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Physico-chemical equivalence of generic antihypertensive medicines in Nigeria
The EQUI-MEDS project aims to catalyze global debate about the Physico-chemical equivalence of generic anti-hypertensive medicines available in retail outlets in Nigeria.
Vamadevan S, Ajay did his PhD in non-communicable disease epidemiology from the London School of Hygiene & Tropical Medicine. His research work in the past five years has been into developing low-cost solutions to improve access and quality of care for cardio-metabolic diseases (CMDs) using smartphone technologies (mHealth) and electronic decision support tools. Application of geographic information system (GIS) technologies, for the surveillance of chronic diseases, is another domain he focuses particularly in the two large, population-based, urban (CARRS-Surveillance Study) and rural (Solan Surveillance Study) cohorts for cardio-metabolic disease research in India.
Jose is a Cardiologist from Peru and Secretary-General of the Peruvian Society of Hypertension. He studied Medicine at Universidad Nacional San Luis Gonzaga de Ica. Facultad de Medicina Humana Dr. Daniel Alcides Carrion. Ica, Peru. In 1997 he specialized in Cardiology at Universidad Nacional Federico Villarreal. Facultad de Medicina Humana. Lima, Peru. He is an active member of the Peruvian Society of Hypertension, The Peruvian Society of Cardiology, the Peruvian Society of Internal Medicine, the Spanish Society of Cardiology, and the European Society of Cardiology.
Julie is Head of the Public Health and Health Services program and Deputy Director of Cardiovascular Division at The George Institute for Global Health. She is also an Associate Professor at Sydney Medical School, University of Sydney and a clinical physiotherapist. Julie has been funded by scholarships and fellowships for the past 10 years through the National Heart Foundation of Australia and the National Health and Medical Research Council of Australia. Julie also serves on many Steering Committees and working groups and she is a Board Member of the Cardiac Society of Australia and New Zealand. Julie is the current Chair of the Allied Health and Technology Council of the CSANZ and co-Chair of the Australian Secondary Prevention Alliance. Julie has authored approximately 60 manuscripts in peer-reviewed journals and has received approximately 5 million dollars in competitive grant funding. She has won many prestigious awards for her research and scientific publications. Julie works on an extensive research program aiming to help more people better manage their heart disease. Her on-going career goal is to improve access to and engagement with secondary prevention strategies worldwide.
Luciano has been working on several research projects to streamline care for patients who are suffering cardiovascular disease, most specifically, STEMI, in order to understand how pre-hospital and emergency care of the tiered health system in Brazil can be improved to streamline the FMC-to-device time and reduce cardiovascular morbidity and mortality. He has participated actively in the Duke Global Health Institute (DGHI) in several projects committed to developing and employing new models of education and research in countries as Rwanda, Sri Lanka and Tanzania. Luciano’s research interests are the factors that lead to delayed treatment for cardiac patients, such as geographic or socio-demographic factors, transport challenges, and primary and tertiary hospital service processes, identifying areas for improvements, suggesting solutions and evaluating the impact these improvements.
Mahmoud’s areas of interest include Acute Heart Failure, Echocardiography, Preventive Cardiology and Heart Disease in HIV. He has published over sixty peer-reviewed scientific papers. Mahmoud combines cardiology practice, research and teaching of medical students and residents. He has been involved in collaborative researches across the African continent which include the Survey of Heart Failure in sub Saharan Africa (THESUS –HF), the Pan African Pulmonary Hypertension Cohort Study (PAPUCO) the Bi-Treatment with Hydralazine/Nitrates versus Placebo in Africans with Acute Heart Failure (B-A-HEF) study, the Cardiac Disease and Maternity registry, the Investigation into the Management of Pericarditis (IMPI) and the Global Rheumatic Heart Disease Registry (The REMEDY study) as a principal investigator. On the international scene, he participated in the RELY – AF Registry as well as the INTERSTROKE study. He together with other colleagues, also co-founded the Nigerian Heart Failure Registry, the Nigerian Hypertension Study group and the Registry for acute coronary events in Nigeria (RACE – Nigeria).
Prasanga brings several years of engineering training and practice into the Global Health field of strengthening health systems. Having spent several years designing the next generation of biological pacemakers, in her current role, Prasanga is responsible for developing and executing core strategies and programs under an overall vision of expanding access to chronic disease care for underserved communities. Her technical lens led to the development of an innovative framework that today serves as the bedrock of Medtronic Philanthropy’s strategy to enhance access to care by focusing on the patient’s journey. Prasanga also leads Medtronic’s response to a portfolio of conditions endemic among low-income populations including Rheumatic Heart Disease and also works to inform policy for chronic and neglected diseases at the UN level, advocating for a multi-sectoral approach to addressing the needs of the underserved. Outside of her work at Medtronic, Prasanga is also inventor of an affordable, culturally sensitive premature infant incubator – the Incupouch™ (patent pending) designed for rural communities in the developing world that do not have access to electricity. She is a certified Biomed and a consultant for non-profits in the global health field. Prasanga holds an MS in Mechanical Engineering and BS in Chemical Engineering from MIT.
