OECD approaches and considerations for regulatory evaluation of endocrine disruptors.

Identifying the potential endocrine disruptor hazard of environmental chemicals is a regulatory mandate for many countries. However, due to the adaptive nature of the endocrine system, absence of a single method capable of identifying endocrine disruption, and the latency between exposure to endocrine disrupting chemical during sensitive life stages and the manifestation of adverse responses, satisfying the regulatory requirement needed to identify a chemical as an endocrine disruptor is a challenge. There are now a variety of validated regulatory tests that can be used in combination to provide evidence that a chemical affects the oestrogen, androgen, thyroid, and steroidogenic pathways of vertebrates, but most rely (at least to some extent) on animal testing and require considerable cost and time to produce the necessary data. Emerging research methods are able to evaluate other endocrine pathways, incorporate more sensitive endpoints, and combine multiple alternative methods to predict in vivo outcomes. Some research approaches may also bridge gaps that have been identified in current endocrine regulatory testing. For the near term, considering new endpoints in a regulatory context may require adding them to existing test methods in order to establish relationships between the traditional and the innovative. From the outset, endocrine testing has always required integration of multiple methods that provide data on different levels of biological organisation, thus, the area of endocrine disruption is particularly adaptable to adverse outcome pathway (AOP) frameworks and integrated test methods built around AOPs. Herein, we provide a review of the status of endocrine disruptors in the OECD context, examples where innovation from research is needed to improve or bridge gaps in endocrine testing, and suggestions for regulators and researchers to facilitate uptake of innovate methods for endocrine disruptor regulatory testing. The increase in several human complex human disorders that include an endocrine component and the alarming decrease in wildlife biodiversity are commanding directives to include the best, most informative, innovative approaches to accelerate the rate and throughput of chemical evaluation for endocrine disruption.

Evaluación positiva de medicamentos: septiembre, octubre y noviembre 2018 / Possitive assesment of drugs: September, October and November 2018

Se reseñan los medicamentos evaluados y con dictamen positivo por la comisión de expertos de la Agencia Española de Medicamentos y Productos Sanitarios o de la Agencia Europea del Medicamento hechos públicos en septiembre, octubre y noviembre de 2018. Se trata de opiniones técnicas positivas previas a la autorización y puesta en el mercado del medicamento

The drugs assessed by the Spanish Agency for Medicines and Health Products or European Medicines Agency made public in September, October and November of 2018, and considered of interest to the healthcare profesional, are reviewed. These are positive technical reports prior to the authorization and placing on the market of the product

The impact of currently licensed therapies on viral and immune responses in chronic hepatitis B: Considerations for future novel therapeutics.

Despite the availability of a preventative vaccine, chronic hepatitis B (CHB) remains a global healthcare challenge with the risk of disease progression due to cirrhosis and hepatocellular carcinoma. Although current treatment strategies, interferon and nucleos(t)ide analogues have contributed to reducing morbidity and mortality related to CHB, these therapies are limited in providing functional cure. The treatment paradigm in CHB is rapidly evolving with a number of new agents in the developmental pipeline. However, until novel agents with functional cure capability are available in the clinical setting, there is a pressing need to optimize currently licensed therapies. Here, we discuss current agents used alone and/or in combination strategies along with the impact of these therapies on viral and immune responses. Novel treatment strategies are outlined, and the potential role of current therapies in the employment of pipeline agents is discussed.

Japan-Specific Key Regulatory Aspects for Development of New Biopharmaceutical Drug Products.

Japan represents the third largest pharmaceutical market in the world. Developing a new biopharmaceutical drug product for the Japanese market is a top business priority for global pharmaceutical companies while aligning with ethical drivers to treat more patients in need. Understanding Japan-specific key regulatory requirements is essential to achieve successful approvals. Understanding the full context of Japan-specific regulatory requirements/expectations is challenging to global pharmaceutical companies due to differences in language and culture. This article summarizes key Japan-specific regulatory aspects/requirements/expectations applicable to new drug development, approval, and postapproval phases. Formulation excipients should meet Japan compendial requirements with respect to the type of excipient, excipient grade, and excipient concentration. Preclinical safety assessments needed to support clinical phases I, II, and III development are summarized. Japanese regulatory authorities have taken appropriate steps to consider foreign clinical data, thereby enabling accelerated drug development and approval in Japan. Other important topics summarized in this article include: Japan new drug application-specific bracketing strategies for critical and noncritical aspects of the manufacturing process, regulatory requirements related to stability studies, release specifications and testing methods, standard processes involved in pre and postapproval inspections, management of postapproval changes, and Japan regulatory authority's consultation services available to global pharmaceutical companies.

