	Trouble has been brewing for a long time in the choppy European waters around treatments for rare diseases, with patients’ demands for attention often going unheeded, drug firms buffeted by rising costs of research, and paying agencies creaking under the strains of austerity-and now the price tags attached to some recent treatments are turning stiff headwinds into a howling gale. 

	Amid this maelstrom, the European Union’s (EU) 15-year-old scheme to incentivize orphan-drug development has become a victim of its own success, with ever more companies taking advantage of it, and the costs and consequences rising accordingly for the European and national authorities that operate it.

	To date, the European Commission has already authorized 114 orphan medicines for the benefit of patients suffering from rare diseases, and has designated 1,243 products as orphans, entitling them to a range of incentives, including protocol assistance, fee waivers and market exclusivity. In mid- November, the Commission released a c

 setting out how the scheme is to be “streamlined.” The consultation runs until February, and the Commission intends to introduce changes in the first half of 2016. The result could be that some potential treatments for rare diseases become orphans of the storm rather than orphan drugs.

	Over recent years, the authorities have shown increasing signs of disquiet, and earlier this year, one of the senior EU committees on pharmaceutical policy formally noted “some weaknesses and challenges in the field of orphans that affect the reputation and the credibility of the system.” Top of the list of priorities for action was “to clarify the requirements to facilitate entry of innovative products with a significant benefit over existing products.”

	Access to the scheme’s incentives is restricted to products that can show they are bringing something new. So, according to the Commission-which is responsible for the rules of the scheme-“we need to clarify what type of data the sponsors need to show to demonstrate the significant benefit over authorised medicines.”

	This is tough love. A product may be designated as an orphan product even if a treatment exists for the intended condition, provided that it represents a significant benefit to those affected by that condition. But the proposed new rules insist that establishing significant benefit “cannot be limited to an assessment of the intrinsic qualities of the product in question without comparing them with the intrinsic qualities of the authorised methods”-and must deliver “a clinically relevant advantage or a major contribution to patient care.”

	This implies, the text goes on to spell out, an investment in research and development that provides improved efficacy, a better safety profile or better tolerability, greater ease of self-administration, or an important and demonstrable improvement in adherence to treatment through a new form.

	At the same time, it makes it clear that significant benefit should not be considered based on just a possible increase in supply when there are shortages (or non-availability) of existing authorized products, or mere enhancement of the pharmaceutical quality of a product or a simple alternative mechanism of action. And any assumptions made about benefit (since there may be little clinical experience with the product when an application is made) will be subject to assessment by the EU’s Committee on Orphan Medicinal Products.

	The criteria must continue to be met when the designated orphan product comes up for marketing authorization, too-and the data requirements will be tougher by that stage. If not, the product will lose its orphan designation (and the advantages that go along with it). “The significant benefit should consider a quantitative element that allows the committee to measure the magnitude of the effect based on direct or, when not possible, indirect comparative clinical trials with already authorized medicinal products,” says the text.

	The new version of the rules also underlines the risks a designated orphan faces if it fails to deliver. Removal of its status can take place “if there is evidence that the basis on which the original designation was granted has changed”-such as lack of data to support earlier assumptions.

	The Commission also envisions closing a loophole that has been used by companies to circumvent the ban on getting a second orphan designation for a new form of the same active substance. To get around this, some companies have asked a third party to apply for the desired orphan designation, which is subsequently transferred back to the original applicant. “This practice can be considered as an attempt to circumvent the intention and the purpose of this provision,” says the Commission. It can also delay the marketing of generic rivals, it adds, indicating that it favors tightening up here, too.

	One or two of the other elements in the consultation might make life a little easier for some applicants. For instance, in the wake of the Ebola crisis, the Commission suggests allowing access to assistance for products currently excluded from the scheme because they have zero incidence in the EU (such as diseases that have been declared eradicated by the World Health Organization). “An infectious disease with a very low prevalence in the EU can very rapidly become a serious threat to public health,” the Commission recognizes. Consequently, the scheme might be modified to apply a risk-based approach to eligibility, so as to encourage the development of orphan products for communicable diseases. And another possible easing of the conditions may be introduced in situations where two authorization application procedures are running in parallel-a situation that has occasionally led to harsh treatment of the second product to reach the authorization stage, since it is faced with the near-impossible task of demonstrating significant benefit over a product that may have been authorized only weeks or months before it.

