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New survey data, coupled with recent research, spotlight the current views and concerns around multi-regional studies.
In our latest survey with our partner SCORR Marketing, Applied Clinical Trials asked its audience about the status of global trials. Overall, many themes that have always concerned industry with multi-regional clinical trials still ring true. While costs and patient population access are the primary drivers for conducting trials outside of the U.S. or Western Europe, the trade-off with good clinical practice (GCP), data quality, and language barriers still exist.
As early as 2002, Applied Clinical Trialsreported on the growing concerns around the globalization of clinical trials. In this article, the author outlines the reasons for then HHS Inspector General Janet Rehnquist’s report “The Globalization of Clinical Trials: A Growing Challenge in Protecting Human Subjects.” During the prior 10 years of the report’s issue, during the 1990s, industry-sponsored research began its move beyond the U.S., the European Union, and Japan. The report was aimed at the protections of human subjects in clinical research, which we now call participants, in Central and Eastern Europe, South America, Asia, and Africa.
In a 2010 report from the Office of Inspector General (OIG), it noted the increase of use of global locations for clinical trials, and highlighted FDA statistics around clinical trials.
The OIG noted the following:
In our own article on a 2010 OIG report at the time, columnist Jill Wechsler noted that Leslie Ball, then-director of the Division of Scientific Investigations in the Center for Drug Evaluation and Research (CDER), noted that the OIG report could prompt FDA to look more critically at the quality of data that comes from non-U.S. studies and at its applicability to domestic approvals. Ball explained that the agency’s evaluation of foreign data depends on the type of patient population studied and disease state, as well as relevant cultural and ethnic factors. Ball noted that CDER had been examining the growing number of applications that have data only from outside the U.S.
Further, the report authors urged increased oversight of study results obtained from other regions to protect patients and ensure data integrity. There are questions about adherence to GCPs by foreign investigators and if regulatory authorities and institutional review boards (IRBs) in developing nations have the capacity and
resources to fully monitor research activities.
The then-FDA deputy commissioner for international programs pointed out that the onus was on the sponsor to make the case that foreign clinical data is valid, is complete, and is able to predict the utility of the product in the U.S. population and the U.S. medical system. Determining the relevance of data from a foreign population involves assessing appropriate primary endpoints, underlying illnesses, concomitant therapies, and cultural issues such as diet and popular herbal remedies.
As the report noted, the globalization of clinical trials flourished through the 2000s, and it wasn’t until 2010 when issues around intellectual property and pharmaceutical sponsor patent case losses started a decline of trials in India. In 2013, increased regulatory demands led to a further decline in that country. Since then, sponsors have looked more to China and the rest of Asia, as well as Eastern Europe for their trials. But while the globalization of clinical trials is here to stay, our survey found that conducting them is not easy. In fact, when asked “Please rate the degree of ease/difficulty in addressing each of the following issues in multi-regional clinical trials,” the majority of responses in three of the areas-ethical, patient-specific, and regulatory-were “somewhat difficult.” Statistical issues came in at neutral.
Ethical and GCP issues
While GCP in the “traditional” markets is a given, concerns around GCP in clinical trials are still an issue. The most often cited GCP violations found by FDA are around protocol adherence, clinical records, informed consent, drug accountability, and adverse events. And these violations are not only global, but also in the traditional markets. However, in our survey, specific to global trials, 36% of respondents noted that investigative sites were selected based on established GCP standards.
In an article appearing in late 2016 on our website, about resource-limited sites, the authors discussed the limited number of ICH-GCP-trained personnel available in resource-limited regions. The authors continue: “Most of the time clinical site personnel are trained on ICH-GCP principles before the study start. These trainings are conducted either face-to-face or via webinars or online courses. Training materials focus on the ICH-GCP principles in terms of human subject protection and requirements of GCP, but lack details regarding daily site operations or the potential impact of non-compliance with ICH-GCP requirements on the study. In addition, most training courses have case studies, but they are often not geared toward the disease indication that will be studied at that site. It is important that the ICH-GCP training for resource-limited clinical sites, especially sites that have not conducted research studies in recent years, be geared to the study/protocol at hand and draw out the stake and risks of non-compliance with ICH-GCP or data documentation. Site personnel sometimes take shortcuts in daily procedures because they do not understand the gravity of that procedure and the impact of their action on the study data. Periodic reinforcement of this training with real-life examples can also go a long way for staff at inexperienced sites. In most cases, it is prudent to supplement the research-naïve site staff with experienced clinical staff from other regions.”
