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Clinical trials in “emerging markets”: Regulatory considerations and other factors
CONCLI-00947; No of Pages 8 Contemporary Clinical Trials xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Contemporary Clinical Trials
3Q1
Romi Singh a,⁎, Ouhong Wang b
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Global Regulatory Affairs and Safety, Amgen, Inc., United States Global Biostatistics, Amgen, Inc., United States
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Article history: Received 7 August 2013 Received in revised form 13 September 2013 Accepted 16 September 2013 Available online xxxx
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Keywords: Emerging markets Clinical trials Regulatory
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1. Background
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For a multinational biopharmaceutical company, there are multiple factors used to select countries for placement of global clinical trials. Historically, clinical studies were placed in “emerging markets” as part of global drug development programs to access large pool of eligible patients with the goal of faster drug registration in primary markets such as US and EU, with a cost effective structure. From the perspective of the biopharmaceutical industry, the definition of “emerging markets” continues to evolve [1]. Countries or regions can be classified as “emerging” or “developing” according to a raft of different criteria such as
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Clinical trials in “emerging markets”: Regulatory considerations and other factors☆
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Clinical studies are being placed in emerging markets as part of global drug development programs to access large pool of eligible patients and to benefit from a cost effective structure. However, over the last few years, the definition of “emerging markets” is being revisited, especially from a regulatory perspective. For purposes of this article, countries outside US, EU and the traditional “western countries” are discussed. Multiple factors are considered for placement of clinical studies such as adherence to Good Clinical Practice (GCP), medical infrastructure & standard of care, number of eligible patients, etc. This article also discusses other quantitative factors such as country's GDP, patent applications, healthcare expenditure, healthcare infrastructure, corruption, innovation, etc. These different factors and indexes are correlated to the number of clinical studies ongoing in the “emerging markets”. R&D, healthcare expenditure, technology infrastructure, transparency, and level of innovation, show a significant correlation with the number of clinical trials being conducted in these countries. This is the first analysis of its kind to evaluate and correlate the various other factors to the number of clinical studies in a country. © 2013 Published by Elsevier Inc.
☆ The views expressed herein represent those of the author and do not necessarily represent the views or practices of the author's employer or any other party. ⁎ Corresponding author. E-mail address: [email protected] (R. Singh).
economic status, industrial development, relative level of per capita income, human development index, etc. Most of the major biopharmaceutical companies have either created groups or reorganized to focus on emerging markets based on the market size or commercial potential of a region rather than by its regulatory systems. However, from a regulatory perspective, the definition and demarcation of “emerging markets” is rather straightforward — the world is broken into “primary markets” and “secondary markets”. The “primary markets” are where the regulatory agencies conduct complete evaluation of safety, efficacy and quality of the product (usually the original ICH countries/regions). The “secondary markets” are the countries that depend on the approval of the primary countries and generally require a Certificate of Pharmaceutical Product (CPP) for drug registration. Thus from a traditional drug development paradigm, the drugs are first registered and approved in “primary markets” followed by approval in “secondary markets” which are mostly the emerging countries.
1551-7144/$ – see front matter © 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.cct.2013.09.006
Please cite this article as: Singh R, Wang O, Clinical trials in “emerging markets”: Regulatory considerations and other factors, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.09.006
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2.1. Regulatory considerations
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Some key emerging countries (e.g., China, Korea, Taiwan, India, Vietnam, Russia) require local clinical trial data as part of the regulatory marketing application (Table 1). Consequently, clinical trials in many emerging countries no longer are primarily focused on just accessing patients as part of global studies but now use the local patients as a means to access the local markets. Thus patients from emerging
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2.2. Clinical factors
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The clinical trial data generated in emerging markets, 128 whether part of the global studies or regional studies, will 129 generally be part of the safety and efficacy analysis. To ensure 130
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markets are either part of a global study, a regional study (e.g., pan-Asian) or a local registration study. Where and when to place the clinical studies are driven by many regulatory considerations such as agency review timelines, content of the dossier, patient requirements (for registration studies), and regional regulatory requirements (Table 1). The regulatory timelines appear to be increasing and the “drug-lag” phenomenon [3] becoming more pronounced in some of the major emerging markets where the regulatory agencies are establishing new regulatory framework outside the ICH guidelines or adapting the ICH guidelines to their local laws and regulations. There are significant differences in the top 10 emerging markets shown in Table 1 in terms of regulatory approval timelines for CTAs and patient requirements for marketing application approvals. For example, compared to other Asian countries, China has long regulatory review and approval timelines which makes China's participation in regional and global studies challenging, especially if the studies are of a shorter duration. Similarly, with China requiring 300 patients as part of a registration study, it could become impractical to include China in global or a regional study if the study design calls for fewer patients and China would then have a disproportionate number of study subjects. Thus one has to consider various regulatory factors such as review timelines, purpose of the study (global vs. local registration), and patient numbers required for local registration, and whether or not it is part of a regional registration study.
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For the purposes of this article, the regulatory framework for clinical trials in the top countries other than the “primary markets” (US, EU, Canada, Australia, Switzerland and Japan) are considered. The ranking of these countries is determined based on the number of registered clinical studies in ClinicalTrial.gov [2]. ClinicalTrials.gov has become a good consolidated source to track clinical trials conducted under an investigational new drug application (IND). While not all the global studies are reflected in this registry, it is a good surrogate to estimate for ongoing international clinical studies. This database was created as a result of the Food and Drug Administration Modernization Act of 1997 (FDAMA). FDAMA required the U.S. Department of Health and Human Services, through National Institutes of Health (NIH), to establish a registry of clinical trials information for both federally and privately funded trials conducted under investigational IND to test the effectiveness of experimental drugs for serious or lifethreatening diseases or conditions. NIH and the FDA worked together to develop the site, which was made available to the public in February 2000. Geographic locations of the studies registered at ClinicalTrials.gov are illustrated in Fig. 1.
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Fig. 1. Map of all studies in ClinicalTrials.gov as of September 2013.
Please cite this article as: Singh R, Wang O, Clinical trials in “emerging markets”: Regulatory considerations and other factors, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.09.006
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Table 1 Comparison of Clinical Trial Application (CTA) requirements in selected emerging markets.
