Type 2 diabetes mellitus (T2DM) is increasingly causing alarm among epidemiologists and diabetologists around the world, according to the American Diabetes Association. Traditionally a lifestyle disease affecting Western populations, numerous epidemiological studies have shown that nearly all populations who adapt to more Westernized lifestyles, including plentiful food, reduced physical labor for work, increased life expectancy and avoidance of communicable infectious diseases are at increased risk for T2DM and its associated complications.1
Clinicaltrials.gov lists more than 200 industry-sponsored type 2 diabetes trials recruiting around the world, which reflects not only the global impact of the disease, but also the sheer number of agents currently under investigation to treat the disease, and its complications and comorbidities. To develop these treatments appropriately for non-traditional risk groups, essentially meaning non-Western, developing world populations, we need to run trials that include these populations and account for any regional differences in diagnosis and treatment. One such trial run during my recent time at a diabetes-focused pharma company provides evergreen lessons that can be applied to diabetes trials under planning today.
The sponsor was typical of many small, therapeutic- or technology-focused, privately-held pharma companies: clinical stage with one or more compounds in early phases, pre-commercial, with a business model of establishing clinical proof of concept to attract a big pharma partner to fund phase III development and eventually, commercialization.
The protocol was designed to achieve robust results on rigorous and convincing endpoints to gain the confidence of both the FDA and the pharma partner. As such there were several design issues that potentially limited enrollment, specifically; single-drug treated T2DM patients who would undergo a variable-length washout period of up to 14 weeks in which subjects were to be maintained on a stable insulin regimen alone.
This required more active disease management by the investigators and resulted in a high dropout rate prior to randomizing the subjects to treatment. Because of this anticipated high dropout rate, massive numbers of subjects would need to be screened to achieve the enrollment target within the timelines set by the corporate partner. To support this high screening throughput, and because most T2DM patients are treated with multiple drugs in the U.S., we decided to combine both developed and developing regions in our recruitment strategy.
Country and Vendor Strategy – And Reality
To facilitate the large screening numbers we knew we would need, we chose India, Israel, and Argentina in addition to the U.S., and our feasibility studies identified between 15-19 sites per country. [Note: at the time of this trial, regulatory and ethics approval in India were expected to take approximately 90 days.]
To level out the different lengths of regulatory review in each region, we started the U.S. and Israel first, expecting both countries to be able to start screening within a couple of months; there was already a U.S. IND in place. We submitted the trial to the Indian authority expecting that country to slot in shortly after the first two.
Finally, we set up Argentina as a backup country due to its long approval timelines, at the time expected to be approximately five months. We deployed an eclectic mix of multinational, country specific, and specialty CROs, particularly “central” labs (located in three cities), to accommodate restrictions on shipping biological samples out of country (India). All of this was managed by two very experienced clinical project managers.
Best Laid Plans
In choosing India, we soon learned that we had to adapt our protocol to local diagnostic realities for T2DM, because our Indian patients (along with African and other Asian patients) tended to be leaner (BMI < 25 kg/m2) than their Caucasian counterparts. Our Indian patients also tended to have more years since diagnosis, and their disease had progressed farther than patients in the other three countries.
As is often the case in clinical studies, the outcome was somewhat different than our expectations. One U.S. site screened a patient almost immediately, but no U.S. sites were able to randomize a single subject for another four months. Israel presented some drama all its own: shortly after the local CRO missed a health authority submission deadline, a war broke out with a neighboring country. After peace resumed and a few more missed submission deadlines, Israel was finally open for screening six months later than planned.
Here, India really saved the day. Approval took only eight weeks (expected 12), and once the sites were open, India provided more than half of the randomized subjects in the trial. India was also the most “efficient” country, consistently converting more than 60 percent of their screened subjects. Indian sites also had the best retention rate, losing only 6.6 percent of the total, compared to an average of 9.6 percent dropout rate in the other three countries combined.
It was a good strategy, and one I would employ again, to seek T2DM patients in less-well traveled countries. The quality of the data was very good in all countries, particularly in India, based on the number and type of queries. It is crucial to be flexible in pursuit of these patients: be aware that the protocol design must account for differences in diagnostic criteria, first line treatment, disease progression, and other disease-related factors. We also saw the importance of creating a team of disparate parts – different countries with strong investigators in each, different vendors with different strengths and weaknesses – to help solve the day-to-day-problems.
Vice President of Clinical Operations
*To learn more about the effects of diabetes, visit http://discoverdiabetes.idf.org/
1 Diabetes Care, “Type 2 Diabetes: An Epidemic Requiring Global Attention and Urgent Action”, (May 2012) http://care.diabetesjournals.org/content/35/5/943