser en obstétrique ou en gynécologie. Par ailleurs, dans le système médical japonais dominé par les hommes, près de la moitié des femmes obstétriciennes et gynécologues cessent de pratiquer dès qu'elles ont elles-mêmes des enfants. La difficulté à bénéficier d'une analgésie obstétricale pendant l'accouchement constitue un autre problème. Même si, au Japon, le faible recours au soulagement de la douleur pendant le travail est généralement imputé à des influences culturelles, le fond du problème est une pénurie d'anesthésistes qualifiés et le manque de souplesse d'un système qui ne permet pas de former d'autres professionnels de santé pour pouvoir pratiquer l'analgésie obstétricale. Les problèmes liés à la réalisation d'une analgésie obstétricale ont donné lieu à 14 décès maternels depuis 2010. Au Japon, les décideurs politiques doivent agir pour rénover les installations obstétricales du pays, réorganiser les systèmes régionaux de santé périnatale, former davantage d'obstétriciens et d'anesthésistes, promouvoir le transfert des tâches et mieux intégrer les soins biomédicaux et les soins traditionnels, non médicaux, pour les femmes enceintes.

El sistema universal de atención sanitaria de Japón hace que sea un país muy seguro para dar a luz. Los resultados perinatales en Japón son excelentes, con baja mortalidad infantil y mortalidad neonatal. Sin embargo, el parto sigue siendo un problema para muchas mujeres japonesas, que se enfrentan a la escasez de lugares para dar a luz, la limitada disponibilidad de analgesia y las normas sociales que favorecen el parto natural. El número de centros de maternidad en Japón sigue disminuyendo a medida que nacen menos niños. El número de personal médico cualificado sigue siendo insuficiente, con una continua falta de mujeres médicas, perpetuada por un prejuicio de género negativo generalizado. Los esfuerzos de reclutamiento están en marcha, pero pocos médicos quieren especializarse en obstetricia o ginecología. Además, alrededor de la mitad de las obstetras y ginecólogas del sistema médico japonés dominado por los hombres dejan de ejercer cuando tienen sus propios hijos. La dificultad para obtener analgesia durante el trabajo de parto es otro problema. Aunque se dice que la baja aceptación del alivio del dolor del trabajo de parto en Japón se debe a influencias culturales, la raíz del problema es la falta de anestesiólogos calificados y la inflexibilidad de un sistema que no permitirá que otro personal esté capacitado para administrar la analgesia del trabajo de parto. Los problemas con la anestesia del trabajo de parto se han relacionado con 14 muertes maternas desde 2010. Los responsables de formular políticas en Japón deben actuar para renovar las instalaciones obstétricas del país, reorganizar los sistemas regionales de atención perinatal, capacitar a más obstetras y anestesiólogos, promover el cambio de tareas e integrar mejor la atención biomédica y la atención no médica tradicional para las mujeres embarazadas.

Lactacystin: first-in-class proteasome inhibitor still excelling and an exemplar for future antibiotic research.

Lactacystin exemplifies the role that serendipity plays in drug discovery and why "finding things without actually looking for them" retains such a pivotal role in the search for the useful properties of chemicals. The first proteasome inhibitor discovered, lactacystin stimulated new possibilities in cancer control. New and innovative uses are regularly being found for lactacystin, including as a model to study dementia, while new formulations and delivery systems may facilitate its use clinically as an anticancer agent. All this provides yet more evidence that we need a comprehensive, collaborative and coordinated programme to fully investigate all new and existing chemical compounds, especially those of microbial origin. We need to do so in order to avoid failing to detect and successfully exploit unsought yet potentially life-saving or extremely advantageous properties of microbial metabolites.

Staurosporine: new lease of life for parent compound of today's novel and highly successful anti-cancer drugs.