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Country
Estimated number of patients for stand-alone registration studies⁎
Estimated number of patients if participated in phase 2 to phase 3
Regulatory approval time for CTA (months)
Comments, special requirements
t1:4
China
100-chemical 300-biologics
16–22
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India
100–200
Variable depending on number of Chinese in global studies 0–100
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S. Korea
100
0–50
2–6
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Taiwan
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0–20
4–6
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Russia
No guidance
No guidance
2–4
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Brazil
Not required
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6–8
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Mexico
Not required
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3–4
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Argentina Not required
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4–5
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S. Africa
Not required
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4–6
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Israel
Not required
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3–4
Extensive CMC section; CTA similar to full MAA; extensive quality testing upfront as part of CTA approval process (see Notes a–c, e–f); EC approval after agency approval New CMC regulations require more information than before (see Notes d–f); EC approval in parallel with agency approval Straightforward CTA approval process; EC approval in parallel with agency approval Straightforward CTA approval process; EC approval in parallel with agency approval Inclusion Russian sites in global development program exempt from mandatory local pre-registration inspection; EC same application as CTA Straightforward CTA approval process; Sequential review process, Local EC first, then National EC (CONEP) and agency (ANVISA) in parallel. Straightforward CTA approval process Sequential process, EC first, then agency (COFEPRIS) Straightforward CTA approval process Sequential review process, EC first, then agency (ANMAT). Straightforward CTA approval process; Pre-defined submission deadlines to MCC, typically 6 review cycles per year. EC approval in parallel with agency approval Straightforward CTA approval process; Sequential review process, EC first and agency review second IF EC decides agency review is required.
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Besides the regulatory and medical considerations, other factors are examined if they would correlate, or predict, the
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that the quality of the data is robust, strict adherence to Good Clinical Practice (GCP) is mandatory. GCP is an international quality standard that defines standards, which governments can transpose into regulations for clinical trials involving human subjects [4]. These guidelines include protection of human rights as a subject in clinical trial. It also provides assurance of the safety and efficacy of the newly developed compounds, and includes standards on how clinical trials should be conducted. They also define the roles and responsibilities of clinical trial sponsors, clinical research investigators, and monitors. While deciding whether to place global or regional studies specifically in emerging markets, the medical infrastructure, disease prevalence and standard of care need to be considered. For example, it needs to be evaluated whether the comparator product is approved for use or is part of the standard of care in the countries where the studies are planned. For example “S-1” (Tegafur/Gimeracil/Oteracil) is a commonly used chemotherapy in Asia for gastric cancer but is not commonly available in the West and is generally not included as a comparator in global studies. Thus it could become a challenge to convince the investigators or even the ethics committees about the choice of comparator product. All these factors need to be considered when placing a study.
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Number of patients can be negotiated depending on therapeutic area, medical need, etc. Approval times can be reduced through special review mechanisms (e.g., orphan drugs). East-Asian countries may use data from other Asian countries (e.g., Taiwan could use Japanese data). d Biologics approval may take a few months longer. e Biological samples (e.g., full blood, tissues) need special permission. f “First in Human” studies not permitted unless molecule “discovered” in country. ⁎ Patients on study drug (may differ for small molecules vs. biologics). b
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number of clinical trials in emerging countries using regression analysis. Such findings could provide informative guidelines for clinical trial placement based on current industry experience. The statistical analysis software employed is JMP (V.10) [5]. Various quantitative indexes were considered. For example, does the prosperity of the country as measured in Gross Domestic Product (GDP) or the labor force in a country correlate to the number of clinical trials? Does a country's spending on healthcare or education predict its likelihood of participating in global clinical trials? Does innovation capability or corruption play a role? Relevant factors like these are selected to examine their magnitude of impact and predictive value. In total, 10 factors are considered in the analyses for their correlation with the number of clinical trials at the country level. Eight are based on published World Bank data [6] including R&D as % of GDP, public education as % of GDP, gross national income adjusted for purchasing power parity (PPP), patent applications by residents, patent applications by non-residents, total labor force, health expenditure per capita, and infrastructure as measured by % internet users. In addition, a country's corruption index is assessed by Transparency International [7], and the country's innovation index is assessed by a consortium of business schools and World Intellectual Property Organization (WIPO) [8]. Factors that reflect a country's economic strength (population and total labor force) are natural selections because they intuitively impact clinical trial placement decisions. Likewise, a country's attention to R&D, education, and healthcare (R&D
Please cite this article as: Singh R, Wang O, Clinical trials in “emerging markets”: Regulatory considerations and other factors, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.09.006
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It's worth pointing out that for all 10 factors, a higher value indicates a better state of a country. For example, a higher value for the innovation index indicates more innovation, and a higher score for the corruption index indicates less corruption. The top 50 “secondary markets” countries represented in ClinicalTrial.gov as of June 2013 are shown in Fig. 2, organized by the number of clinical trials in descending order. A preliminary analysis including all 50 countries in Fig. 2 is shown in Table 2, depicting the relationship between each of the 10 factors and the number of clinical trials. These are univariate analysis examining the 10 factors one at a time. The Table shows the predicted change in number of clinical trials for each unit increase of the particular factor, as indicated by the regression analysis. It's effectively the slope of the regression line. The correlation, which takes a value between − 1 and 1, measures the strength of the relationship between clinical trial number and a particular factor. The closer it is to either 1 or − 1, the stronger the relationship, with a positive correlation indicating synergy and a negative correlation indicating a detrimental effect. The last column, the p-value, measures the level of confidence our analysis has for the calculated correlation. A p-value less than 0.05 is considered statistically