Informed consent is a primary concern in clinical trial participation. As noted in our survey, informed consent was rated, by 22%, a concern around ethical trials. Health literacy-another concern that informs the ability of a person to understand clinical trials, and, therefore, the ability to consent-was also rated 22% by respondents. Another necessity in global trials is translation services that can accurately create native language materials for participants. But also, there are language barriers for verbal communication, and as our respondents noted, it is important to choose a country/region that already has an existing pool of qualified translators (25%) or is capable of developing qualified translators (25%).
Informed consent is a very popular topic right now, and has gained attention in the past five years, with the growth of patient engagement practices. As Jeffrey Litwin, MD, and Applied Clinical Trials Editorial Advisory Board member, noted in his article, “Prior to a patient’s enrollment in a clinical trial, the prospective participant is often handed a document that is 15 to 25 pages long. Known as the informed
consent form (ICF), the document is largely comprised of a combination of medical terminology and ‘legalese’ that even members of the pharmaceutical community would have difficulty comprehending in full. To further complicate matters, important information on the benefits and risks of the clinical trial experience that patients are about to undergo is often only a small part of the document.”
Sponsors and CROs have been trying to improve the comprehension of ICFs by using more reader-friendly words, as well as writing to lower grade-level reading scores. Technology providers have been offering electronic consent, or eConsent, which can use a number of tools to improve comprehension, including video, linked words for explanation, recordings, and pictorial descriptions. In 2015, FDA issued its “Use of Electronic Informed Consent in Clinical Investigations Questions and Answers Guidance for Industry” to help sponsors, CROs, and IRBs understand the FDAs viewpoint.
Emerging market considerations
In the resource-limited article noted earlier, the authors outline some of the most frequently encountered compliance and patient safety challenges. However, the authors observe that follow-up on compliance challenges after the study start often leads to a continuously reactive cycle of addressing compliance issues toward or at the end of the clinical trial in form of corrective actions, deviations, note to files, etc., which can lead to the loss of collected data.
The challenges in conducting trials in resource-limited regions include facilities, electric supply, buildings and roads, and basic equipment. For example, limitations may involve lack of available built space.
Electricity supply considerations at the site should include a generator and a back-up generator. Also important is verification of the capacity of the generators, as well as records to show execution of a maintenance plan.
As for other equipment such as refrigerators, freezers, centrifuges, and coolers, they are either already present at the clinical research site and are in use for other trials or patient care or are brought in specifically for the purpose of a particular study. If such equipment is already in place, it is important to ensure the installation and calibration documentation is complete and available for review by auditors/inspectors. Additionally, If new equipment is added, the clinical team must ensure the installation, qualification, and calibration of this equipment is executed and documented. In all scenarios, monitoring and maintenance of such equipment should be documented and available for review at all times. Staff at inexperienced sites are unfamiliar with strict maintenance schedules and need to be instructed that these schedules are requirements not suggestions.
Clinical supplies and study samples
In our survey, we asked “Which of the following is most important regarding setting clinical supply standards in emerging markets?” The majority-39%-selected choosing a country/region that already has an existing supply chain (including cold chain) infrastructure.
The authors of the resource-limited article concur around that statistic and noted: “If a clinical site is processing and storing study samples even for short intervals, lack of documentation of proper functioning of equipment can jeopardize the integrity of collected samples, leading to loss of data. The same applies to the study product; if the site cannot provide evidence of proper and consistent storage, the integrity of the drug can be questioned in the regulatory inspections. Planning can help avoid such high-risk issues.” Additionally, they note even if the clinical site is located in a larger building (hospital, university, etc.) the clinical samples or study product may need to be transported periodically from one location to another. It is critical that the clinical teams proactively consider the logistics to ensure regulatory compliance and documented chain of custody on the movement of any clinical trial related samples/files/product. Lack of temperature monitoring or chain of custody can result in loss of data/samples/study product.
In a study of global clinical supply professionals conducted by Tufts Center for the Study of Drug Development (CSDD) in 2016, it noted that economics of supply chain management and distribution have grown substantially due to study complexity and increases in shipping costs, labor costs, technology solutions costs, and changes in drug therapy properties requiring additional shipping and packaging considerations (e.g., cold chain and temperature sensitive shipping requirements; combination therapies; and companion diagnostics).
Survey respondents indicated that drugs and supplies were shipped across all regions, with the largest proportion of shipments in North America (78%), followed by Western Europe (66%), Eastern Europe (63%), Latin America (29%), Asia-Pacific (22%), and Rest of World (18%). (Percentages represent percent of total shipments and do not add up to 100%). Companies reported that their top regional hubs are in Western Europe (38%), Asia-Pacific (31%), and Rest of World (13%). Top local depot locations are in Latin America (49%), North America (41%), and Asia-Pacific (36%) regions. Distribution strategies varied, with 31 studies (42%) using a centralized approach, 30 (41%) managed regionally, and 12 (16%) locally managed. A centralized approach is defined as one depot for a global study distributing to all sites. Regional hubs were defined as the main distribution hub responsible for shipping to each country within a wider region, and local depots were depots with regular shipping only to domestic locations.
