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Clinical trials in the Middle East and North Africa (MENA) Region: Grandstanding or Grandeur?
Contemporary Clinical Trials 36 (2013) 704–710
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Contemporary Clinical Trials journal homepage: www.elsevier.com/locate/conclintrial
Clinical trials in the Middle East and North Africa (MENA) Region: Grandstanding or Grandeur? Satish Chandrasekhar Nair a,⁎, Halah Ibrahim a, David D. Celentano b a b
Department of Academic Affairs, Medical Affairs, Tawam Hospital, Post Box 15258, Al Ain United Arab Emirates Johns Hopkins University Bloomberg School of Public Health, Department of Epidemiology, 615N Wolfe Street, Suite W6041, Baltimore, MD 21205-2103, USA
a r t i c l e
i n f o
Article history: Received 1 March 2013 Received in revised form 9 May 2013 Accepted 17 May 2013 Available online 25 May 2013 Keywords: Middle East North Africa Clinical trials Regulatory Recruitment Disease pool Gas price index
a b s t r a c t Background: Nearly 31% of the world's clinical trials are conducted outside the US and 25% of the new drug applications include data from international sites. The high population growth, demand for medication, increased prevalence of life-style related and rare genetic diseases in the MENA countries should be associated with a consequent scale-up of clinical trials in these countries. However, the region sponsors under 1% of global clinical trials. Methods: Determinants including the regulatory environment, patient protection, physicianpreparedness, types of diseases, costs of trials and pace of subject recruitment, were analyzed to identify critical factors that influence barriers to the conduct clinical trials in MENA. Results: Strategic planning by the CRO can help overcome challenges related to regulatory and oversight requirements. Barriers related to trial quality and subject protection can be mitigated by risk-based monitoring. Growing healthcare infrastructure and communication technologies provide clear advantages for subject recruitment. Low operating costs combined with the increase in pharmaceutical sales provide incentives for the future conduct of clinical trials. Limitations: Although the opportunities and challenges cited are common to the MENA region, further studies are needed to assess other potential contributing variables for the conduct of clinical trials specific to each MENA country. Conclusion: Challenges in drug importation and site oversight can be overcome with systematic interventions. Social media network and community awareness programs can assist reductions in barriers in obtaining effective informed consents. Increasing pharmaceutical sales, population growth, high prevalence of genetic and life-style related diseases and reduced clinical trial development costs offer expanding opportunities for future clinical trials in MENA. © 2013 Elsevier Inc. All rights reserved.
1. Introduction The pharmaceutical industry is a leading global industry, exploiting recent revolutions in technological advances and taking advantage of trends in globalization to enhance its assets and thereby influencing global healthcare. Clinical trials are required to test the safety and efficacy of new drugs or devices to lessen the burden of common diseases such as cancer and diabetes. In the past quarter of a century, the pharmaceutical industry witnessed unparalleled growth ⁎ Corresponding author. Tel.: +971 50 3398701. E-mail address: [email protected] (S.C. Nair). 1551-7144/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cct.2013.05.009
in developed countries with sales performance outpacing GDP growth. In the 1990's less than 15% of clinical trials were conducted outside of the United States [1]. Recent reports indicate that nearly a third (31%) of the world's clinical trials are currently being conducted outside of the US and onequarter of investigational new drug (IND) applications include data from clinical trials conducted at international study sites [2]. Many of these clinical trials are conducted in lowand middle-income countries such as India, China, Egypt, the emerging economies of Central and Eastern Europe (CEE) and the Commonwealth of Independent States (CIS) [3]. In addition to regulatory reasons for the conduct of clinical trials in these diverse countries, strategic and economic factors have also
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stimulated the globalization of trials. The need for diverse patient populations for research, decreased trial costs, improved subject accrual, and access to rare diseases is an additional driving force for the expansion of international clinical research. The clear beneficiaries of the recent wave of globalization of clinical trials have been the CEE and the CIS countries. The CEE and CIS combined provided 10.74% of the total global clinical trial sites, ahead of both Latin America (4.6%) and Asia — excluding Japan (4.5%) [4]. The Middle East/Northern Africa (MENA) region covers a surface of nearly fifteen million square kilometers from Morocco to Iran and includes the six Gulf Cooperation Council (GCC) countries. The GCC is a political and economic union of six Arab states bordering the Persian Gulf (United Arab Emirates, Bahrain, Qatar, Kuwait, Oman and Saudi Arabia). The MENA region accounts for 385 million people or 6% of the world's population [5,6] and is growing at an average annual rate of 1.8% compared to the global population average growth of 1.2% [7]. Demand for medications in the region has surged because of high population growth, improved life expectancy, lower mortality rates and the increased prevalence of life-style related diseases, all associated with rapid economic development [4,5]. Yet, the optimism projected by pharmaceutical business forecasts has not been translated into a significant increase in trial participation in the MENA region, especially when compared to other emerging markets such as India, China, Russia and Mexico (Table 1). This review identifies the various challenges and opportunities for the expansion of clinical trials in the MENA region.
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to monitor and adhere to many regulatory changes. Clinical Research Organizations (CROs) and trial sponsors need to constantly monitor regulatory change to avoid delays or disruptions in on-going trials. Drug importation procedures required for new investigational drugs vary among the MENA countries [5]. Legal rights to experimental drugs can also vary from region to region. The process of importing an Investigational New Drug (IND) is dictated by each country's Ministry of Health and includes approval of each protocol by the involved institutions followed by research ethics committee approval [5]. Drug importers must adhere to country specific labeling, licensing, expiration and shipping requirements. Several countries in the MENA region, including Egypt, Jordan, Saudi Arabia and the United Arab Emirates, average 60–90 days for the overall approval time for investigational new drug importation, from the initial submission of the protocol to the research ethics committee to the first patient enrollment [5,8]. Poor protocol documentation and lack of consistent follow-up are major contributors to the delayed start of studies. CROs with a local presence have a substantial advantage in that they may better understand the local regulatory environment and the logistic needs specific to each country. It is not unusual for local CRO offices to collaborate with local drug depots to store medications and supplies, thereby reducing the risk of delays in the importation process. The establishment of local CROs will be an important step in overcoming the regulatory bottlenecks to conducting clinical trials in the MENA region. 2.2. Oversight
2. The challenges 2.1. Regulatory firewall One of the challenges in conducting clinical trials in countries new to research opportunities is the diligent need Table 1 Clinical trials in the MENA region in comparison to other emerging markets. Countries
2010 estimated population (million)
Number of open studies (Dec 2012)a
Number of studies with known status (Dec 2012)a
MENA (GCC) Bahrain Kuwait Oman Qatar Saudi Arabia UAE
1.2 3.5 2.7 1.7 28.3 8.2
2 13 6 16 105 17
13 40 16 36 235 66
MENA (non-GCC) Egypt Iran Morocco Syria Tunisia Turkey
82 73.9 32 20.1 10.4 72.7
115 73 13 5 35 265
395 424 64 11 133 1091
Other emerging markets China 1359 India 1220 Mexico 116.1 Russia 141.2
1400 505 843 515
3306 2136 3711 2182
a Data derived from clinicaltrials.gov (www.clinicaltrials.gov) accessed December 30 2012.
