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Clinical pharmacology in research teaching and health care - Considerations by IUPHAR, the International Union of Basic and Clinical Pharmacology

1. Executive Summary 531 2. Introduction 532 3. Definition of Clinical Pharmacology 533 4. History of Clinical Pharmacology 533 5. The Global Medicine Scene 534 6. Roles of Clinical Pharmacology 535 6.1 Research 535 6.2 Teaching 537 6.3 Patient care 540 6.4 Pharmaceutical industry 542 6.5 Governments 544 7. Organization 546 8. The Relationship with Other Drug Experts 547 9. Emerging Roles of Clinical Pharmacology and Therapeutics: Biologics and Biosimilars 547 10. The Contribution of Clinical Pharmacology to the Global Public Health 548 11. Overview 551 12. Addendum I: Model Core Curriculum for Clinical Pharmacology, Therapeutics and Prescribing for Medical Students 553 13. Addendum II: Model Curriculum for Specialization in Clinical Pharmacology 555 14. References 557 15. Editors and Contributors 558 16. Abbreviations and Glossary 559

World Health Organisation (WHO)

Much progress has been achieved over the last 50 years in the field of pharmaceuticals, both in terms of introducing new medicines and improving the regulation of medicines. This progress is felt most deeply in highly industrialized countries where citizens can benefit from new innovative drugs and enjoy access to quality assured multisource (generic) medicines as well. Lack of access to quality essential drugs, the majority of which are multisource (generic) medicines, remains a serious health problem and global disequilibrium of quality continues to threaten patients in many parts of the world [1]. The overall tendency is that resource-constrained or resource-poor countries are less likely to control the quality of products on the market, enjoy political support for the regulators, or have properly resourced and functioning regulatory authorities [2]. It is no wonder that in many resource-poor settings patients do not trust locally authorized multisource (generic) products.

Regulatory framework for access to safe, effective quality medicines

Medicines of uncertain quality, safety and efficacy can be worse than no treatment at all. It is the responsibility of national medicines regulatory authorities to protect patients from harm. Yet, there are great disparities in regulatory capacity globally, preventing large populations from accessing the benefits of advances in the pharmaceutical field. This article describes the main regulatory functions and how they are applied to assure the quality, safety and efficacy of different types of medicines in different environments. It gives examples of initiatives that have increased access to good quality medicines worldwide and - more importantly - are laying the groundwork for collaborative approaches aiming to ensure that pharmaceutical products meet the same, stringent quality standards in all parts of the world.

Treating snake bites--a call for partnership.

1 The Lancet. Snake bite—the neglected tropical disease. Lancet 2015; 386: 1110. 2 Mechanisms to reverse the public health neglect of snakebite victims; Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Sept 22–23, 2015. 3 WHO. WHO model list of essential medicines. 15th list, March 2007. http://www.who.int/ medicines/publications/essentialmedicines/ en/ (accessed Nov 10, 2015). 4 WHO. Rabies and envonomings: a neglected public health issue. Report of a consultative meeting. Jan 10, 2007. http://www.who.int/ bloodproducts/animal_sera/Rabies.pdf (accessed Sept 20, 2015). 5 WHO. Venomous snakes distribution and species risk categories. http://apps.who.int/ bloodproducts/snakeantivenoms/database/ (accessed Sept 20, 2015). 6 WHO. WHO guidelines for the production, control and regulation of snake antivenom immunoglobulins. http://www.who.int/ bloodproducts/snake_antivenoms/ snakeantivenomguideline.pdf (accessed Sept 20, 2015). together key players to identify mechanisms to “reverse the public health neglect of tropical snakebite victims”. But we do not agree with the Editors that snake bites are “largely invisible to WHO”. Antivenoms are highly eff ective in treating snake bite envenoming and were therefore included in the WHO Essential Medicines List in 2007. Also in 2007, WHO convened stakeholders to identify what should be done next; many of their recommendations are still valid. In 2009, WHO published Rabies and envenomings: a neglected public health issue and launched a global database with up-to-date information on venomous snake distribution and species risk categories, available antivenoms, and antivenom producers. In 2010, a WHO guideline to support production, control, and regulation of antivenoms (adopted by the WHO Expert Committee on Biological Standardization) was published. In brief, WHO developed— consensually—a clear vision on how to move this area of public health forward. An obvious next step would be to include antivenoms in the products invited for WHO prequalification. As shown with fixed-dose combination drugs for HIV/AIDS, WHO prequalification facilitates market penetration and increases the availability of quality-assured health products where they are needed most. The WHO Prequalification Team has considerable experience in working with manufacturers and regulators to get needed products onto the market and maintain supply. The team has worked closely with African regulators to help with assessment of complex products. In the longer term, more advanced products—for example, based on monoclonal antibodies—should be developed, but this will need investment and time. Unfortunately, despite all eff orts, we have failed to attract the attention of the donor community and support and implemented to meet the goal of providing 15 million individuals with basic, life-saving needs. WHO received less than 20% of the fi nancial support needed to deal with the crisis in Yemen, leaving a funding gap of 80%. Agencies such as WHO and UNICEF should work in collaboration to avoid duplication of eff orts and to provide frequent, updated reports to allow for adjustment of existing plans.