	But, overall, the effect of the envisioned changes is likely to be greater constraints on drug developers. Already under the existing rules, there has been some attrition of orphans. By the end of 2014, when the magic figure was reached of 100 marketing authorizations granted to products with an orphan indication, there had also been 80 failures, with 69 applications withdrawn and 11 refused. And 13 applications that had received marketing authorization then lost their orphan designation when they were reviewed. The new rules are intended to improve the performance of the scheme-but could do so at the cost of increasing the failure rate.

	Some leading industry figures have suggested that protocol assistance might have prevented many of these failures, since the records show that where protocol assistance is used, chances of success in product registration are higher. Kerstin Westermark of Genzyme said earlier this year that protocol assistance is in fact the main incentive provided by the regulation. A clearer presentation of the available incentives and conditions might also help. An inventory of the incentives at EU and national level to support research, development, and availability of orphans, which the Commission is required to provide, has not been updated since 2005; the Commission is working on a new version, which may appear before the end of the year.

	But the principal stumbling block remains the issue of patient access, even when orphan designation and marketing authorization runs smoothly. Yann Le Cam, head of the European rare patients’ organization Eurordis, has pointed out that even where rare disease treatments exist, 30% of patients across the EU are still unable to access them, because they are not reimbursed by national authorities, who are often deterred by the high price of individual products. He argues that the overall burden of treatments for rare disease is not high. Le Cam estimates that they account for only 1-2% of healthcare spending today, and might reach 5% by 2020.

	That is an argument that appeals to the end users of orphan medicines, and to the companies developing them. But the authorities in the middle- responsible for designating orphans and for paying for them-are finding the argument less compelling, and orphans may still face neglect. 

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium

Articles

View from Brussels

Despite orphan-drug R&D and approval being all the rage, issues such as patient access could leave these treatments out in the rain.

Orphans of the Storm

	This spring, members and guests of the Drug Information Association (DIA) will converge in Hamburg to sample the German city’s legendary oysters and traditional Aalsuppe (sweet-and-sour soup with ham, dried plums and apple), and navigate through the area’s extensive network of canals, discovering the delights of the Alstadt (Old Town). But the matters at hand inside the walls of the Congress Center Hamburg, the site of  DIA’s 28th Annual EuroMeeting, which which begins on April 6, will focus heavily on technology and innovation throughout the R&D process.  
	
	The congress will explore how clinical research is incorporating new and upcoming technologies like gene therapy, discuss options in linking novel diagnostic opportunities like next-generation sequencing with targeted treatments, and evaluate the use of digital tools in research, development, and patient treatment, noted conference co-chair Dr. Kemal Malik in an email interview with 

.
	
	“Patients and their families expect to receive innovative and well-developed medicinal products of a high qualitative standard and in a timely manner. At the same time, we have to accept the challenges we are facing with respect to private and public budget constraints,” said Malik, who is responsible for innovation and the North America and Latin America regions for Bayer AG, and was appointed to the company’s Board of Management in February 2014. “The early exchange of information in a transparent way is key to improving health and to maintaining high standards. Clinical researchers have an active role in shaping procedures and decisions for the benefit of patients and being part of the development of products and services that benefit people and improve the quality of life.”
	
	Hamburg-“the gateway to the world,” Malik  believes-is thought to be an ideal place to exchange experience, get new insights on innovation, and align all required stakeholders. Delegates will get the chance to learn about the renowned medical research done in city’s University Clinic Hamburg-Eppendorf (UKE) and share views and discuss new legislation and its implementation, as well as new information on patient interaction tools, according to Malik.

	Malik’s co-chair will be Prof. Karl Broich, who has been president of the Federal Institute for Drugs and Medical Devices (BfArM) in Bonn, Germany, since August 2014.
	
	The title of the EuroMeeting is “Innovation-Do You Win by Being In?” The central themes are innovation, clinical research, clinical trials, regulatory science, medical affairs, e-health/big data, pharmacovigilance, lifecycle benefit/risk management/post-approval, and availability of medicinal products access/shortages. Other sessions will focus on globalization, special populations, medical devices and combination products, health technology assessment, and medical writing.
	
	For updates leading up the event and to view a short video featuring the co-chairs, click 

News

The discussions will center on ways clinical research can harness gene therapy and new and emerging diagnostic tools.