significant; in other words, the actual correlation is believed to be different from 0. Nine of the 10 factors, excluding public education as % of GDP, show a significantly positive correlation with the number of clinical trials. While this is an interesting and encouraging result, two refinements are then made due to the following considerations. First, some of the 50 countries have either a small economy or small number of clinical trials. Their inclusion does not provide useful information. Therefore, the subsequent analyses only included countries with more than 450 clinical trials, resulting in 23 countries. Secondly, the entire population in a large country does not have the same exposure to clinical trial opportunities. Urban population tends to be a more relevant indicator than the entire population. Hence the number of clinical trials for each country is standardized by the number of urban population (number of clinical trials per 1,000,000 urban population). Note that Taiwan's urban population is not available from the World Bank database and thus only 22 countries are analyzed. These results are tabulated in Table 3. These 22 countries, from South Korea to Egypt, represent the vast majority of biopharmaceutical industry's “emerging market” interest. The factors that positively correlate with clinical trials and are found to be significant include a country's attention to R&D (R&D as % of GDP), its level of healthcare (health expenditure per capita), modern infrastructure (% internet users), transparency (corruption index), and level of innovation (innovation index). As a guiding principle the findings make intuitive sense, and are also consistent with industry's past experience. Some of the regression lines together with the actual data points are shown in Fig. 3. While the analyses in Table 3 is more relevant to multinational companies since most of the clinical studies in emerging markets are generally conducted in urban parts of the country, the factors measuring a country's absolute size of economy (Gross National Income, patent applications by
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as % of GDP, public education as % of GDP, health expenditure per capita) likely correlates with its capability in conducting clinical trials since clinical trials are generally associated with R&D, mostly the ‘D’ component. Additionally, clinical trials and data management are progressively being managed electronically and are extensively dependent on a good internet infrastructure. The World Bank index that measures internet usage per 100 persons is therefore a meaningful scale to look into for its correlation with the number of clinical trials. For research-based multinational biopharmaceutical companies, Intellectual Property (IP) is a key asset that needs to be protected. Intellectual property is not only limited to the data that is submitted to regulatory agencies and sites; it also includes data protection and data exclusivity. WIPO issues annual indicators covering various areas of intellectual property: patents, utility models, trademarks, industrial designs, microorganisms and plant varieties protection. It draws on data from national and regional IP offices, WIPO, the World Bank and UNESCO [9]. It is critical that research-based multinational companies consider the IP regime of a particular country before committing sending data as part of their clinical trial application (or marketing application), especially as it relates to Chemistry, Manufacturing and Controls (CMC). In our analysis, a country's IP regime is reflected in two factors: patent applications by residents and non-residents, and the innovation index. As detailed in the GCP guidelines, ability by the trial subject to understand and agree to the consent form is a requirement. A functional literacy could provide a measure of trial subject's level of comprehension of the consent form. The Human Development Index (HDI) provides a single statistic that serves as a frame of reference for both social and economic development. This includes health, education and living standard measures. The public education as % of GDP factor and the health expenditure per capita factor in our analysis partially touch on this aspect. The clinical data needs to be “clean” with no element of fraud or study misconduct. Transparency International's mission is to stop corruption and promote transparency, accountability and integrity at all levels and across all sectors of society. This organization generates annual surveys of corruption index by countries which is a relevant factor included in our analysis. It could indirectly provide a measure of the quality of the ethics committees, data integrity and the practices of the regulatory agencies. Note that the quality of the data also relates to the training of clinical research personnel, GCP adherence and education—factors that are discussed separately. The Global Innovation Index relies on two sub-indexes, the Innovation Input Sub-Index and the Innovation Output Sub-Index, each built around pillars. Five input pillars capture elements of the national economy that enable innovative activities: (1) Institutions, (2) Human capital and research, (3) Infrastructure, (4) Market sophistication, and (5) Business sophistication. Two output pillars capture actual evidence of innovation outputs: (6) Knowledge and technology outputs and (7) Creative outputs. The Global Innovation Index could be relevant to where the clinical trials are conducted since it could indicate areas with differing quality of health care professional and healthcare infrastructure (e.g., hospitals).
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Fig. 2. Number of registered clinical trials in ClinicalTrials.gov in top 50 countries representing “emerging markets” (outside “primary markets”).
Table 2 Relationship between predictive factors and the number of clinical trials — top 50 countries.
t2:3
Factors
Unit
Δ in # CT/unit ↑
Correlation
P-value
t2:4 t2:5 t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13
R&D as % of GDP Public education as % of GDP Gross national income — PPP Patent applications (res) Patent applications (non-res) Total labor force Health expenditure per capita % Internet users Corruption index Innovation index
% % $ Trillion Thousand Thousand Million $ Thousand % One One
957 145 462 14 48 4.1 1181 25 22.8 68.6
0.77 0.18 0.63 0.59 0.70 0.48 0.51 0.43 0.29 0.57
b0.0001 0.2611 b0.0001 0.0001 b0.0001 0.0004 0.0002 0.0021 0.0425 b0.0001
Please cite this article as: Singh R, Wang O, Clinical trials in “emerging markets”: Regulatory considerations and other factors, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.09.006
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Table 3 Relationship between predictive factors and the number of clinical trials standardized by urban population — top 22 countries. Factors
Unit
Δ in # CT/unit ↑
Correlation
P-value
R&D as % of GDP Public education as % of GDP Gross national income — PPP Patent applications (res) Patent applications (non-res) Total labor force Health expenditure per capita % Internet users Corruption index Innovation index
% % $ Trillion Thousand Thousand Million $ Thousand % One One
80.9 38.3 −13.5 −0.2 —0.6 —0.2 177.7 3.4 4.4 7.7
0.64 0.29 −0.23 −0.10 —0.11 —0.23 0.82 0.50 0.54 0.63
0.0055 0.2409 0.3273 0.6822 0.6417 0.3114 b0.0001 0.0170 0.0092 0.0021
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in Table 2 when the clinical trial numbers were not standard- 312 ized for the number of urban population. The results there 313 should be expected; however, the difference illustrates how 314
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both residents and non-residents, and total labor force) all show non-significant correlation. Surprisingly, they all have negative correlations. Note that these were all highly significant
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Fig. 3. Selected regression analysis of the number of clinical trials standardized by urban population on various predictive factors — top 22 countries (the highest point on each panel represents Israel).
