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International Clinical Trials

Eastern Time

China is a rapidly growing pharmaceutical market: the desire to conduct clinical studies in the country continues to increase because it offers an attractive pool of treatment-naďve patients to facilitate clinical study enrolment in highly competitive or saturated therapeutic areas. Carrying out clinical trials in China presents unique challenges that can be proactively addressed with proper knowledge and preparation. Furthermore, drug developers that can utilise integrated clinical trial management and central laboratory services may derive needed efficiencies from this market.

From an infectious disease perspective, China can play a significant role. Hepatitis C infection is one indication for which a number of new, combination treatments are currently in development. According to current estimates, three per cent of China’s population is infected by this disease. In a country with more than 1.3 billion people, that equates to around 40 million potential patients – a number that is expected to rise to more than 45 million by 2020.

Market Challenges

The large number of clinical studies now being performed in infectious diseases has created significant pressure to identify additional sites with substantial patient pools to support study enrolment. The clinical study environment in China has strong potential, but it also faces protracted regulatory approval timelines, cultural barriers, issues with the national insurance system and intense competition for resources at the few hospitals in the country currently conducting clinical studies.

In addition, there are significant restrictions regarding exportation of medical specimens from China. These present hurdles for specialised testing when a specific assay is not available or when a single laboratory must be used for analysis in a multicentre trial, as when establishing breakpoints for new antibiotics. Extra time should be expected to obtain licences for exportation. Alternatively, validating the special assays in laboratories located in China may be preferred.

Local Standards and Practices

In China, only State Food and Drug Administration (SFDA) qualified hospitals are permitted to conduct clinical research. For studies requiring a relatively small patient contribution (for example, global Phase 3 studies), it may be possible to primarily use sites at large, experienced medical centres in first-tier cities. For national Phase 3 studies or other studies requiring enrolment of a large number of Chinese patients, inclusion of hospitals in second-tier cities will also be required.

It is important to note that institutions in second-tier cities may have substantially less experience in clinical research. Local therapeutic experts in China recommend that experienced sites could be used in collaboration with the less-experienced sites in second-tier cities in such situations. This would enable good patient access through geographically diverse areas and minimise the need for patients to travel long distances to study sites, which may facilitate follow-up. Such a model would also enable sites in second-tier cities to gain additional research experience over time.

Antibiotics Regulation

Individual study protocols frequently prohibit or limit the duration of antibiotics that patients may have received prior to enrolment. Patients’ use of traditional Chinese medicine or antibiotics outside a physician’s direction could potentially impact study efficacy and safety assessments. Furthermore, for studies in which prior antibiotic use is restricted or exclusionary, widespread access to these products could limit the number of patients eligible for participation.

Though antibiotics are regulated as prescription medication in China, they are often readily available to the public through local pharmacies that may treat them as over-the-counter medications. The availability still persists today, despite increasing attempts by the Chinese government to curtail this practice. Investigators must be vigilant when interviewing potential subjects for clinical studies to obtain accurate information regarding the recent use of antibiotics or traditional Chinese medicines.

Patient Catchment

Patients in China are often willing to travel long distances to obtain care from major institutions in first-tier cities – a practice that presents both opportunities and risks to clinical research. Institutions in major cities will have a large patient catchment area, which increases the number of patients treated at these facilities. However, patients from geographically distant locations may have difficulty in complying with study visit schedules. Appropriate follow-up is a particular risk with acute bacterial and viral infections that require inpatient treatment, as well as longer-term outpatient follow-up.

Several mitigation strategies exist to encourage patients’ compliance with follow-up visits. Appropriate investigator training should be provided and investigators should approach only those patients who are likely to be able to comply with the study visit schedule. This may require participation primarily by patients who live relatively near the study site.

Reimbursement for patients’ travel, lodging and meals should be provided to facilitate compliance with the visit schedule for those who will need to travel longer distances for follow-up visits. Local experts in China indicate that specific regulations governing permitted compensation do not exist. However, patients’ compensation or reimbursement for time required for study participation should be reasonable, according to good clinical practice (GCP) guidelines.

Insurance Impact

China’s national insurance system may also impact patient recruitment and follow-up. While the system provides coverage for specified medications, individual provinces may or may not list the same therapies covered for residents of their specific province. Patients receiving care at a hospital outside their home province may not have coverage for the precise medications in use at the institution.

For this reason, it is often easier to recruit patients receiving care outside their home provinces to participate in clinical studies due to the potential gaps in their insurance coverage. However, as previously noted, enrolment of such a population could affect compliance with follow-up visits.

Regulatory Considerations

The lengthy timelines for receipt of SFDA approval for study conduct in China is another consideration for clinical research sponsors. A variety of factors contribute to these timelines, including the relatively low number of SFDA staff dedicated to reviewing submitted drug dossiers. In addition, the level of detail required in technical and clinical dossiers for application to initiate a clinical trial in China surpasses those of other Asian countries. For vaccine-based clinical trials, the SFDA approval process stipulates that the vaccine be currently licensed by a major regulatory authority elsewhere in the world before an application can be made for testing in China. Finally, early drug testing is not feasible for foreign companies because of regulations requiring that only drugs discovered by Chinese-owned companies can enter Phase 1 (first-in-human) trials in China.