Staurosporine, together with such examples as penicillin, aspirin, ivermectin and sildenafil, exemplifies the role that serendipity has in drug discovery and why 'finding things without actually searching for them' retains a prominent role in drug discovery. Hitherto not clinically useful, due to its potency and promiscuity, new delivery technology is opening up new horizons for what was previously just the parent compound of innovative, highly-successful anti-cancer agents.

Ivermectin and malaria control.

As the world begins to realize the very real prospect of eliminating malaria as a public health problem globally, the scientific community is acutely aware that novel and innovative new tools will be required if that lofty goal is to be accomplished. Moreover, the need for comprehensive, integrated products and interventions is being recognized in order for the critical 'final steps' toward elimination to be taken successfully. Failure to take these crucial last steps have dogged all past global disease elimination programmes, except for smallpox. The success of ivermectin in driving two of the most devastating and disfiguring neglected tropical diseases (NTD) to the brink of elimination has been well documented. The drug also bestows immeasurable non-target benefits, increasing the health and socioeconomic prospects of all communities where mass drug administration (MDA) has been carried out. Ivermectin kills a variety of parasites and insects, including the Anopheline vectors of malaria parasites. In view of long-standing MDA programmes, increasing attention is now being paid to the potential offered by re-formulating and re-purposing ivermectin to function as a feed-though mosquitocidal tool. This will provide a comprehensively beneficial weapon, for the anti-malarial armamentarium, as well as for probably improving the impact on existing target diseases. Prospects currently look highly promising, especially as the drug is already proven to be extremely safe for human use. However, for maximum impact, detailed analysis of various analogues of the unique ivermectin, as well as the parent avermectin compounds, will need to be undertaken. 'Ivermectin' comprises an imprecise mix of two compounds, both of which are potent anthelmintics. Yet recently, it has been confirmed that only the minor of the two component compounds is molluscicidal. Further structure activity relationship studies may well identify the analogue, analogues or combination thereof best suited for use in a concerted initiative to simultaneously tackle malaria and other NTD in poly-parasitized communities.

Ivermectin: enigmatic multifaceted 'wonder' drug continues to surprise and exceed expectations.

Over the past decade, the global scientific community have begun to recognize the unmatched value of an extraordinary drug, ivermectin, that originates from a single microbe unearthed from soil in Japan. Work on ivermectin has seen its discoverer, Satoshi Omura, of Tokyo's prestigious Kitasato Institute, receive the 2014 Gairdner Global Health Award and the 2015 Nobel Prize in Physiology or Medicine, which he shared with a collaborating partner in the discovery and development of the drug, William Campbell of Merck & Co. Incorporated. Today, ivermectin is continuing to surprise and excite scientists, offering more and more promise to help improve global public health by treating a diverse range of diseases, with its unexpected potential as an antibacterial, antiviral and anti-cancer agent being particularly extraordinary.

Ivermectin: panacea for resource-poor communities?

The 2014 Gairdner Global Health Award was conferred for discovery of the unique microorganism that is the sole source of the endectocidal avermectins, and the Public sector/Private sector Partnership that developed innovative biopharmaceuticals with immeasurably beneficial impact on public health worldwide. Ivermectin is already labelled a 'wonder drug', essential for campaigns to eliminate two disfiguring and devastating tropical diseases. New uses for it are identified regularly, including possible antibacterial, antiviral, and anticancer potential. Hundreds of millions of people are taking ivermectin to combat various diseases and afflictions, and mass administration of ivermectin in polyparasitised poor communities around the world is increasingly recognised as a mechanism to easily and cost-effectively improve overall health and quality of life for everyone.

The advent of ivermectin: people, partnerships, and principles.

The 2014 Gairdner Global Health Award has been given for the discovery of the microorganism and industry partnership that resulted in the appearance of ivermectin, possibly the world's most successful human health tool. The chemist responsible for the discovery, Satoshi Omura, also found many other microbial metabolites which have been the origin of novel, impactful drugs. The award emphasizes that multidisciplinary and equitable partnerships, often international in scope, are the key to advances in virtually all branches of science in the modern era.