Technology-Driven R&D to be Prime Topic at DIA’s EuroMeeting

	While personalized medicine and immune-based treatment approaches continue to drive novel efforts in drug development, they also contribute to the growing complexities of clinical programs. Fortunately, technological advancements foster the

 evolution of clinical trials despite these challenges. Here, we examine how three particularly key technology areas could reshape global trials over the next 10 years.

	In today’s clinical trial model, patient data flows from the patient/site to the sponsor and ultimately, and in aggregate, to the regulatory body. Electronic medical records (EMRs) provide a streamlined data flow-in some cases, directly from the patient to regulators. However, a lack of standardization has raised concerns over safety and security problems. 

	There are over 250 EMR providers registered with the Office of the National Coordinator for Health Information Technology (HealthIT.gov) in the U.S. alone. While the top five providers account for 50% of revenue, the lack of consistency and ability to share data effectively across EMR platforms creates tremendous challenges in the direct capture of trial data. HealthIT.gov abandoned its “Meaningful Use” implementation objective for electronic exchange of key clinical information in 2013 due to “technical and change management challenges.” These challenges are being addressed through various initiatives driven by regulatory and industry bodies and consortiums, yet will take time to address on a local and global basis. Registry data is one approach sponsors can use to access key patient safety and outcome data directly for trials. An example is the FDA’s 

 pilot project, which aims to monitor the safety profiles of post-marketed products using pre-existing electronic healthcare data from multiple sources, including EMRs and insurance claims.  

	According to IHS, the wearable technology market will drive an estimated $30 billion in revenue by 2018. At a basic level, mobile technology is currently being used to increase patient compliance within studies through the use of mobile communication ranging from daily medication and clinic visit reminders to social media to inform and involve trial participants.

	With the proper safeguards in place, medical tracking via wearables should advance monitoring and reporting. Opportunities include tracking and documenting insulin levels, cardiac activity, and respiratory rate. This type of visibility offers sponsors and CROs accurate, real-time data that would otherwise be difficult to manage. Take the study from Scripps Translational Science Institute published in the 

, in which a wearable patch was compared with traditional testing to measure cardiac rhythms. The study found that the patch was preferred by the patient, was better at capturing data, and cost less for all stakeholders. As a result, the patch is now being reimbursed.

	By 2025, improved data access and flow should become more the norm than the exception. But enhanced data access comes with concerns. We anticipate data privacy rules and considerations will become more complex, causing what could lead to significant changes to the now 19-year-old Health Insurance Portability and Accountability Act (HIPAA).

	We already are seeing early signs of this with 

 introduced to address HIPAA and needed improvements to how a patient’s mental health information is disclosed to family members. A 

 introduced by the FDA in March on modernizing informed consent through electronic informed consent furthers this point.

 is Executive Vice President, Clinical Monitoring, Novella Clinical 

A Closing Thought

Exploring three pivotal technology areas that could reshape global studies over the next 10 years.

How Will Technology Drive Global Clinical Trial Change by 2025?

	The European Union (EU) Regulation 536/2014 was approved by the European Parliament in April 2014, replacing the decade-old Directive 2001/20/EC, commonly referred to as the Clinical Trials Directive. While the new law was approved in 2014, it does not apply until, at the earliest, May 28, 2016-leaving interested parties still with almost six months to prepare for its arrival.

	The benefits associated with the new Regulation include a single submission portal, standardized content of clinical trial applications, information about subject protection and informed consent, more stringent requirements for reporting trial progress, and greater transparency about clinical trials. The operational database for clinical trials and a portal for submissions was planned to be set up by the European Medicines Agency (EMA) by January. The portal must have six months of functionality before the regulation comes into effect, thus determining the earliest date as May 28. 

	However, even with these benefits, the past Directive is linked with the uncertainty of the future regulation, as came to light in a survey conducted last summer. Applied Clinical Trials and SCORR Marketing surveyed our audience on global regulatory issues, with the new Directive central to the questionnaire. In the survey, we asked if Directive 2001/20/EC has impacted your organization. The majority-57%-said yes. When asked how, the respondents said increased costs, followed by increased bureaucracy, at 54% and 46%, respectively. Our EU expert and Brussels correspondent Peter O’Donnell noted, “The nature of the impact is in line with general concerns expressed by the clinical trial community during and since the Directive’s genesis: the increased bureaucracy is nearly as inimical as the increased cost.”

	There has been concern that there is a marked decline in clinical trials placed in Western Europe, which is a direct result of the Directive 2001/20/EC. However, when asked if the Directive has made Europe a less attractive place to conduct trials, 59% said no and 41% yes. The EU Regulation 536/2014 will be applied fully in all Member States, with no need for separate national legislation, with the hope the result will be uniform application throughout the EU. 