Oversight of a clinical trial is essential for the sponsor to ensure that the study is conducted in accordance with the protocol, following Good Clinical Practice (GCP), assessing Standard Operating Procedures (SOP) in accordance with standard regulatory requirements. The nature of monitoring is dictated by the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. Regardless of the study design and complexity, frequent visits by the sponsor monitor to the clinical investigator site to assess trial conduct and review data remain the primary method for sponsors to monitor trial progress. The time and financial investment for trial monitoring are significant factors discouraging the pharmaceutical industry from conducting clinical trials in the MENA countries [4,5,8]. Training local clinical staff to monitor trials in which they are not involved will enable more efficient management of trained human resources in the region and will also ensure trial quality [9]. Risk-based monitoring where the focus is on critical data elements that contribute to trial quality and subject protection is slowly gaining momentum and promises to overcome this identified oversight barrier. 2.3. Informed consent The principle of informed consent was born in the context of medical research where conflict can exist between the patient's and the physician-scientist's interests. It signifies the ethical and legal rights of the subject to be fully informed of the anticipated effects of the investigational drug and the responsibility of the physician to protect the subject from harm. The apex regulatory bodies, such as the European
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Medicines Agency and United States Food and Drug Administration, emphasize the need for subjects to fully understand the informed consent that details factors related to their care and participation in a clinical trial [10]. In multinational studies, it is critical that study materials be consistently and accurately translated to avoid miscommunication and consequent misinterpretation. Complete disclosure of complex medical procedures honestly and accurately, including potential benefits and risks, in a language that is easy to understand for the participating patient is essential [11]. Similar to India, China and Russia, informed consent in the MENA region is also subject to language, cultural and social challenges. Arabic is the most common language spoken by the national populations of the region. In most of the GCC, English, Urdu, Tagalog and Malayalam constitute 64% of the spoken languages of expatriates [8,12]. Adherence to the elements of informed consent, such as disclosure, comprehension, capacity, voluntariness and consent, becomes effective only when the consent documents are translated into each of the local languages of potential participants. Accurate translation presents its own challenges. For example, it is not uncommon to find “Investigator” translated in Arabic as “Interrogator,” which can have entirely different connotations. The issue is further compounded by the low literacy rates in the region. Based on the health literacy elements postulated by Baker et al. [13], our assessment of health literacy at a tertiary care center in the UAE indicated that nearly 19% of the patients are functionally illiterate and an additional 18% have marginal literacy skills (Table 2). These data suggest that a substantial number of patients may be unable to read and understand the consent forms. Investigators and sponsors are often challenged by the local research ethics committees because of the technical complexity of their consent forms. To overcome this challenge, consent forms must be simplified and translated (and back translated) in to several different languages. Clinical trial subjects must also be allowed adequate time to discuss trial requirements with their extended family in order to make informed decisions about their health and subsequent decision regarding trial enrollment. Another challenge common in the MENA region, especially in the GCC countries, is the difficulty to draw a clear distinction between “voluntary participation” and “free treatment opportunity.” Expatriates constitute 80–90% of the total population of the GCC countries and the vast majority of them are unskilled laborers [12]. Given the low wages and poor economic status of the expatriate laborers, great care must be taken to avoid exploitation of their financial situation. Informed consent challenges for clinical trials in the MENA in relation to language, cultural, social and health literacy are similar to other emerging regions. The growing popularity of social media network, smartphone technologies and community health awareness programs in the region should help to circumvent these challenges. 2.4. Medical schools and teaching hospitals The MENA region has a rich tradition in science and innovation. Nearly a millennium ago, IbnSina (or Avicenna) proposed the theory of applying logical systems to drug testing, while Al Razi (or Rhazes) stressed the need to produce proofof-concept in the practice of medicine [6]. MENA is the home to at least 74 medical schools and teaching hospitals, 34 of them
Table 2 Assessment of health literacy rates at Tawam Hospital, a tertiary care center in the emirate of Abu Dhabi, United Arab Emirates (N = 119). N (%) Gender Male Female
67 (56) 52 (44)
Age (years) 18–30 31–50 51–70 >71
18 38 49 14
Education Less than fifth grade High school Higher diploma/degree
63 (53) 30 (25) 26 (22)
Health literacy Adequate literacy Marginal literacy Inadequate literacy
75 (63) 22 (18) 23 (19)
(15) (32) (41) (12)
Health Literacy Survey Arabic (HLSA) was used to obtain information from adults visiting the hospital as Out Patients by a qualified health researcher. The interview questions in Arabic included the five domains, previously described by Baker et al. [13]. Of the 144 Out Patients from the polyclinic who agreed to participate between May 2012 and July 2012, only 121 signed informed consents and 119 completed the in-person interviews that included 16 screening questions for limited health literacy. The interview survey tool was pretested to obtain good internal consistency and reliability (Cronbachα = 0.88 for all items combined).
in the GCC states alone [8]. However, medical schools and teaching hospitals have poorly prepared their graduates to conduct scientific trials and clinical research. Research design and methodology is not included in the formal curriculum of most MENA medical schools or in post-graduate training programs. Additionally, there are very limited numbers of publications by MENA medical trainees in peer-reviewed journals. A lack of willingness of many physicians to encourage their patients to participate in clinical trials is another major challenge. Other barriers include the lack of protected time [14] for conducting clinical trials, communication difficulties between the mainly Arabic speaking trainees and the non-Arab speaking trial subjects, conflicts between the role of physician and that of a scientist, and the lack of rewards and recognition for physicians conducting research. Many barriers related to the system for physicians to participate in clinical research can be addressed through education and training in the fundamentals of clinical research design and methodology. To create a culture of innovation, clinical research education must be incorporated into the undergraduate medical education curriculum and post-graduate training, and then reinforced through continuing medical education. Recently, the GCC, led by Qatar and the emirate of Abu Dhabi in the UAE, has taken a bold initiative to embrace the standards of the Accreditation Council for Graduate Medical Education International (ACGME-I). Adopting these standards will help to create a generation of residents and medical students attuned to the research culture by fostering the development of inquiry and encouraging evidence-based medical practice.
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3. Opportunities 3.1. Disease pool Genetic and cultural differences within the local populations of the MENA offer unique opportunities for medical research. The different ethnicities, the high rate of consanguineous marriages and the geographic isolation of subpopulations making up the region all contribute to the distinct gene pool of the MENA region [15]. Community studies from Western countries show that approximately 3% of all pregnancies result in the birth of a child with a significant genetic disease that manifests as physical disability, mental retardation or early death [16]. Although genetic and congenital defects data are not easily available in the Arab communities, the high rate of consanguinity and lack of prenatal genetic screening indicate that these disorders are quiet frequent in the population. For example, the high prevalence of inherited blood disorders, such as sickle cell anemia and thalassemia, in the region prompted the Saudi government to institute mandatory pre-marriage screening in 2003 [17]. Epidemiological data for the region indicates a growing incidence of chronic respiratory diseases such as asthma, COPD and bronchitis [18]. Chronic respiratory diseases in Turkey contributed to 9% of the total mortality, between 3 and 5% for Qatar, Kuwait, Lebanon, and Tunisia and 2% for the UAE [18]. Additionally, despite the abundant sunshine which should facilitate vitamin D synthesis throughout the year, the MENA region registers the highest rates of hypovitaminosis D worldwide [19]. Children, adults, pregnant women and the elderly are equally affected. Studies indicate that 20–80% of apparently healthy individuals have suboptimal levels of vitamin D, thus exposing them to an increased fall risk, osteoporotic fractures in the elderly, poor skeletal health and a decline in muscular function [20].
