Challenges and opportunities in global clinical trials

Zheng Su

Genentech

This month’s focus on pharmaphorum is clinical trials, so who better to share their view on global clinical trials than Zheng Su, Editor-in-Chief of the Contemporary Clinical Trials journal. Zheng discusses the differences in rules and regulations across the world in clinical trials, looking at areas such as patient recruitment and clinical research.

The past decades have witnessed the globalization of clinical trials. The registry ClinicalTrials.gov alone contains over one hundred thousand clinical trials conducted in 180 countries. The globalization of clinical research provides great opportunities for significantly improving the efficiency of the drug development process. For pharmaceutical companies, the benefits of conducting trials not only in North America and Western Europe, but also in emerging regions such as Asia Pacific, South America and Eastern Europe, include lower overall development cost, faster timelines, and increased patient populations. In particular, global clinical trials can potentially lead to simultaneous launches of new medical products in multiple regions across the globe, as conducting research in multiple regions allows sponsors to lay the groundwork for regulatory approvals in these regions.

Global trials are also beneficial to patients who hope to participate in clinical research and to obtain treatments that would otherwise not be available to them due to their financial constraints. For certain drug development programs, global trials are not only beneficial but also necessary. For example, the advent of targeted therapies against specific uncommon genotypic variations has made timely recruitment of sufficient numbers of patients unfeasible without the involvement of investigators and centers from the emerging markets. In addition, for trials that are designed to assess the risk and benefit of experimental medicines in patients who have not been heavily treated, the emerging regions can be a source of treatment-naïve patients, which can be rare in the United States or Western Europe.

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“For certain drug development programs, global trials are not only beneficial but also necessary.”

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While the appeal of conducting trials in the global setting has never been stronger, global trials also pose daunting challenges to many major aspects of clinical trials, including, but not limited to, design, conduct, analysis, ethics, law and regulation. At the design stage, trialists need to carefully consider many key design aspects, including the potential impact of ethnic diversity on the risk-benefit assessment, the worldwide differences in ethical practices, medical standards of care, research infrastructure, access to care, and legal and regulatory requirements. A solid understanding of these aspects will be essential to the county / site selection process for a global trial. For example, when either the prognosis of the disease under study or the risk-benefit assessment of an experimental medicine is expected to be dependent on ethnicity, trials will need to be designed to ensure that a sufficient number of patients within each ethnical group are enrolled to adequately quantify the impact of ethnicity on trial results. Carefully designed feasibility studies will need to be conducted in all potential regions to evaluate these key design aspects.

At the execution stage, many logistical challenges need to be overcome to maintain the quality and integrity of trials. For example, distribution of study material and shipment of biospecimens can be challenging due to varying legal requirements in various regions. Tailored strategies for study start-up, patient enrollment and retention, data collection, and site monitoring and inspections need to be developed taking into account region-specific characteristics. In addition, depending on the unique features of each region, an individualized plan for risks and mitigations needs to be developed at the study start-up stage and updated through regular interim lessons learned meetings. At the analysis stage, due to the heterogeneity in many trial aspects, the interpretations of the results for a global trial can be markedly more difficult than those for a single-region trial with a homogeneous patient population. Trialists need to carefully assess any subgroup effects that may exist, and in the meantime, carefully control the rigor of the subgroup analyses.

Another major challenge of global trials is the difference in regulatory requirements for study initiations and drug approvals across various regions. For example, the average amount of time needed to have a Clinical Trial Application approved by the State Food and Drug Administration (SFDA) of China is significantly longer than that for the Food and Drug Administration (FDA) of the United States, and the SFDA has strict requirements on the number of local patients needed in various phases of drug development. Well thought-out regulatory strategies for global trials should be an indispensable component of the overall strategic context of a global drug development program.

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“…trials will need to be designed to ensure that a sufficient number of patients within each ethnical group are enrolled to adequately quantify the impact of ethnicity on trial results.”

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Global clinical trials can be a double-edged sword. Well designed and conducted studies can markedly improve the efficiency of the drug development process by satisfactorily addressing multiple key questions simultaneously. However studies with poor designs or conducts may leave sponsors in a situation where few of the questions can be adequately addressed. Trialists around the globe should take advantage of the traditional and modern information exchange platforms, to share not only their success stories in global trials, but also equally importantly, failures and lessons learned to shed light on potential solutions for tackling many of the challenges that are currently faced in global trials.

A close collaboration between government, industry and academia globally is absolutely essential to the advancement of methodologies for global clinical trials. For example, the Office of Rare Diseases Research at the National Institutes of Health, United States has been collaborating with the industry and academia on the development of a comprehensive global registry for patients with rare diseases1-2, which has the potential to significantly impact global clinical trials for rare diseases. Some may wonder how effective a collaboration between these groups can be as there may be seemingly inevitable conflicts of interest when important decisions need to be made. As Dr. William Mayo once told the graduating class of Rush Medical College over 100 years ago:

“The best interest of the patient is the only interest to be considered, and in order that the sick may have the benefit of advancing knowledge, union of forces is necessary”.

By joining forces, trialists in the government, industry, and academia as a whole can, and will, make a world of difference for patients anywhere around the world.

References

1. Rubinstein, YR, et al. Creating a global rare disease patient registry linked to a rare diseases biorepository database: RareDisease-HUB (RD-HUB). Contemporary Clinical Trials 31: 394-404 (2010)

2. Rubinstein, YR, et al. Informed consent process for patient participation in rare disease registries linked to biorepositories. Contemporary Clinical trials, 33: 5-11 (2012)

EU-Clinical-Trial-Directive-Regulatory-Requirements-20Sep12

About the author:

Zheng Su, PhD, is Senior Statistical Scientist at Genentech Inc. and Editor-in-Chief of Contemporary Clinical Trials, which provides a platform for trialists in the global clinical trials community to exchange ideas on the design, execution and analysis of contemporary clinical trials. Dr Su has over ten years of experience in the field of clinical trials and has published over forty articles on clinical trial methodologies in peer reviewed journals.

Dr Su received his PhD degree from Stanford University. Prior to joining Genentech Inc., Dr Su was a postdoctoral scholar at Stanford University, an Assistant Professor at The State University of New York – Stony Brook, and a Visiting Assistant Professor at Stanford University.

How can we overcome some of the challenges in global clinical trials?