A number of other factors impact distribution, creating additional challenges for clinical supply executives. One challenge is the delay caused by obtaining import licenses. The top countries listed where this is an issue were Argentina, Russia, China, Colombia, and India.
In this article, we summarized the global trial history, landscape, and top concerns among clinical trial industry professionals currently conducting global trials. Most respondents to our survey expected the globalization of clinical trials to continue and accelerate. For a free copy of the survey report, please visit here.
In India, the primary driver for clinical trials, historically, was cost savings of 50% to 60% as compared to the U.S. In 2013, the Indian government tightened its regulatory requirements, including the mandatory registration and accreditation of ethics boards; better compensation schemes for the injured and families of deceased victims in clinical trials; and a requirement that all clinical trials must record on video a
participant’s informed consent, which later was named a cause of declining enrollment. Since 2010, clinical trials in India have declined. However, according to recent sources, the country is on its way back. This webcast from QuintilesIMS, highlighted efforts to provide regulatory consistency, improved governance at clinical research sites, as well as a rollback on the number of trials allowed per investigator, and no more limits on the number of beds at a site, leaving that to ethics committees to decide. And the video requirement for informed consent was also stricken, except for a selective few studies. Regulatory approval timelines in India have also been improved from 15 months to six to seven months. ClinicalTrials.gov currently lists 3,812 studies in the country. In May, the FDA’s Office of International Programs and its India Foreign Office held its first joint training workshop for Indian regulators, academic representatives, and the drug industry on scientific and ethical standards for clinical trials. Representatives from EMA, the Indian Central Drugs Standard Control Organization, and the DIA also attended.
#2 Russia/Eastern Europe
The second-most affordable country Region is russia/eastern Europe. Putting aside the current political discourse around Russia, it, along with the countries of Eastern Europe (e.g., Ukraine, Moldova, Lithuania, Georgia) and Central Eastern Europe (e.g., Poland, Czech Republic, Slovakia, Hungary) were rated as the second-most affordable regions in which to conduct trials. However, Russia and Eastern Europe were also
ranked as the most difficult to conduct trials by 18% of survey respondents. And a Tufts CSDD report noted that Russia is one of five countries where there are delays caused by obtaining import licenses. But, not to be deterred, upon its opening of a new investigational drug depot in Moscow last year, specialty logistics provider World Courier noted that Moscow remains an area of interest for clinical trials, and of the 123 new drug therapies approved by CDER in 2015, 50 were studied in Russia. Russia is currently ranked 10th globally based on the number of commercial clinical trials sites, with just under 7,000 in 2016. Forecasts for the Russian market are mixed. Some say increased investment in healthcare and regulations has improved clinical trial quality, but rapidly changing regulations and corruption remain concerns for multinational suppliers. Experts in Eastern European trials suggest the market could double by 2020. There are a total of 4,419 studies currently in the full region. Data from the European Union Clinical Trials Register indicates that Hungary and Poland are the leading countries from the CEE region, followed by the Czech Republic, for trials placed in oncology.
The Third-Ranked Place for Affordable trials is China. This is due, in part, to advantages with the existing pharmaceutical structure, as well as the large patient population. However, 32% also ranked the country as most difficult to conduct a trial. In a survey SCORR Marketing and Applied Clinical Trials conducted two years ago on the China trials market, respondents were asked their concerns around conducting trials in the
country. The top reasons given were lack of GCP compliance, general concerns over the quality of trials, and study start-up delays. This proved somewhat accurate in 2016, when the CFDA found that 80% of data in Chinese trials had been fabricated. However, the CFDA, in April 2017, proposed stiff penalties for those caught, including non-acceptance of NDA application for drugs in that same category for three years, as well as all NDAs for a year. The CFDA has also addressed other concerns: It improved approval timelines from 12-18 months to 60-day reviews; allows the use of non-Chinese data in the approval process for new drugs; and adopted an accelerated approval pathway for breakthrough therapies. As of June 2016, China was ranked 13th globally, with an estimated 5,628 commercial clinical trial sites. Currently, there are 10,132 trials being conducted in China. Nearly half (48%) of active commercial clinical trials in China are for oncology indications. Two of the top 10 commercial trial sponsors in 2016 were domestic sponsors, creating further competition for multinational companies. Although local sponsors have experienced strong growth, multinational pharma companies still dominate the top 10 in China, with Novartis, Bayer, AstraZeneca, and Johnson & Johnson.