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Metabolic risk prevalence data reflects the potential health risks for the population of this region. Alarmingly, nearly one-third of the MENA population [18] is obese and an additional third are at risk for hyperlipidemia, hypertension, diabetes and coronary heart disease (Fig. 1). At least 57% of the total deaths [18] on average (Fig. 2) in the region are due to the three major non-communicable diseases of cardiovascular disease (37%), cancer (13%) and diabetes (7%). In fact, the UAE has the second highest prevalence of diabetes in the world (18.7%) compared to the global average of 6.4% [21]. The International Diabetes Federation estimates a two-fold increase in Type I diabetes in children 14 years or younger by 2030 for the region [18,21]. The high prevalence of Type 2 diabetes among the local population in the GCC, particularly in the UAE, has encouraged the partnership between Imperial College London and Mubadala Development Company to establish diabetes treatment and research centers throughout the emirate of Abu Dhabi. There is also a high prevalence of hepatitis in the region, especially hepatitis C in Egypt. The World Health Organization (WHO) estimates that there are at least 21.3 million Hepatitis C Virus (HCV) carriers in the Eastern Mediterranean countries. There are two main patterns for the distribution of HCV genotypes in the Middle East: genotype 4 is prevalent in most of the Arab countries and genotype 1a or 1b in the non-Arab countries [22]. Genotype 4 presents the biggest challenge to hepatologists with its high percentage of treatment resistance [8]. The link between smoking and heart disease has been well described in populations all over the world. Although, specific statistics for cardiovascular disease across the MENA region are not available, the smoking prevalence for Saudi Arabia adults was approximately 22% [23]. Arab countries such as Bahrain, Lebanon and Tunisia, have significantly higher ratios of lung cancer incidence and mortalities in both
80 70
Prevalence %
60 50 40 Overweight 30
Obesity Diabetes
20 10 0
MENA Countries Fig. 1. Prevalence of overweight, obesity and diabetes in MENA countries. Data for the MENA region was compiled and generated from World Health Organization Non-communicable Diseases, Country profiles 2011 [18]. Body mass index: 25–29.9 (overweight) and >30 (obese).
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S.C. Nair et al. / Contemporary Clinical Trials 36 (2013) 704–710 Table 3 Comparison of clinical trial subject density and the number of clinical trial sites between the leader markets and emerging market such as MENA.
UAE Turkey
MENA Countries
Tunisia
Region
Syria Saudi Arabia Qatar
CVD Cancer Diabetes
Oman Morocco Kuwait Iran Egypt Bahrain 0
10
20
30
40
50
60
70
Percentage of Total Dealths Fig. 2. Contribution of CVD, cancer and diabetes towards the percentage of total deaths in MENA countries. Data for the MENA region was compiled and generated from World Health Organization Non-communicable Diseases, Country profiles 2011 [18].
males and females linked to the high prevalence of tobacco smoking [24]. The high prevalence of congenital, metabolic and life style related diseases in the population make the MENA region an ideal location for the conduct of clinical trials. 3.2. Recruitment Clinical trials are important for the advancement of medical science but are highly dependent on the recruitment of sufficient numbers of eligible subjects in a timely manner. Recruitment issues in the United States are a major reason for the increase in clinical trials in international sites. A recent report indicates that only 6% of eligible subjects actually participate in a clinical trial [25]. Despite the fact that subject recruitment costs amount to approximately 23% of the total trial cost, 87% of US trials fail to meet temporal recruitment and enrollment milestones [25]. In order to access the critical number of patients necessary for the development of large global programs, sponsors must recruit clinical trial subjects outside of traditional US markets to meet study goals. Despite its large population, the MENA region, excluding Israel, still accounts for only about 0.5% of global clinical trial sites. The clinical trial subject density, expressed as actual number of clinical trial subjects per million population is less than 1% for the MENA region [4]. This number reflects the fact that the region has a sizable population that has not yet been tapped (Table 3). A preferential advantage for recruitment from the MENA region is that the patients are study naïve and are not enrolled in competing clinical trials. Additionally, clinical trial productivity measured as aggregated average number of patients per site is almost two-fold higher in the MENA region than developed markets in the West [4]. Subject recruitment prospects in Egypt may be higher because of the large population, medical infrastructure and the relatively mature regulatory system. Subject recruitment is anticipated to grow significantly in the GCC cluster given the economic development,
Mature markets North America Western Europe Australia/New Zealand Emerging markets CEE & CIS Asia (with Japan)** Latin America MENA (without Israel) Arab Middle East GCC Cluster
Clinical trial subject densitya
Number of clinical trial sitesb
101 65 58
73,376.00 37,313.00 2800.00
98 5 17 0.7 0.5 0.1
16,255.00 11,263.00 6982.00 751.00 160.00 22.00
a Clinical trial subject density is expressed as actual number of clinical trial subjects per million population. b Japan contributed 4.427 CT sites to the total in Asia [26]. ⁎⁎ Indicates that Japan contributed 4427 of the total 11263 sites for Asia.
state-of-the-art hospitals and medical centers, joint ventures between public hospitals and international health care providers and the growth of Joint Commission International (JCI) accredited health facilities [26]. In addition, technological advancements of the GCC states such as internet connectivity and smartphones provide newer opportunities for patient recruitment and healthcare delivery models. The population characteristics, growing healthcare infrastructure and the state-of-the-art communication technologies provide clear advantages for clinical trial subject recruitment in the MENA region. 3.3. Cost saving Nearly one-third of Phase 3 trials for the 20 largest US pharmaceutical companies are being conducted outside of the United States and 55% of these sites are overseas [27]. One reason for outsourcing is that international clinical trials often cost less than they do in the US. Total trial costs, including costs for selection of a trial site, patient enrollment, experimental drug administration, subject monitoring and data management, all contribute to high trial costs. Large outcome trials that require enrollment of thousands of patients followed over lengthy periods of time can result in significant cost savings for the sponsor if the trial is conducted outside the US [28]. In the US, activities ranging from pre-IRB submission to post study follow up to enroll and treat a group of 20 study subjects have been estimated to consume up to 3900 h [29]. This is irrespective of whether it is a NIH sponsored clinical research study or an industry sponsored trial. Fifty-eight percent of those hours are for activities related to study office visits and 16% for data analysis and management. Physicians contributed less than 9%, nurses 32%, data managers 36%, and pharmacists and other administrators 23% [29]. Physician salary is a critical denominator for the cost effectiveness of a clinical trial [30]. MENA physicians are paid on average one-third less (range: 21–44%, unpublished observation) than their US counterparts. Clinical trial cost-savings for the MENA region, particularly the GCC states, was assessed relative to the global gas/petrol price index [31], which allows for objective comparison of costs
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between countries. Recently, analysis of several price movement factors indicated that oil and gas prices considerably affect Consumer Price Index and inflation [32]. Oil and gas prices affect basic elements of cost of living such as food, housing, clothing, transportation, personal care and entertainment. Using the gas price index, our data reflects that the MENA region may be promising for clinical trial cost savings (Table 4). Clinical trials cost significantly less (59%) in the GCC and MENA countries, respectively, as compared to the average total cost of 300 million US dollars for a clinical trial in the US [27,30]. Lower physician salaries and lower operating costs derived from low gas prices make the MENA region a financially attractive location for the conduct of clinical trials. 3.4. Emerging markets Global sales forecasts for the pharmaceutical industry in 2012 were expected to be around 960 billion US dollars, with the US and the European Union sales reaching 330 and 150 billion, respectively [33]. A July 2012 market forecast from IMS Health predicts annual spending on medicines in emerging markets to reach $ 375 billion in 2016 from a base of $ 194 billion in 2011 [24]. This increase is fueled by rising global incomes, improved access to treatment and the competitive costs of drugs. The Middle East combined with the African Pharmaceutical market is projected to grow at a compound annual growth rate of around 11–14% during 2010–2013 [34]. Additionally, economic development is changing the epidemiological health profile in the MENA region, with the increasing prevalence of non-communicable diseases thus increasing the Table 4 Average cost saving based on gas price index for conducting clinical trials in the MENA region. Countries
Gas price US $a
Mature regions United States UK Germany
1.02 1.92 1.9
1 1.88 1.86
0.8
0.78 22
0.61 0.51 0.69 0.69
0.59 0.50 0.68 0.68
0.27 0.22 0.31 0.22 0.16 0.47
0.26 0.22 0.30 0.21 0.16 0.46 59.30
Other emerging regions Russian Federation RF average cost saving (%)c MENA (non-GCC) Egypt Iran Syria Tunisia MENA(GCC) Bahrain Kuwait Oman Qatar Saudi Arabia UAE MENA average cost savingd(%)
Gas price indexb
a Gas/petrol (unleaded) was normalized to price per liter in US $ from data obtained from http://data.worldbank.org/indicator/EP.PMP.SGAS.CD and AIT/FIA Information Center-OTA on November 27, 2012. b Gas price index was derived using United States as the normalized bench mark at 1 $/L. c RF average cost saving is for Russian Federation or CIS countries. d Average cost saving for the MENA region and Russian Federation was estimated relative to the gas price index of the United States.
