Fresh Take on How to Conduct Rare Disease Clinical Trials

By Deborah Borfitz 

July 11, 2024 | A boutique clinical trial program launched less than two years ago to redirect the way clinical trials for rare diseases are conducted now knows it “vastly underestimated” demand. Uncommon Cures, a privately held U.S. company, already has eight signed contracts, is negotiating five more, and is actively talking with more than 50 clients about possible trials, according to CEO Marshall Summar, M.D. 

“It turns out there was some pent-up need and a lot of it was dissatisfaction with the classic CRO model,” says Marshall, who has worked in the rare disease field for more than four decades. Uncommon Cures does many of the same regulatory tasks as contract research organizations, but blends that with a bricks-and-mortar facility where trials get run in a “very concierge-based” manner. 

The model can be thought of as a scaled-up, regulatory-grade version of “old school” trials run from start to finish by a clinical investigator, he says. Except here, in-house experts are working alongside study sponsors from the Investigational New Drug application process to phase 4 post-marketing studies. 

It’s an entirely new concept that will be expanding internationally, says Summar.  The primary facility, based in Washington, D.C., has a sophisticated medication dispensary as well as negative and positive pressure rooms to ensure patient safety during study visits. A second site will soon open in Utah, and a program in Santiago, Chile, is in the build stage. International sites are under rollout in Switzerland and the United Arab Emirates with others planned in the future, he adds.    

Global reach is critical to find rare disease patients “where they are” and give them opportunities to try investigational therapies, Summar continues. “I wouldn’t be unflattered if people decided to copy the [Uncommon Cures] model. “There are 12,000 different rare diseases, so we are not going to run out of stuff to work on.” 

The new approach, which focused heavily on protocol-related holdups, is sorely needed, Summar points out. Three-fourths of all orphan clinical trials fail, largely because they are out of touch with the realities of patients and too cumbersome to conduct and participate in.  

By and large there is only a single therapy under development for any one rare disease, meaning “we can’t really afford those failures,” says Summar. As it is, payer pushback on the cost of approved therapies has helped dampen investor interest in rare disease research that is unlikely to self-correct until the cost, or at least the time, it takes to bring new therapies to market gets under control. 

The Obstacles

Up to now, rare disease clinical trials have been done based on practices derived from studies of drugs for more common conditions afflicting hundreds of thousands if not millions of patients, says Summar. Since passage of the Orphan Drug Act in 1983, both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency have shifted to more adaptive trial designs more accommodating of smaller patient pools where interim analysis of results are used to modify the study’s course in accordance with pre-specified rules. 

But many industry sponsors are better versed in traditional fixed design trials and therefore tend to make it their default choice across the board, he says. Meanwhile, the companies specializing in rare disease trials will set up anywhere between 10 to 20 academic sites—and, in some cases, double or triple that number—in hopes of meeting accrual goals, putting a “huge drag” on study timelines.    

The slow pace of contract negotiations with these universities, each insisting on their own institutional review board having the opportunity to review the protocol and consent form, can eat up two to four years “right off the bat,” says Summar. An added problem is that, outside of oncology, it tends to require “reinventing the wheel” every time. 

If a pediatric medical specialist with expertise in a particular rare disease is available at all, that doctor probably already has a 10 to 12 month wait time and the institution won’t be eager to extend that out further. “I spent many years as a division chief [in academia], and I said no to about half the trials that came across our doorstep,” he says. 

Beyond the backlog, clinicians who are tops in their field are probably going to be too busy to add a clinical trial to the mix, Summar adds. The rare disease expert at an institution may also be more engrossed in basic research and not even specialize in taking care of patients. 

Summar learned all this firsthand. “I have been involved in well over 100 clinical trials, either at the level of PI or peon,” Summar says. He has served as chairman of the board of directors for the National Organization for Rare Disorders, as a clinical division chief, done basic science research, and had some of his own laboratory-developed products go through the FDA regulatory process. 

“There are just so few of us [in the rare disease field] that you have to wear a lot of hats,” says Summar. “Over the years I noticed that trials were taking a lot longer than they needed to and that meant patients weren’t getting treated and... [in some cases] companies went out of business because trials were taking too long, and they didn’t have enough runway.” 

Protocol Problems

Based on studies looking at the dismal success rate of orphan drug-designated trials, the primary determinant was not the science, notes Summar. That only explained about 20% of the failures. “The biggest predictor [55%-57%] is under-recruitment.” 

