Report from the EPAA workshop: In vitro ADME in safety testing used by EPAA industry sectors

There are now numerous in vitro and in silico ADME alternatives to in vivo assays but how do different industries incorporate them into their decision tree approaches for risk assessment, bearing in mind that the chemicals tested are intended for widely varying purposes? The extent of the use of animal tests is mainly driven by regulations or by the lack of a suitable in vitro model. Therefore, what considerations are needed for alternative models and how can they be improved so that they can be used as part of the risk assessment process? To address these issues, the European Partnership for Alternative Approaches to Animal Testing (EPAA) working group on prioritisation, promotion and implementation of the 3Rs research held a workshop in November, 2008 in Duesseldorf, Germany. Participants included different industry sectors such as pharmaceuticals, cosmetics, industrial- and agro-chemicals. This report describes the outcome of the discussions and recommendations (a) to reduce the number of animals used for determining the ADME properties of chemicals and (b) for considerations and actions regarding in vitro and in silico assays. These included: standardisation and promotion of in vitro assays so that they may become accepted by regulators; increased availability of industry in vivo kinetic data for a central database to increase the power of in silico predictions; expansion of the applicability domains of in vitro and in silico tools (which are not necessarily more applicable or even exclusive to one particular sector) and continued collaborations between regulators, academia and industry. A recommended immediate course of action was to establish an expert panel of users, developers and regulators to define the testing scope of models for different chemical classes. It was agreed by all participants that improvement and harmonization of alternative approaches is needed for all sectors and this will most effectively be achieved by stakeholders from different sectors sharing data.     

Herbal drug patenting in India: IP potential

Ethnopharmacological Relevence

Herbal drugs are gaining worldwide prominence due to their distinct advantages. Developing countries have started exploring the ethnopharmacological approach of drug discovery and have begun to file patents on herbal drugs. The expansion of R&D in Indian herbal research organizations and presence of manufacturing units at non-Indian sites is an indication of the capability to develop new products and processes. The present study attempts to identify innovations in the Indian herbal drug sector by analyzing the patenting trends in India, US and EU.

Methodology

Based on key word and IPC based search at the IPO, USPTO, Esp@cenet and WIPO databases, patent applications and grant in herbal drugs by Indian applicants/assignees was collected for the last ten years (from 1st January 2001 to 31st October 2010). From this collection patents related to human therapeutic use only were selected. Analysis was performed to identify filing trends, major applicants/assignees, disease area and major plant species used for various treatments.

Result

There is a gradual increase in patent filing through the years. In India, individual inventors have maximum applications and grants. CSIR, among research organizations and Hindustan Unilever, Avesthagen, Piramal Life Science, Sahajanand Biotech and Indus Biotech among the companies have the maximum granted patents in India, US and EU respectively. Diabetes, cancer and inflammatory disorders are the major areas for patenting in India and abroad. Recent patents are on new herbal formulations for treatment of AIDS, hepatitis, skin disorders and gastrointestinal disorders.

Conclusion

A majority of the herbal patents applications and grants in India are with individual inventors. Claim analysis indicates that these patents include novel multi-herb compositions with synergistic action. Indian research organizations are more active than companies in filing for patents. CSIR has maximum numbers of applications not only in India but also in the US and EU. Patents by research organizations and herbal companies are on development of new processes for active compound isolation and standardization of such components in addition to new compositions for therapeutic use. Pharmaceutical companies such as Ranbaxy, Lupin and Panacea Biotec are increasingly patenting on herbal drugs. There is increased patenting activity related to diabetes, cancer, cardiovascular diseases, asthma and arthritis in India and abroad.     