	Survey respondents were divided on the potential positive benefits of the new Regulation. Fifty-one percent believe the measure will go far enough to address some of the obstacles to doing research in Europe, while 49% are not convinced.

While approved in 2014, Europe's new regulation governing clinical studies is set to take effect in May-leaving interested parties only six more months to prepare for its arrival.

New EU Trials Law: Headway, Concerns

Will the recently released European clinical trial regulation No. 536/2014 achieve its ambitious harmonization objectives? We will have to wait at least until 2016 to find out. But for the moment, something is already happening in the very heart of Europe … Switzerland. Switzerland is a country small in size, but big in innovation that has always been an attractive location for clinical trials. 

From 2010 to 2013, approximately 200 to 250 clinical trials a year were approved in Switzerland

 and only a negligible number (1.5%) were rejected.

Figure 1: Number of clinical trials approved in Switzerland 2010-2013

Until last year, the main regulation for clinical trials in Switzerland was the law Vklin/Oclin 812.214.2, released in 2001. This was a brief—but wide purpose—document describing the key procedures and requirements for submitting and conducting a clinical trial in Switzerland, including safety reporting, archiving, ethics committee organization, inspections, and administrative procedures. 

A clinical study application started with the ethics committee approval and was followed by the central national authorities review (Swissmedic or Swiss Agency for Therapeutic Products; hereafter referred to as “Agency”) in a sequential, two-step process.
   
  Even if the purposes of the ethics committee and Agency reviews were in principle different, a certain extent of duplication in the evaluation was still present and led to conflicting comments at times. 

Switzerland now has a new rational, properly organized set of regulations governing most aspects of human research, including those that were loosely regulated before. One general regulation and three implementing ordinances greatly increased clarity and understanding of the requirements and procedures for carrying out a research project in Switzerland. 

On Sept. 30, 2011, the Swiss Confederation approved the new federal law on research on human being—the Human Research Act, HRA [810.30].

 This law aims at improving the protection of the dignity, privacy, and health of human beings involved in research and at the same time:

Creating favorable conditions for research involving human beings

The law regulates the research on human diseases and on the structure and function of the human body, which involves:

 research involving embryos, research on anonymized biological material or on anonymously collected or anonymized health-related data were excluded from the purposes of the law.

On Sept. 20, 2013 the Swiss Confederation approved the HRA-associated implementing ordinances:

Ordinance on Clinical Trials in Human Research

 
  This ordinance describes the procedure for approval and notification of clinical trials as well as the specific role and responsibilities of the ethics committees and central authorities. 
  
  

    Ordinance on Human Research with the Exception of Clinical Trials

 
    This ordinance describes the procedure for approval and notification of research projects that are not clinical trials (e.g., observational studies, research on deceased persons, studies with biological material and health-related personal data, etc.)
    
  

Ordinance on Organizational Aspects of the Human Research Act

This ordinance mainly describes the organization of ethics committees.

The new legislation entered into force on Jan. 1, 2014.

Figure 2: Overview of the new Swiss regulations

According to the Swiss Federal Council, "

The Human Research Act [...] sets a new framework for research on humans and establishes clearer, simplified procedures for approving and conducting research projects. The new law also makes it easier to conduct clinical studies over several locations.

Only the most relevant innovations will be summarized in this article, limiting the discussion to trials with therapeutic agents.

As discussed, with the previous regulation, the evaluation of trials by the local ethics committees and the central authority was performed sequentially. This process (double-control principle) was time consuming and not always the most efficient. 

With the new procedure, a parallel submission can be performed. The specific and different area of competence of local ethics committees and the Agency has been clearly defined, avoiding relevant duplication.

The ethics committees are mainly responsible for the evaluation of good clinical practice (GCP) compliance, scientific value, inclusion criteria, risk/benefits, ethical aspects of the trial, protection of study participants, consenting procedures, study insurance, contractual agreements, suitability of study personnel, and facilities.

The Agency, depending on the type of trial, is mainly responsible for the evaluation of the safety of tested drugs for study subjects (for trials with therapeutic agents), including review of clinical pharmacology, toxicological, pharmacokinetical data, and all pre-clinical information, GMP compliance if applicable, and product quality.

In addition to the added clarity, this new parallel submission allows a considerable shortening of the evaluation process.

