Abstract
In this issue of TIRS, as part of our ongoing collaboration with TransCelerate, we have two contributions addressing central monitoring and data quality. We also have three additional papers addressing outcomes in clinical trials, following up on our special section in the November issue. I want to offer special thanks to Dr Joseph Cappelleri for assembling this outstanding series of contributions on a vital topic for all who engage in and evaluate clinical trials.
We have consciously grouped together a series of articles addressing global medical product development in this issue. We are fortunate to have several international contributions, including papers by authors from Japan, China, the Netherlands, Denmark, Germany, as well as the European Medicines Agency (EMA), an FDA analysis of US and non-US treatment effects in a multiregional clinical trial for Alzheimer disease, and a US-based industry evaluation of definitions of “regions” in multiregional studies. Recognizing the increasingly global nature of medical product discovery, development, and regulation, we have been seeking more such submissions.
Recently, I had the opportunity to participate in the 12th Annual DIA Japan Meeting in Tokyo, and my experiences there reinforced for me that we need to do even more in this realm. We had 2 outstanding keynote addresses—one by Dr Christopher Austin, Director of The National Center for Advancement of Translational Sciences (NCATS) at the US NIH, and Dr Makoto Suematsu, President, Japan Agency for Medical Research and Development (AMED). Both spoke eloquently about recent advances in understanding the molecular underpinnings of disease, particularly “rare diseases,” and how this is impacting remarkable advances in targeted, precision therapeutics. One aspect of their talks particularly impressed me. As we explore the human genome and its relationship to biologic and medical outcomes, the complexity demands data sharing globally. Progress has depended upon, and will increasingly depend upon, open, transparent access to genomic data and ever-more-sophisticated analysis of the phenotypes associated with given genomic variants in large numbers of patients. A given gene’s effects obviously can play out differently due to modifying gene variants, as well as environmental (broadly defined, including diet) influences. Warfarin anticoagulation, as an example, is affected by several genetic variants impacting the pharmacokinetics and dynamics of the drug. However, since it acts as a vitamin K antagonist, different intakes of dietary vitamin K (which varies around the globe) also impact the dose of the drug necessary to achieve the desired endpoint. Listening to the discussion at the meeting, it is clear that increased transparency, open global discourse, and collaboration are going to be increasingly important in advancing translational science.
I participated as a speaker/panelist in 2 sessions at the meeting. The first, in which I participated with colleagues from Japan, the EU, and the US, dealt with benefit:risk analysis from the vantage points of drug development and regulation. It quickly became apparent that we all struggle to understand the balance of benefit and risk. We all are trying to be more quantitative in thinking about these issues. We discussed the growing trends of “precision medicine” in improving efficacy, while more often than not, still relying on less rigorous clinical ascertainment on the safety side. We talked about the need for validated biomarkers and better clinical measures for safety as well as efficacy. We also recognized the sociocultural differences we face across countries, with different “meaning” and “significance” of outcomes—positive and negative—depending on the disease being treated, the anticipated benefit, and the severity of side effects. We discussed the increasing role of patients working in partnership with physicians, drug developers, and regulators in defining patient-centric benefit:risk equations, and how this may play out in different countries and regions.
In a session on pediatric drug development, we similarly discussed initiatives to enhance pediatric clinical investigation in Japan, the US, and the EU. We examined similarities and differences in the regulator environments in these regions, and recognized, not dissimilarly to the discussion of translational science and genomics, that we need international collaboration to successfully study medicines in children, to develop the knowledge needed to safely and effectively use new medicines to treat sick children. ICH E-11, which deals with international pediatric drug development, is 15 years old, and the three regions are now working to update the document to further enhance global collaboration and harmonization, facilitating sharing and utilization of data from all studies internationally. And, we discussed the formation of global investigative networks to facilitate studies, and of global children’s networks to improve “child-centric” understanding of health and disease, of risk and of benefit.
The discussions were exciting, optimistic, and realistic—we have a great deal of work to do. An open, collaborative spirit is not only desirable to drive the agenda forward; it is vital. TIRS will continue to serve the needs of patients globally, by being increasingly global in our publications. One thought that kept recurring to me during the meeting in Tokyo was that as we harmonize our science, we do not, we should not “harmonize away” our different social, cultural, philosophical backgrounds. The very nature of our differences, when we discuss them openly as global colleagues, enhances and enriches the way in which we approach therapeutics, medicine, and health for all.