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Applied Clinical Trials
Examining why newly registered trials have fallen in Central and Eastern Europe, relative to other regions.
There are several reasons for the increasing number of clinical trials globally. Some of these factors are aging of the population, the high prevalence of chronic diseases, the embrace by physicians and payers of evidence-based medicine, and the patients´ common belief that they will benefit from the medical technologies and treatment. Patients volunteer into clinical trials to gain early access to medication, treatment, and medical care.1 In some countries, the participation in clinical trial, is still the only possibility to be treated.
Approximately 340 new drugs and biologics came to the market between 2000 and 2011.2 On the other hand, only 2 out of 10 marketed drugs return revenues that match or exceed R&D costs.3 There are approximately 3,200 NCEs in development4 and the number is constantly on the rise. Economic difficulties and financial crises have led to an increased need for precision in the planning of CTs to minimize risks and eventual losses.
Currently, 66% of clinical trials are conducted in North America, Western Europe and Australia. The U.S. hosts 49% of clinical trial sites5 and generates approximately 40% of clinical data. However, other regions have arisen in recent years.1 The main reasons behind this globalization trend are the availability of highly skilled professionals in new research markets,6 lower costs, faster patient recruitment that allows for earlier drug application approvals and concentrations of huge populations for future drug sales.
These new countries, with growing economies, increase healthcare investments and new markets spring up. As they adopt International Conference on Harmonization (ICH) good clinical practice (GCP) guidelines, clinical trials follow.
Just as the number and regional distribution of studies shift, so too does the number and placement of studies by Phase.
Changes in the Global Clinical Trial Landscape
We adopted the geographical regions as classified by clinicaltrials.gov
Table 1: # of Newly Registered IND CTs per region: 2006 vs. 2012 (Absolute Numbers & % Relative Change per Region)
Between 2006 and 2012, the absolute number of clinical trials registered annually has grown by 39%. We observe this increase in every part of the world except in Central America and Pacifica, where the number dropped about 15%.7 The biggest relative change between 2006 and 2012 of newly registered clinical trials is observed in Japan (+94%), East Asia (+217%), South Asia (+45%), Southeast Asia (+42%) and the Middle East (+40%). North America demonstrated a rise of +36% and Europe, a +32% increase in 2012 compared to 2006. It is safe to say that a Northern Hemisphere focus has been gradually shifting towards the East, i.e. from North America and Europe to Asia. This has to do with economic development allowing countries to invest more in healthcare8 and the increase in populations, which make these countries excellent targets for future growth of pharmaceutical sales.
On the other hand, quite recently, some of these countries exhibit levels of instability. Lack of GCP standards, ethical misconduct and even frauds are still big concerns in these regions. India, for example, has no specific law pertaining to scientific fraud.9
Analyses of the changes in number and distribution of clinical trials from 2006 – 2012 unveil some curious developments. To understand the true growth of clinical trials in a region, we tie the relative change of newly registered clinical trials within a region (in %) to the overall, absolute number of registered IND studies per year globally (100%). This calculation gives a percentual substitution rate per region and tells where real growth has occurred.
Table 2: Percentual substitution rates by regions in 2006 and 2012.
Figure 1: Relative number versus percentual substitution per region in 2006 and 2012.
Table 2 and Figure 1 demonstrate that the growth of the relative number of clinical trials in 2006-2012 was registered everywhere (blue bars), except Central America and Pacifica. However, expressed in percentual substitution (red bars), the data actually demonstrate declines for almost all regions. For example, there was a 32% growth of the number of studies in Europe. On the other hand, in light of the total number of newly registered trials around the world, it turns into a 5% decline. Similarly, a relative 36% growth in NA actually represents a 2.4% decline in percentual substitution.
Markedly, the share of East Asia, South Asia, Southwest Asia, Japan and the Middle East is growing, especially in East Asia.
