Subscribe to eTOC

Bigger, Faster, Cheaper
Is it Time to Reconsider Clinical Trial Strategies?

ARTICLE IN BRIEF

Figure

No caption available.

A New York Times article about a shift in the National Heart, Lung, and Blood Institute's approach to supporting clinical trials spurs discussion about the funding environment and strategies at the National Institute of Neurological Disorders and Stroke.

When an October 16 feature in the New York Times reported that the National Heart, Lung, and Blood Institute (NHLBI) was modifying its approach to funding clinical trials, investigators in the US took notice. “Hundreds of millions of dollars has been going to heart studies that are too small and narrow to yield results meaningful enough to get into a journal,” the Times science correspondent Gina Kolata wrote.

Three years ago, NHLBI officials, including then-director of the Division of Cardiovascular Sciences Michael Lauer, MD — now deputy director for extramural research at the National Institutes of Health (NIH) — found that of the more than 200 clinical trials the institute had funded over the course of a decade, to the tune of some $2 billion, about 40 percent had either gone unpublished or only hit print after extensive delays.

In response, Kolata wrote, the NHLBI will be focusing on better, faster, and cheaper trials, cutting back on funding smaller studies, and requiring major cost-cutting in larger studies. It's stressing “pragmatic” trials with what Kolata calls “outcomes that matter,” like reductions in heart attacks or deaths.

When Neurology Today reached out to the NHLBI, the response was somewhat more nuanced, however. “This doesn't mean that the institute is moving wholesale to one particular type of trial, or mandating particular limits on clinical trials' budgets,” Gail Pearson, MD, SciD, director of the Adult and Pediatric Cardiac Research Program at NHLBI, told Neurology Today. “I wouldn't say there have been any sudden, recent changes. We want a balanced portfolio. But we are certainly encouraging investigators to think creatively about ways to cut costs.”

Figure

DR. ROBERT G. HOLLOWAY JR.: “We need smaller, well-designed phase 2 pilot studies to help us refine our approach and best inform us how to conduct larger, simpler trials that can be more streamlined.”

She pointed to recent funding opportunities for pragmatic trials that can be built into existing electronic health records, limited to about $500,000 per year. The institute is also encouraging investigators to publish trials that are embedded in registries. “That's another example of making a trial efficient.”

THE NINDS APPROACH

Will the National Institute of Neurological Disorders and Stroke (NINDS) be taking a similar approach? Not necessarily, experts told Neurology Today.

The concept of focusing on large, simple trials, for example, is not new to NINDS. Big, pragmatic real-world studies were once a major area of emphasis in neurology. “That was the approach in the stroke world,” said Robert G. Holloway Jr., MD, MPH, FAAN, a professor and chair of neurology at the University of Rochester Medical Center and associate director of research education for its Clinical & Translational Science Institute (CTSI), and associate editor for Neurology Today. “The large international stroke trials had very simple outcome measures. The case report forms were sometimes only one page long.”

But stroke is one of only a few neurologic conditions where the outcome measures for a trial can be nearly as straightforward as those the NHLBI will insist on for many cardiac trials. “Cardiac trials can have clear-cut endpoints. Did you have a heart attack? Did you die? When testing novel treatments in neurology, that doesn't help us too much,” said NINDS director Walter J. Koroshetz, MD, FAAN.

“In cardiovascular disease they are often doing comparative effectiveness trials, testing compound A vs. compound B, both of which are proven therapies,” he said. “In neurology, we tend do a lot more trials of compounds that have never been seen before in the particular population, and the outcome measures may be less straightforward.”

However, comparative effectiveness trials in neurology, in which the endpoints are clear-cut — such as stroke, death, time seizure-free, number of MS exacerbations, and modified Rankin scale score at six months — should be streamlined and performed with minimal cost per patient, Dr. Koroshetz affirmed. “NINDS is currently limited by resource availability in the research it can fund, and funds can only be directed to collect the data that is essential to answer the clinical trial question.”

Figure

DR. WALTER J. KOROSHETZ: “We dont release funds until after certain milestones have been met, so were not paying people when theyre still stuck in the IRB approval process and arent accruing patients. And we dont accept clinical trials unless they already have an Investigational New Drug approval from the Food and Drug Administration. We work with people to make sure that the clinical trial as it comes in is going to be very high-quality and feasible, and that solves a lot of problems.”

Dr. Holloway agreed. “So many of our diseases are rare and heterogeneous, and do not lend themselves to large, simple studies,” he said.

If anything, NINDS is placing more of a focus on smaller, biomarker-informed clinical studies, Dr. Holloway noted. “For example, the whole NeuroNEXT network is focused on phase 2 biomarker-informed clinical trials, like pilot studies, to ultimately inform larger trials.”

