Tomas Novak

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.

 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.

  On the other hand, only 2 out of 10 marketed drugs return revenues that match or exceed R&D costs.

  There are approximately 3,200 NCEs in development

 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 sites

 and generates approximately 40% of clinical data.  However, other regions have arisen in recent years.

  The main reasons behind this globalization trend are the availability of highly skilled professionals in new research markets,

 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

				East Asia (China, Hong Kong, Korea, Mongolia, Taiwan)

				North America (NA - Canada, USA, Mexico)

				North Asia (post Soviet countries, incl. Russia and Ukraine)

				Pacifica (including Australia and New Zealand)

				Southeast Asia (including Indonesia, Malaysia, Philippines, Singapore, Thailand and Vietnam)

			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%.

  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 healthcare

 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.

			Percentual substitution of CTs per region.

			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) approval

 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.

Articles

Examining why newly registered trials have fallen in Central and Eastern Europe, relative to other regions.

Decline of Trials in CEE: Fluctuation or Trend?

			These new countries, with growing economies, increase healthcare investments and new markets spring up.  As they adopt ICH GCP guidelines, clinical trials follow.  

			This is an interesting observation and most probably is connected to the recent financial crisis. Some countries still haven’t fully recover. 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) approval

In some countries, the participation in clinical trial, is still the only possibility to be treated.

Tomas Novak

Articles

Decline of Trials in CEE: Fluctuation or Trend?

Decline of Clinical Trials in Central and Eastern Europe: Fluctuation or Trend?