Working on a detailed analysis of Europe, we made an intriguing discovery. We split Europe into three large entities: Western Europe (WE), Central and Eastern European members of the EU (CEE-EU) and the non-European states in Central and Eastern Europe (CEE-non-EU). The last group is not discussed in this manuscript.
In 2013, Western Europe participated in 86% of the total number of studies in Europe and approximately 34% globally. Treatment methods are similar to those of the US and thus, logically, a complement to US sites.
Table 3: Numbers of newly registered studies in WE countries in 2006 and 2012.
Figure 2: Percentual Substitution of Clinical Trials in WE countries: (2006 at baseline vs. 2012)
Figure 2a: Percentual Substitution of Clinical Trials in WE countries: (2006 at baseline vs. 2012) continued
Table 3 and Figures 2 & 2a show, by percentual substitution, the minimal growth of clinical trials in 2006-2012 in WE. i.e. approximately 1.5% overall. Countries like France, UK, Sweden and Spain enjoyed an increase in the number of clinical trials. However, countries like Denmark, Germany, Greece, the Netherlands, and Switzerland remained stagnant while Portugal, Austria, Finland and the remainder have declined.
This is an interesting observation and most probably is connected to the financial crisis of 2008-2012. Some countries still haven’t fully recovered. In some other countries the approval procedure is becoming more complex through years. For example in Germany, there is a need to have BfS (The Bundesamt für Strahlenschutz, Federal Office for Radiation Protection) approval10 for some studies (extended procedure since 2011). Such approval can take around 6 months and represents unwelcome delay in the study start-up.
This region participates in about 13% of clinical trials conducted in Europe and in about 5% of those conducted globally. However, this number was as high as 7.5% in 2006. In relative terms, the decline here goes as far as 28% over the last six years. It has been observed in all countries of this region, especially Poland, Croatia and the Baltic states (Table 4 and Figure 3). This is a most surprising finding since the CEE-EU region is considered to be especially well positioned for clinical trials 8.
Table 4: Numbers of newly registered studies in CEE-EU countries in 2006 and 2012.
Figure 3: Percentual Substitution of Clinical Trials in CEE-EU countries (2006 at baseline vs. 2012)
As shown in Figure 1, East Asia and South Asia are the fastest growing regions although, within the regions, clinical trial activity varies by country. Taiwan and Hong Kong saw a sharp decline in the number of clinical trials (-39% and -69% respectively). Simultaneously, a great hike has been registered in South Korea (+29%) and China (+30%). These two countries are represented in almost 7% of newly registered studies globally, which is more than the whole of CEE-EU.
China’s CRO market grew in the early 2000s after it joined the WTO and developed regulations for the drug industry. It is estimated that China will soon be the second largest Asian pharmaceutical market after Japan.11
India, with an almost 40% growth, stands out especially and has been considered advantageous for a number of reasons such as good patient recruitment, acceptable quality of services, reasonable cost-quality ratio, existence of regulatory agencies, high standards of care and English-speaking skills. As in China, the FDA has opened an office there.12 (As of this publication date, new Indian clinical trials have slowed dramatically for regulatory reasons.)
Over the course of recent years, as the number of newly registered clinical trials has increased, we see an expected growth in Phases I and II studies. Interestingly, and perhaps logically, the number of Phase III studies have declined. Along with this shift to earlier phase studies, we also see a change in the geographical placement of studies by phase.
The biggest increase (of 82%) occurred in Phase I studies, Phase II expanded by 21% and Phase III declined 10%. Post-marketing Phase IV studies went up by 19%.13
Phase I studies made up 23% of all clinical trials initiated in 2012 and their expansion is truly explosive. Such a trend is present in several regions, including Europe (+52%). Within Europe, Western Europe has seen the majority of this increase due to healthcare practices being similar to the US. When US sponsors consider ex-US placement of Phase I studies, they look to Western Europe as a familiar region in which to work. (Figure 4).