The shortage of patients is of course one reason, but study design is the other more important culprit, he says. When studies are designed to be more flexible—e.g., adaptive clinical trials or crossover studies where participants receive the same treatments but in a randomized order—fewer patients are needed than with a classic double-blind, placebo-controlled trial. 

Studies are also generally first done in adults, which limits the patient pool further and often there is not even a relevant population. The “point of maximum impact” for a therapy treating a rare disease is almost always early in life, potentially before affected individuals reach their third birthday, says Summar. To instead enroll patients who have survived into their 20s, with a milder form of the disease or other genetic factors at play that make them clinically different from those younger patients, may succeed only in creating a “survivor bias.” 

Outcome markers and measures in rare disease trials also need to be carefully selected and “tend to be more binary” than in other patient populations, he continues, such as whether individuals lived or died or if they did or didn’t have significant health issues. That can be a “real advantage” when designing these studies relative to, for example, tracking subtle changes in systolic and diastolic blood pressures in hypertension trials. 

The Redirect

Uncommon Cures officially launched in March 2023. It grew out of discussions between Summar, emergency room physician Rob Freishtat, M.D., (now company president), and MIT economist Andrew Lo, Ph.D., and parent-scientist Simon Frost (both of whom serve on the company’s board of directors) about why rare disease trials take so long and costs so much—and what they might do about it. 

They settled on a “centralized hub” approach that operates outside the university setting and makes study participation as seamless as possible, beginning with “making sure the trial design doesn’t have [patients] coming in any more than they absolutely have to,” says Summar. Uncommon Cures will fly in and put up patients as necessary, such as for initial infusion to check for potential adverse reactions, but otherwise pushes trial-related activities to patients’ home or community.   

Decentralized trial components include lab draws and patient monitoring in the home that is not only more convenient for participants and their loved ones but produces better data simply because they’re in their natural environment rather than a clinical research center, he notes. 

Minimizing unnecessary exclusion criteria in the study protocol is critical, says Summar. In clinical trials for common conditions, the idea is to narrow the participant pool to the “ideal” patients who don’t have characteristics that might interfere with the study's success, so the list of exclusions can be lengthy. 

When applied to rare diseases, the principle doesn’t work because the candidate pool is already small and the patients are all complex, Summar says. “I have seen a number of trials where there were so many exclusion criteria that almost none of the patients passed screening.” These criteria often include “things that are just normal for the disease,” such as heart disease in Down syndrome or liver disease in conditions like tyrosinemia, versus what is necessary to get a signal or prevent undue harm. 

For patient screening, Uncommon Cures works closely with patient advocacy organizations and patient registries, he says. The company also builds relationships with clinicians caring for patients with rare diseases and is endeavoring to create key opinion leader groups around different disease areas. 

The team supporting all this work currently numbers 18 and is about to flip into the 20s, Summar reports, which is much faster than initially anticipated. On the roster are five physicians in addition to nurses with clinical research experience, clinical research associates, a laboratory team, and financial experts devoted to cost control. “Everybody is cross trained, so people can wear different hats,” says Summar.  

Doing Better

At this time next year, Summar expects Uncommon Cures will be actively working on 15 clinical trial projects. Customers range from big pharma to startup companies, but also include multiple groups that are parent- or patient-organization driven “where there is not any immediate financial reward, if ever,” he says. Investor groups have also been turning to Uncommon Cures to evaluate whether certain research projects have a “clinical path forward” and warrant their financial support.   

The company has collected enough data to produce good estimates of the time and cost of running a rare disease clinical trial, says Summar. “What we’re finding is a substantial cost savings, north of 40%, over the current market trend for equivalent level studies.” 

That’s a reassuring sign that the new model is working as intended. Interestingly, the time savings matters more than the cost savings to study sponsors—and that’s exactly what Uncommon Cures plans to deliver, he says. 

“We can do rare disease clinical trials better, and not just Uncommon Cures,” Summar says. “The whole field can do them better, and we have to.” 

The only reason this hasn’t happened before now is that the field of rare disease is so young, so there hasn’t been any institutional experience to pull from, he says. People working in the field are also being pulled tight because the demand for experts exceeds the supply. “That’s one reason I am still doing this in my 60s.” 

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