Over the last decade, efforts around globalizing clinical trials into emerging markets have intensified significantly. While such activity may be leveling off for large biopharmaceutical companies, where global-trial strategies have been entrenched in their business models for years, medium-sized and smaller companies are noticeably increasing the number of trials that include sites in areas such as Asia Pacific, Central and Eastern Europe, Latin America, and the Middle East. Driving the overall growth has been a greater understanding of the need for global trials and the benefits of these studies for biopharms and local medical communities. Global trials are necessary in today’s world to both find hard-to-reach patients for rare disease studies and in response to the continued spread of traditional “Western diseases” such as heart disease and cancer. In turn, the key benefits for global drug developers are often faster patient recruitment, operational cost savings, and expanded brand exposure for future therapies. The value for investigators and sites in developing nations is gaining knowledge on the latest disease discoveries and experimental treatment approaches, and the chance to improve site equipment and resources.
Nevertheless, conducting trials outside of established markets continues to pose a number of challenges, with activity in certain regions remaining slow since the global economic crisis. Though regulatory climates have evolved for some, related barriers are still prevalent in many countries. Pursuits in global trials must also take into account the differing cultural, scientific, ethical, and logistical issues present in each region. Governments in emerging markets are increasingly encouraging investment in clinical research from abroad, creating opportunities for global biopharms and contract research organizations (CROs) to deliver important new therapies to more patients who need them. Doing so effectively, however, requires the use of innovative strategies designed to overcome the diverse challenges associated with clinical research in these regions. For CROs supporting trials in emerging markets, it is critical that they implement best practices in several key areas.
World View
Developed markets in the United States, Western Europe, Germany, and Japan still generate the lion’s share of clinical trial activity. However, growth trends in non-traditional regions have been evident. Nearly 31% of the world's clinical trials are reportedly conducted outside of the United States and 25% of new drug applications (NDAs) include data from international sites [1]. A recent analysis found that from 2007 to 2011, there was a rise in clinical trials registered in emerging countries and a drop in studies registered in the United States and Western Europe [2]. According to the report, China, India, and Korea are the most active settings for clinical trials among developing nations. With particularly strong opportunities for market access, countries in Asia Pacific and Latin America remain prime destinations for clinical research outsourcing. In 2012, the Brazilian and Chinese pharmaceutical markets grew by 16% and 21% respectively, compared to an average market growth of minus 2% for the five major European markets and minus 1 % for the U.S. market [3].
In Asia Pacific, home to two-thirds of the world’s population, there are clear advantages in patient recruitment and clinical trial start-up timelines. The region has a diverse number of disease states and therapeutic conditions compared to other markets, particularly around infectious disease. Meanwhile, governments in Asia Pacific increasingly view biomedical research as an economic growth area, and therefore dedicate more financial support to the segment. For example, China and Singapore are considered to have some of the largest government-funded life sciences research parks and incubator centers [4]. With improved clinical research infrastructure in many Asia-Pacific markets, global drug developers have ramped up investments as well. For instance, in China, which is predicted to supplant Japan as the world’s second-largest pharmaceutical market by 2015 [5], some of the top multinational biopharms have built R&D project management hubs to oversee their regional and global trials in Asia Pacific. In addition, CROs are more actively working with academic sites in China in efforts to develop them into potential research centers. Similar R&D initiatives, but on a lesser scale, are becoming more common in countries such as the Philippines, Thailand, and Indonesia as well.
Trials in Latin America reportedly cost about 30 percent less than those in the United States or Western Europe. The greatest savings are usually associated with patient enrollment and retention, given the region’s abundant treatment-naïve patient populations and concentration of people within large metropolitan areas. Latin America’s high urban density also provides cost efficiencies in clinical trial monitoring. With just two languages spoken in its 22 countries – Spanish and Portuguese – there are less potential barriers in translating informed consent forms and other documents, as well as communicating with trial stakeholders. Although these countries are not members of the International Conference on Harmonisation (ICH), the region is also appealing in that their regulations all comply with ICH good clinical practice (GCP) guidelines. Tougher ethical standards and increased government emphasis on patient protection has resulted in better quality oversight in Latin America as well, including the implementation of more sites inspections. Longer study start-up timelines have resulted in less trial opportunities in countries such as Brazil and Argentina, while there has been a noticeable rise in clinical trial participation in other Latin American nations, particularly Guatemala, Ecuador, and Panama.
