Applied Clinical Trials
FDA officials, academic leaders seek more efficient, informative research system to support medical product development.
At a time when advances in genomics, nanotechnology, proteomics and other scientific breakthroughs are generating high expectations for the development of important new treatments for disease, the inefficiencies in the current system for conducting clinical trials threatens to limit the ability of researchers to translate new discoveries into viable medical products. Under existing practices, research sponsors in industry and academia have to enroll scores of patients into multiple clinical trials to collect data sufficient to assure regulatory authorities of a product’s safety and effectiveness. This system is enormously expensive, which inherently limits resources available to test the growing number of promising compounds.
Pressure on researchers to produce even more data is mounting, moreover, as demand grows for more post-approval safety studies on medical products. Health officials want to know more about the cardiovascular effects of new medicines for diabetes and other conditions. And the clamor for “personalized medicine” and for comparative effectiveness research will require more complex trials that need to study large patient populations in “real-world” settings.
Meanwhile, the clinical trial system is in a state of near-collapse, according to research experts. It is increasingly difficult to find trained investigators to conduct studies and enough eligible patients to populate all the desired trails. The burgeoning “transparency” campaign is likely to make these efforts even more difficult, as physicians become increasingly fearful of being stigmatized by public disclosure of payments from drug companies, even for legitimate research activities.
Regulatory requirements only add to the burden. Institutional Review Board procedures are confusing and unpredictable; adverse event reporting generates redundant efforts; and a lack of common terms and standards creates confusion in establishing registries and filling out case report forms. The National Institutes of Health (NIH) is trying to develop uniform templates for clinical trial agreements and site contracts, but adoption by research organizations is very slow. Despite these problems, clinical research is soaring. More than 10,000 clinical trials are being conducted in the United States that aim to enroll some 2.8 million subjects, according to an analysis by Ronald Krall, formerly head of research at GlaxoSmithKline, for an October workshop on “Transforming Clinical Research in the U.S.” sponsored by the Institute of Medicine Forum on Drug Discovery, Development and Translation.
The total is dominated by Phase II studies, many for cancer therapies, but Phase III trials enroll the most patients, particularly for cardiovascular treatments. Phase IV research accounts for almost 30% of studies, and that number is growing. Krall’s assessment confirms the serious problems facing the research enterprise: most investigators participate in only one trial; almost one-third of investigators never enroll any subjects; and 75% of studies miss enrollment targets.
Integrating research & care
The solution, according to IOM panel members, lies in building a “learning health care system” that eliminates the divide between real-world clinical practice and the conduct of clinical trials to support R&D. Under a more integrated approach, health care outcomes would be systematically measured as part of medical practice, and that knowledge would be rapidly translated back into guidelines for recommended patient treatment.
Unfortunately, participants in this workshop provided ample evidence that the current health care system in the United States provides little support for testing innovations in medical products and practice. Being a clinical investigator is a “painful experience” that leads most first-time investigators to be last-time investigators, commented Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA).
The problems are particularly acute for practicing physicians, who lose money from clinical research, pointed out Robert Califf of Duke University. Conducting clinical trials also undermines their medical practices and opens the door to media attacks for accepting payments from drug companies, Califf added, noting that “many physicians are getting out of clinical trials because they can’t afford it.”
Woodcock went on to paint a distressing picture of the nation’s research system: Clinical studies impose “crushing” administrative burdens on sponsors, and patients have a hard time identifying appropriate trials and dealing with the paperwork and informed consent. The current one-off nature of trial organization, with each sponsor setting up a new research operation for every development program, means that it takes years to recruit patients and to launch studies. A lack of trained site managers, insufficient reporting standards and inadequate study monitoring result in protocol adherence errors. Study results frequently are useless or require extensive “clean-up,” which only drives up costs and raises questions about data reliability. Not surprisingly, the public has a strong distrust of clinical research, particularly of industry-sponsored trials.
One response from sponsors is to off-shore clinical research; pharmaceutical companies and contract research organizations are conducting more trials in China, India, and Eastern Europe to gain access to ample patient pools and to decrease operational costs. This development, though, raises new challenges in ensuring study quality and in bridging data to U.S. populations.
Woodcock would like to see a clinical research infrastructure established in the U.S. on a parallel with the nation’s infrastructures for highway transportation and for energy supply. Scientific inquiry should be recognized as “a societal good” that enjoys stable funding and broad support, she commented. Research should be organized regionally and nationally around diseases or practice areas, providing support for core research personnel trained to manage trials and to produce reliable data. Sponsors in academia as well as industry would have access to a core community research network that would enjoy local trust and be able to enroll patients rapidly into a research-ready organization. Professional “trialists” would have support to pursue clinical research as a career.
Efforts to improve clinical research operations, such as the Clinical Trials Transformation Initiative (CTTI), a cooperative undertaking by Duke, FDA, and public and private organizations involved in clinical research, offer some hope for addressing these problems. Initial CTTI projects are to streamline reporting of unexpected serious adverse events that occur during clinical trials and to improve methods for study monitoring by sponsors to assure quality and adherence to good clinical practices. These address important problems, but fall short of any major overhaul.
An opportunity to realize the vision for transforming the nation’s research enterprise may come from rising public demand for more information on the value of health care products and processes. Increased government funding of Comparative Effectiveness Research (CER) aims to support new research on how medical products and procedures work in real-world settings. It is important for such studies to be conducted by community-based medical professionals if the resulting discoveries are to be translated effectively into practice guidelines accepted by health professionals and patients, Woodcock further explained at a conference on CER and personalized medicine sponsored by the Personalized Medicine Coalition and the National Pharmaceutical Council. This approach has the added advantage of allowing patients to obtain treatment from local practitioners, instead of having to travel to distant research centers.
Such research, though, requires “an infrastructure that doesn’t exist in the U.S. right now,” Woodcock pointed out. The CER priority research list issued by the IOM in June proposes many topics for further study of what treatment works best for whom that “far exceeds the current research capacity,” she noted, adding that “we are not going to get from point A to where we want to be without this kind of investment” in a research infrastructure that supports both academic and community health professionals.
One model could be the broad clinical research networks established by disease foundations, as seen with cystic fibrosis and juvenile diabetes. These offer pharmaceutical and biotech companies, as well as independent researchers, ready access to physicians and patients familiar with the condition and highly motivated to support new research. Academic medical centers are well-positioned to coordinate studies and to provide infrastructure and support for such research networks, including assistance in dealing with IRBs and regulatory agencies, in negotiating licensing agreements and other issues critical to launching and conducting clinical trials.
In addition to reducing delays and waste, the campaign to improve the clinical research infrastructure addresses important ethical issues, Woodcock observed at the IOM workshop. It is considered unethical to conduct trials that yield no interpretable results due to the risks imposed on trial participants. But studies conducted at poorly managed sites often produce useless data, she noted, an outcome that emphasizes the dire need for system reform.
Jill Wechsleris the Washington Editor of Applied Clinical Trials, (301) 656-4634, firstname.lastname@example.org