Novel approaches to address challenges in global drug development.

Abstract

At first blush, drug development, although expensive to undertake, does not appear to be a complicated endeavor. First there is an idea, based on basic science, that interdiction of some target will have a positive outcome on a disease. At this point a search is made to find a molecule that is highly specific for the target and has other “drugable” properties. Once a group of candidates are discovered, in vivo and in vitro tests are undertaken to determine which candidate appears best. Toxicology studies are then undertaken in order to start the process of narrowing the dose range. Assuming that these studies look good, clinical trials in humans are begun. The clinical trial paradigm is well known as phase 1, phase 2, and phase 3. Through this process decisions need to be made whether the molecule really is promising and warrants moving forward in development. If progression is determined then decisions about the dose need to be made that will hopefully lead to dosing regimens that would be used for phase 3 and eventually marketed. Although there is only a 10% chance of success if the drug candidate progresses from preclinical to clinical development, it seems as if it is just a question of doing trials in order to prove the original hypothesis that interdiction of the target has a positive outcome on the disease. This seems conceptually simple. Although drug development was certainly not ever as simple as the above paragraph purports, as with all industries, globalization has had a large impact on the pharmaceutical and biotechnology industries. Many of these changes not only have positive implications for the companies developing new molecules by increasing markets available for their compounds, but also have a positive impact on patients across the globe who now have available to them treatments that once would have only been available, mostly, to patients in “developed” countries. Table 1 shows the rapid growth in “pharmemerging” countries from 2009 to 2013.1 Yet at the same time it has made drug development a much more complex process. Differences in patients due to factors such as genetics and standards of healthcare practice must be considered and explored. In addition, with more markets there are a larger number of regulatory considerations to take into account. Approval to sell in a market is not necessarily sufficient, since in many countries healthcare is paid for by governments and organizations must demonstrate that in addition to it effectively treating an illness, the molecule is worth the cost that is charged. Lastly, since clinical trials themselves have tended to become larger in order to prove safety and efficacy, patient populations in clinical trials have become necessarily more diverse.2 This means that clinical trial sites can come from all over the world. This produces an obvious concern from drug regulators, who may have confidence in clinical investigators from their country or other localities, but now are faced with clinical data from locations where they have little experience. As can be seen, drug development in a global environment is much more complex than when it was done on a regional basis. Although there are other factors that have contributed to the increasing cost of drug development, this complexity added from globalization has been a contributor to this trend. In this issue we investigate some of the issues associated with global drug development. This is done through two mechanisms. The first are articles that directly examine issues in global development. The second is with articles that examine cutting-edge scientific technologies that could improve drug development in general but were not created with issues of global drug development as the motivation. Of the former class of articles are two articles that review ethnic differences in drug response. Schuck et al.3 argue that by concentrating clinical trials in a certain geographic region, there may be genetic differences or other factors, either the overall safety or efficacy results may not truly represent expected drug outcomes in other regions. In Ramamoorthy et al.4 there is a review of ethnic differences of new molecular entities that have been submitted to the US Food and Drug Administration (FDA). In the second class of articles, Jones et al.5 discuss physiological-based pharmacokinetic (PBPK) models and the use of these models in industry. This topic is pertinent to global drug development, as PBPK models have the potential to help the pharmaceutical and biotechnology industries gain an understanding of ethnic difference in pharmacokinetics at an early stage in drug development. In addition, Romero et al.6 discuss the role of model-based clinical trial design for the development of Alzheimer's disease therapies and demonstrate collaborative efforts from scientists from industry and regulatory agencies. Use of models is just one of the technologies that have been recognized by the FDA's Critical Path Initiative, which was introduced in 2004 (ref. 7 and references therein). In Parekh et al.8 we get an update on the initiative and learn of progress that has been made on issues brought up in the original document. Obviously, progress toward the original goals will have a tangible effect on drug development that can be applied globally. One development in drug discovery is the use of biologics in order to treat many different diseases. Many critical therapies have been developed that are protein based. Yet these products present a challenge to global health. First, they are typically complex to produce, making them much more expensive to produce than more traditional pharmaceuticals. Second, they are extremely complex molecules, making it challenging to produce equivalent or near-equivalent generics. Regulatory agencies in Europe and the United States have made great efforts in describing a regulatory path for what is termed biosimiliars. McCamish et al.9 contend that interchangeability (the ability to switch) ought to be the ultimate goal and they suggest approaches for testing of products to allow interchangeability. Unfortunately, the productivity of the pharmaceutical and biotechnology industry has not been as great as we all would hope. As understanding of genetics increases, however, it becomes clear that some diseases that are seemingly unrelated may have common genetic roots. This implies that there may be existing effective drugs for one indication that could be repositioned for another indication, which could greatly increase the number of promising therapies available to patients. In Wang et al.10 they discuss different methods for drug repositioning and then suggest that integrating these approaches may be the best strategy. Another approach to increasing productivity of the pharmaceutical and biotechnology industry and thus increasing the number of promising new therapies to patients may not involve a particular technology, but a new way of thinking about drug approval, at least for particularly grievous diseases in areas without effective therapies. The idea is for an organization to get approval to market a compound for a targeted patient population with the thought that development for these patients would be streamlined. Once approved, the molecule could be conditionally sold to other patient populations with some requirement to track outcomes. This along with results from future clinical trials would provide the evidence needed to expand the label indications, but in addition would be used to increase the evidence regarding the safety of the molecule. This notion of adaptive licensing is discussed more fully in Eichler et al.11 The feasibility and use of elements of “adaptive licensing” under the US regulatory framework has been discussed previously (Table 2). These and other technologies give us hope that more efficient and effective drug development can and will be possible. Yet at the same time drug development has become more complex and it is due in part to the fact that drugs are no longer developed for only “developed” countries, they are developed for the world. Only through recognition of these issues will drug developers be able to prosper and patients be treated with therapies that have the potential to revolutionize human health. We can only hope that new technology outpaces the increasing complexities. The manuscript reflects the views of the authors and should not be construed to represent the FDA's views or policies. The authors have no conflicts of interest to report.