Assuming that the documents of the application are complete and no additional information is needed, the ethics committee and the Agency could reach a decision within 30 days, plus an initial seven days for validation and control of compliance of the application documents. Previously, the sequential evaluation of the application could add up to at 60 days (30 days for each party). 

For multicenter clinical trials, the coordinating investigator (the person responsible in Switzerland for coordination of the investigators responsible at the individual trial sites) will submit the application documents to the lead committee. After control of formal completeness of the application, at the request of the lead committee, the coordinating investigator shall submit the required application documents to the ethics committees responsible at the other trial sites. These shall review the local conditions and inform the lead committee of their assessment within 15 days. The lead committee shall reach a decision within 45 days of acknowledgement of receipt of the formally correct application. 

Risk classification of medicinal products research projects

One of the most relevant innovations of the new regulation is a three-level system of classification of research projects based on anticipated risk of projects.

 research projects are lower risk and involve medicinal products already authorized in Switzerland used in accordance with the prescribing information or with a different dosage or indication but in the same disease group and with a lower dosage.

 research projects are intermediate risk and include medicinal products already authorized in Switzerland used beyond the indications of Category A.

 research projects are higher risk medicinal products not authorized in Switzerland.

Figure 3: Categorization of clinical trials of medicinal products (art. 19 of Swiss Ordinance on Clinical Trials in Human Research).

A similar and simplified classification (two categories) was also introduced in trials with medical devices.

The classification of trials according to their risk is the foundation of a tailored and optimized evaluation procedure. Lower-risk studies benefit from exemption from Agency evaluation and could benefit from reduced liability coverage requirements as well as lower documentation burden for adverse event documentation. For lower-risk trials, a simplified ethical review of the application has also been introduced.

One of the most relevant aspects of the new EU Clinical Trials Regulation is the attention paid to the transparency of clinical trials, with the introduction of a public central database developed by the European Medicines Agency (EMA). Study milestones, a summary of the trial results, a summary for laypersons, and the clinical study report (when the trial is intended to be used for obtaining a marketing authorization) will have to be submitted in the database.

The underlying assumption of the European regulators is that, in principle, the data of clinical trial reports should not be considered commercially confidential.

 
  
This concept is very much debated by the industry, with important concerns expressed over data protection and disclosure of commercially relevant information.

Switzerland, with the new regulation, has also created an independent portal for public access to information on ongoing and completed trials in the country—the Swiss National Clinical Trials Portal (SNCTP).

The registration in the database should be integrated with the additional entry in existing registers, such as those listed by the World Health Organization (WHO) in the International Clinical Trials Registry Platform (ICTRP)

 or the registry of the U.S. National Library of Medicine.

The registration should occur before the clinical trial is conducted.

Phase I trials with adults must also be registered, however, a one-year exemption after the completion of the clinical trial has been granted, in order to protect sponsors' intellectual property.

SNCTP aims to make information on clinical trials in Switzerland more accessible to the public (data shall be entered in one of the Swiss national languages) and in the end, more transparent. However, the extent of disclosure, especially of study results, is more limited than it will be probably required in Europe when the new EU regulation will be fully operative. 

Organization of research ethics committees 

The new regulation introduces important changes for research ethics committees, with modification of both their organization (with the introduction of scientific secretariats) and their procedures.

The ethics committees will take their decision in the following three different modalities:

: This is the normal procedure, with participation of at least seven members with different expertize to guarantee an expert and interdisciplinary assessment of the application.
  

: Under this procedure, only three members from different disciplines are required. This procedure will be generally applied to category A clinical trials and research projects or for the evaluation of significant changes to authorized research projects, if they raise particular ethical, scientific, or legal issues.
  

 A decision directly taken by the chair or vice-chair of the ethics committee on minor issues, such as research projects involving existing biological material, or existing health-related personal data, or significant changes to authorized research projects which do not raise any particular ethical, scientific, or legal issues.

Switzerland has introduced a new, advanced legal framework of regulations for clinical research. The foundation of the new system is the introduction of a risk-based system that will decrease and rationalize the bureaucratic burden of research. This approach is in line with the recommendations of the Organization for Economic Co-operation and Development (OECD) in its recent document "Recommendation of the Council on the Governance of Clinical Trials" that suggests introducing a risk-based "

Shortly after the implementation of the Swiss laws, Europe has finally published its new clinical trial regulation. While drafting its rules, Switzerland reviewed the changes in European legislation, proceeded in the same direction, and anticipated some of its innovations. This effort will continue once the European regulation is implemented.
   