Figure 4: Relative % Change in Placement of Phase I Clinical Trials from 2006 to 2012.
Phase II studies made up 34% of the total clinical trial numbers in 2012 and this segment increased by 21% since 2006. As with Phase I, here the increase is mostly notable in Europe, Japan and Asia. The steepest, significant declines have been observed in North and Central America and Pacifica.
Figure 5: Relative % Change in Placement of Phase II Clinical Trials from 2006 to 2012.
Phase III studies are the most expensive, frequently require recruitment of thousands of patients and can encompass up to 90% of all expenses incurred during the clinical development of a drug.14
The 10% decrease of Phase III studies since 2006 probably demonstrates more effective planning of drug development. Nevertheless, Phase III still makes up 27% of all clinical trials. As with Phases I and II, a large increase in the number of Phase III studies is observed in East Asia. It is safe to presume that, financial reasons aside, the huge pool of patients available for these big and expensive projects and the potential of creating a major new market has played an important role in this phenomenon.
Figure 6: Relative % Change in Placement of Phase III Clinical Trials from 2006 to 2012
When speaking of Phase IV studies, we should remember that they are more often conducted as non-interventional trials and thus may not be easily calculated . Nevertheless, a 19% increase has been noted in this segment, i.e. 15% of all clinical trials in 2012. (Figure 7)
The shift of phase IV studies from NA, EU and Japan to Asia and LA seems logical. Funding and marketing reasons are definitely important; however, efforts to register new drugs in these countries are also a factor.
Figure 7: Relative % Change in Placement of Phase IV Clinical Trials from 2006 to 2012.
There is a substantial growth in clinical trials all over the world. Certainly, this trend was tempered by the global financial crisis and long-term conclusions will be visible only later.
When we compare relative numbers of clinical trials tied to the total number of newly registered studies, we make the conclusion that there is a de facto decrease of newly registered clinical trials in Europe and CEE-EU, in particular.
The largest growth in relative numbers has been observed in Asia, namely in China, which has become more open for clinical trials, but also India that has turned into a more accessible place over the recent years with a population that is fast approaching that of China’s. When we consider additional factors, such as population growth, spread of business-English usage or economic boom, the changes become understandable.
On the other hand, the instability of the region, risk with quality management and other elements need to be taken into consideration. Also cultural differences and inconsistency with subjective medical analyses and interpretation or insufficient communication during safety reporting, lack of GCP certification and others are important factors to be weight and several sponsors already re-considered their opinion about several countries in Asia.
The analyses we made give an important negative signal regarding clinical trials in CEE-EU. This signal should be considered by investigators, regulators and clinical research professionals to develop action plans, which may result in the increase of CEE’s attractiveness in a highly competitive clinical trials market.
Although all CEE-EU countries adopted EU regulations, local legislation is still in place in a number of countries. These requirements can impose additional burdens of time, resources and finances on potential sponsors. The countries of CEE-EU would undoubtedly benefit from embracing fully EU regulations and limiting restrictive local laws. Such a response may include changes of existing standards in individual countries as well as adoption of uniform rules applicable throughout Europe.
Paradoxically, the decrease of competitive studies may be good news for investigators. Once newly registered studies migrate to other regions, the availability of patients, clinical centers and investigators increase, resulting in better interactions with CROs and sponsors. Finally, yet importantly, a larger pool of available patients enables greater recruitment within the same center, making its cooperation in a trial even more financially attractive.
The number of global clinical trials keeps growing. Percentual substitution, however, indicates a gradual decline existing currently in all CEE-EU countries (approximately 5% per year). This decline of the CT share in CEE-EU is an important signal for all stakeholders, including regulators, sponsors, CROs and principal investigators.
Tomas Novak, PharmD (Czech Republic); Maxim Belotserkovsky, MD (Germany); Ginny Payeur, RN (U.S.), all with PSI CRO AG, Zug, Switzerland