In Central Europe, among the countries of Bulgaria, Czech Republic, Hungary, Poland, Romania, and Slovakia, the number of new clinical studies is predicted to rise by 6% to 7% in 2014 [6].In Eastern Europe, Russia remains an attractive location for clinical research, despite its traditionally challenging regulatory environment. Close to 2,700 trials were ongoing in Russia in 2012and the number of studies hosted in the country by foreign companies has tripled in the last decade [7, 8].The wide use of centralized health systems is helping drive the growth of global studies in Central and Eastern Europe. These systems have taken advantage of the region’s improved infrastructure to establish large medical centers, which allow investigators to recruit patients from the regional population more quickly, thus benefiting efforts in conducting large-scale studies. Markets in the Middle East and North Africa (MENA) region only sponsor 1% of global clinical trials, but are predicted to increase their clinical R&D spend almost 10-fold in the next decade [9]. Contributing factors to the scale-up will be high population growth, demand for novel treatments, and increased prevalence of lifestyle-related and rare genetic diseases [1].
Changes Spur Need
Despite the varying dynamics from region to region, it is clear that the overall clinical development landscape is transforming, further illustrating the need for globally-focused strategies. With heightened regulatory guidelines now in place in many global markets, the complexity of clinical trial protocol designs has increased considerably. As a result, factors such as stricter patient inclusionary/exclusionary criteria can often dictate the need to expand trials globally. In these cases, biopharms and CROs must ensure that the medical standards in the newly-targeted countries comply with the protocol complexities. The rising prevalence of westernized diseases in emerging markets, including lifestyle diseases such as diabetes and obesity, has also necessitated greater implementation of global trials. An increase in protocols seeking patients with psychiatric disorders, including schizophrenia, depression, and bipolar diseases, have also become more common in emerging markets. Recognizing opportunities to participate in medical innovation, many regulators have demonstrated a willingness to promote global trials in their countries. In some nations, this has included public hearings on potential policy changes impacting clinical research. Regulators are also mindful of the long-term benefits of global trials for their local communities, ranging from greater investigator knowledge on future marketed drugs to improved practices at areas sites and institutions.
Addressing the Challenges
Delivering optimal value from global trials relies on the ability to address the diverse challenges inherent to these studies. Global trials involve multiple regulatory frameworks and research cultures, but are required to apply the same clinical data. To that end, it is critical that biopharms leverage CRO partners that have global capability support, but also strong localized presence and expertise in the targeted regions. CROs that possess dedicated resourcing and staffing in emerging markets are better able to use strategic planning to address various global trial challenges, particularly those related to regulatory and oversight requirements. For instance, having robust processes in place for regulatory intelligence gathering can help local clinical teams stay current with any changes or revisions that could affect their studies. CROs maintaining fluent communications with the regulatory agencies is also crucial to these efforts. Discussing protocol reviews directly with regulators can ensure ongoing compliance with their requirements and also aid in the development of the regulatory plan during study start-up.
When planning a global trial, there are several unique ethical and scientific issues that should be considered in each market. These include whether the country will require the provision of the investigational drug at the end of the study and what the nation’s views are on placebo-controlled studies. Not all clinical trial programs are able to commit to providing the drug after the study. In certain regions such as Latin America, the acceptability of placebo-controlled trials has been dwindling. Other key considerations include the country’s drug coverage, particularly for concomitant medications, and their policies governing confidentiality. An increasing number of countries have implemented more stringent data protection laws in recent years. Additionally, social issues should be carefully evaluated when exploring global trials. For example, in the Philippines, a predominately Catholic country, there have been notable issues concerning contraception requirements in clinical trials, which have affected the design of global-run studies there. Ethics guidelines in certain countries have also posed difficulties in developing and implementing pediatric studies.
When initiating global sites, it is crucial to assess financial-related issues. For example, in Latin America, there is more transparency today involving site contract agreements. CROs are now required, in some cases, to submit contract templates. In addition, hospital and site administrators have greater visibility into the details of site contacts and are more involved in their review. These trends point to the increased likelihood of longer contract negotiation timelines and, thus, potential delays in study start-up. Therefore, strategies in Latin America should focus on beginning the site activation process as early as possible. The introduction of new insurance requirements in emerging markets has also created challenges. For instance, in Latin America, companies traditionally were able to secure global insurance and use it for all their studies in the region. Today, however, organizations must first ensure that each site contract can be executed in the individual countries and comply with the local rules. Addressing these extra steps requires the involvement of local teams to ensure that sites in each country are able to qualify.
Challenges in language translation have generally lessened in recent years in developing markets as global expertise in managing these activities has grown, and arrangements with language service providers are now well-established. Nevertheless, the planning of translation activities is critical when setting up trials, as are the related communication approaches. It is important to allot time for quality control reviews of translation documents. In the case of informed consent forms, sites must ensure that patients will be able to read and clearly understand the document. That may require adjusting certain wording to better fit the particular language variation in the country. For example, the mention of a specific adverse event may need to be worded differently in one country compared to another. Local CRO staff can help in implementing these sorts of subtleties where necessary.