Raghu has worked in a number of roles from General Practitioner in tribal and rural India to Clinical Trial and Project Manager in the pharmaceutical sector, to his current role as an Associate Professor in the Department of Epidemiology at the Public Health Foundation of India – Indian Institute of Public Health, Hyderabad. During this time he has worked in epidemiological and clinical trials research, notably as the Principal Investigator for operational research capacity building project funded by the IUATLD (2009-10), and on clinical decision support systems for management of hypertension in primary care settings of India as a Wellcome Trust PHFI PhD Research Fellow at University of Cambridge, UK (2010-2013). He also holds an MPH from the University of Pittsburgh, USA. He has high impact factor publications in NEJM and Plos One journals. He has developed course content and has been teaching on epidemiology, research methods, operational research, drug discovery, nutritional epidemiology, GCP and clinical trial modules for courses at IIPHH since 2009. He also holds an Adjunct Faculty position at the University of Hyderabad, where he teaches both epidemiology I and II modules for the MPH program.
Rufus’s research and clinical interest are in cardiopulmonary rehab, Exercise Science and physical activity & environment. He is currently coordinating the cardiopulmonary Rehab and fitness unit of the Medical Rehabilitation Department, Obafemi Awolowo University Teaching Hospitals complex and is the Chairman of the Nigeria Cardiorespiratory Physiotherapy Specialty group. Rufus is an erudite scholar with over eighty publications in peer-reviewed Journals. He has served as editor-in-Chief of the Journal of the Nigeria Society of Physiotherapy; reviewer and contributor to several international journals. He has served as a visiting lecturer and external examiner to many institutions in Nigeria including the University of Ghana. Because of his publications and contributions to the area of respiratory care, Rufus was awarded “International Fellow in Respiratory Care” by the American Respiratory Care Foundation and Association of American Respiratory Care Foundation in 2008. He is the first Nigerian and 3rd African to receive this prestigious award.
To inform the evidence-base and catalyze global debate about the physico-chemical equivalence of generic anti-hypertensive medicines available in retail outlets in Nigeria.
Burden of hypertension
High blood pressure (BP), often termed hypertension, is one of the most important public health problems worldwide affecting one billion people, three-quarters of which live in the low income and middle-income countries. High BP is also the leading cause of cardiovascular disease (CVD) and is responsible for 13% of deaths globally. In most individuals, adequate management and control of BP are associated with a reduction in deaths and disability from a number of conditions including cerebrovascular, cardiovascular, and renal disease. Therefore, prevention and optimal management of high BP in the general population is paramount to the achievement of the World Heart Federation (WHF) goal of reducing premature CVD mortality by 25% by the year 2025 and to the World Health Organization (WHO) goal of reducing premature mortality from non-communicable diseases (NCDs) by 25% by the year 2025. Most importantly, widespread access to good quality antihypertensive medicines is critical to successful implementation of effective BP control.
Substandard medicines are defined as medicines that do not meet the legally required quality specifications of a country’s regulators. In recent years it has emerged that the availability of substandard medicines is widespread and is a crucial public health problem in developing countries. In these countries, half of the medicines for major diseases, such as Malaria, have been found to be substandard in quality and it is concerning that they often have little or no active ingredient. In more developed countries, medicine safety is generally more highly regulated but substandard medicines still exist and have been shown to result in thousands of adverse reactions and some deaths. The problem of modern-day substandard medicines was first highlighted in 1985 at a conference in Nairobi. Unfortunately, the market of substandard generic medicines has continued to grow and has indeed spread all over the world during the last decade. According to the World Health Organisation (WHO), 25% of all medicines available in developing countries are substandard. Substandard generic medicines are a major contributor and have been shown to constitute 40-50% of all medical supplies in Nigeria and Pakistan and one-third of all antibiotics and anti-malarial medicines in Nigeria and Thailand. A government-led study in India has shown that 9% of medicines are substandard, with 15,000 generics manufacturers in India. The problem is widespread but the extent of the issue as it relates to antihypertensive medicines remains unclear.
Substandard generic medicines share a huge market as estimated by WHO at more than US$35 billion which represents more than 15% of the pharmaceutical market worldwide. More than 60% of the market generated from substandard medicines comes from developing countries (35-90% in South East Asia). Substandard medicine products provide attractive opportunities for producers because the financial benefits are high, production costs are relatively low and the risks limited. Producers are generally able to prepare large batches of substandard medicines before moving on to start-up another opportunity in a different location. In addition, substandard medicines are generally easily transportable, have a high value per unit and their quality cannot be scientifically or legally assessed without a quality testing laboratory. For all these reasons developing countries, including Nigeria, are targets for producers and traders.