Please cite this article as: Singh R, Wang O, Clinical trials in “emerging markets”: Regulatory considerations and other factors, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.09.006
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The biopharmaceutical industry is one of the most regulated industries and cost of product development is one of the highest. As per some estimates, it costs about $1.2 billion to develop a drug and can take up to 10 years to bring it to the market [11]. One of the largest contributors is the cost of clinical studies, which can account for up to 80% of development costs [12]. Moreover, the pharmaceutical industry is rapidly changing. While pharmaceutical market growth in US, EU is expected to be slow or flat, the “emerging markets” to grow 14–17% and account forapproximately one-quarter of the total global pharmaceutical market [13]. As per the IMS report, in mid-2000, there was only one country (China) listed in the top-10 global pharmaceutical sales list; by 2016 it is expected there will be 5 emerging countries on that list with China expected to occupy the number 2 slot. With such vast opportunities in emerging markets, placement of clinical trials in these countries can be hugely variable, and can benefit from both the industry's collective experiences and evidence-based guidelines. This paper is an attempt on both fronts. We have demonstrated that regulatory considerations, clinical considerations, and country-specific characteristics are all important and valid factors in making such decisions. While the regulatory and clinical considerations make intuitive sense, the correlation analysis involving quantitative factors provides insights that a country's R&D, healthcare expenditure, infrastructure, transparency, and innovation capability are all strong indicators that the biopharmaceutical industry can rely on. When these factors score high for a country, past evidence suggests that we have more confidence in placing clinical trials there, and the chance of these clinical trials contributing to the overall commercial success of the compound is also high. Notice that the standardized percent or per capita measures are better suited for this analysis than the gross measures that more reflect a country's size of economy. One limitation of this research is the fact that some of these factors are naturally correlated among themselves, and an attempt was made to perform multivariate analysis to examine them simultaneously. However, the available dataset came from multiple data sources and had many missing values. Even when only the percent and per capita measures were focused on, only 12 countries out of the top 23 had complete data. With only about 5° of freedom available for error, such analysis would not be informative. Further research can be done when more complete datasets are available to narrow the focus to a couple of comprehensive factors that may or may not be observable. Since many key emerging markets require clinical studies as part of the registration process, placement of clinical trial for “commercial attractiveness” now also should be a major selection criterion. In conclusion, when considering clinical trials in emerging markets, it is no longer about accessing patients and cost savings. Multiple other factors need to be considered and evaluated. Ultimately, it comes down to timely access of patients, markets, talent and cost-effectiveness in emerging markets.
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country's size of economy including gross national income, 376 patent applications, and total labor force, show no apparent 377 correlation. 378
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population alone is a poor predictor for our purpose, and the diversity of the population in terms of urban and rural splits can add little value to our understanding of the real picture. For example, patent filings are not reflective of the IP regime enforcement in a country — a more relevant measure for the MNCs planning clinical studies in the country. Similarly, the total labor force does not directly correlate to the technical expertise required to conduct clinical trials. In other words, large population of physicians does not necessarily correlate to the high talent pool of clinical research investigators or clinical research associates. Also, as per 2012 Population Reference Bureau report [10], the world population was just over 7 billion. The population of the “top-10” countries listed in Table 1 accounted for over 3.2 billion, or 46% of the world population. In contrast, the total number of clinical trials (as listed in ClinicalTrial.gov) in these top-10 countries is about 19% of the global studies. While there is some correlation, population of a country by itself is not a predictor where the clinical studies are conducted. The gross national income or GDP is very high among top oil producing nations and the majority of them are not on the list of top clinical trial destinations; thus while a country may be “rich”, that does not necessarily translate to higher number of clinical studies. However, “prosperity” of a country may contribute to factors such as R&D investment and health care expenditure where we see positive correlation. It is noticeable, perhaps contrary to common belief, that a country's spending on public education is not a major factor. If it was not for Israel which scores the highest on this factor and also with the largest number of standardized clinical trials, the regression line would be even more flat. Also, the specialized nature of clinical trials may not be captured in the public education and would require more of post-secondary and post-baccalaureateeducation/training — perhaps that would be a better measure and analysis to conduct. Along similar lines, Israel stands out in almost all these analyses due to its large number of clinical trials and highly urbanized population. As a result, it has the highest number of clinical trials per million urban population, making it easily identifiable in all the panels of Fig. 3 (the highest point). A sensitivity analysis was performed with Israel excluded, to examine its influence on the analysis. The result shows that the regression lines for all factors become more flat, but the statistical significance still holds except for R&D as % of GDP. This demonstrates that Israel adds an upward pull to the regression line in a way that is different compared with most other countries. The highly successful clinical trial placement experience from Israel is probably difficult to be extrapolated elsewhere due to its uniqueness. Thus, at a high level, our preliminary analysis shows that nine out of ten different factors show a significantly positive correlation with the number of clinical trials in the countries. Surprisingly a different correlation structure was observed when only the relevant countries were included and only the urban population was considered since that appeared to be a more relevant area where global clinical trials are generally conducted. The number of clinical trials correlates well with R&D as % of GDP, healthcare expenditure per capita, % internet users, low corruption index, and innovation index. On the other hand, absolute measures of a
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Please cite this article as: Singh R, Wang O, Clinical trials in “emerging markets”: Regulatory considerations and other factors, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.09.006
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[8] Dutta Soumitra, Lanvin Bruno. The Global Innovation Index 2013, The Local Dynamics of Innovation. http://www.globalinnovationindex.org/; 2013. [9] WIPO. 2012 World Intellectual Property Indicators. http://www.wipo.int/ ipstats/en/wipi/; 2012. [10] PRB. World Population Data Sheet, 2012. www.prb.org; 2012. [11] DiMasi JA, Grabowski HG. The cost of biopharmaceutical R&D: is biotech different? Manage decis econ 2007;28:469–79. [12] DiMasi JA, Grabowski HG. R&D costs and returns to new drug development: a review of the evidence. In: Danzon PM, Nicholson S, editors. The Oxford Handbook of the Economics of the Biopharmaceutical Industry. Oxford, UK: Oxford University Press; 2012. p. 21–46 [chapter 2]. [13] IMS. Annual report. http://www.imshealth.com/portal/site/ims/; 2011.
