Equivalence in active pharmaceutical ingredient of generic antihypertensive medicines available in Nigeria (EQUIMEDS): A case for further surveillance

Background: Widespread access to good quality antihypertensive medicines is a critical component for reducing premature cardiovascular disease (CVD) mortality. Poor quality medicines pose serious health concerns however, there remains a knowledge gap about the quality of cardiovascular medicines available in low- and middle-income countries (LMICs). The aim of this study was to determine the quality of generic antihypertensive medicines available in the retail market of a developing country. Methods: Samples of the two most commonly prescribed classes of anti-hypertensive medicines were collected from three states in three different geopolitical zones in Nigeria following a semi-random sampling framework. Medicine samples were purchased by mystery shoppers from 22 pharmacy outlets from six local government areas across the three states. Medicine quality was determined by measuring the amount of stated active pharmaceutical ingredient using high-performance liquid chromatography with photodiode array detection and classified according to their compliance to the specified pharmacopeia tolerance, limits for each antihypertensive. Results: Amlodipine and Lisinopril were identified as the most commonly prescribed antihypertensive drugs in Nigeria. In total, 361 samples from 22 pharmacies were collected and tested. In total, 24.6% of Amlodipine and 31.9% of Lisinopril samples were of substandard quality and significantly more samples purchased in rural (59/161, 36.7%) compared to urban (32/200, 16%) outlets were found to be of substandard quality (p<0.001). No falsified samples of either Amlodipine or Lisinopril were detected. There was large variation in price paid for the antihypertensive medicines (range ₦150-9750). Of the 24 pharmacy outlets surveyed, 46% stated that patients did not always require a prescription and 21% had previously reported a medicine as falsified or substandard.


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Management of hypertension can largely be achieved through availability of and adherence to qualitative evidence-based medicines. There is very little research examining the quality of anti-hypertensive medicines available in the retail market of low-and middle-income countries (LMICs).
• In total, 361 samples of Amlodipine and Lisinopril were collected from 22 pharmacies and their stated active pharmaceutical ingredient (SAPI) measured.
• More than a quarter of some commonly prescribed anti-hypertensive medicines available in Nigeria appear to be of substandard quality (samples had more or less SAPI, than stated in the United States Pharmacopeia specified tolerance, limits range).
• The proportion of substandard quality was not statistically different for Amlodipine and Lisinopril, however, significantly more samples purchased in rural compared to urban outlets were of substandard quality. The aim of this study was to determine the quality of generic antihypertensive medicines available in the retail market of a developing country.
Methods: Samples of the two most commonly prescribed classes of anti-hypertensive medicines were collected from three states in three different geopolitical zones in Nigeria following a semi-random sampling framework. Medicine samples were purchased by mystery shoppers from 22 pharmacy outlets from six local government areas across the three states. Medicine quality was determined by measuring the amount of stated active pharmaceutical ingredient using high-performance liquid chromatography with photodiode array detection and classified according to their compliance to the specified pharmacopeia tolerance, limits for each antihypertensive. Conclusion: More than a quarter of some commonly prescribed anti-hypertensive medicines available in Nigeria may be of substandard quality. Enhanced quality assurance processes in LMICs, such as Nigeria, are needed to support optimum management.

INTRODUCTION
Elevated 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 (LMICs). 1 High BP is also the leading cause of cardiovascular disease (CVD) and is responsible for 13% of deaths globally. 2,3 In most individuals, adequate management and control of BP is associated with a reduction in deaths and disability from a number of conditions including cerebrovascular, cardiovascular, and renal disease. 4 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 widespread access to good quality antihypertensive medicines is a critical component for achieving the goal. 5 The last decade has seen increasing attention focused on the quality of medicines available, especially antimalarials, and it has emerged that the availability of substandard medicines is widespread. 6 This 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 often have little or no active ingredient. 7 Substandard medicines are defined as medicines that are produced with inadequate attention to good manufacturing practices and may have contents or dissolution times that are outside the pharmacopeia specifications of acceptance limits range. [7][8][9][10][11] Substandard generic medicines are a major contributor 12 and have been shown to constitute 40-50% of all medicine supplies in Nigeria, 13 one-third of all antibiotics and anti-malarial medicines in Nigeria and Thailand and 9% of medicines in India. 14 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. 15 8 The US Pharmacopoeia (USP) medicine quality and information program listed antihypertensive medicines among a class of possible substandard medicines in the African region. 15 A study carried out in Philippines found that the antihypertensive medicine Adalat (Nifedipine) was one of the top five substandard medications. 16 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. Importantly, poor quality medicines can directly impact on the health of patients if their effectiveness is reduced and this may contribute to ongoing and worsening disease which in turn leads to an increase in population health and economic burden. 13 Therefore, the aim of this study was to determine the quality of generic antihypertensive medicines available in the retail market of Nigeria. Retailers at selected pharmacies were also surveyed for their opinions regarding falsified and substandard medicines in their local area.