Substandard antihypertensive medicines
Almost all kinds of medicines can be substandard however, most existing studies have investigated anti-malarial medicines and antibiotics. The US Pharmacopoeia drug quality and information program listed anti-hypertensive medicines among a class of possible substandard medicines in the African region. A study carried out in the Philippines found that the antihypertensive medicine Adalat (Nifedipine) was one of the top five counterfeit medications. However, there is currently very little research being done to assess the quality of generic antihypertensive medicines. Importantly, given that people with high BP often require lifelong adherence to indicated medicines, the problem of substandard anti-hypertensive medicines is potentially a serious public health issue.
In summary, WHF has set a target of reducing avoidable CVD mortality by 25% by 2025 and a priority area for achieving that target is improved BP management and control. The availability of and access to quality anti-hypertensive medicines globally is, therefore, a vital strategy needed to achieve the target. However, there is currently a scarcity of knowledge about the quality of antihypertensive medicines available in developing countries. Such information is important for enforcing laws to ensure quality of generic anti-hypertensive medicines. In this proposal, we propose to conduct a pilot study that catalyzes global debate about the physico-chemical equivalence of generic antihypertensive medicines available in the retail market of a developing country.
In this research work, a mixed-methods design will be adopted, which includes literature search, landscape assessment, collection and analysis of medical samples. Ethics approval will be obtained from relevant institutions in the three areas being investigated.
According to the 2006 Census, the Federal Republic of Nigeria has a population of about 140 million. It has an area is 923,772 square kilometers (about 356,700 square miles). It is the most densely populated country in Africa and represents about 20% of the total population of sub-Saharan Africa. Although Nigeria has a large number of ethnic groups (approximately 250) the three dominants are the Hausas in the North, Yorubas in the West and Ibos in the Eastern part of Nigeria. We purposively selected a state from every 3 geopolitical zones (Kano, Osun State, Enugu states). Kano state has a population of approximately 9 million. It’s a major industrial center of the North part of Nigeria. Osun State has populations of approximately 3 million and the people are mostly traders, artisans and farmers. Enugu State is one of the five Ibos states with a population of over 3 million people. The chosen areas of Nigeria have been previously identified as a “hotspot” for the availability of substandard antimalarial medicines and also affords practical benefits for this pilot study given the location of our team members and the connections available. In addition, Nigeria has relatively ‘porous’ borders, a huge population, a high level of corruption and ease of medication purchase. However, this proposal identifies the first step in a broader program of work and debate related to the quality of antihypertensive medicines available in developing countries.
Objective 1: Assessment of health systems and contextual features
To examine and understand health systems and contextual features that may enable the availability of substandard antihypertensive medicines we will;
1. Map the local supply chain of antihypertensive medicines and explore medicine regulation to determine factors enabling substandard medicines. To do this we will conduct interviews with key informants and analyze publically available local policy documents in order to obtain a legal and administrative overview.
2. Document presence and reasons for expired or degraded medicines at the point of collection, stockouts of generally available samples and the cost of medicines
3. Review the content of patient information leaflets as well as the way it is presented, to determine whether they are user-friendly.
Objective 2: Physico-chemical equivalence
To identify which generic brands to include for sampling we will initially review the five classes of anti-hypertensive medicines (Calcium channel blockers, beta-blockers, ACE inhibitors, ARBs and centrally acting drugs) based on information available through the National Agency Food and Drug Administration and Control (NAFDAC) agency. We will then determine the most commonly prescribed medicines in each class through a combination of literature searches and through consultations with local clinicians/experts and key opinion leaders. We will randomly select 10 generics from each class for collection.
In each of the three states, we will obtain a list of local government areas from which we will randomly select one rural and one urban area. Therefore, across the three states, we will then have a total of six local government areas (three rural and three urban). We will then using geographical mapping to divide each of the included local government areas into four geographical regions or quadrants ie, north, east, south and west. Therefore, in each state, we will identify eight regions (four from the rural local government area and four from the urban local government area). This will give a total of 24 regions for sampling across the three states. From within each of the 24 geographical regions, one pharmacy shop and one patent medicine store will be randomly selected. To do this we will use GIS software to create a mesh of points from the respective regions. Therefore, in total there will be two retail outlets from each of the 24 geographical regions giving a total of 48 retail outlets altogether. We estimate approximately 10 samples will be obtained for each medicine class from each outlet however, we acknowledge this will vary between outlets. Physical and chemical equivalence will be measured (methods described elsewhere). Descriptive statistics will be carried out for comparing the generic medicines on their physical and chemical characteristics with the reference product (medicine). In addition, we will compare equivalence in rural versus urban areas and based on retail type (namely pharmacy or other ‘local drug outlet’).