, Mohammed Al-Rubaie2, Stuart Walker3 and Sam Salek4
(1)
Regulatory Affairs Consultant Executive Directive, Kuwait Advancement for Conference and Exhibition Management, Kuwait, Kuwait
(2)
Ministry of Health, Directorate General of Pharmaceutical Affairs and Drug Control, Muscat, Oman
(3)
Founder of Centre for Innovation in Regulatory Science, London, UK
(4)
Department of Pharmacy School Life & Medical Sciences, University of Hertfordshire, Hatfield, UK
The regulation of medicines has evolved over the last five decades in response to serious adverse events in relation to medicinal products. The early regulatory standards, which mainly relate to ensuring the quality of pharmaceutical products and subsequent advances in the early 1960s, led to the development of new standards for assessing the safety and efficacy of medicines.
Today, medicines are manufactured, marketed, distributed and dispensed across the globe. However, the globalisation of pharmaceutical markets and production has also increased the spread and prevalence of unsafe medicines. These can be divided into two categories, namely, counterfeit medicines which are deliberately forged and mislabelled with respect to identity, content and/or source and substandard medicines which have been legally authorised for manufacturing and marketing by national or regional regulatory authorities, but do not meet the required quality or safety standards (Torstensson and Pugatch 2010).
Currently, approximately 20 % of countries have fully operational medicines regulations, 50 % have regulations of varying capacity and 30 % have either none or very limited drug regulation. Many developing countries are incapable of ensuring safety, efficacy and quality of the pharmaceutical products available in their markets because they are resource constrained in terms of staffing, standard systems and training (WHO Drug Information 2008).
The primary aim of drug regulation is protection of public health. However, it is claimed by some that the balance between controlling pharmaceuticals in the interests of ensuring public health and encouraging the development of the pharmaceutical industry has shifted in favour of the innovative industry. Regulation is perceived as an obstacle to the availability of medicines in national or regional markets and has placed a significant demand on regulators to accelerate reviews and evaluations to approve new medicines in the shortest possible time and to expedite the review of the benefits and harms to ensure continuous safety and efficacy of the marketed medicine. Furthermore, Hill and Johnson (2004) suggested that the political climate is currently in favour of multinational companies demanding the availability of new medicines for local patients in a timely manner without fully understanding the importance of supporting effective legislation to ensure access to, and availability of, effective and safe medicines. However, medicines regulation is the foundation of any country’s national drug policy that ensures a viable pharmaceutical industry as well as a high-standard drug approval process.
The World Trade Organisation (WTO) established a global patent protection act named TRIPS (Trade-Related Aspects of Intellectual Property Rights) (WHO 2003a, b) in regard to new chemical entities (NCEs) in 1994. Patents can relate directly to active ingredients, formulations, pharmaceutical salts, isomers, polymorphs, combinations and manufacturing processes. The patent holder has the complete freedom to set the price and the TRIPS agreement eventually resulted in a price increase for new medicinal products, which were considered unaffordable to most people living in developing countries (WHO 2004).
The Middle East and North Africa (MENA) region comprises around 2 % of the global pharmaceutical market, with an average annual growth of 10.4 %; the Arab market (22 Arab countries) comprises 1.5 %, valued at around US$6.2 billion, of which the largest market is Saudi Arabia, valued at around US$1.2 billion (Nixon and Trombe 2013). The increasing number of conferences and studies on the central drug registration process reflects the need for greater harmonisation in medicines regulation within the Middle East, with particular attention to the Gulf Cooperation Council (GCC) states being the focus of this book.
The Gulf Cooperation Council (GCC) is a political and economic union involving six Arab states in the Gulf with shared economic and social objectives. It was created on May 25, 1981, comprising Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and United Arab Emirates (UAE) (Fig. 1.1). Therefore, these countries are often referred to as the GCC states.
Fig. 1.1
Map of the seven Gulf Cooperation Council (GCC) states (Source: Wikipedia, the Free Encyclopedia)
Yemen is currently in negotiation for full GCC membership and hopes to join by 2016 as the seventh state. The GCC has already approved Yemen’s accession to some areas such as the GCC Council of Health Ministers and the GCC Council of Labour and Social Affairs Ministers. However, due to the dramatic differences in socioeconomic status between Yemen and the other six Gulf states, a comparative assessment, which aims at identifying the similarities and differences between the countries, will not be of value for Yemen. The six states have always shared similarities in all areas, such as history, culture and economy, which makes the establishment of standardisation in their systems achievable.