Infrastructure Support
Many of the challenges in clinical trial globalization can be overcome by ensuring that the correct infrastructure is in place and logistics strategies are sound. In the area of data management, global CROs are able to leverage their own integrated clinical trial management systems when conducting trials in emerging markets. Providing a single technology capsule allows for much more seamless and efficient data collection compared to trials run by smaller domestic CROs that often feature multiple disparate systems. Setting up laboratory testing arrangements is another key infrastructure component of global trials. Larger-sized CROs tend to work closely with international preferred vendors for sample testing in global studies. CROs, in many cases, can provide their clients with a single vendor based locally in the country targeted. In these arrangements, biopharms can more easily access the global infrastructure, and take advantage of a very clear communication path and process for managing their global trials. Partnering with an international vendor can also help to avoid the logistical issues in biological sample shipping that exist in many developing nations. These issues are especially prominent in countries such as Russia and China where import/export laws often complicate the shipping of samples to a central laboratory, as well as the import of devices used in clinical research. In addition, many emerging regions do not allow shipping from the United States to the investigative site.
Early planning and project management is essential in navigating the various logistical challenges in global trials. These issues can potentially delay the initiation of site activation and patient enrollment, among other start-up activities. Early planning should involve preparing the necessary paperwork for the study, particularly pertaining to the investigative and comparator drugs; securing the drug import license; and planning all the shipments. When clinical trial supplies are imported into a country, it is important for CRO staff to work with the broker on ensuring that all invoices, permissions, and documentation are in place to clear customs.
Closer Site Management
In certain emerging regions, clinical research is still a relatively young field, and, therefore, sites in these locations generally have less experience running trials than those in more mature markets. In these cases, there is a need for sites to be more closely managed. The capabilities of local investigators and sites must be carefully reviewed and detailed monitoring plans established. Also critical is the ability of clinical research associates (CRAs) and clinical monitoring associates (CMAs) to cultivate strong relationships with the less-seasoned sites, including the development of innovative strategies in communication, training and education. Global biopharms and CROs must approach sites in emerging countries differently than they do for those in the United States or Western Europe, adjusting their strategies based on the site-specific needs in each country. In some regions, due to site saturation, there has been a noticeable drop in the number of hospitals and clinics participating in clinical trials. This has led to increased competition for the same sites in the more active therapeutic R&D segments. CROs need to continue to work closely with their clients in developing more sites in emerging markets to meet the growing demand.
References
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- George M et al. Globalization of Clinical Trials - Where are We Heading? Curr Clin Pharmacol. 2013, 8(2):115-123, http://www.ncbi.nlm.nih.gov/pubmed/22963351
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- Stefańczyk M. Almost 2,300 Clinical Trials to be Conducted in Central Europe in 2014. PMR Publications. 2012, http://www.paiz.gov.pl/files/?id_plik=18296
- Clinical Research in Russia – Regulations and Trends. International Conference and Exhibition on Pharmacovigilance & Clinical Trials presentation. 2012, http://www.omicsonline.org/2161-1459/2161-1459-S1.004-001.pdf
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Author Biographies
Garth Tierney is Executive Vice President, Asia/Pacific for INC Research, a therapeutically focused global clinical research organization (CRO). He has nearly two decades of experience in CROs including roles as Clinical Research Manager, General Manager, Managing Director and most recently Regional General Manager. In addition to his CRO experience, Mr. Tierney also has six years of experience in clinical research in pharmaceutical companies including roles as CRA, SCRA and Clinical Research Manager. Mr. Tierney established the South Australian operations for a global CRO which became the region’s biometric hub for the global CRO. He also established the first Singapore project for the same global CRO. Mr. Tierney was a founder, owner and Managing Director of Trident Clinical Research Pty Ltd, a company started in 1997 with operations in Australia, New Zealand and India. That company became the largest independent CRO in Australia and was acquired by INC Research in 2011. Email: [email protected]. Website: www.incresearch.com.
Dr. Silvia Zieher is Vice President, Clinical Development and Latin America Operations at INC Research. She has nearly two decades of experience in clinical research in roles including Clinical Team Leader, Clinical Development Manager of a top ten pharmaceutical company in Argentina and as CRO Clinical Research Director, Executive Director and Vice President of Clinical Development for Latin America. In addition to research experience, Dr. Zieher worked in pediatrics in public and private institutions in Argentina. Her responsibilities have been focused on clinical operations activities in monitoring, project management as well as regulatory activities for the implementation of Phase II to III studies in Latin America. As Clinical Development Manager, Dr. Zieher contributed to the development of the PAHO (Pan American Health Organization) guidelines: titled: “GCP: Document of the Americas” that were published in 2005, being the FIFARMA (Latin America Global Pharma industry) representative of the GCP expert working group at PANDRH (Pan American Network for Drug Regulatory Harmonization). This guideline is the foundation of many regulations in Latin America. She has conducted academic activities in clinical research and is a frequent presenter in international conferences as DIA. Email: [email protected]. Website: www.incresearch.com.