Deficiencies in generic product dossiers as submitted to the WHO Prequalification of Medicines Programme

This study was undertaken to determine the type and extent of deficiencies in generic product dossiers in the therapeutic areas of HIV/AIDS, tuberculosis, malaria and reproductive health, as submitted to the WHO Prequalification of Medicines Programme. There were considerably more quality-related deficiencies in tuberculosis, malaria and reproductive health dossiers compared to HIV dossiers, especially in the category specification of active pharmaceutical ingredients, development pharmaceutics, manufacturing method and finished pharmaceutical product specifications. The deficiencies related to the efficacy/safety portion of the dossiers displayed a trend similar to that observed in the quality portion in that the most critical deficiencies such as an incorrect study design, the use of an unacceptable comparator or the failure to include a study occurred considerably more frequently in the tuberculosis, malaria and reproductive health dossiers than in the HIV dossiers. The frequency of dossier-related deficiencies as determined on screening and assessment of the dossiers seemed to be inversely related to the number of product dossiers that had been prequalified by the end of 2010. The results of this study stress the need for continued capacity building of local generic manufacturers, further development of pharmacopoeial monographs by WHO (PhInt) and other pharmacopoeial commissions, not least to promote development of generic products, as well as development of new guidelines (WHO guidelines for development of generic and paediatric products and a technology transfer guidance document are currently being finalized). To our knowledge, this is the first comprehensive review of the quality and efficacy/safety portions of generic product dossiers, originating from pharmaceutical companies in emerging markets, and comparison of dossier deficiencies across four critically important therapeutic areas.

Accelerating access to new medicines: Current status of facilitated regulatory pathways used by emerging regulatory authorities

Objectives: We assessed the characteristics of currently implemented expedited (facilitated) regulatory pathways (FRPs) used by national regulatory authorities (NRAs) in emerging economies to speed access to important new medicines. Methods: We identified NRAs with FRPs through Thomson Reuters Cortellis Regulatory Intelligence and through agency Websites. We developed a list of 27 FRP characteristics. We categorised characteristics as procedural or substantive and based them on five sequential regulatory activities. Findings: We assessed 29 countries with 33 FRPs. The regions with the characteristics described most extensively by their FRPs were the Middle East/North Africa and Eastern Europe. The Sub-Saharan African region included the FRPs that were least specific in describing characteristics. Overall, FRPs presented at least twice as many procedural as substantive characteristics. Conclusions: We observed diversity by region in FRP characteristics, suggesting a role for further engagement with emerging NRAs in their design and implementation. Common processes could advance regulatory alignment initiatives and help the WHO inform the development of novel, globally aligned accelerated development and regulatory pathways for products that fulfil serious unmet public health needs.

PROMOTING GMP IMPLEMENTATION: DEVELOPING TRAINING MATERIALS FOR THE INTERNATIONAL AUDIENCE

This paper outlines the development of a CD-ROM training package entitled: The WHO Basic Training Modules on GMP, intended to support the creation of training courses aimed particularly at government compliance officials who inspect pharmaceutical manufacturing facilities. The material was created over a three-year period in collaboration with a team of external experts, WHO regional and local offices, and Drug Regulatory Authorities of participating countries. The nine training workshops and courses that contributed to the development and evaluation processes were attended by approximately 240 participants from 47 countries. To date over 5,800 copies of the CD-ROM have been distributed.