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overall pharmaceutical sales in this part of the world. Although Egypt, Jordan and Turkey boast robust domestic pharmaceutical manufacturing, population expansion is unable to meet domestic demands. The majority of the GCC countries are characterized by low domestic pharmaceutical production. While domestic manufacturing satisfies 90% of the demands in Egypt (predominantly generics), Saudi Arabia and other GCC countries import 85% of their pharmaceutical product [8]. Another indicator for growth in the GCC cluster is the average per capita expenditure on healthcare. GCC cluster spending at US $ 895 is placed higher than the global average (US $ 864). When compared to the UK (US $ 3285), Germany (US $ 4629) and the United States (US $ 7410), the average per capita expenditure on healthcare is at least 7–9 times less [5,8]. The expected growth of pharmaceutical sales alone is a strong driving force to move clinical trials to this emerging market region. CRO are an integral part of the drug development outsourcing of large pharmaceutical companies. CRO revenue, an indicator of the clinical trial industry performance, is expected to rise to US $ 32.7 billion in 2015 from US $ 21.6 billion in 2010 [5,6]. CRO roles include formulating protocols, generating regulatory documents, overseeing compliance, and monitoring and managing multiple sites within the realm of International Conference on Harmonization and Good Clinical Practice guidelines. Selection of the CROs by the pharmaceutical sponsors is based on several factors including cost effectiveness, familiarity with the local language, relationships with the institutions/investigators, audit status of the CRO and presence of local offices in the region. The MENA region has witnessed enhanced operations of several international and local CROs in the past five years. Although most countries in the MENA do not insist on licensing CROs, many require them to be registered in the country of operation. 4. Conclusion The unprecedented sales performance in mature economies of the world limited the pharmaceutical industry's ability to explore opportunities in regions such as Asia, Latin America and the MENA region. Globalization of clinical research ensures involvement of diverse patient populations and improved subject recruitment numbers and pace, both critical to hasten development and approval of new drugs, especially those that are life-saving, and make them available world-wide. Issues with legal rights to the experimental drug and delays caused by different drug importation procedures required by different ministries of health in the MENA region can be overcome by local CRO meticulous vigil over the regulatory and logistic needs of each specific country. The overall approval time of 60– 90 days in the MENA region is at par with mature markets such as Australia and that of China. The rising popularity of riskbased monitoring and cross-training of healthcare providers in the region should be an encouragement for sponsors to limit their own trial site monitoring. Similar to other emerging markets for clinical trials, informed consent in the MENA region is also subject to language, cultural, social and health literacy challenges. Social media network and smartphone technologies, aided by community health literacy education programs, should enable more effective recruitment and management of a large number of marginally and functionally illiterate research
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subjects. Mandatory introduction of clinical research curriculum in medical schools and investigator training on International Conference on Harmonization and Good Clinical Practice will diminish the gap in regional differences in the practice and reporting of clinical research. The distinct opportunities provided by the MENA region due to population growth, economic affordability, medication demand, lower mortality rates and increased prevalence of genetic and life-style related diseases suggest the high potential for clinical research. Faster recruitment pace, reduced clinical trial development costs and healthy global pharmaceutical sales forecast, further make this region attractive for the future conduct of clinical research. Abbreviations CEE Central and Eastern Europe CIS Commonwealth of Independent States CROs Clinical Research Organizations CVD Cardio Vascular Diseases GCC Gulf Cooperation Council GDP Gross Domestic Product IND Investigational New Drug SOP Standard Operating Procedures
Submission declaration The authors declare that this manuscript has not been previously published and is not under consideration for publication elsewhere and, further that it is approved by all authors. Acknowledgments The authors wish to thank Dr. Ronald Krall, Steamboats Spring, Colorado, USA for reading a draft of the manuscript. SCN was awarded “Leadership in Global Clinical Research Awareness 2012” by the ACRP (USA) and GCC, the outstanding chapter outside the US. The study was granted ethics approval by the Al Ain Medical District Human Research Ethics Committee (AAMDHREC) #12/55. MindSmart UAE is acknowledged for technical assistance with the manuscript. This study was not supported by grants/funds except for time to conduct the study for the principal investigator (SCN) and collaborators (HI) by Tawam Hospital and Johns Hopkins Bloomberg School of Public Health (DDC). References [1] Smith WT. FDA requires foreign clinical studies be in accordance with good clinical practices to better protect human subjects. ABA Health Source 2008;5:1–3. [2] Rajadhyaksha V. Conducting feasibilities in clinical trials: an investment to ensure a good study. Perspect Clin Res 2010;1:106–9. [3] Desai PB, Anderson C, Sietsama WK. A comparison of the quality of data assessed using query rates from clinical trials conducted across developed versus emerging regions. Drug Info J 2012;46:455–63. [4] Misik V. Shifting sands. Eur Pharma Contract September 2011:66–70. [5] Nair SC. Clinical trials opportunities and challenges: Middle East and North Africa (MENA) Region. In: Kinkley S, editor. ACRP Annual Conference, Seattle, WA 10–15April 2011, paper noS702. Virginia: ACRP; 2011.
[6] Al-Rawi Y, Al-Tajir G. MENA Region. ACRP Monitor; September 2012 33–7. [7] United Nations, Department of Economic and Social Affairs — Population Division, Population Estimates and Projections Section — World Population Prospects (2010 Revision) accessed December 30 2012. [8] Nair SC. Critical components for the conduct of effective clinical trials in the UAE. Next Level Pharma conference on Achieving Clinical & Regulatory Excellence in Turkey, the Middle East & North Africa. Istanbul, Turkey, 7–9 June 2012, Paper no. G121; 2012. [9] Nyka A, Kilama W, Ghilengi R, Tangwa G, Tindana P, Ndebele P, et al. Composition, training needs and independence of ethic review committees across Africa: are the gatekeepers rising to emerging challenges. J Med Ethics 2009;35:189–93. [10] Nightingale SL. Regulatory overview: protection of human subjects — IRBs and informed consents. Drug Info J 1987;2:15–6. [11] Kegley JAK. Challenges to informed consent. EMBO 2004;5:832–5. [12] Kapiszewski A. Arab versus Asian migrant workers in the GCC countries. Conference on Transnational Migration-Foreign Labor and Its Impact in the Gulf. Italy: Bellagio Center; June 20–25, 2005. [13] Baker DW, Parker RM, Williams MV, Pitkin K, Parikh NS, Coates W, et al. The health care experience of patients with low literacy. Arch Fam Med 1996;5:329–34. [14] Young RA, Dehaven MJ, Passmore C, Baumer JG. Research participation, protected time, and research output by family physicians in family medicine residencies. Fam Med 2006;38:341–8. [15] Steensma DP, Hoyer JD, Fairbanks VF. Hereditary red blood cell disorders in Middle Eastern patients. Mayo Clin Proc 2001;76:85–93. [16] Center for Disease Control. Update on overall prevalence of major birth defects. MMWR 2008;57(01):1–5. [17] Al-Shahrani M. Steps toward the prevention of hemoglobinopathies in the kingdom of Saudi Arabia. Hemoglobin 2009;33(Suppl. 