The ongoing effort to modernize clinical trials through the 21st Century Cures initiative came before the Subcommittee on Health of the House of Representatives Energy and Commerce Committee Wednesday morning in the first of a two-part hearing. Witnesses from academia and industry agreed the traditional clinical trials process needs to leverage advances in science and technology, from increased use of biomarkers and surrogate endpoints to improved application of electronic health records. They acknowledged, however, that potential perils loom if shortcuts are taken in reforming the system.
Speaker after speaker acknowledged the raft of challenges in getting clinical trials up and running, especially for small companies, and the number of trials moving overseas as a direct result of the time and cost associated with the process in the U.S.
Some subcommittee members seemed more cognizant than others of the opportunities and hazards in reforming the process. Henry Waxman (D-Calif.), ranking member of the full committee, called U.S. clinical trials "the bedrock of modern medical product development" and said the success of studies is dependent on the willingness of people to volunteer for them. "We want to make sure that clinical trials are conducted using the most modern tools and technology that science has to offer and in the most efficient manner possible," he added.
But how to ensure that end without compromising what Robert Meyer, director of the Virginia Center for Translational and Regulatory Sciences at the University of Virginia School of Medicine, called the "gold standard" of drug development is no mean task, witnesses agreed. A number of drivers have contributed to larger, longer and more complex phase III programs. "It is important to not solely focus on this issue as being a consequence of regulatory requirements, as the drivers are multidimensional," Meyer said.
He cited the development of clinical trial networks with identified patient populations and clinic sites and master protocols as two potential solutions.
"While interdisciplinary oversight committees aimed at achieving simplified, efficient trial designs are being implemented by some sponsors, this is still not the norm," Meyer insisted. He suggested that streamlined protocol designs should be encouraged by the FDA during end-of-phase II discussions with sponsors.
Paula Brown Stafford, president of clinical development for Quintiles, was more succinct.
"We collect too much data," Stafford said in response to a question by Renee Ellmers (R-N.C.). She credited "multiple voices at the table" for expanding study protocols beyond the boundaries needed for approval by seeking extraneous information.
Combining adaptive design within master protocols, which allows multiple drugs to be evaluated in the same trial, is an approach the EMA is considering for wider adoption, Stafford said. She cited I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2), by Puma Biotechnology Inc., of Los Angeles, as an example of an adaptive trial using a master protocol.
With the FDA's blessing, I-SPY 2 was designed to test whether, based on Bayesian predictive probability, a regimen containing neratinib, a pan-HER tyrosine kinase inhibitor, as neoadjuvant therapy in metastatic breast cancer likely would prove statistically superior to standard therapy in an equally randomized, 300-patient confirmatory trial. Findings from the phase II trial, reported in April, were mixed. (See BioWorld Today, April 9, 2014.)
Roy Herbst, professor of medicine and chief of medical oncology and associate director for translational research at the Yale Cancer Center, cited another potential example of adaptive design in the Lung-MAP effort, which he co-chairs. The groundbreaking trial is designed to advance the development of targeted therapies for squamous cell lung cancer by providing a mechanism to genomically screen large but homogeneous cancer populations and subsequently assign and accrue patients simultaneously to a multisubstudy master protocol, resulting in a prospective, randomized phase II/III registration protocol.
POST-APPROVAL SURVEILLANCE NO 'WHITE KNIGHT'
Despite such initiatives, all designed to reduce the time and resources consumed by clinical trials, Meyer cautioned against proposals to move regulatory decisionmaking earlier in the drug development process and shift confirmatory phase III trials largely to the post-approval setting.
"The fact that many products fail in phase III reflects the realities of science as much as any issue correctable in the design and conduct of trials," he said, noting that half of phase III failures result from lack of efficacy, signaling "a clear cautionary note for lessening the demands" in pivotal trials.
Eliminating development "white space" by transitioning seamlessly from a successful phase II into a phase III sounds attractive, Meyer said, but raises significant issues, including loss of the ability to "learn and confirm" sequentially about the safety and efficacy of a given drug.
"We're not at a point in the science where we can shift FDA decisionmaking" to the end of phase II, he maintained.
In fact, Aaron Kesselheim, assistant professor of medicine at Harvard Medical School and director of the Program On Regulation, Therapeutics And Law, or PORTAL, in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women's Hospital, maintained the FDA is not a bottleneck in reviewing drug applications, compared to other regulators. From 2001 through 2010, the FDA approved nearly two-thirds of new therapeutic agents earlier than the EMA, he said.
Kesselheim also worried that patient health could be risked if drugs and devices are approved without vetting in rigorous, albeit time-consuming, trials. Fast track designation, for example, reduced the average clinical development time for a new drug from 8.9 years to 6.2 years, and drugs benefiting from accelerated approval averaged just 4.2 years, he said, while new drug application review times have decreased from more than 30 months in the 1980s to 14.5 months by 1997 and 9.9 months for applications received in 2011.
"We did a study and found that cancer drugs tagged with the 'orphan drug' label were overwhelmingly more likely to be tested in methodologically weaker assessments" during trials, Kesselheim said, including nonrandomized, unblinded, single-arm studies that considered disease response rather than overall survival. "More drugs being approved on the basis of uncertain data will inevitably lead to more drugs being withdrawn from the market after showing safety problems or weaker-than-expected effectiveness in widespread clinical use."
He warned that post-approval surveillance programs like the Sentinel initiative don't constitute a "white knight" that can remedy errors in the conduct of clinical trials.
Witnesses generally supported the development of new biomarkers and surrogate endpoints, especially for conditions with unmet medical need. But Meyer questioned which stakeholders should drive the process. While the FDA should be involved in such efforts, the agency has neither the resources nor expertise to take the lead, he said. He cited drug development efforts in Alzheimer's disease, noting that "everybody would like smaller, more focused trials" incorporating surrogate endpoints but that current biomarkers don't warrant that approach.
Kesselheim agreed, explaining to subcommittee members that the purpose of surrogate endpoints is to shorten clinical trial timetables. If surrogate endpoints are not properly connected to clinical endpoints, however, they won't yield valid clinical data, he cautioned. Kesselheim cited the experience with statins – some of which lower low-density lipoprotein but don't behave as predicted in lowering overall cardiovascular risk – as just one example.
Moreover, as the industry seeks to move toward more efficient trial designs to shrink the drug development timetable, compounds likely will be tested on even smaller numbers of patients, making it even harder to achieve the goal of greater diversity in recruiting patients.
On Friday, the subcommittee will reconvene to hear witnesses from industry, patient advocacy organizations and the FDA discuss the patient perspective in modernizing clinical trials.