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Contents lists available at ScienceDirect
Contemporary Clinical Trials
3Q1
Romi Singh a,⁎, Ouhong Wang b
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Global Regulatory Affairs and Safety, Amgen, Inc., United States Global Biostatistics, Amgen, Inc., United States
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Article history: Received 7 August 2013 Received in revised form 13 September 2013 Accepted 16 September 2013 Available online xxxx
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Keywords: Emerging markets Clinical trials Regulatory
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1. Background
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For a multinational biopharmaceutical company, there are multiple factors used to select countries for placement of global clinical trials. Historically, clinical studies were placed in “emerging markets” as part of global drug development programs to access large pool of eligible patients with the goal of faster drug registration in primary markets such as US and EU, with a cost effective structure. From the perspective of the biopharmaceutical industry, the definition of “emerging markets” continues to evolve [1]. Countries or regions can be classified as “emerging” or “developing” according to a raft of different criteria such as
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Clinical trials in “emerging markets”: Regulatory considerations and other factors☆
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journal homepage: www.elsevier.com/locate/conclintrial
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Clinical studies are being placed in emerging markets as part of global drug development programs to access large pool of eligible patients and to benefit from a cost effective structure. However, over the last few years, the definition of “emerging markets” is being revisited, especially from a regulatory perspective. For purposes of this article, countries outside US, EU and the traditional “western countries” are discussed. Multiple factors are considered for placement of clinical studies such as adherence to Good Clinical Practice (GCP), medical infrastructure & standard of care, number of eligible patients, etc. This article also discusses other quantitative factors such as country's GDP, patent applications, healthcare expenditure, healthcare infrastructure, corruption, innovation, etc. These different factors and indexes are correlated to the number of clinical studies ongoing in the “emerging markets”. R&D, healthcare expenditure, technology infrastructure, transparency, and level of innovation, show a significant correlation with the number of clinical trials being conducted in these countries. This is the first analysis of its kind to evaluate and correlate the various other factors to the number of clinical studies in a country. © 2013 Published by Elsevier Inc.
☆ The views expressed herein represent those of the author and do not necessarily represent the views or practices of the author's employer or any other party. ⁎ Corresponding author. E-mail address: [email protected] (R. Singh).
economic status, industrial development, relative level of per capita income, human development index, etc. Most of the major biopharmaceutical companies have either created groups or reorganized to focus on emerging markets based on the market size or commercial potential of a region rather than by its regulatory systems. However, from a regulatory perspective, the definition and demarcation of “emerging markets” is rather straightforward — the world is broken into “primary markets” and “secondary markets”. The “primary markets” are where the regulatory agencies conduct complete evaluation of safety, efficacy and quality of the product (usually the original ICH countries/regions). The “secondary markets” are the countries that depend on the approval of the primary countries and generally require a Certificate of Pharmaceutical Product (CPP) for drug registration. Thus from a traditional drug development paradigm, the drugs are first registered and approved in “primary markets” followed by approval in “secondary markets” which are mostly the emerging countries.
1551-7144/$ – see front matter © 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.cct.2013.09.006
Please cite this article as: Singh R, Wang O, Clinical trials in “emerging markets”: Regulatory considerations and other factors, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.09.006
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2.1. Regulatory considerations
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Some key emerging countries (e.g., China, Korea, Taiwan, India, Vietnam, Russia) require local clinical trial data as part of the regulatory marketing application (Table 1). Consequently, clinical trials in many emerging countries no longer are primarily focused on just accessing patients as part of global studies but now use the local patients as a means to access the local markets. Thus patients from emerging
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2.2. Clinical factors
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The clinical trial data generated in emerging markets, 128 whether part of the global studies or regional studies, will 129 generally be part of the safety and efficacy analysis. To ensure 130
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markets are either part of a global study, a regional study (e.g., pan-Asian) or a local registration study. Where and when to place the clinical studies are driven by many regulatory considerations such as agency review timelines, content of the dossier, patient requirements (for registration studies), and regional regulatory requirements (Table 1). The regulatory timelines appear to be increasing and the “drug-lag” phenomenon [3] becoming more pronounced in some of the major emerging markets where the regulatory agencies are establishing new regulatory framework outside the ICH guidelines or adapting the ICH guidelines to their local laws and regulations. There are significant differences in the top 10 emerging markets shown in Table 1 in terms of regulatory approval timelines for CTAs and patient requirements for marketing application approvals. For example, compared to other Asian countries, China has long regulatory review and approval timelines which makes China's participation in regional and global studies challenging, especially if the studies are of a shorter duration. Similarly, with China requiring 300 patients as part of a registration study, it could become impractical to include China in global or a regional study if the study design calls for fewer patients and China would then have a disproportionate number of study subjects. Thus one has to consider various regulatory factors such as review timelines, purpose of the study (global vs. local registration), and patient numbers required for local registration, and whether or not it is part of a regional registration study.
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For the purposes of this article, the regulatory framework for clinical trials in the top countries other than the “primary markets” (US, EU, Canada, Australia, Switzerland and Japan) are considered. The ranking of these countries is determined based on the number of registered clinical studies in ClinicalTrial.gov [2]. ClinicalTrials.gov has become a good consolidated source to track clinical trials conducted under an investigational new drug application (IND). While not all the global studies are reflected in this registry, it is a good surrogate to estimate for ongoing international clinical studies. This database was created as a result of the Food and Drug Administration Modernization Act of 1997 (FDAMA). FDAMA required the U.S. Department of Health and Human Services, through National Institutes of Health (NIH), to establish a registry of clinical trials information for both federally and privately funded trials conducted under investigational IND to test the effectiveness of experimental drugs for serious or lifethreatening diseases or conditions. NIH and the FDA worked together to develop the site, which was made available to the public in February 2000. Geographic locations of the studies registered at ClinicalTrials.gov are illustrated in Fig. 1.
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Fig. 1. Map of all studies in ClinicalTrials.gov as of September 2013.
Please cite this article as: Singh R, Wang O, Clinical trials in “emerging markets”: Regulatory considerations and other factors, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.09.006
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Table 1 Comparison of Clinical Trial Application (CTA) requirements in selected emerging markets.