Review of Quality Deficiencies Found in Active Pharmaceutical Ingredient Master Files Submitted to the WHO Prequalification of Medicines Programme

PURPOSE The aim of this work was to determine the number and type of active pharmaceutical ingredient (API) quality deficiencies in API Master Files (APIMFs) as submitted to the World Health Organization (WHO) Prequalification of Medicines Programme (PQP). METHODS We conducted a retrospective review of API quality deficiencies identified following the assessment of new APIMFs for non-sterile APIs during a 6-year period from 1 January 2007 to 31 December 2012. All deficiencies were collected, classified and quantified according to the Common Technical Document (CTD) sections and subsections and as groups of commonly raised questions. RESULTS There were 5446 deficiencies collected from 159 APIMF deficiency letters by CTD section, by selected CTD subsections and by selected CTD subsections and year. More than 50% of the total number of deficiencies related to the manufacturing sections of the CTD, followed by deficiencies concerning the impurities, the API specification and the stability sections of the CTD. A pattern of API deficiencies across the different CTD subsections and over time was identified. CONCLUSIONS The most frequent critical deficiencies were related to how the specific manufacturing process and the key materials used, in particular the API starting material, impact the API impurities content. The number and pattern of APIMF deficiencies did not change over time. The results are compared to the findings in similar studies as reported by the United States Food and Drug Administration (USFDA), the European Directorate for the Quality of Medicines (EDQM) and the European Medicines Agency (EMA) and similarities and differences are discussed. Our findings highlight the need for greater guidance and technical assistance for API manufacturers submitting APIMFs to the PQP.

Regulatory policy for research and development of vaccines for public health emergencies.

The recent outbreak of the Ebola virus disease (EVD) with an average case fatality rate of around 50% – and case fatality rates from 25% to 90% in past outbreaks [1] – highlighted the need to strengthen national and international systems to detect, respond to, and prevent the spread of future health threats [2]. The Ebola public health emergency challenged research and development frameworks, including regulatory systems, both globally and in affected countries. Given the urgent need to provide access to treatments and identify effective interventions, an international Ethics Panel, convened by WHO, confirmed in August 2014 the ethical imperative to use and evaluate unregistered medical interventions under the specific circumstances of the Ebola outbreak, and defined the conditions that needed to be met in terms of safety, clinical care, ethical standards, data collection, transparency, and information-sharing [3]. In September 2014, WHO convened experts in the areas of public health, ethics, policy, research and development, manufacturing, and regulation to articulate interim WHO guidance on the development and potential use of Ebola vaccines and therapies [4]. Between February and April 2015, vaccine Phase 3 clinical trials were initiated in the three most affected countries with two candidate vaccines which had never been tested in man before September 2014, demonstrating that compressing steps which usually take several years into just five months was possible in case of emergency. Based on this experience and at the request of its 194 Member States in May 2015, WHO convened a broad coalition of experts to develop an R&D Blueprint for Action to Prevent Epidemics [5]. The R&D Blueprint will develop options to reduce the time lag between the identification of a nascent outbreak and approval of the most advanced products that can be used to save lives and stop larger crises. In November 2015, the report of the Harvard-LSHTM Independent Panel on the Global Response to Ebola recognized positively WHO’s efforts related to Ebola R&D [6].

Ongoing Monitoring of Antiretroviral Products as Part of WHO's Prequalification Project

The supply of quality medicines used in the treatment of HIV/AIDS has become a major concern at both international and country level. The Prequalification Project, set up in 2001, is a service provided by the World Health Organization (WHO) to facilitate access to medicines that meet unified standards of quality, safety and efficacy for HIV/AIDS, malaria and tuberculosis. The main purpose of the project with respect to HIV/AIDS is to assess the quality, safety and efficacy of medicines (both antiretrovirals [ARVs] and medicines for HIV/AIDS care) in accordance with international standards and to ensure that good manufacturing practice is applied at the manufacturing sites. The assessment further includes reviewing bioequivalence data and inspecting respective contract research organisations where the clinical trials were conducted for compliance with good clinical practice. Only products meeting all the requirements are listed on the prequalified products list. As part of the quality assurance element of the Prequalification Project, samples of 33 HIV/AIDS products, of which 24 were ARVs and 9 were for HIV/AIDS care, submitted for prequalification were subjected to quality control (QC) testing in 2002. This was followed by a second round of QC testing during 2004 on 11 ARV products, including comparison of dissolution profiles of generic products against the relevant innovator products. Some of the products tested appear on the current Prequalification list. All samples but one met the shelf-life specifications for content and, where tested, for identification of the active pharmaceutical ingredient, dissolution, average mass and uniformity of mass. One product sample did not meet the content specifications; however, the number of tablets required for assay testing and consequently also for confirmative retesting was insufficient, and therefore the result cannot be considered conclusive. Another product did not meet the requirements for similarity of dissolution profile against the innovator product, though it proved to be rapidly dissolving.