1):S21–4. [18] World Health Organization non-communicable diseases, Country profiles 2011 accessed December 31 2012. [19] Fuleihan GEH. Vitamin D, deficiency in the Middle East and its health consequences for children and adults. Clin Rev Bone Miner Metab 2009;7:77–93. [20] Gannage-Yared MH, Maalouf G, Khalife S, Challita S, Yaghi Y, Ziade N, et al. Prevalence and predictors of vitamin D inadequacy amongst Lebanese osteoporotic women Br. J Nutr 2009;101:487–91. [21] Fahed AC, El-Hage-Sleiman AKM, Farhat TI, Nemer GM. Diet, genetics, and disease: a focus on the Middle East and North Africa Region. J Nutr Metab 2012:1–19. [22] Ramia S, Eid-Fares J. Distribution of hepatitis C virus genotypes in the Middle East. Int J Infect Dis 2006;10(4):272–7. [23] Bassiony MM. Smoking in Saudi Arabia. Saudi Med J 2009;30:876–81. [24] Elsayed SI, Jazieh AR, Moore MA. Lung cancer incidence in the Arab league countries; risk factors and control. Asia Pac J Cancer Prev 2011;12:17–34. [25] Bansal N. The opportunities and challenges in conducting clinical trials globally. Clin Res Regul Aff 2012;29:9–14. [26] Misik V. Expected growth of industry-sponsored clinical trials in the Middle East bench marked on other global regions.http://www.quintiles. com/information-library/media-coverage . [accessed August 2012]. [27] Glickman SW, McHutchison JG, Peterson ED, Caims CB, Harrington RA, Califf RM, et al. Ethical and scientific implications of the globalization of clinical research. New England J Med 2009;360:816–23. [28] Malakoff D. Clinical trials and tribulations: spiraling costs threaten gridlock. Science 2008;322:210–3. [29] Emanuel EJ, Schnipper LE, Kamin DY, Levinson J, Lichter AS. The costs of conducting clinical research. J Clin Oncol 2003;21:4145–50. [30] Johnston SC, Hauser SL. Clinical trials cost: rising limit innovation. Ann Neurol 2007;62(6):A6–7. [31] World Bank. Global indicator.http://data.worldbank.org/indicator/EP. PMP.SGAS.CD&AIT/FIA . [information center OTA accessed December 30 2012]. [32] Ajmera R, Kook N, Crilley J. Impact of commodity price movements on CPI inflation. Mon Labor Rev April 2012:29–41. [33] Sales forecast for Global Pharmaceutical Business.http://www.statista. com/statistics/215817/sales-forecast-for-the-pharmaceuticalindustry-worldwide-by-region/ . [accessed October 29 2012]. [34] IMS Health. The global use of medicines: outlook through 2016.http:// www.imshealth.com/portal/site/ims/menuitem./?vgnextoid= 4d47d1822e678310VgnVCM10000076192ca2RCRD[accessed October 29 2012].
Contents lists available at ScienceDirect
Contemporary Clinical Trials journal homepage: www.elsevier.com/locate/conclintrial
Clinical trials in the Middle East and North Africa (MENA) Region: Grandstanding or Grandeur? Satish Chandrasekhar Nair a,⁎, Halah Ibrahim a, David D. Celentano b a b
Department of Academic Affairs, Medical Affairs, Tawam Hospital, Post Box 15258, Al Ain United Arab Emirates Johns Hopkins University Bloomberg School of Public Health, Department of Epidemiology, 615N Wolfe Street, Suite W6041, Baltimore, MD 21205-2103, USA
a r t i c l e
i n f o
Article history: Received 1 March 2013 Received in revised form 9 May 2013 Accepted 17 May 2013 Available online 25 May 2013 Keywords: Middle East North Africa Clinical trials Regulatory Recruitment Disease pool Gas price index
a b s t r a c t Background: Nearly 31% of the world's clinical trials are conducted outside the US and 25% of the new drug applications include data from international sites. The high population growth, demand for medication, increased prevalence of life-style related and rare genetic diseases in the MENA countries should be associated with a consequent scale-up of clinical trials in these countries. However, the region sponsors under 1% of global clinical trials. Methods: Determinants including the regulatory environment, patient protection, physicianpreparedness, types of diseases, costs of trials and pace of subject recruitment, were analyzed to identify critical factors that influence barriers to the conduct clinical trials in MENA. Results: Strategic planning by the CRO can help overcome challenges related to regulatory and oversight requirements. Barriers related to trial quality and subject protection can be mitigated by risk-based monitoring. Growing healthcare infrastructure and communication technologies provide clear advantages for subject recruitment. Low operating costs combined with the increase in pharmaceutical sales provide incentives for the future conduct of clinical trials. Limitations: Although the opportunities and challenges cited are common to the MENA region, further studies are needed to assess other potential contributing variables for the conduct of clinical trials specific to each MENA country. Conclusion: Challenges in drug importation and site oversight can be overcome with systematic interventions. Social media network and community awareness programs can assist reductions in barriers in obtaining effective informed consents. Increasing pharmaceutical sales, population growth, high prevalence of genetic and life-style related diseases and reduced clinical trial development costs offer expanding opportunities for future clinical trials in MENA. © 2013 Elsevier Inc. All rights reserved.
1. Introduction The pharmaceutical industry is a leading global industry, exploiting recent revolutions in technological advances and taking advantage of trends in globalization to enhance its assets and thereby influencing global healthcare. Clinical trials are required to test the safety and efficacy of new drugs or devices to lessen the burden of common diseases such as cancer and diabetes. In the past quarter of a century, the pharmaceutical industry witnessed unparalleled growth ⁎ Corresponding author. Tel.: +971 50 3398701. E-mail address: [email protected] (S.C. Nair). 1551-7144/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cct.2013.05.009
in developed countries with sales performance outpacing GDP growth. In the 1990's less than 15% of clinical trials were conducted outside of the United States [1]. Recent reports indicate that nearly a third (31%) of the world's clinical trials are currently being conducted outside of the US and onequarter of investigational new drug (IND) applications include data from clinical trials conducted at international study sites [2]. Many of these clinical trials are conducted in lowand middle-income countries such as India, China, Egypt, the emerging economies of Central and Eastern Europe (CEE) and the Commonwealth of Independent States (CIS) [3]. In addition to regulatory reasons for the conduct of clinical trials in these diverse countries, strategic and economic factors have also
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stimulated the globalization of trials. The need for diverse patient populations for research, decreased trial costs, improved subject accrual, and access to rare diseases is an additional driving force for the expansion of international clinical research. The clear beneficiaries of the recent wave of globalization of clinical trials have been the CEE and the CIS countries. The CEE and CIS combined provided 10.74% of the total global clinical trial sites, ahead of both Latin America (4.6%) and Asia — excluding Japan (4.5%) [4]. The Middle East/Northern Africa (MENA) region covers a surface of nearly fifteen million square kilometers from Morocco to Iran and includes the six Gulf Cooperation Council (GCC) countries. The GCC is a political and economic union of six Arab states bordering the Persian Gulf (United Arab Emirates, Bahrain, Qatar, Kuwait, Oman and Saudi Arabia). The MENA region accounts for 385 million people or 6% of the world's population [5,6] and is growing at an average annual rate of 1.8% compared to the global population average growth of 1.2% [7]. Demand for medications in the region has surged because of high population growth, improved life expectancy, lower mortality rates and the increased prevalence of life-style related diseases, all associated with rapid economic development [4,5]. Yet, the optimism projected by pharmaceutical business forecasts has not been translated into a significant increase in trial participation in the MENA region, especially when compared to other emerging markets such as India, China, Russia and Mexico (Table 1). This review identifies the various challenges and opportunities for the expansion of clinical trials in the MENA region.