The demographic structure of the six Gulf states (Table 1.1) reveals that the total area of Gulf region comprising the six GCC states (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and UAE) is 2,572,954 km2 with a total population of 47.5 million people having a median age of 29.1 years and an average life expectancy of 75.4 years.
Table 1.1
Demographic structures of the Gulf Cooperation Council (GCC) states
Country | Area/km2 | Population/million (2014) | Median age (years) | Life expectancy at birth (years) | % Population age (25–64 years) | % Population age over 65 | GDP ($) in billion | GDP per capita ($) |
|---|---|---|---|---|---|---|---|---|
Bahrain | 760 | 1.3 | 31.6 | 75.2 | 58.9 | 2.6 | 23.0 | 18,334 |
Kuwait | 17,818 | 3.3 | 28.9 | 74.7 | 54.5 | 2.1 | 176.6 | 56,514 |
Oman | 309,500 | 3.3 | 24.9 | 73.3 | 45.9 | 3.2 | 71.8 | 23,731 |
Qatar | 11,586 | 2.1 | 32.6 | 78.3 | 70.8 | 0.8 | 173.0 | 90,523 |
Saudi Arabia | 2,149,690 | 28.3 | 26.4 | 74.1 | 48.6 | 3.1 | 576.8 | 20,777 |
UAE | 83,600 | 9.2 | 30.3 | 76.7 | 62.1 | 1 | 360.2 | 40,363 |
Total | 2,572,954 | 47.5 | – | – | – | – | – | |
Mean | – | – | 29.1 | 75.3 | 56.8 | 2.1 | 230.4 | 41,707 |
The country with the largest population and a dominating economy in the region is Saudi Arabia. The highest median age and the longest life expectancy at birth were shown to be in Qatar. Bahrain is the smallest of the countries with the lowest population and the lowest GDP, but has the second highest median age and the third highest life expectancy in the region (Table 1.1).
The demographic pattern of the GCC states may have an impact on the demand for pharmaceutical products in the region. In 2014, the proportion of population over 65 years old had reached an average of 2.1 %, whilst the percentage of younger population aged from 25 to 64 years had reached an average of 56.8 % in 2014. According to Alpen Capital 2013, the youth makes up the highest proportion of the GCC population. Nevertheless, the life expectancy, coupled with lower birth rates, is experiencing a gradual escalation leading to an expected increase in the median age. This means that the Gulf states will likely witness a substantial increase in population aged over 60 years during the next few decades which will require a surge in the healthcare expenditure because the elderly generally need to seek more medical care than younger people. Mourshed et al. (2007) indicated that improvements in the life expectancy over the past quarter of a century have left the GCC countries with an increasing number of elderly people requiring medical care. Alpen Capital Report 2013 expects a growth rate of the overall population at a compound annual growth rate (CAGR) of 6.1 % from 2012 to 2050.
Furthermore, the increased urbanisation and per capita income coupled with the hot weather in the GCC states have promoted the consumption of unbalanced diets and sedentary lifestyle leading to high incidence of related diseases such as obesity, diabetes and cardiovascular ailments. The high-income levels of the resident population in general have impacted the consumer’s preference for locally manufactured pharmaceutical products. They exhibit a strong inclination towards branded products, which continue to experience an increasing demand even after patent expiry and availability of cheaper generic substitutes (Alpen capital 2013).
The structures of the individual GCC regulatory authorities were explored through personal communication with key regulators in the region (Table 1.2). The GCC authorities’ official names are as follows: Bahrain National Health Regulatory Authority, Kuwait Drug and Food Control, The Directorate General of Pharmaceutical Affairs and Drug Control Oman, The Pharmacy and Drug Control Department Qatar, Saudi Food & Drug Authority, and The Registration and Drug Control Department UAE. Five authorities are under the autonomy of the Ministry of Health and fully funded by their respective governments. Saudi Arabia, however, is an independent stand-alone authority that relies on registration fees as the major source of its funding. The six GCC authorities regulate pharmaceutical products for human use with their main scope of activities revolving around marketing authorisation, post-marketing surveillance and quality control analysis. They also have a variety of other responsibilities depending on the size and resources available for each regulatory authority.