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Estimated number of patients for stand-alone registration studies⁎
Estimated number of patients if participated in phase 2 to phase 3
Regulatory approval time for CTA (months)
Comments, special requirements
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China
100-chemical 300-biologics
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Variable depending on number of Chinese in global studies 0–100
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No guidance
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Brazil
Not required
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Mexico
Not required
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Argentina Not required
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S. Africa
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Israel
Not required
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Extensive CMC section; CTA similar to full MAA; extensive quality testing upfront as part of CTA approval process (see Notes a–c, e–f); EC approval after agency approval New CMC regulations require more information than before (see Notes d–f); EC approval in parallel with agency approval Straightforward CTA approval process; EC approval in parallel with agency approval Straightforward CTA approval process; EC approval in parallel with agency approval Inclusion Russian sites in global development program exempt from mandatory local pre-registration inspection; EC same application as CTA Straightforward CTA approval process; Sequential review process, Local EC first, then National EC (CONEP) and agency (ANVISA) in parallel. Straightforward CTA approval process Sequential process, EC first, then agency (COFEPRIS) Straightforward CTA approval process Sequential review process, EC first, then agency (ANMAT). Straightforward CTA approval process; Pre-defined submission deadlines to MCC, typically 6 review cycles per year. EC approval in parallel with agency approval Straightforward CTA approval process; Sequential review process, EC first and agency review second IF EC decides agency review is required.
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Besides the regulatory and medical considerations, other factors are examined if they would correlate, or predict, the
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that the quality of the data is robust, strict adherence to Good Clinical Practice (GCP) is mandatory. GCP is an international quality standard that defines standards, which governments can transpose into regulations for clinical trials involving human subjects [4]. These guidelines include protection of human rights as a subject in clinical trial. It also provides assurance of the safety and efficacy of the newly developed compounds, and includes standards on how clinical trials should be conducted. They also define the roles and responsibilities of clinical trial sponsors, clinical research investigators, and monitors. While deciding whether to place global or regional studies specifically in emerging markets, the medical infrastructure, disease prevalence and standard of care need to be considered. For example, it needs to be evaluated whether the comparator product is approved for use or is part of the standard of care in the countries where the studies are planned. For example “S-1” (Tegafur/Gimeracil/Oteracil) is a commonly used chemotherapy in Asia for gastric cancer but is not commonly available in the West and is generally not included as a comparator in global studies. Thus it could become a challenge to convince the investigators or even the ethics committees about the choice of comparator product. All these factors need to be considered when placing a study.
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Number of patients can be negotiated depending on therapeutic area, medical need, etc. Approval times can be reduced through special review mechanisms (e.g., orphan drugs). East-Asian countries may use data from other Asian countries (e.g., Taiwan could use Japanese data). d Biologics approval may take a few months longer. e Biological samples (e.g., full blood, tissues) need special permission. f “First in Human” studies not permitted unless molecule “discovered” in country. ⁎ Patients on study drug (may differ for small molecules vs. biologics). b
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number of clinical trials in emerging countries using regression analysis. Such findings could provide informative guidelines for clinical trial placement based on current industry experience. The statistical analysis software employed is JMP (V.10) [5]. Various quantitative indexes were considered. For example, does the prosperity of the country as measured in Gross Domestic Product (GDP) or the labor force in a country correlate to the number of clinical trials? Does a country's spending on healthcare or education predict its likelihood of participating in global clinical trials? Does innovation capability or corruption play a role? Relevant factors like these are selected to examine their magnitude of impact and predictive value. In total, 10 factors are considered in the analyses for their correlation with the number of clinical trials at the country level. Eight are based on published World Bank data [6] including R&D as % of GDP, public education as % of GDP, gross national income adjusted for purchasing power parity (PPP), patent applications by residents, patent applications by non-residents, total labor force, health expenditure per capita, and infrastructure as measured by % internet users. In addition, a country's corruption index is assessed by Transparency International [7], and the country's innovation index is assessed by a consortium of business schools and World Intellectual Property Organization (WIPO) [8]. Factors that reflect a country's economic strength (population and total labor force) are natural selections because they intuitively impact clinical trial placement decisions. Likewise, a country's attention to R&D, education, and healthcare (R&D
Please cite this article as: Singh R, Wang O, Clinical trials in “emerging markets”: Regulatory considerations and other factors, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.09.006
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It's worth pointing out that for all 10 factors, a higher value indicates a better state of a country. For example, a higher value for the innovation index indicates more innovation, and a higher score for the corruption index indicates less corruption. The top 50 “secondary markets” countries represented in ClinicalTrial.gov as of June 2013 are shown in Fig. 2, organized by the number of clinical trials in descending order. A preliminary analysis including all 50 countries in Fig. 2 is shown in Table 2, depicting the relationship between each of the 10 factors and the number of clinical trials. These are univariate analysis examining the 10 factors one at a time. The Table shows the predicted change in number of clinical trials for each unit increase of the particular factor, as indicated by the regression analysis. It's effectively the slope of the regression line. The correlation, which takes a value between − 1 and 1, measures the strength of the relationship between clinical trial number and a particular factor. The closer it is to either 1 or − 1, the stronger the relationship, with a positive correlation indicating synergy and a negative correlation indicating a detrimental effect. The last column, the p-value, measures the level of confidence our analysis has for the calculated correlation. A p-value less than 0.05 is considered statistically significant; in other words, the actual correlation is believed to be different from 0. Nine of the 10 factors, excluding public education as % of GDP, show a significantly positive correlation with the number of clinical