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to monitor and adhere to many regulatory changes. Clinical Research Organizations (CROs) and trial sponsors need to constantly monitor regulatory change to avoid delays or disruptions in on-going trials. Drug importation procedures required for new investigational drugs vary among the MENA countries [5]. Legal rights to experimental drugs can also vary from region to region. The process of importing an Investigational New Drug (IND) is dictated by each country's Ministry of Health and includes approval of each protocol by the involved institutions followed by research ethics committee approval [5]. Drug importers must adhere to country specific labeling, licensing, expiration and shipping requirements. Several countries in the MENA region, including Egypt, Jordan, Saudi Arabia and the United Arab Emirates, average 60–90 days for the overall approval time for investigational new drug importation, from the initial submission of the protocol to the research ethics committee to the first patient enrollment [5,8]. Poor protocol documentation and lack of consistent follow-up are major contributors to the delayed start of studies. CROs with a local presence have a substantial advantage in that they may better understand the local regulatory environment and the logistic needs specific to each country. It is not unusual for local CRO offices to collaborate with local drug depots to store medications and supplies, thereby reducing the risk of delays in the importation process. The establishment of local CROs will be an important step in overcoming the regulatory bottlenecks to conducting clinical trials in the MENA region. 2.2. Oversight
2. The challenges 2.1. Regulatory firewall One of the challenges in conducting clinical trials in countries new to research opportunities is the diligent need Table 1 Clinical trials in the MENA region in comparison to other emerging markets. Countries
2010 estimated population (million)
Number of open studies (Dec 2012)a
Number of studies with known status (Dec 2012)a
MENA (GCC) Bahrain Kuwait Oman Qatar Saudi Arabia UAE
1.2 3.5 2.7 1.7 28.3 8.2
2 13 6 16 105 17
13 40 16 36 235 66
MENA (non-GCC) Egypt Iran Morocco Syria Tunisia Turkey
82 73.9 32 20.1 10.4 72.7
115 73 13 5 35 265
395 424 64 11 133 1091
Other emerging markets China 1359 India 1220 Mexico 116.1 Russia 141.2
1400 505 843 515
3306 2136 3711 2182
a Data derived from clinicaltrials.gov (www.clinicaltrials.gov) accessed December 30 2012.
Oversight of a clinical trial is essential for the sponsor to ensure that the study is conducted in accordance with the protocol, following Good Clinical Practice (GCP), assessing Standard Operating Procedures (SOP) in accordance with standard regulatory requirements. The nature of monitoring is dictated by the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. Regardless of the study design and complexity, frequent visits by the sponsor monitor to the clinical investigator site to assess trial conduct and review data remain the primary method for sponsors to monitor trial progress. The time and financial investment for trial monitoring are significant factors discouraging the pharmaceutical industry from conducting clinical trials in the MENA countries [4,5,8]. Training local clinical staff to monitor trials in which they are not involved will enable more efficient management of trained human resources in the region and will also ensure trial quality [9]. Risk-based monitoring where the focus is on critical data elements that contribute to trial quality and subject protection is slowly gaining momentum and promises to overcome this identified oversight barrier. 2.3. Informed consent The principle of informed consent was born in the context of medical research where conflict can exist between the patient's and the physician-scientist's interests. It signifies the ethical and legal rights of the subject to be fully informed of the anticipated effects of the investigational drug and the responsibility of the physician to protect the subject from harm. The apex regulatory bodies, such as the European
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Medicines Agency and United States Food and Drug Administration, emphasize the need for subjects to fully understand the informed consent that details factors related to their care and participation in a clinical trial [10]. In multinational studies, it is critical that study materials be consistently and accurately translated to avoid miscommunication and consequent misinterpretation. Complete disclosure of complex medical procedures honestly and accurately, including potential benefits and risks, in a language that is easy to understand for the participating patient is essential [11]. Similar to India, China and Russia, informed consent in the MENA region is also subject to language, cultural and social challenges. Arabic is the most common language spoken by the national populations of the region. In most of the GCC, English, Urdu, Tagalog and Malayalam constitute 64% of the spoken languages of expatriates [8,12]. Adherence to the elements of informed consent, such as disclosure, comprehension, capacity, voluntariness and consent, becomes effective only when the consent documents are translated into each of the local languages of potential participants. Accurate translation presents its own challenges. For example, it is not uncommon to find “Investigator” translated in Arabic as “Interrogator,” which can have entirely different connotations. The issue is further compounded by the low literacy rates in the region. Based on the health literacy elements postulated by Baker et al. [13], our assessment of health literacy at a tertiary care center in the UAE indicated that nearly 19% of the patients are functionally illiterate and an additional 18% have marginal literacy skills (Table 2). These data suggest that a substantial number of patients may be unable to read and understand the consent forms. Investigators and sponsors are often challenged by the local research ethics committees because of the technical complexity of their consent forms. To overcome this challenge, consent forms must be simplified and translated (and back translated) in to several different languages. Clinical trial subjects must also be allowed adequate time to discuss trial requirements with their extended family in order to make informed decisions about their health and subsequent decision regarding trial enrollment. Another challenge common in the MENA region, especially in the GCC countries, is the difficulty to draw a clear distinction between “voluntary participation” and “free treatment opportunity.” Expatriates constitute 80–90% of the total population of the GCC countries and the vast majority of them are unskilled laborers [12]. Given the low wages and poor economic status of the expatriate laborers, great care must be taken to avoid exploitation of their financial situation. Informed consent challenges for clinical trials in the MENA in relation to language, cultural, social and health literacy are similar to other emerging regions. The growing popularity of social media network, smartphone technologies and community health awareness programs in the region should help to circumvent these challenges. 2.4. Medical schools and teaching hospitals The MENA region has a rich tradition in science and innovation. Nearly a millennium ago, IbnSina (or Avicenna) proposed the theory of applying logical systems to drug testing, while Al Razi (or Rhazes) stressed the need to produce proofof-concept in the practice of medicine [6]. MENA is the home to at least 74 medical schools and teaching hospitals, 34 of them
Table 2 Assessment of health literacy rates at Tawam Hospital, a tertiary care center in the emirate of Abu Dhabi, United Arab Emirates (N = 119). N (%) Gender Male Female
67 (56) 52 (44)
Age (years) 18–30 31–50 51–70 >71
18 38 49 14
Education Less than fifth grade High school Higher diploma/degree
63 (53) 30 (25) 26 (22)
Health literacy Adequate literacy Marginal literacy Inadequate literacy
75 (63) 22 (18) 23 (19)
(15) (32) (41) (12)
Health Literacy Survey Arabic (HLSA) was used to obtain information from adults visiting the hospital as Out Patients by a qualified health researcher. The interview questions in Arabic included the five domains, previously described by Baker et al. [13]. Of the 144 Out Patients from the polyclinic who agreed to participate between May 2012 and July 2012, only 121 signed informed consents and 119 completed the in-person interviews that included 16 screening questions for limited health literacy. The interview survey tool was pretested to obtain good internal consistency and reliability (Cronbachα = 0.88 for all items combined).
in the GCC states alone [8]. However, medical schools and teaching hospitals have poorly prepared their graduates to conduct scientific trials and clinical research. Research design and methodology is not included in the formal curriculum of most MENA medical schools or in post-graduate training programs. Additionally, there are very limited numbers of publications by MENA medical trainees in peer-reviewed journals. A lack of willingness of many physicians to encourage their patients to participate in clinical trials is another major challenge. Other barriers include the lack of protected time [14] for conducting clinical trials, communication difficulties between the mainly Arabic speaking trainees and the non-Arab speaking trial subjects, conflicts between the role of physician and that of a scientist, and the lack of rewards and recognition for physicians conducting research. Many barriers related to the system for physicians to participate in clinical research can be addressed through education and training in the fundamentals of clinical research design and methodology. To create a culture of innovation, clinical research education must be incorporated into the undergraduate medical education curriculum and post-graduate training, and then reinforced through continuing medical education. Recently, the GCC, led by Qatar and the emirate of Abu Dhabi in the UAE, has taken a bold initiative to embrace the standards of the Accreditation Council for Graduate Medical Education International (ACGME-I). Adopting these standards will help to create a generation of residents and medical students attuned to the research culture by fostering the development of inquiry and encouraging evidence-based medical practice.