TRIALS THAT FAIL TO SHOW A BENEFIT

One problem facing neurology is the number of clinical trials of novel therapeutics that have failed to show benefit for patients. Because of this, “the NINDS is now focusing on demonstrating that an intervention meets its biologic target in phase 2 trials before embarking on long, expensive phase 3 trials, and before asking hundreds of patients to take on risk and contribute their time and effort,” Dr. Koroshetz said.

NINDS has already tried and largely rejected the idea of embedding more trials in the midst of general clinical practice. “That was what we were trying to do when I first came to NINDS,” said Dr. Koroshetz. “It didn't work. The practitioners were just too busy, and we didn't get much traction. We put quite a bit of money into that and got one good trial out of it, in headache, but that was primarily because the major headache research centers joined in.”

NINDS has its own strategies for seeking efficiencies and improving results, Dr. Koroshetz said. He noted that when he first arrived at the agency as deputy director in 2008, inefficiency plagued its phase 3 trials. “The people submitting grants were often doing it for the first time, so it took years to get things set up, with money flowing out but not much happening,” he said. That's one of the primary reasons why, in 2008, NINDS converted all of its clinical trials from investigator-initiated R01s to U01s — cooperative agreements.

“We have gotten a little hard on investigators,” Dr. Koroshetz said. “We don't release funds until after certain milestones have been met, so we're not paying people when they're still stuck in the IRB [institutional review board] approval process and aren't accruing patients. And we don't accept clinical trials unless they already have an Investigational New Drug [IND] approval from the Food and Drug Administration. We work with people to make sure that the clinical trial as it comes in is going to be very high-quality and feasible, and that solves a lot of problems.”

NHLBI is also employing a phased approach to continuing funding for at least some of its trials, said Dr. Pearson. “Investigators are given a year to get things set up with a relatively low budget, and at the end of that, a group reviews their progress relative to the milestones laid out and decides if they can continue.”

NeuroNEXT, the Neurological Emergency Treatment Trial (NETT) Network, and the NINDS Stroke Trials Network are all designed to maximize efficiencies and streamline the development of high-quality neurology trials, Dr. Koroshetz said. “A learning network that can get better and better each time is a big advantage in an area where there is expected to be a high volume of trials,” he said.

As a result, several measures of trial efficiency at NINDS, such as pace of accrual into trials and the time between when a grant notice goes out and the study's enrollment of its first patient, have improved significantly, he said, although specific numbers weren't available at press time.

MISHANDLED PILOT STUDIES

It's true that the efficiency and quality of pilot studies — in neurology and elsewhere — could also be improved. In a critique published October 20 in the Journal of the American Medical Association, a team of Boston University scientists wrote that pilot studies “have often involved reporting inconsistencies, misapplication of research techniques, and misinterpretation of results, with significant implications for intervention research.”

“We all can do better on these,” Dr. Holloway acknowledged. “The smaller studies that Dr. Lauer and the NHLBI point to as not getting published and not delivering their results — a lot of that stems from mishandled pilot studies. They're often not powered well and they haven't spent a lot of time determining the ideal pilot design to inform a larger study.”

Neurology Editor-in-chief Robert A. Gross, MD, PhD, FAAN, a professor of neurology and of pharmacology and physiology at the University of Rochester, said that the problem sometimes starts even further up the pipeline, at the preclinical level. “A lot of preclinical studies, particularly for new products, are not reproducible, therefore providing a basis for clinical trials that might be more likely to fail than not. We need better preclinical models so that trials in humans are more likely to succeed.”

“It's too early to say how changes in the funding environment will affect the pipeline of published papers in neurology,” said Annals of Neurology Editor-in-chief Clifford B. Saper, MD, FAAN, the James Jackson Putnam professor of neurology and neuroscience at Harvard Medical School and chairman of the department of neurology at Beth Israel Deaconess Medical Center. “Manuscripts to journals are the very last step in this process, so it comes years after the work is started, and sometimes years after it is completed, so we are looking at a lagged sample.” He noted that Annals of Neurology has a low acceptance rate, running at just under 10 percent.

Figure

DR. ROBERT A. GROSS: “A lot of preclinical studies, particularly for new products, are not reproducible, therefore providing a basis for clinical trials that might be more likely to fail than not. We need better preclinical models so that trials in humans are more likely to succeed.”

The neurologic community will have to continue to place significant emphasis on both types of trials, Dr. Holloway said. “We need smaller, well-designed phase 2 pilot studies to help us refine our approach and best inform us how to conduct larger, simpler trials that can be more streamlined.”

LINK UP FOR MORE INFORMATION:

•. The New York Times: “A New, Life-or-Death Approach to Funding Heart Research”: http://bit.ly/NYT-clinicaltrials
    •. Kistin C, Silverstein M. Viewpoint: Pilot studies: A critical but potentially misused component of interventional research http://jama.jamanetwork.com/article.aspx?articleid=2463266. JAMA 2015:314(15):1561–1562.