Preliminary appraisal of clinical drug trials is changing.

The EU Clinical Trials Regulation will change the preliminary appraisal of trials and lighten the bureaucracy. Routines of the member states will be standardized, processing of applications provided with tighter time limits, and the licensing procedure made more flexible by using a common European portal. At the same time, definitions will be provided for low intervention trials subject to more flexible rules of follow-up, requirements of master file content, and traceability of test drugs. Implementation of the regulation depends on the completion of the EU portal, currently estimated to take place in the autumn of 2018. Preparations for execution in Finland are carried out by a working group appointed by the Ministry of Social Affairs and Health. On the national level, preparations are in progress to e.g. reorganize ethical evaluation, because the deadlines of evaluation of applications cannot be met with the current structure. Furthermore, regulations concerning insurances and collaterals, language requirements and possibilities of petitioning relating to the applications will also be decided on a national basis.

Miracle drug: Brazil approves never-tested cancer medicine.

Background Brazil recently approved synthetic phosphoetanolamine, a popularly dubbed 'cancer pill', a substance that has been shown to kill cancer cells in lab animal models but was not yet formally accessed in humans, and thus despite the existence of any evidence of its efficacy and safety. Methods The authors describe the recent decision of Brazil to aprove phosphoetanolamine in the context of growing 'judicialization' to promote access to medicines and thus reinforcing a growing sense of legal uncertainty. Results The approval of phosphoetanolamine despite the existence of any evidence of its efficacy and safety represents to the authors one of the saddest and surrealistic episodes in Brazil's recent public health history. Brazil's current economic crisis is fueling the 'judicialization' to promote access to medicines and thus reinforcing a growing sense of legal uncertainty in the context of rising economic constrains and a progressive failing state. The authors state that the Phosphoetanolamine's approval bill violates current legal prohibition of commercialisation of drugs without the Brazilian national drug regulatory agency's approval and thus may represent a potential menace to Brazil's pharmacogovernance and the country's governance to health technology assessment at the Brazilian national health systems. Conclusion Phosphoetanolamine's approval illustrates that the combination of flawed decision making, economic crisis and political interference may threaten weak governance mechanisms for drug regulation and health technology assessment and thus representing an extra burden in the sustainability of universal access-based national health systems.

How Safe and Innovative Are First-in-Class Drugs Approved by Health Canada: A Cohort Study.

INTRODUCTION: First-in-class drugs use a unique mechanism of action. This study assessed the therapeutic innovativeness and safety of these drugs approved by Health Canada from 1997-2012. METHODS: A list of new drugs was compiled and a database from the Food and Drug Administration was used to determine first-in-class status. Post-market safety warnings and drugs withdrawn for safety reasons were identified from the MedEffect Canada website. Therapeutic innovation evaluations came from the Patented Medicine Prices Review Board (PMPRB) and Prescrire International. The proportion of first-in-class drugs that were innovative was compared to the proportion of non-first-in-class drugs that were innovative. Kaplan-Meier survival curves assessed safety. RESULTS: In all, 462 drugs were approved by Health Canada during the period under study. Among these, 345 were evaluated by PMPRB and/or Prescrire, and first-in-class data were available for 292. Ninety-eight of the 292 were first-in-class and 16 were innovative compared to 9 of 194 drugs that were not-first-in-class. There was no difference in safety between the two groups. DISCUSSION: Overall, the benefit-to-harm ratio of first-in-class drugs, as measured by post-market safety warnings/withdrawals, is better than those that were not-first-in-class.