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3. Opportunities 3.1. Disease pool Genetic and cultural differences within the local populations of the MENA offer unique opportunities for medical research. The different ethnicities, the high rate of consanguineous marriages and the geographic isolation of subpopulations making up the region all contribute to the distinct gene pool of the MENA region [15]. Community studies from Western countries show that approximately 3% of all pregnancies result in the birth of a child with a significant genetic disease that manifests as physical disability, mental retardation or early death [16]. Although genetic and congenital defects data are not easily available in the Arab communities, the high rate of consanguinity and lack of prenatal genetic screening indicate that these disorders are quiet frequent in the population. For example, the high prevalence of inherited blood disorders, such as sickle cell anemia and thalassemia, in the region prompted the Saudi government to institute mandatory pre-marriage screening in 2003 [17]. Epidemiological data for the region indicates a growing incidence of chronic respiratory diseases such as asthma, COPD and bronchitis [18]. Chronic respiratory diseases in Turkey contributed to 9% of the total mortality, between 3 and 5% for Qatar, Kuwait, Lebanon, and Tunisia and 2% for the UAE [18]. Additionally, despite the abundant sunshine which should facilitate vitamin D synthesis throughout the year, the MENA region registers the highest rates of hypovitaminosis D worldwide [19]. Children, adults, pregnant women and the elderly are equally affected. Studies indicate that 20–80% of apparently healthy individuals have suboptimal levels of vitamin D, thus exposing them to an increased fall risk, osteoporotic fractures in the elderly, poor skeletal health and a decline in muscular function [20].
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Metabolic risk prevalence data reflects the potential health risks for the population of this region. Alarmingly, nearly one-third of the MENA population [18] is obese and an additional third are at risk for hyperlipidemia, hypertension, diabetes and coronary heart disease (Fig. 1). At least 57% of the total deaths [18] on average (Fig. 2) in the region are due to the three major non-communicable diseases of cardiovascular disease (37%), cancer (13%) and diabetes (7%). In fact, the UAE has the second highest prevalence of diabetes in the world (18.7%) compared to the global average of 6.4% [21]. The International Diabetes Federation estimates a two-fold increase in Type I diabetes in children 14 years or younger by 2030 for the region [18,21]. The high prevalence of Type 2 diabetes among the local population in the GCC, particularly in the UAE, has encouraged the partnership between Imperial College London and Mubadala Development Company to establish diabetes treatment and research centers throughout the emirate of Abu Dhabi. There is also a high prevalence of hepatitis in the region, especially hepatitis C in Egypt. The World Health Organization (WHO) estimates that there are at least 21.3 million Hepatitis C Virus (HCV) carriers in the Eastern Mediterranean countries. There are two main patterns for the distribution of HCV genotypes in the Middle East: genotype 4 is prevalent in most of the Arab countries and genotype 1a or 1b in the non-Arab countries [22]. Genotype 4 presents the biggest challenge to hepatologists with its high percentage of treatment resistance [8]. The link between smoking and heart disease has been well described in populations all over the world. Although, specific statistics for cardiovascular disease across the MENA region are not available, the smoking prevalence for Saudi Arabia adults was approximately 22% [23]. Arab countries such as Bahrain, Lebanon and Tunisia, have significantly higher ratios of lung cancer incidence and mortalities in both
80 70
Prevalence %
60 50 40 Overweight 30
Obesity Diabetes
20 10 0
MENA Countries Fig. 1. Prevalence of overweight, obesity and diabetes in MENA countries. Data for the MENA region was compiled and generated from World Health Organization Non-communicable Diseases, Country profiles 2011 [18]. Body mass index: 25–29.9 (overweight) and >30 (obese).
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S.C. Nair et al. / Contemporary Clinical Trials 36 (2013) 704–710 Table 3 Comparison of clinical trial subject density and the number of clinical trial sites between the leader markets and emerging market such as MENA.
UAE Turkey
MENA Countries
Tunisia
Region
Syria Saudi Arabia Qatar
CVD Cancer Diabetes
Oman Morocco Kuwait Iran Egypt Bahrain 0
10
20
30
40
50
60
70
Percentage of Total Dealths Fig. 2. Contribution of CVD, cancer and diabetes towards the percentage of total deaths in MENA countries. Data for the MENA region was compiled and generated from World Health Organization Non-communicable Diseases, Country profiles 2011 [18].
males and females linked to the high prevalence of tobacco smoking [24]. The high prevalence of congenital, metabolic and life style related diseases in the population make the MENA region an ideal location for the conduct of clinical trials. 3.2. Recruitment Clinical trials are important for the advancement of medical science but are highly dependent on the recruitment of sufficient numbers of eligible subjects in a timely manner. Recruitment issues in the United States are a major reason for the increase in clinical trials in international sites. A recent report indicates that only 6% of eligible subjects actually participate in a clinical trial [25]. Despite the fact that subject recruitment costs amount to approximately 23% of the total trial cost, 87% of US trials fail to meet temporal recruitment and enrollment milestones [25]. In order to access the critical number of patients necessary for the development of large global programs, sponsors must recruit clinical trial subjects outside of traditional US markets to meet study goals. Despite its large population, the MENA region, excluding Israel, still accounts for only about 0.5% of global clinical trial sites. The clinical trial subject density, expressed as actual number of clinical trial subjects per million population is less than 1% for the MENA region [4]. This number reflects the fact that the region has a sizable population that has not yet been tapped (Table 3). A preferential advantage for recruitment from the MENA region is that the patients are study naïve and are not enrolled in competing clinical trials. Additionally, clinical trial productivity measured as aggregated average number of patients per site is almost two-fold higher in the MENA region than developed markets in the West [4]. Subject recruitment prospects in Egypt may be higher because of the large population, medical infrastructure and the relatively mature regulatory system. Subject recruitment is anticipated to grow significantly in the GCC cluster given the economic development,
Mature markets North America Western Europe Australia/New Zealand Emerging markets CEE & CIS Asia (with Japan)** Latin America MENA (without Israel) Arab Middle East GCC Cluster
Clinical trial subject densitya
Number of clinical trial sitesb
101 65 58
73,376.00 37,313.00 2800.00
98 5 17 0.7 0.5 0.1
16,255.00 11,263.00 6982.00 751.00 160.00 22.00
a Clinical trial subject density is expressed as actual number of clinical trial subjects per million population. b Japan contributed 4.427 CT sites to the total in Asia [26]. ⁎⁎ Indicates that Japan contributed 4427 of the total 11263 sites for Asia.