trials. While this is an interesting and encouraging result, two refinements are then made due to the following considerations. First, some of the 50 countries have either a small economy or small number of clinical trials. Their inclusion does not provide useful information. Therefore, the subsequent analyses only included countries with more than 450 clinical trials, resulting in 23 countries. Secondly, the entire population in a large country does not have the same exposure to clinical trial opportunities. Urban population tends to be a more relevant indicator than the entire population. Hence the number of clinical trials for each country is standardized by the number of urban population (number of clinical trials per 1,000,000 urban population). Note that Taiwan's urban population is not available from the World Bank database and thus only 22 countries are analyzed. These results are tabulated in Table 3. These 22 countries, from South Korea to Egypt, represent the vast majority of biopharmaceutical industry's “emerging market” interest. The factors that positively correlate with clinical trials and are found to be significant include a country's attention to R&D (R&D as % of GDP), its level of healthcare (health expenditure per capita), modern infrastructure (% internet users), transparency (corruption index), and level of innovation (innovation index). As a guiding principle the findings make intuitive sense, and are also consistent with industry's past experience. Some of the regression lines together with the actual data points are shown in Fig. 3. While the analyses in Table 3 is more relevant to multinational companies since most of the clinical studies in emerging markets are generally conducted in urban parts of the country, the factors measuring a country's absolute size of economy (Gross National Income, patent applications by
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as % of GDP, public education as % of GDP, health expenditure per capita) likely correlates with its capability in conducting clinical trials since clinical trials are generally associated with R&D, mostly the ‘D’ component. Additionally, clinical trials and data management are progressively being managed electronically and are extensively dependent on a good internet infrastructure. The World Bank index that measures internet usage per 100 persons is therefore a meaningful scale to look into for its correlation with the number of clinical trials. For research-based multinational biopharmaceutical companies, Intellectual Property (IP) is a key asset that needs to be protected. Intellectual property is not only limited to the data that is submitted to regulatory agencies and sites; it also includes data protection and data exclusivity. WIPO issues annual indicators covering various areas of intellectual property: patents, utility models, trademarks, industrial designs, microorganisms and plant varieties protection. It draws on data from national and regional IP offices, WIPO, the World Bank and UNESCO [9]. It is critical that research-based multinational companies consider the IP regime of a particular country before committing sending data as part of their clinical trial application (or marketing application), especially as it relates to Chemistry, Manufacturing and Controls (CMC). In our analysis, a country's IP regime is reflected in two factors: patent applications by residents and non-residents, and the innovation index. As detailed in the GCP guidelines, ability by the trial subject to understand and agree to the consent form is a requirement. A functional literacy could provide a measure of trial subject's level of comprehension of the consent form. The Human Development Index (HDI) provides a single statistic that serves as a frame of reference for both social and economic development. This includes health, education and living standard measures. The public education as % of GDP factor and the health expenditure per capita factor in our analysis partially touch on this aspect. The clinical data needs to be “clean” with no element of fraud or study misconduct. Transparency International's mission is to stop corruption and promote transparency, accountability and integrity at all levels and across all sectors of society. This organization generates annual surveys of corruption index by countries which is a relevant factor included in our analysis. It could indirectly provide a measure of the quality of the ethics committees, data integrity and the practices of the regulatory agencies. Note that the quality of the data also relates to the training of clinical research personnel, GCP adherence and education—factors that are discussed separately. The Global Innovation Index relies on two sub-indexes, the Innovation Input Sub-Index and the Innovation Output Sub-Index, each built around pillars. Five input pillars capture elements of the national economy that enable innovative activities: (1) Institutions, (2) Human capital and research, (3) Infrastructure, (4) Market sophistication, and (5) Business sophistication. Two output pillars capture actual evidence of innovation outputs: (6) Knowledge and technology outputs and (7) Creative outputs. The Global Innovation Index could be relevant to where the clinical trials are conducted since it could indicate areas with differing quality of health care professional and healthcare infrastructure (e.g., hospitals).
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Fig. 2. Number of registered clinical trials in ClinicalTrials.gov in top 50 countries representing “emerging markets” (outside “primary markets”).
Table 2 Relationship between predictive factors and the number of clinical trials — top 50 countries.
t2:3
Factors
Unit
Δ in # CT/unit ↑
Correlation
P-value
t2:4 t2:5 t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13
R&D as % of GDP Public education as % of GDP Gross national income — PPP Patent applications (res) Patent applications (non-res) Total labor force Health expenditure per capita % Internet users Corruption index Innovation index
% % $ Trillion Thousand Thousand Million $ Thousand % One One
957 145 462 14 48 4.1 1181 25 22.8 68.6
0.77 0.18 0.63 0.59 0.70 0.48 0.51 0.43 0.29 0.57
b0.0001 0.2611 b0.0001 0.0001 b0.0001 0.0004 0.0002 0.0021 0.0425 b0.0001
Please cite this article as: Singh R, Wang O, Clinical trials in “emerging markets”: Regulatory considerations and other factors, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.09.006
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Table 3 Relationship between predictive factors and the number of clinical trials standardized by urban population — top 22 countries. Factors
Unit
Δ in # CT/unit ↑
Correlation
P-value
R&D as % of GDP Public education as % of GDP Gross national income — PPP Patent applications (res) Patent applications (non-res) Total labor force Health expenditure per capita % Internet users Corruption index Innovation index
% % $ Trillion Thousand Thousand Million $ Thousand % One One
80.9 38.3 −13.5 −0.2 —0.6 —0.2 177.7 3.4 4.4 7.7
0.64 0.29 −0.23 −0.10 —0.11 —0.23 0.82 0.50 0.54 0.63
0.0055 0.2409 0.3273 0.6822 0.6417 0.3114 b0.0001 0.0170 0.0092 0.0021
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in Table 2 when the clinical trial numbers were not standard- 312 ized for the number of urban population. The results there 313 should be expected; however, the difference illustrates how 314
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both residents and non-residents, and total labor force) all show non-significant correlation. Surprisingly, they all have negative correlations. Note that these were all highly significant
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Fig. 3. Selected regression analysis of the number of clinical trials standardized by urban population on various predictive factors — top 22 countries (the highest point on each panel represents Israel).