Resultados de una metodología para la identificación de distribución inversa de medicamentos en oficinas de farmacia / Methodology for identification of inverse drug distribution, Spain

FUNDAMENTOS: El fenómeno del tráfico inverso en la cadena legal de suministro de medicamentos es una práctica ilícita con graves riesgos para la Salud Pública. El objetivo de este trabajo fue identificar de forma proactiva, oficinas de farmacia que realizan estas conductas ilegales. MÉTODOS: Se cruzaron los datos de facturación al SAS de 52 millones de envases de medicamentos con los de las 496 farmacias de la provincia en un periodo de 29 meses (abril de 2012 a agosto de 2014). Junto con la aplicación del indicador específico definido denominado "porcentaje de sobrecompra", permitió identificar los establecimientos farmacéuticos con alto riesgo de estar implicados en el comercio ilícito. RESULTADOS: Se comprobó que hubo desvío en dos oficinas de farmacia, una rural (de 5.130 envases de medicamentos y beneficio ilícito obtenido de 9.591,78 €) y otra urbana (9.982 envases y 26.885,11 €), los cuales habían pasado desapercibidos en anteriores actuaciones inspectoras. CONCLUSIONES: La metodología implantada permite definir un perfil de oficina de farmacia infractora de alto riesgo en estas prácticas ilícitas, identificarlas, ponderar los fármacos destinados a este comercio ilegal y determinar nuevos medicamentos objeto de desvío. Ayuda a ajustar de forma precisa el cálculo del beneficio ilícito obtenido

BACKGROUND: The phenomenon of reverse drug trafficking in the legal supply chain is an unlawful practice to serious risks to public health. The aims was to identify proactively pharmacies that carry out these illegal activities. METHODS: An analysis was performed through the crossing billing data to SAS of 52 million packs of medicines for the 496 pharmacies in the province over a period of 29 months with the drug packaging data supplied by the distribution entities of the provincewith the implementation of specific indicator defined called 'percentage overbought' allows us to detect those pharmacies at high risk of being involved in this illicit trade. RESULTS: It was tested in two pharmacies one rural and other urban a detour of 5.130 medicine containers and an illicit profit obtained from € 9,591.78 for the first and 9.982 packaging and € 26,885.11 for the second; they had gone unnoticed in previous inspections. CONCLUSIONS: The methodology implemented to define a profile of infringing pharmacies high risk in these illicit practices, identify new ones that had not been sanctioned, weigh the drugs for illegal trade and to identify new drugs subject to diversion; also added as a challenge, it helps to adjust accurately and effectively calculate the illicit profit obtained

Evaluación positiva de medicamentos: junio, julio y agosto 2015 / Positive assessment of drugs: June and July 2015

Se reseñan los medicamentos evaluados y con dictamen positivo por la comisión de expertos de la Agencia Española de Medicamentos y Productos Sanitarios o de la Agencia Europea del Medicamento hechos públicos en junio y julio de 2015. Se trata de opiniones técnicas positivas previas a la autorización y puesta en el mercado del medicamento

The drugs assessed by the Spanish Agency for Medicines and Health Products or European Medicines Agency made public in june and july of 2015, and considered of interest to the healthcare professional, are reviewed. These are positive technical reports prior to the authorization and placing on the market of the product

Revocation of General Safety Test Regulations That Are Duplicative of Requirements in Biologics License Applications. Final rule.

The Food and Drug Administration (FDA) is amending the biologics regulations by removing the general safety test (GST) requirements for biological products. FDA is finalizing this action because the existing codified GST regulations are duplicative of requirements that are also specified in biologics license applications (BLAs), or are no longer necessary or appropriate to help ensure the safety, purity, and potency of licensed biological products. FDA is taking this action as part of its retrospective review of its regulations to promote improvement and innovation, in response to the Executive order.

Health Canada's use of its priority review process for new drugs: a cohort study.