state-of-the-art hospitals and medical centers, joint ventures between public hospitals and international health care providers and the growth of Joint Commission International (JCI) accredited health facilities [26]. In addition, technological advancements of the GCC states such as internet connectivity and smartphones provide newer opportunities for patient recruitment and healthcare delivery models. The population characteristics, growing healthcare infrastructure and the state-of-the-art communication technologies provide clear advantages for clinical trial subject recruitment in the MENA region. 3.3. Cost saving Nearly one-third of Phase 3 trials for the 20 largest US pharmaceutical companies are being conducted outside of the United States and 55% of these sites are overseas [27]. One reason for outsourcing is that international clinical trials often cost less than they do in the US. Total trial costs, including costs for selection of a trial site, patient enrollment, experimental drug administration, subject monitoring and data management, all contribute to high trial costs. Large outcome trials that require enrollment of thousands of patients followed over lengthy periods of time can result in significant cost savings for the sponsor if the trial is conducted outside the US [28]. In the US, activities ranging from pre-IRB submission to post study follow up to enroll and treat a group of 20 study subjects have been estimated to consume up to 3900 h [29]. This is irrespective of whether it is a NIH sponsored clinical research study or an industry sponsored trial. Fifty-eight percent of those hours are for activities related to study office visits and 16% for data analysis and management. Physicians contributed less than 9%, nurses 32%, data managers 36%, and pharmacists and other administrators 23% [29]. Physician salary is a critical denominator for the cost effectiveness of a clinical trial [30]. MENA physicians are paid on average one-third less (range: 21–44%, unpublished observation) than their US counterparts. Clinical trial cost-savings for the MENA region, particularly the GCC states, was assessed relative to the global gas/petrol price index [31], which allows for objective comparison of costs
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between countries. Recently, analysis of several price movement factors indicated that oil and gas prices considerably affect Consumer Price Index and inflation [32]. Oil and gas prices affect basic elements of cost of living such as food, housing, clothing, transportation, personal care and entertainment. Using the gas price index, our data reflects that the MENA region may be promising for clinical trial cost savings (Table 4). Clinical trials cost significantly less (59%) in the GCC and MENA countries, respectively, as compared to the average total cost of 300 million US dollars for a clinical trial in the US [27,30]. Lower physician salaries and lower operating costs derived from low gas prices make the MENA region a financially attractive location for the conduct of clinical trials. 3.4. Emerging markets Global sales forecasts for the pharmaceutical industry in 2012 were expected to be around 960 billion US dollars, with the US and the European Union sales reaching 330 and 150 billion, respectively [33]. A July 2012 market forecast from IMS Health predicts annual spending on medicines in emerging markets to reach $ 375 billion in 2016 from a base of $ 194 billion in 2011 [24]. This increase is fueled by rising global incomes, improved access to treatment and the competitive costs of drugs. The Middle East combined with the African Pharmaceutical market is projected to grow at a compound annual growth rate of around 11–14% during 2010–2013 [34]. Additionally, economic development is changing the epidemiological health profile in the MENA region, with the increasing prevalence of non-communicable diseases thus increasing the Table 4 Average cost saving based on gas price index for conducting clinical trials in the MENA region. Countries
Gas price US $a
Mature regions United States UK Germany
1.02 1.92 1.9
1 1.88 1.86
0.8
0.78 22
0.61 0.51 0.69 0.69
0.59 0.50 0.68 0.68
0.27 0.22 0.31 0.22 0.16 0.47
0.26 0.22 0.30 0.21 0.16 0.46 59.30
Other emerging regions Russian Federation RF average cost saving (%)c MENA (non-GCC) Egypt Iran Syria Tunisia MENA(GCC) Bahrain Kuwait Oman Qatar Saudi Arabia UAE MENA average cost savingd(%)
Gas price indexb
a Gas/petrol (unleaded) was normalized to price per liter in US $ from data obtained from http://data.worldbank.org/indicator/EP.PMP.SGAS.CD and AIT/FIA Information Center-OTA on November 27, 2012. b Gas price index was derived using United States as the normalized bench mark at 1 $/L. c RF average cost saving is for Russian Federation or CIS countries. d Average cost saving for the MENA region and Russian Federation was estimated relative to the gas price index of the United States.
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overall pharmaceutical sales in this part of the world. Although Egypt, Jordan and Turkey boast robust domestic pharmaceutical manufacturing, population expansion is unable to meet domestic demands. The majority of the GCC countries are characterized by low domestic pharmaceutical production. While domestic manufacturing satisfies 90% of the demands in Egypt (predominantly generics), Saudi Arabia and other GCC countries import 85% of their pharmaceutical product [8]. Another indicator for growth in the GCC cluster is the average per capita expenditure on healthcare. GCC cluster spending at US $ 895 is placed higher than the global average (US $ 864). When compared to the UK (US $ 3285), Germany (US $ 4629) and the United States (US $ 7410), the average per capita expenditure on healthcare is at least 7–9 times less [5,8]. The expected growth of pharmaceutical sales alone is a strong driving force to move clinical trials to this emerging market region. CRO are an integral part of the drug development outsourcing of large pharmaceutical companies. CRO revenue, an indicator of the clinical trial industry performance, is expected to rise to US $ 32.7 billion in 2015 from US $ 21.6 billion in 2010 [5,6]. CRO roles include formulating protocols, generating regulatory documents, overseeing compliance, and monitoring and managing multiple sites within the realm of International Conference on Harmonization and Good Clinical Practice guidelines. Selection of the CROs by the pharmaceutical sponsors is based on several factors including cost effectiveness, familiarity with the local language, relationships with the institutions/investigators, audit status of the CRO and presence of local offices in the region. The MENA region has witnessed enhanced operations of several international and local CROs in the past five years. Although most countries in the MENA do not insist on licensing CROs, many require them to be registered in the country of operation. 4. Conclusion The unprecedented sales performance in mature economies of the world limited the pharmaceutical industry's ability to explore opportunities in regions such as Asia, Latin America and the MENA region. Globalization of clinical research ensures involvement of diverse patient populations and improved subject recruitment numbers and pace, both critical to hasten development and approval of new drugs, especially those that are life-saving, and make them available world-wide. Issues with legal rights to the experimental drug and delays caused by different drug importation procedures required by different ministries of health in the MENA region can be overcome by local CRO meticulous vigil over the regulatory and logistic needs of each specific country. The overall approval time of 60– 90 days in the MENA region is at par with mature markets such as Australia and that of China. The rising popularity of riskbased monitoring and cross-training of healthcare providers in the region should be an encouragement for sponsors to limit their own trial site monitoring. Similar to other emerging markets for clinical trials, informed consent in the MENA region is also subject to language, cultural, social and health literacy challenges. Social media network and smartphone technologies, aided by community health literacy education programs, should enable more effective recruitment and management of a large number of marginally and functionally illiterate research
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subjects. Mandatory introduction of clinical research curriculum in medical schools and investigator training on International Conference on Harmonization and Good Clinical Practice will diminish the gap in regional differences in the practice and reporting of clinical research. The distinct opportunities provided by the MENA region due to population growth, economic affordability, medication demand, lower mortality rates and increased prevalence of genetic and life-style related diseases suggest the high potential for clinical research. Faster recruitment pace, reduced clinical trial development costs and healthy global pharmaceutical sales forecast, further make this region attractive for the future conduct of clinical research. Abbreviations CEE Central and Eastern Europe CIS Commonwealth of Independent States CROs Clinical Research Organizations CVD Cardio Vascular Diseases GCC Gulf Cooperation Council GDP Gross Domestic Product IND Investigational New Drug SOP Standard Operating Procedures
Submission declaration The authors declare that this manuscript has not been previously published and is not under consideration for publication elsewhere and, further that it is approved by all authors. Acknowledgments The authors wish to thank Dr. Ronald Krall, Steamboats Spring, Colorado, USA for reading a draft of the manuscript. SCN was awarded “Leadership in Global Clinical Research Awareness 2012” by the ACRP (USA) and GCC, the outstanding chapter outside the US. The study was granted ethics approval by the Al Ain Medical District Human Research Ethics Committee (AAMDHREC) #12/55. MindSmart UAE is acknowledged for technical assistance with the manuscript. This study was not supported by grants/funds except for time to conduct the study for the principal investigator (SCN) and collaborators (HI) by Tawam Hospital and Johns Hopkins Bloomberg School of Public Health (DDC). References [1] Smith WT. FDA requires foreign clinical studies be in accordance with good clinical practices to better protect human subjects. ABA Health Source 2008;5:1–3. [2] Rajadhyaksha V. Conducting feasibilities in clinical trials: an investment to ensure a good study. Perspect Clin Res 2010;1:106–9. [3] Desai PB, Anderson C, Sietsama WK. A comparison of the quality of data assessed using query rates from clinical trials conducted across developed versus emerging regions. Drug Info J 2012;46:455–63. [4] Misik V. Shifting sands. Eur Pharma Contract September 2011:66–70. [5] Nair SC. Clinical trials opportunities and challenges: Middle East and North Africa (MENA) Region. In: Kinkley S, editor. ACRP Annual Conference, Seattle, WA 10–15April 2011, paper noS702. Virginia: ACRP; 2011.
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