Table 1.2
The structure, responsibilities and scope of activities within each of the seven Gulf Cooperation Council (GCC) regulatory authorities
Country | Bahrain | Kuwait | Oman | Qatar | Saudi Arabia | UAE | |
|---|---|---|---|---|---|---|---|
Name of authority | National Health Regulatory Authority | Kuwait Drug and Food Control | The General Directorate of Pharmacy and Drug Control | The Pharmacy and Drug Control Department | Saudi Food & Drug Authority | The Registration and Drug Control Department | |
Independent stand-alone authority | ✓ | ✗ | ✗ | ✗ | ✓ | ✗ | |
Budget/GBP | NA | 2 million | NA | NA | 85 million | 1.6 million | |
Fees/GBP | 9 | 230 | 130 | None | >5,000 | NA | |
Scope of registration responsibilities | Medicines for human use | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
Veterinary medicines | ✗ | ✓ | ✗ | ✗ | ✓ | ✓ | |
Medical devices and in vitro diagnostics | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | |
Cosmetic products | ✗ | ✓ | ✗ | ✗ | ✗ | ✗ | |
Food supplements | ✗ | ✓ | ✗ | ✗ | ✗ | ✗ | |
Herbal medicines | ✗ | ✓ | ✗ | ✗ | ✗ | ✗ | |
Scope of activities | Marketing authorisation | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
Post-marketing surveillance | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | |
Sample analysis | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | |
Advertising control | ✗ | ✓ | ✓ | ✗ | ✓ | ✓ | |
Price regulation | ✓ | ✓ | ✗ | ✓ | ✓ | ✓ | |
GMP inspection | ✓ | ✓ | ✗ | ✗ | ✓ | ✗ | |
Clinical trial authorisation | ✗ | ✗ | ✓ | ✗ | ✓ | ✓ | |
Regulatory Approval Times and Patient Access to Medicines
The timeliness with which regulatory authorities approve new medicines for marketing affects healthcare professionals and patients. Likewise, the pace of evaluating the benefits and risks affects the continuity of access to safe and effective medications by healthcare professionals and patients. An unnecessarily long regulatory procedure delays access to medicines that may improve patients’ health status. Variation in the availability of safe and effective drugs in different countries has been studied since the early 1970s (Rawson 2000), and some marked differences have been found. The length of review time was perceived as one of the most important barriers to the pharmaceutical industry, which is endeavouring to reduce the time required for review and approval of new applications (CMR Briefing 32B 2001).
Therefore, efforts have been made by many national authorities to allow patients’ access to medicinal products in a timely manner by reviewing their strategies to monitor the efficiency of the review process, as well as the performance of the regulatory authorities (WHO 2010). The timeliness with which national regulatory authorities approve new medicines has an effect on stakeholders, namely, the pharmaceutical industry, patients and regulatory authorities (Anderson 2004).
The length of the review process depends on the type of products being registered and marketed as well as on the requirements of the approval process of new medicines and the authorisation of the pharmacovigilance (PV) practices carried out to ensure the safety and efficacy of the marketed medicines. Different countries impose different registration and pharmacovigilance requirements on the manufacturers. However, it is possible to exploit these differences for the benefit of both the pharmaceutical industry and the regulatory authorities. For the manufacturers, registering new products in countries that have fewer requirements, this can help them produce evidence to support registration in other countries. On the other hand, such regulatory authorities will have the opportunity to compare themselves against other international systems. However, the first registering authority may not be sufficiently competent or recognised by the subsequent registering authorities. This may have an impact on the standard of the registration process of a pharmaceutical product elsewhere and the level of regulatory control in the countries where the product is approved. Therefore, authorisation by developed regulatory agencies not only leverages the standard of pharmaceutical products’ registration elsewhere but provides an opportunity to establish a global market for the product in both developed and developing countries.