  While the challenges of the application of a single regulation for human research across Europe still have to be faced, Switzerland is already benchmarking with success many of the same key principles. The paths of European and Swiss human research are leading in the same direction. It is not easy to speculate about the extent of harmonization that will be reached, since this will depend upon both technical and political agreements. 

Performing trials in Switzerland still remain advantageous for sponsors due to the country’s high standards of research, excellence of clinical sites, minimal, no-nonsense bureaucracy, and now, with the new regulations, even faster and effective regulatory approvals.

Mario E. Corrado is Quality Assurance Manager, CROss Alliance Group, 

Federal Act on Research involving Human Beings (Human Research Act, HRA), 810.30; 

http://www.admin.ch/ch/e/rs/810_30/index.html#id-ni1

Ordinance on Clinical Trials in Human Research (Ordinance on Clinical Trials, ClinO), 810.305; 

http://www.admin.ch/ch/e/rs/8/810.305.en.pdf

Ordinance on Human Research with the Exception of Clinical Trials (Human Research Ordinance, HRO), 810.301; 

http://www.admin.ch/ch/e/rs/8/810.301.en.pdf

Ordinance on Organizational Aspects of the Human Research Act (HRA Organization Ordinance, OrgO-HRA), 810.308; 

http://www.admin.ch/ch/e/rs/8/810.308.en.pdf

https://www.news.admin.ch/message/index.html?lang=en&msg-id=51455

Data from Swissmedic Clinical Trials Division. 

810.305 Swiss Ordinance of 20 September 2013 on Clinical Trials in Human Research (Clinical Trials Ordinance; ClinO); 

http://www.admin.ch/opc/en/classified-compilation/20121176/index.html

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/10/news_detail_002181.jsp

http://www.kofam.ch/en/swiss-clinical-trials-portal.html

http://acts.oecd.org/Instruments/ShowInstrumentView.aspx?InstrumentID=281&InstrumentPID=304&Lang=en&Book=

Feature Article

The country’s introduction of a new legal framework has it in sync with European law on clinical research.

Switzerland Guides Innovation in Clinical Trial Regulations

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.

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

Decline of Trials in CEE: Fluctuation or Trend?

Until the end of the 1990s, the majority of clinical sites were based in traditional regions such as Western Europe and North America. In the last two decades, the geographic area of clinical trials has expanded to include more sites in other regions. Today, many sponsors include Eastern European sites in their multinational Phase III studies. In this article, we use the term Eastern Europe to include the Ukraine, Belarus, Russia, Moldova, and Georgia-those countries that inherited and still utilize post-USSR management style, healthcare system structure, and corporate culture. These sites offer the benefit of high recruitment rates, moderate costs, and large treatment-naïve populations, as well as motivated investigators and quality data.

	But we believe there are still challenges facing sponsors in dealing with sites in this region. To overcome and address these hurdles, we sought to clearly understand regional-specific risks and challenges. Our purpose was to evaluate actual site performance in Eastern Europe in comparison with other core clinical trial regions to determine whether Eastern European countries are still considered attractive destinations for clinical trials from pharmaceutical and contract research organization (CRO) viewpoints.

	A web-based survey was conducted among clinical trial professionals from more than 20 countries in North America, South America, Asia, and Europe. The survey consisted of six question categories to determine the following:

		Main location and experience of responders.

		How often responders are facing site-specific issues that affects their study course.

		Differences between clinical sites in various geographic areas.

		Differences between clinical sites with respect to different therapeutic areas in Eastern Europe region.

		Typical site-specific challenges in Eastern Europe.

		Possibility and main reason to involve sites from this region for prospective clinical trials.

	Clinical sites were attributed to three categories according to the nature and severity of the detected issues:

 - sites with a negligible number of rarely arising issues that can be easily resolved, and which affects neither the quality nor timelines of the collected data.

 - sites with medium expression of problems, where issues are systemic, appear quite often, and require time and effort to resolve. These clinical sites may require extra attention, but with specific controls put into place, issues can be resolved and do not largely affect quality of data and study conduct.

 - sites where issues that might significantly affect quality and timelines are common. These study sites require continuous quality control.

	Respondents were selected based on information from LinkedIn profiles and the authors’ personal network. Overall, 57 replies were collected during the period from September 2014 until January 2015. More than 90% (92.15%) of respondents had managerial experience in more than five projects. The majority, approximately three quarters (72.55%), had managed more than 10 projects.