OBJECTIVES: Priority reviews of new drug applications are resource intensive and drugs approved through this process have a greater likelihood of acquiring a serious safety warning compared to drugs approved through the standard process. Therefore, when Health Canada uses priority reviews, it is important that it accurately identifies products that represent a significant therapeutic advance. The purpose of this study is to compare Health Canada's use of priority reviews to therapeutic ratings from two independent organisations, the Patented Medicine Prices Review Board (PMPRB) and the French drug bulletin Prescrire International, over the period 1 January 1997-31 December 2012. DESIGN: Cohort study. DATA SOURCES: Annual reports of the Therapeutic Products Directorate, and the Biologics and Genetic Therapies Directorate; evaluations of therapeutic innovation from PMPRB and Prescrire International; WHO Collaborating Centre for Drug Statistics Methodology. INTERVENTIONS: Assessments by PMPRB and Prescrire International treated as a gold standard for postmarket therapeutic value. PRIMARY AND SECONDARY OUTCOME MEASURES: Drug-by-drug comparison between the review status from Health Canada and the therapeutic status from PMPRB/Prescrire using κ values, and positive and negative predictive values. Analysis of the per cent of all new drug applications put into the priority review category over the 16-year period. RESULTS: Health Canada approved 426 new drugs, and 345 were evaluated by PMPRB and/or Prescrire. 91 had a priority review and 52 were assessed as innovative (p=0.0003). Agreement between Health Canada and PMPRB/Prescrire was only fair (κ=0.330). The positive predictive value for Health Canada's review assignments was 36.3% and the negative predictive value was 92.5%. CONCLUSIONS: Health Canada's assignment of a priority approval to a new drug submission is only a fair predictor of the drug's therapeutic value once it is marketed. Health Canada should review its criteria for using priority reviews.

Evaluación positiva de medicamentos: septiembre/octubre/noviembre 2014 / Possitive assesment of drugs: September, October and November 2014

Se reseñan los medicamentos evaluados y con dictamen positivo por comisión de expertos de la Agencia Española de Medicamentos y Productos Sanitarios o de la Agencia Europea del Medicamento hecho públicos en septiembre, octubre y noviembre de 2014, y considerados de mayor interés para el profesional sanitario. Se trata de opiniones técnicas positivas que son previas a la autorización y puesta en el mercado del medicamento

The drugs assessed by the Spanish Agency for Medicines and Health Products or European Medicines Agency made public in September, October and November of 2014, and considered of interest to the healthcare profesional, are reviewed. These are positive technical reports prior to the authorization and placing on the market of the product

Regulatory Forum Opinion Piece*: Transgenic/Alternative Carcinogenicity Assays: A Retrospective Review of Studies Submitted to CDER/FDA 1997-2014.

The International Conference on Harmonization (ICH; S1B of 1997) allows a second species carcinogenicity study to be an alternative to one of the traditional 2-year studies. In the past 17 years, the FDA's Center for Drug Evaluation and Research's (CDER) Executive Carcinogenicity Assessment Committee received 269 alternative carcinogenicity assay protocols for review. This committee's recommendations regarding choice of animal model and dose selection are generally followed by sponsors conducting these studies to increase the acceptability of such studies. The P53(+/-) assay is generally considered appropriate for genotoxic products, and the TgRasH2 assay is appropriate for non-genotoxic or genotoxic drugs. In the United States, the TgAC assay is not used any more and the animals are no longer available. The TgAC assay can detect both tumor promoters and complete carcinogens, and consequently more than half of the dermal TgAC assays resulted in a positive assessment. Currently, more than 75% of mouse carcinogenicity studies are conducted in TgRasH2 mice. Behavior of genotoxic and non-genotoxic drugs in the various assays is reviewed.

[Common questions and suggestions of evaluation for NDA of TCM].

According to the existing Provisions for Drug Registration (SFDA Order No. 28), applications for new drugs of traditional Chinese medicine are divided into two parts: the applications for drug clinical trial and for drug production (including new drug certificate). It will last for about 10 years from the application for drug clinical trial to get approving, and it also remains many problems and the low probability to succeed. From the sight of pharmaceutical review, there are mainly two aspects of regulatory compliance and technical issues, mainly for changes without approval of the competent authorities of the country. For example, sample preparation and approval of clinical trial process are significant changes. Technical problems are reporting incomplete data or information submitted does not comply with the technical requirements for review, such as: production process validation does not provide information, the preparation of samples for clinical trials and field inspection, production information, or the information provided does not meet the technical requirements. This paper summarizes the frequently asked questions and to make recommendations to advise applicants concerned, timely detection of problems, avoid risk, improving the quality and efficiency of the application for registration.