Another concern with such practice resides in the time taken to register a pharmaceutical product, which differs from country to country and from product to product. However, it is possible to complete the review process within a reasonable time frame if the data are available and adequate. Many countries have legislative maximum times allowed for the review of dossiers. For example, the target time frame for completing the review process in the EU centralised system is 210 days. This authorisation period has two points – known as ‘clock stops’ – at day 120 and day 180. A timescale of 3 and 1 month, respectively, are enforced for applicants to respond, and these periods may be doubled upon request (EMA 2009). The longest review time usually occurs when the benefits of the product are not apparent. This is used as a strong argument for carrying out the assessment at a regional level, rather than at a country level. The sharing of the evaluation work is currently what happens in the Gulf Cooperation Council Drug Registration (GCC-DR) system, where the assessment process is shared amongst the GCC states and the decision is made by agreement. The challenge is not to implement a new centralised system, but to establish an effective method for sharing workload amongst the countries, which requires leveraging the standard of the regulatory practices in each individual authority. The GCC-DR committee, with a total of 14 members, two senior managers from each of the six authorities and Yemen, manages the GCC review process, but is not able to function as a single authority, such as the United States Food and Drug Administration (US FDA) with approximately 3,000 staff or the European Medicines Agency (EMA) with around 800 staff to cover the European member states (EMA, Recruitment at EMA 2012). In the Gulf region, each country has its own authority with its respective identity that plays a prominent role in the overall functioning of the GCC-DR committee. Another important aspect to consider is that manufacturers monitoring the safety and efficacy of medicines marketed in countries with differing, few or no pharmacovigilance legislations will not be able to produce valuable benefit-risk data relevant to these countries.
The efficiency of a regulatory process is judged by the overall times from submission of the new application to the date of patients’ access to new medicines (Rawson 2000; Anderson et al. 2002) and after the issuance of the marketing authorisation covering the whole life cycle of the medicinal product. An attempt was previously made to evaluate the length of the milestones and stages involved in the regulatory review processes for different authorities (Hirako et al. 2007), and a similar study of the GCC regulatory authorities was carried out by Hashan (2005) highlighting important aspects of the drug approval procedures in each of the six GCC member states. However, the study provided limited information about the approval timelines and the lengths of the milestones and stages involved in the review process simply because the authorities did not have an electronic tracking system to monitor such activities. This made it difficult, if not impossible, to allow cohorts of pharmaceutical products to be traced retrospectively.
However, the study carried out on established authorities assessed the review timelines, length of milestones and data points involved in the review process conducted in the United States, European Union, Canada and Australia. The data were obtained on applications for NASs that had not been previously approved by the authority in question and were collected according to the year of submission rather than by the year in which the review process was completed. This method allowed meaningful comparisons to be made across these developed countries and identified variations in the length of the approval time in each authority (Hirako et al. 2007). This study highlighted differences in timelines through variations in review practices and procedures. For example, in the Therapeutic Goods Administration (TGA), Australia, the advisory committee’s evaluation procedure is an additional step to the scientific assessment process, whilst in the United States Center for Drug Evaluation and Research (CDER), the advisory committees’ evaluation process is part of the overall scientific assessment procedure. Likewise, Kuwait is the only authority that has a pricing department, which is independent from the registration department, and the pricing process is not part of the review process, whilst the pricing step in the other GCC authorities is part of the review process. Such factors may have an impact on the length of the approval time in any regulatory authority.
Anderson (2004) commented on the importance of timeliness for national regulatory authorities in order to approve new medicines, which may influence directly the stakeholders and patients during the process. A lengthy approval process results in a delay in marketing new approved medicines for patients. Normally, the length of the review process depends on the type of products being registered, the requirements of the approval process and the type of review carried out.
Governments are obligated to provide their citizens with access to safe and effective medicines and therapies when they are needed. In other words, conducting safety and efficacy reviews of marketing authorisation applications for new medicines and biotherapy products in a timely manner should be a major priority for safeguarding and enhancing public health, which is part of the core mission of health authorities. However, expediting the review process for new medicines and biological products to ensure it is completed within predefined deadlines should never mean that regulatory standards can be compromised as they are essential to proving the safety, efficacy and quality of new medicines.
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