Experts familiar with local situations recommend that clinical trial sponsors who intend to obtain marketing authorisation in China include this country early in the study planning process and enable China to participate in the global Phase 3 study. Provided that adequate planning is undertaken and sufficient patients from China are enrolled, this strategy may alleviate the need to conduct additional studies in China and enable sponsors to submit an application for marketing authorisation after completing a small pharmacokinetic study.

The use of such a strategy can reduce the time required to obtain marketing authorisation in China by three to four years, compared to conducting a separate Phase 3 study in China, and may enable authorisation as early as one year after receiving US marketing authorisation.

Laboratory Logistics

Laboratory services are a vital part of any clinical trial, and China’s permit process for sample exportation is not compatible with time-sensitive tests such as viral load in blood, slides for Gram stain or confirmation of bacterial genus, species and susceptibility patterns. Although Chinese logistics is maturing, it might not be possible to transport viable specimens – for example, fresh wound material or blood for viral load – over long distances, and studies may require local analysis.

While the SFDA has guidelines for laboratory procedures, data to be used for global regulatory submissions must meet the more stringent international guidelines for sample integrity and data quality. These requirements include instrumentation qualification and validation, strict quality control procedures, and participation in an external quality assurance/quality control programme to gauge performance in comparison to peer laboratories. Adherence to these standards demonstrates that data generated from the laboratory are reliable, traceable and auditable, as required to meet global regulatory submissions.

Local laboratories may adhere only to the less-stringent Chinese regulatory requirements, making the data unsuitable for combination with data generated at other sites due to variations in quality standards. For example, a local laboratory may use locally sourced reagents, or instruments that have not been validated against international standards and reference ranges. Internal quality assurance practices can often be limited, as local laboratories may not perform peer comparisons to ensure reliable results between machines and between analysts.

Best Practices

Laboratories associated with global contract research organisations (CROs) adhere to a variety of best practices, including GCP, good data recording practice, and test-specific guidelines such as the NGSP (National Glycohemoglobin Standardisation Programme) for haemoglobin A1C testing. These laboratories are usually accredited by the College of American Pathology (CAP), participate in CAP blind profi ciency testing and local proficiency surveys, and adhere to US Food and Drug Administration regulations regarding electronic records and signatures. While good laboratory practices are not directly relevant to clinical studies, labs run by global CROs frequently utilise the principles to guide their operations.

There are additional benefits for sponsors that can work with a global CRO that provides integrated clinical trial management and central lab services. In addition to eliminating the need to navigate China’s complex sample export processes, drug developers that can use combined clinical trial management and lab services can consolidate the business administration that streamlines processes, eliminates redundancies, and decreases complexity and potential for errors.

In this arrangement, the sponsor interacts with a single central team at the CRO, and that team provides consistent, unified direction to all clinical trial sites. If clinical and laboratory data can be automatically integrated on a daily basis, query identification and resolution can be accelerated, significantly reducing the data reconciliation cycle.

Potential Opportunities

China will continue to be a country of interest for conducting infectious disease studies. The benefits of providing patients access to investigational drugs to address unmet medical needs is warranted given the large patient pool. However, the lengthy approval timelines, cultural hurdles, national insurance system and competition for hospital resources offset these positives to some degree.

Methods for addressing these issues include: using experienced sites in collaboration with less-experienced sites in second-tier cities; enrolling only those patients who have a high probability of being able to comply with the study visit schedule; conducting robust feasibility assessments; and increasing educational budgets for GCP-International Conference on Harmonisation training in hospitals in second-tier cities.

In addition, drug developers that can utilise integrated clinical trial management and central lab services may be in a unique position to benefit from cost and time savings in what is a challenging but promising clinical development market.

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Steven Lobel PhD, MSc, Vice-President of Laboratory Operations for PPD’s central labs, earned his degrees from The State University of New York – Buffalo. He also holds an MBA from Loyola College in Baltimore and Six Sigma black belt certifi cation. He is a co-author of dozens of abstracts and articles on subjects within his therapeutic areas of expertise. Certified by the American Board of Medical Laboratory Immunology, he has more than 30 years of clinical lab experience.

Carol Olson MD, PhD, is PPD’s Executive Medical Director and Therapeutic Area Head for Infectious Diseases. An infectious diseases physician with more than 35 years of clinical research experience, Carol attended the University of Chicago Pritzker School of Medicine. Her primary areas of expertise include strategic planning and execution of clinical programmes from drug candidate status through registration, launch and post-approval.

Beth Tulip, Director of Global Feasibility Strategy at PPD, has nearly 15 years of clinical and project management experience, primarily in infectious diseases indications. Beth has broad therapeutic experience in the global paediatric and adult populations, and has been the feasibility strategist and operations lead on several infectious diseases programmes and trials. She holds a BSc from the University of North Carolina at Wilmington.
Steven Lobel
Carol Olson
Beth Tulip
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