MATERIALS AND METHODS
An observational study design was adopted. The methodology is detailed elsewhere and was based on published guidelines and recommendations. 17

Context
Nigeria was chosen as the country in which medicines will be collected for this study based on the knowledge that it is a LMIC with a large population who suffer from high prevalence of hypertension. It is the most densely populated country in Africa and according to the 9 World Health Organization, in 2016 over half a million Nigerians died from noncommunicable diseases, including cardiovascular diseases. 19 Population research has reported that 35% of Nigerian adults had elevated blood pressures in 2008 20 with rates being highest amongst urban dwellers. 21 Therefore, when combined with the large population, Nigeria contributes a substantial proportion of the total burden of hypertension in Africa. 22 This increasing burden requires that health planners and implementers ensure the availability of high quality evidence-based medicines for hypertension. 23

Geographical sampling framework
The stepwise and semi-random sampling framework developed to determine which retail outlets would eventually be included in the study has been detailed in our previous publication. 24 The purpose and concept behind the sampling framework was to identify a combination of urban and rural locations in northern and southern states of Nigeria via a stratified and systematic approach. Firstly, three states of Nigeria ( Figure 1) representing varied geopolitical areas were selected via consultation with local experts (purposive sample).
Secondly, for each state, one urban and one rural local government area (LGA) was randomly selected therefore, providing a total of six LGAs across the three states (three rural and three urban). Thirdly, geographical mapping software (QGIS Geographic Information System, version 2.8.3-Wien, 2015) was used to randomly select four geographical co-ordinates in each of the selected LGAs. Using those coordinates, the pharmacy outlet nearest to each of the coordinates was identified. The total sample included 22 retail outlets (pharmacy shops) from six LGAs across three states in different geopolitical zones of Nigeria.

Identification and collection of generic hypertensive medicines
For this study, the intention was to purchase samples of the generic brand antihypertensive medicines representing the two most commonly prescribed brands. The most two commonly prescribed antihypertensive medicines (Amlodipine and Lisinopril) prescribed in Nigeria were identified using the National Agency Food and Drug Administration and Control (NAFDAC) agencies publicly available data. A complete list of all available generic medicines for Amlodipine and Lisinopril was then obtained and a computerised random sequence was then used to randomly select 10 generic brands (where available) of each of Amlodipine and Lisinopril. Using this process, we aimed to collect approximately 20 generic medicines from each outlet for subsequent quality testing. Where less than 10 generic brands were available at an outlet, all available brands were collected.
To purchase the samples of generic medicines, a research assistant (who spoke local language) acted as a mystery shopper and visited each of the identified pharmacy outlets and systematically purchased a full box (usually 28 or 30 tablets) of each of the pre-selected generic brands for each medicine. The covert approach was used to minimise the risk that a seller might realise they are to be a part of a research project and therefore raise suspicion and minimise risk that the seller might decline to sell the required samples. In total, 361 samples

Classification and analysis of samples
Medicine quality was determined by measuring the SAPIs using HPLC-PDA and we classified samples according to the latest World Health Assembly definitions (falsified, substandard or unregistered) 25 and compliance with the authorised specifications published in USP monograph for each antihypertensive. 'Falsified' medicines are defined as medical products deliberately/fraudulently misrepresent their identity, composition or source. 25 'Substandard' medicines are "out of specification" and are defined as authorised medical products that fail to meet either their quality standards or their specifications, or both. 24 'Unregistered' is defined as any medical products that have not undergone evaluation and/or approval by the national or regional regulatory authority. 25

Medicine quality
Overall, 260 (72.0%) samples of antihypertensive were found to be compliant with the USP specified tolerance, limits range and hence classified as acceptable quality (will deliver the therapeutic dose) and 101 (28.0%) did not comply with the pharmacopeia specified tolerance, limits and hence classified as substandard ( and Portugal (n=1).

Pharmacy outlet survey
Provider surveys were collected from a total of 24 pharmacy outlets (13 urban and 11 rural).
The majority of those completing the survey, 71% were men and they had an average of 12.3 (± 9.10) years of experience. In 46% of the pharmacies, patients did not always need a prescription and only 29% (n=7) stored their medicines in an air-conditioned space. The 16 majority (16/22, 73%) of pharmacy providers stated that all patients paid for their medicines without insurance and 87% stated that the price difference between innovator and generic medicines was a hindrance to patients. In total 83% of those surveyed said they were aware of surveillance programs to check for falsified and substandard medicines, 87% claimed they knew how to report falsified and substandard medicines but only 21% had ever reported such an issue. In total, 46% reported that they had had reason to stock or sell medicines without a NAFDAC registration number. Only

