Around the globe, investigators struggle to expedite clinical research
For physician-scientists such as Ana Maria Gonzalez-Angulo, MD, MSc, United States-based clinical trials require a tremendous amount of effort and time.
Based on her experiences and conversations with colleagues in different countries, Gonzalez quickly rattles off a list of challenges with clinical trials in the United States: significantly more expense than in trials overseas, lengthy and overly complex regulatory processes at the national and local levels (including big academic institutions), and low patient participation exacerbated by confusing informed consent forms.
“It takes a very long time, and it requires a lot of endurance and perseverance,” says Gonzalez, of Houston's M.D. Anderson Cancer Center, who is principal investigator of a large randomized phase III study, with multiple sites in nearly every state, that uses a genomic test in assigning trial options for patients with hormone receptor–positive breast cancer.
Many other aspects of biomedical research are accelerating rapidly. But with a few exceptions, such as recent reforms at the National Cancer Institute (NCI), the process of conducting clinical trials has been grinding slower and slower for decades, researchers say.
Two significant issues plague government-sponsored clinical trials—efficiency and effectiveness, says David Dilts, PhD, director of the Center for Management Research in Healthcare at the Oregon Health & Science University's Knight Cancer Institute in Portland. “Opening a phase III cooperative group therapeutic trial requires 769 steps, 36 approvals, and a median of approximately 2.5 years from formal concept review to study opening,” Dilts and his colleagues reported last year (Clin Cancer Res 2010;16:5381–9). “The longer it takes to open a trial, the less likely it is to succeed in accruing patients,” he notes.
It took almost twice as long to open about 30 phase II industry-sponsored trials in the United States as in Italy, according to a recent study of lung cancer clinical trials at two major academic medical centers (J Clin Oncol 2010;28:3803–7).
A Worldwide Wait
The problem is global, says Brad Thompson, PhD, chief executive officer of Oncolytics Biotech in Calgary, Alberta, Canada. “The entire process is getting slower no matter where you are.”
At the national regulatory level, Thompson describes the Food and Drug Administration (FDA) as “one of the more user-friendly agencies” motivated by wanting new and safe drugs.
In contrast, top-level regulatory drug approval may take longer in the European Union with additional sign-off needed by member nations, an obstacle acknowledged in an April 2011 report from the European Clinical Infrastructures Network.
On the other hand, some very large trials are running successfully in Europe, and some countries maintain massive medical databases that make it easier to launch and track these.
Many have long expected a massive shift in clinical trials to developing countries, especially India and China.
Partly driven by the challenges in conducting clinical research in the United States, the number of trials with overseas sites is climbing. About 80% of 121 FDA drug and biologics approvals in 2008 contained data from foreign clinical trials. Western Europeans accounted for roughly 60% of foreign trial subjects.
Source: Challenges to FDA's Ability to Monitor and Inspect Foreign Clinical Trials, Office of the Inspector General, Department of Health and Human Services, 2010.
Partly driven by the challenges in conducting clinical research in the United States, the number of trials with overseas sites is climbing. About 80% of 121 FDA drug and biologics approvals in 2008 contained data from foreign clinical trials. Western Europeans accounted for roughly 60% of foreign trial subjects.
Source: Challenges to FDA's Ability to Monitor and Inspect Foreign Clinical Trials, Office of the Inspector General, Department of Health and Human Services, 2010.
“There is no question that during the past decade an increasing proportion of trials have been placed overseas,” says Kenneth Getz, MBA, a faculty member of the Tufts Center for the Study of Drug Development and the founder and owner of CenterWatch. “But there is a lot of hype claiming that growth in the placement of trials in emerging regions will accelerate at a dramatic pace.”
The reality in India and China is more of a trickle, the June 2011 CenterWatch Monthly reported. Clinical trials in emerging markets can have tangible drawbacks, such as an immature clinical infrastructure and weak professional oversight. “There's too much riding on the success of testing an expensive drug for a company to nickel and dime for an investigative site,” Getz says.
Around the world, the solutions for expediting trials are not straightforward. “It's like pushing a cloud,” Thompson declares. “There is no one authority over the whole process. In the U.S., the FDA has authority over approval. Each trial site has authority over different parts but not all of the process. Doctors are accountable to ethics requirements. Pharmaceutical oversight groups review handling procedures for safety. It's a process that got out of hand, and smart people on all sides know it. But because of the diversity of the input, nobody can figure out how to deal with it.”
However, evidence of the problem is making a difference. After learning that accrual inversely correlates with the time from study concept to national Institutional Review Board (IRB) approval to open, the NCI adopted strict deadlines for phase III cooperative group trials, replaced back-and-forth paperwork with a conference call, and installed a web-based tracking system with target timelines that notes when the approval process stalls. The rules took effect in January.
“We have dramatically cut the turnaround time for national IRB approval from 800 days to 300 days without spending any extra money,” says James Doroshow, MD, deputy director for clinical and translational research at NCI. Out of several hundred trials in the NCI pipeline, only two have been canceled for missing the target.
