Plotting Efficient Paths for Clinical Development

Clinical development is a complex puzzle, with regulatory requirements, epidemiology, technology and specific clinical expertise all involved in how efficiently a product is developed and ultimately brought to market. Many elements of this puzzle are closely related to geography and vary from one region to another. As a result, thoughtfully considering the role of geographic region in development strategy pays off in bringing a therapy through development to prepare for approval.

Epidemiology

Geographic variation in disease prevalence affects clinical development strategy in subtle ways. Regulators are more engaged with development teams addressing areas of clear need – which can involve indications that are very common but lacking satisfactory therapeutics as well as indications that are relatively rare. For example, liver cancer is a leading cause of cancer deaths across Asia, with no effective treatment currently available. This high need makes the prospect of an accelerated development pathway more likely in this region.

Of the 780,000 new cases of liver cancer diagnosed worldwide every year, half are in mainland China. When developing a new drug in oncology, TLC388, Phase 1 data supported the potential for multiple indications. Based on business considerations, we chose to first evaluate this drug in liver cancer. The result is that TLC388 has been accepted into the accelerated ‘Green Path’ regulatory review procedure in mainland China. Because liver cancer is a rare disease in Western countries, TLC388 was able to obtain orphan drug designations in both the US and in Europe. Orphan drug status will not only help to accelerate development, but can also lead to market exclusivity of seven and ten years, respectively, in these markets. Following a successful Phase 1 trial at sites in the US and Taiwan, we are now conducting a Phase 2 study investigating the efficacy of TLC388 in liver cancer at sites in Taiwan and mainland China.

The prevalence of liver cancer in Asian populations also makes it easier to focus on a narrow subset of patients within this indication and still address a substantial need. For TLC388, we are first looking to determine efficacy as a second-line treatment in patients at advanced stages of disease, where patient survival is typically less than three months. The Phase 2 trial investigates treatment for a subset of patients with portal vein tumour thrombosis, which makes up about 35 to 40 percent of all liver cancer patients. Data from a pilot study with TLC388 demonstrated the potential for TLC388 to expand treatment options for these patients–specifically, creating the opportunity to consider a minimally invasive procedure called Trans Arterial Chemo Embolization (TACE) that can be used following a sufficient amount of tumour shrinkage and reduced blockage of the portal vein.

Aiming for one trial to be conducted quickly in a specific patient subgroup and a second trial directed at a larger, more broadly distributed, patient population to help with the speed of enrolment is a development strategy that captures the best of both worlds in disease epidemiology. Our second planned trial for TLC388 reflects this strategy. This trial looks to address an indication that is prevalent worldwide, colorectal cancer. Colorectal cancer is the third most common cancer globally, with over 1.3 million new cases estimated in 2012. Countries with the highest incidence rates include Australia, New Zealand, Canada and the United States.

Culture

While disease prevalence is one potential factor that contributes to the efficiency of enrolment, another factor related to geography is the presence of an established clinical research culture. This culture is associated with welldeveloped healthcare systems that help ensure that a trial is conducted according to accepted global standards. Also, patients’ trust in the healthcare system is reflected in high rates of participation in clinical trials and low drop-out rates. Several regions in Asia are notable for cultural factors that lead to a good track record of clinical development, notably Taiwan, as well as South Korea, Singapore and Hong Kong.

Regulatory priorities

Regulatory differences between regions can dramatically influence the efficiency of drug development. For example, developers interested in the mainland China market may take advantage of the mutual recognition mechanism between Chinese and Taiwanese regulators. By conducting early stage clinical trials in Taiwan, developers benefit from clinical expertise with exploratory clinical trials. By conducting larger Phase 2 trials in China, developers benefit from the larger pool of patients. In the case of TLC388, we were able to move straight into Phase 2 trials using data from the Phase 1 study conducted in Taiwan, without having to reproduce safety studies in China. This has reduced development time considerably.

Technology platform

The specific class of technology is also relevant to the choice of where to develop a particular type of therapy. A product applying a new delivery technology, for example, can often make use of the 505(b)(2) pathway in the US, which is a tried-and-true path for accelerated development. In mainland China, recent reforms provide similar benefits for new formulations by increasing the priority of these drugs in the process of regulatory review. These reforms echo a trend in the emergence of new formulation drugs as away to create improved therapeutics. These policies may reflect that incremental improvements to existing drugs through new formulations can help to satisfy unmet market needs in a more timely and lower-risk manner in comparison to developing drugs from scratch. Keeping current with policies and trends related to particular technologies is critical for seizing opportunities as they arise.

Another example of the potential relevance of a technology platform in the choice of development region could be regenerative medicine therapies using stem cell technology. Countries like Australia and Japan may be more receptive to these approaches from regulatory or cultural acceptance perspectives. Developers with stemcell-based platforms may choose to prioritise these countries for clinical development.

Regional expertise

Clinical expertise also varies by geography and can be a significant factor in the efficiency of a clinical development program. By choosing sites with clinical investigators who have specific experience with previous studies for a particular indication, developers can avoid potentially serious difficulties in trial execution. For our new osteoarthritis therapy designed for sustained effect, we included Australian trial sites in our Phase 2 plan because these sites had experience conducting trials for osteoarthritis with similar endpoints and design.

To find an efficient development path, drug developers should carefully consider how factors related to geography relate to each attribute of a particular new therapeutic. What matters most to regulators in different regions? How will disease prevalence influence patient recruitment, create opportunities for specific indications and affect future markets? What kinds of technology are favoured? The answers are rarely immediately evident. However, by carefully matching a therapeutic candidate to features of the global development landscape, developers can more efficiently navigate the path of clinical development.

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