Apixaban and Valve Thrombosis After Transcatheter Aortic Valve Replacement: The ATLANTIS-4D-CT Randomized Clinical Trial Substudy

BackgroundSubclinical obstructive valve thrombosis after transcatheter aortic valve replacement (TAVR) is of uncertain frequency and clinical impact.ObjectivesThe aim of this study was to determine the effects of apixaban vs standard of care on post-TAVR valve thrombosis detected by 4-dimensional (4D) computed tomography.MethodsThe randomized ATLANTIS (Anti-Thrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events After Trans-Aortic Valve Implantation for Aortic Stenosis) trial demonstrated that apixaban 5 mg twice daily was not superior to standard of care (vitamin K antagonists or antiplatelet therapy) after successful TAVR and was associated with similar safety but with more noncardiovascular deaths. Three months after randomization, 4D computed tomography was proposed to all patients to determine the percentage of patients with ≥1 prosthetic valve leaflet with grade 3 or 4 reduced leaflet motion or grade 3 or 4 hypoattenuated leaflet thickening (the primary endpoint) in the intention-to-treat population.ResultsSeven hundred sixty-two participants had complete multiphase datasets and were included in the 4D computed tomographic analysis. The primary endpoint occurred in 33 (8.9%) and 51 (13.0%) patients in the apixaban and standard-of-care groups, respectively. It was reduced with apixaban vs antiplatelet therapy (OR: 0.51; 95% CI: 0.30-0.86) but not vs vitamin K antagonists (OR: 1.80; 95% CI: 0.62-5.25) (P_interaction = 0.037). The composite of death, myocardial infarction, any stroke, or systemic embolism at 1 year occurred in 10.7% (n = 9 of 84) and 7.1% (n = 48 of 178) of patients with and without subclinical valve thrombosis at 90 days, respectively (HR: 1.68; 95% CI: 0.82-3.44).ConclusionsApixaban reduced subclinical obstructive valve thrombosis in the majority of patients who underwent TAVR without having an established indication for anticoagulation. This study was not powered for clinical outcomes. (Anti-Thrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis [ATLANTIS]; NCT02664649)     

Developing governance models and funding mechanisms of state–civil society partnerships for HIV/AIDS treatment and prevention based on lessons from Ghana

The contribution of civil society organisations (CSOs) to national HIV/AIDS responses in sub-Saharan African countries, with Global Health Initiatives’ (GHIs) funding channelled through National AIDS Commissions (NACs), is well researched. Less well understood are the governance models and funding mechanisms being used to successfully engage CSOs in the HIV/AIDS response. Using data from government, donor, CSO and documentary sources, this article characterises the organisational principles and practices and unique funding models adopted by the Ghana AIDS Commission (GAC) to effectively and efficiently engage CSOs in the HIV/AIDS response. It found four major governance principles and practices that target: 1) strategic planning for service delivery; 2) focussed expressions of interest; 3) competitive tendering and contracting for service delivery; and 4) adoption of results-based management. It also identified three predominant funding models that illustrate the application of these guiding principles to harness the inherent strengths of CSOs to more effectively respond to HIV/AIDS, namely: 1) direct funding of locally-based CSOs; 2) funding international and national NGOs to engage local CSOs in partnership; and 3) funding umbrella organisations. These findings are significant for Ghana but they may also have relevance for other low- or middle-income countries (LMICs) that have limited experience delivering HIV/AIDS services through state–civil society partnerships, as well as broader debates on the role of donors, governments and CSOs working in partnership to fight HIV/AIDS.     

Future development of Good Agricultural Practice in China under globalization of traditional herbal medicine trade

Traditional herbal medicine (THM) is an important part of the traditional Chinese medicine culture. Due to its high medicinal potential, it should not only serve for the Chinese people''s medical use, but also contribute to the world medicine, THM for the international market must be standardized and large-scale, and produced according to the “Good Agriculture Practice” (GAP). The quality of THM directly affects the patient''s treatment status and safety of use. Therefore, the quality assurance of THM runs through the entire process of research and development, production and clinical practice. The standardized production and cultivation of THM is the starting point of the THM industry chain and plays a decisive role in the economic development of the THM industry. This article summarizes the development history, limitations and future development of GAP, and clarifies the opportunities for THM in the rapid development of the international and domestic Chinese medicine industry. In addition, analyzing the deficiencies that were existing in the former GAP implementation process and by suggesting science-based quality measures, it is hoped to stipulate improved GAP guidelines in the future and to lay the foundation for a modern THM international trade.