Please cite this article as: Singh R, Wang O, Clinical trials in “emerging markets”: Regulatory considerations and other factors, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.09.006
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The biopharmaceutical industry is one of the most regulated industries and cost of product development is one of the highest. As per some estimates, it costs about $1.2 billion to develop a drug and can take up to 10 years to bring it to the market [11]. One of the largest contributors is the cost of clinical studies, which can account for up to 80% of development costs [12]. Moreover, the pharmaceutical industry is rapidly changing. While pharmaceutical market growth in US, EU is expected to be slow or flat, the “emerging markets” to grow 14–17% and account forapproximately one-quarter of the total global pharmaceutical market [13]. As per the IMS report, in mid-2000, there was only one country (China) listed in the top-10 global pharmaceutical sales list; by 2016 it is expected there will be 5 emerging countries on that list with China expected to occupy the number 2 slot. With such vast opportunities in emerging markets, placement of clinical trials in these countries can be hugely variable, and can benefit from both the industry's collective experiences and evidence-based guidelines. This paper is an attempt on both fronts. We have demonstrated that regulatory considerations, clinical considerations, and country-specific characteristics are all important and valid factors in making such decisions. While the regulatory and clinical considerations make intuitive sense, the correlation analysis involving quantitative factors provides insights that a country's R&D, healthcare expenditure, infrastructure, transparency, and innovation capability are all strong indicators that the biopharmaceutical industry can rely on. When these factors score high for a country, past evidence suggests that we have more confidence in placing clinical trials there, and the chance of these clinical trials contributing to the overall commercial success of the compound is also high. Notice that the standardized percent or per capita measures are better suited for this analysis than the gross measures that more reflect a country's size of economy. One limitation of this research is the fact that some of these factors are naturally correlated among themselves, and an attempt was made to perform multivariate analysis to examine them simultaneously. However, the available dataset came from multiple data sources and had many missing values. Even when only the percent and per capita measures were focused on, only 12 countries out of the top 23 had complete data. With only about 5° of freedom available for error, such analysis would not be informative. Further research can be done when more complete datasets are available to narrow the focus to a couple of comprehensive factors that may or may not be observable. Since many key emerging markets require clinical studies as part of the registration process, placement of clinical trial for “commercial attractiveness” now also should be a major selection criterion. In conclusion, when considering clinical trials in emerging markets, it is no longer about accessing patients and cost savings. Multiple other factors need to be considered and evaluated. Ultimately, it comes down to timely access of patients, markets, talent and cost-effectiveness in emerging markets.
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country's size of economy including gross national income, 376 patent applications, and total labor force, show no apparent 377 correlation. 378
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population alone is a poor predictor for our purpose, and the diversity of the population in terms of urban and rural splits can add little value to our understanding of the real picture. For example, patent filings are not reflective of the IP regime enforcement in a country — a more relevant measure for the MNCs planning clinical studies in the country. Similarly, the total labor force does not directly correlate to the technical expertise required to conduct clinical trials. In other words, large population of physicians does not necessarily correlate to the high talent pool of clinical research investigators or clinical research associates. Also, as per 2012 Population Reference Bureau report [10], the world population was just over 7 billion. The population of the “top-10” countries listed in Table 1 accounted for over 3.2 billion, or 46% of the world population. In contrast, the total number of clinical trials (as listed in ClinicalTrial.gov) in these top-10 countries is about 19% of the global studies. While there is some correlation, population of a country by itself is not a predictor where the clinical studies are conducted. The gross national income or GDP is very high among top oil producing nations and the majority of them are not on the list of top clinical trial destinations; thus while a country may be “rich”, that does not necessarily translate to higher number of clinical studies. However, “prosperity” of a country may contribute to factors such as R&D investment and health care expenditure where we see positive correlation. It is noticeable, perhaps contrary to common belief, that a country's spending on public education is not a major factor. If it was not for Israel which scores the highest on this factor and also with the largest number of standardized clinical trials, the regression line would be even more flat. Also, the specialized nature of clinical trials may not be captured in the public education and would require more of post-secondary and post-baccalaureateeducation/training — perhaps that would be a better measure and analysis to conduct. Along similar lines, Israel stands out in almost all these analyses due to its large number of clinical trials and highly urbanized population. As a result, it has the highest number of clinical trials per million urban population, making it easily identifiable in all the panels of Fig. 3 (the highest point). A sensitivity analysis was performed with Israel excluded, to examine its influence on the analysis. The result shows that the regression lines for all factors become more flat, but the statistical significance still holds except for R&D as % of GDP. This demonstrates that Israel adds an upward pull to the regression line in a way that is different compared with most other countries. The highly successful clinical trial placement experience from Israel is probably difficult to be extrapolated elsewhere due to its uniqueness. Thus, at a high level, our preliminary analysis shows that nine out of ten different factors show a significantly positive correlation with the number of clinical trials in the countries. Surprisingly a different correlation structure was observed when only the relevant countries were included and only the urban population was considered since that appeared to be a more relevant area where global clinical trials are generally conducted. The number of clinical trials correlates well with R&D as % of GDP, healthcare expenditure per capita, % internet users, low corruption index, and innovation index. On the other hand, absolute measures of a
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[1] Morrison A, Singh R. Rethinking emerging markets for regulatory affairs. Regul rapporteur 2012;9(4):5–7. [2] ClinicalTrials.gov. See studies on map. http://clinicaltrials.gov/ct2/search/ map; 2013. [3] Sivaramakrishan V, Bhide M. Comparative analysis of drug-lag in emerging markets. Regulatory focus online; 2013 [www.raps.org]. [4] ICH. Guideline for Good Clinical Practice, E6 (R1). http://www.ich.org/ products/guidelines/efficacy/efficacy-single/article/good-clinical-practice. html; 1996. [5] SAS Institute. Using JMP; 2012 [Cary, NC]. [6] World Bank. http://data.worldbank.org/indicator; 2013. [7] Transparency International. http://www.transparency.org/research/cpi/ overview; 2013.
[8] Dutta Soumitra, Lanvin Bruno. The Global Innovation Index 2013, The Local Dynamics of Innovation. http://www.globalinnovationindex.org/; 2013. [9] WIPO. 2012 World Intellectual Property Indicators. http://www.wipo.int/ ipstats/en/wipi/; 2012. [10] PRB. World Population Data Sheet, 2012. www.prb.org; 2012. [11] DiMasi JA, Grabowski HG. The cost of biopharmaceutical R&D: is biotech different? Manage decis econ 2007;28:469–79. [12] DiMasi JA, Grabowski HG. R&D costs and returns to new drug development: a review of the evidence. In: Danzon PM, Nicholson S, editors. The Oxford Handbook of the Economics of the Biopharmaceutical Industry. Oxford, UK: Oxford University Press; 2012. p. 21–46 [chapter 2]. [13] IMS. Annual report. http://www.imshealth.com/portal/site/ims/; 2011.
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Please cite this article as: Singh R, Wang O, Clinical trials in “emerging markets”: Regulatory considerations and other factors, Contemp Clin Trials (2013), http://dx.doi.org/10.1016/j.cct.2013.09.006
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