	Main geographic regions were assessed in terms of issues that arise at clinical trial sites. Figure 1 illustrates the rating of core clinical trials regions from a site-specific perspective. 

	The weighted average reflects a level of problems in a specific region-the higher weighted average value, the more problematic the region. Based on results of the survey, sites with fewer problems were based in Australia and North America, while the most problematic sites were based in South America and Asia.

	The survey revealed that site performance is a serious challenge even in traditional and “clinically prosperous” regions. The survey showed that a combined 36% of sites in Australia and 37.5% of sites in North America were considered “Moderately” and “Highly” problematic, requiring close monitoring and additional site-management efforts. In comparison, 78% of sites in Eastern Europe were considered “Medium” or “Highly” problematic (see Figure 2).

	The data confirmed that sites in different regions require different levels of site management, with those in traditional clinical site regions requiring less effort, and those in newer emerging regions, such as Eastern Europe and South America, requiring greater input from sponsors and  CROs.

	One of the objectives of the survey was to explore whether any discrepancies in performance between sites exists, with respect to different therapeutic areas. The majority of respondents admitted such dissimilarity (See Figure 3).

	The replies suggested that oncology clinical sites are most challenging in terms of performance. This could be explained by the highest saturation of trials in this therapeutic area, and the generally extensive routine workload of oncology specialists.

	We then examined why Eastern Europe is still underutilized with respect to clinical research site potential. Respondents acknowledged that diverse and complicated contract procedures with study sites and investigators present 

significant challenge for CROs and sponsors (see table at right; click 

 to enlarge). Furthermore, at state hospitals, which represent the greater majority of the study sites, management and investigators regularly undervalue the importance of contractual obligations that affect timelines and might delay initiation at an individual site.

	About 80% of respondents admitted facing this problem, and for almost 20%, it is a recurrent and crucial hurdle that potentially might influence prospective collaboration with the study centers. Table 1 presents the prevalence of typical site-specific challenges in this region.

	Liaison with local ethics committees (ECs) has been recognized as another specific challenge in Eastern Europe. Quite often, these relationships are underestimated and might be neglected by investigators. However, in this region, it is not a common practice to delegate administrative and technical tasks associated with ECs to a dedicated study coordinator, as such posts do not exist in clinics and hospitals. These tasks are often performed by sub-investigators, who have to manage patients as well as administrative tasks.

	Our survey revealed that some study sites are poorly resourced and inadequately supplied. In some cases, clinical sites may lack basic tools such as access to the Internet or fax. This could be due to lack of support and restricted funding from state governments; a lack of motivation to investing internally by investigators and local hospital management; or a lack of focus or knowledge of changing market factors. Specifically, if the increasing requirements that sponsors place on clinical study sites are ignored by the Eastern European professionals, the sites inevitably will be a less attractive option to sponsors.

	The respondents acknowledged a positive trend for involving sites in Eastern Europe in clinical trials and growing the clinical research experience of these centers. More than 35% of sites in the region were considered to have sufficient level of experience in the industry-sponsored clinical studies, and over 40% of sites have adequately-trained personnel.

	Teamwork defined as smooth integrated functioning of the involved parties has always been considered challenging in medicine and science. Eastern European clinical investigators are not an exception of this rule. Sixtyâtwo percent of survey respondents noticed a lack of teamwork at sites in Eastern Europe.

	The respondent data presented in Table 1 provides a snapshot of a typical Eastern European clinical study site from the viewpoint of an international CRO or pharmaceutical company. It can be summarized as follows:

		Not always well-equipped site that is still keen to participate in a clinical trial; can ensure fast enrollment and high patient retention rates; committed to generate good quality data; often tends to neglect applicable regulatory agency (RA)/EC reporting procedures; with overloaded site staff; where internal miscommunication is not rare, and might affect adherence to timelines, quality, and compliance; Sponsors often heavily struggle executing Clinical Trial Agreement with the site due to complicated local legal and administrative procedures.

	In spite of the above listed challenges, over 43% of survey respondents confirmed that they would definitely include Eastern European clinical sites in their trials. About 30% of respondents indicated that likelihood is very high (see Figure 4).

 quality of data (see Figure 5 at right; click 

Survey sheds light on the regional-specific risks of managing clinical trial sites in Eastern Europe.

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