DISCUSSION
This is one of the first studies to explore the quality of generic antihypertensive medicines in an African country, namely Nigeria. The results showed that more than a quarter of the samples analysed for content were of substandard quality but there were no falsified samples identified. Substandard medicines can lead to under dosing and overdosing. Overdosing on anti-hypertensives requires consumption of several times (up to 5 times) the therapeutic range. However, patients can experience side effects such as headaches, dizziness and palpitations on even taking double the required dose. Hence, taking a tablet which contains more than USP specified tolerance, limits range of SAPI may not in itself be enough to cause an "overdose". Moreover, many anti-hypertensive medicines have varying strengths (e.g. the strength of lisinopril varies from 5mg to 40 mg), so at present data is lacking on whether a dose of greater than the specified tolerance, limits range of SAPI for a 5mg tablet for example can be harmful to a particular patient. Both medicines analysed in this study, do not have a narrow therapeutic index so clinically, more harm will be done by having lower doses than the reverse.
The study also highlighted there is significant variation in cost of the generic antihypertensive medicines and that substandard quality medicines were more commonly collected from outlets located in rural areas. In addition, surveys of pharmacy retailers showed that many commonly do not require a prescription for patients to purchase antihypertensive medicines but that the majority were aware of surveillance programs aimed at falsified and substandard medicines. Also, most retailers knew how to report substandard medicines but only around 20% had ever done so.
Blood pressure lowering is one of the priority areas identified for action by the WHF if the target of a 25% reduction in premature CVD mortality by 2025 is to be achieved. 26 Therefore, understanding the quality of available antihypertensive medicines is also vital. Nigeria is a LMIC that is responsible for the greatest hypertension burden in Africa due to the combination of prevalence and population. 19 It is therefore anticipated that a representative sample from the three chosen Nigerian states is highly relevant and potentially generalisable across Africa and other developing countries. Whilst this research offers an initial step and suggests there is a high prevalence of substandard quality medicines, greater surveillance is needed. It is anticipated that the results will attract attention to the issue of substandard antihypertensive medicines and sensitise policy-makers, national drug regulatory authorities and governments so as to facilitate debate among health providers, national Cardiology 18 societies/associations and civil society organisations. Ultimately, improving medicine quality and associated surveillance will reduce the disease burden and improve health at a population level.
Whilst the public health and criminal issues associated with falsified medicines has gained increasing attention in recent years, the potential effects of substandard medicines cannot be underestimated and is emerging as a major health concern. A recent report highlights that substandard medicines are also reaching patients because of poor manufacturing and qualitycontrol practices in the production of genuine medicines (either innovator or generic). 27 In their review, Johnston and Holt (2014) found 29 studies where substandard quality medicines were identified and in some cases all the sampled antibiotics or antimalarials were found to contain API concentrations outside the quality limits range. 27 One small study tested the quality of antihypertensive medicines in Rwanda and found 20% of samples were substandard at the time of purchase. 28 Whilst the focus of the Rwandan study was on storage facilities, it found similar results to the present study in terms of substandard quality antihypertensives in Africa. Another African study tested 1185 samples from across 10 sub-Saharan African countries and found that among the generic medicines, 24% were of substandard quality. 29 In terms of storage, we found only 29% of outlets surveyed stored their medicines in air-conditioned spaces and given the average Nigerian climate, it is likely to indicate that the this may have impacted on medicine quality, stability and expiry. 27 Overall, the problem of substandard quality antihypertensive medicines has now been reported across several independent studies and hence requires urgent attention.
Given the prevalence of substandard antihypertensive medicines and the potential public health impact, the concept of improving the situation presents both challenges and opportunities. Johnston and Holt (2014) state that "a concerted effort is required on the part of governments, medicine manufacturers, charities and healthcare providers to ensure that only medicines of acceptable quality reach the patient." 27 In the present study, we found that most retailers were aware of potential surveillance programs but very few had ever report substandard of falsified medicines. Therefore, perhaps programs are there but more publicity, random checking and reinforcement is required to inform retailers and enable them to have the knowledge and skills to understand when and how to report substandard medicines and why it is important for public health within their country. Another important step is to continue to collect systematic data and gain a detailed and objective understanding of the problem across the supply chain including from manufacture to retail. 27 Overall, more research and surveillance will help sensitize policy makers, national drug regulatory authorities and key regional and national governments as well as facilitate discussion and debate among health providers, national cardiology societies/associations and civil society representatives. 23 For this research we limited the sample collection to three states of Nigeria because of the extent of hypertension in Nigeria and for practical reasons. However, extensive preliminary sampling processes were employed to a balance between generalisable and random collection. It should also be noted that despite rapid collection, attention to detail in terms of storage and analysis, some samples were past their expiry date at the time of laboratory period of four years and, removing samples from each site at regular intervals and measuring the SAPIs. Loss of SAPIs in these "naturally aged" samples was 0 to 7% over 3 years (~12 months beyond the stated expiry) and remained within the USP specified tolerance limits for each of those antimalarials. 30 In addition, this research was limited to generic medicines only and future research should also include innovator medicines. Despite this, the proliferation of generic medicines encouraged by national policies, makes this an essential group to understand and interrogate. Finally, the surveys conducted were limited to a relatively small number of retail outlets although these represented both rural and urban outlets and hence the results are considered highly generalisable.

CONCLUSIONS
More than a quarter of some commonly prescribed anti-hypertensive medicines available in Nigeria appear to be of substandard quality. However, no falsified samples of Amlodipine or Lisinopril were found. Provider surveys indicated that the majority of retailers were aware of surveillance programs to check for falsified and substandard medicines but that very few had ever made a prior report and there was a reported lack of awareness of guidelines. This study suggests that the quality of antihypertensive medications available in Nigeria is suboptimal and therefore public health management of hypertension could be negatively impacted. Our