Rare diseases research brings special challenges

Confidentiality, expertise key to protocol review

Those advocating research into rare diseases often have an uphill battle, searching for funding and trying to garner public support for treating conditions that don't have the same widespread recognition as HIV or breast cancer.

The research also comes with unique challenges for protecting human subjects — both because of the rarity of the conditions being studied and the greater concern about confidentiality, says Kathleen Paulus, CIP, protocol manager for the Rare Diseases Clinical Research Network at the University of South Florida, Tampa.

"If you're looking at dots on a map [that represent patients with rare diseases in the United States], you could theoretically identify somebody by their dot on the map," she says. "If you were a physician who lived and worked in Texas and saw a dot on the map in Texas for, say, a genetic steroid disorder, then it would be pretty obvious to you if you had ever had contact with that one person in Texas who had that disorder who that person was."

Paulus says people suffering from rare diseases, many of which are genetic in origin, have understandable fears about potential loss of health insurance or employability if others learned about their conditions.

"We're extraordinarily careful and use the most cutting-edge practices," Paulus says of the research network, which includes 10 consortia, each representing a group of similar rare diseases such as bone marrow failure diseases, rare lung diseases, or various forms of vasculitis.

"We have sites in Japan, Canada, Europe, and South America," she says. "Since we are storing all these data from all over the world, we have to ensure that it's stored appropriately and getting to us [in a secure way]. We have these electronic on-line data capture forms that go directly into our systems here."

But she notes that beyond secure computers and proper data storage techniques, her network must consider issues that pharmaceutical companies or researchers with large patient populations may take for granted — for example, the confidentiality problems raised by plotting their subjects on a map.

"If someone wanted to show on a map how many individuals they have in their study of heart disease, it wouldn't make any difference, because so many Americans have heart disease," Paulus points out.

Expertise sometimes lacking

In addition to issues of confidentiality and HIPAA compliance, Paulus says reviewing rare diseases research raises other issues in IRB review:

Lack of expertise. Because the disorders involved are so rare and not particularly lucrative for the pharmaceutical industry, there is a dearth of scientists who specialize in them. As a result, IRBs may have not have members on their boards with expertise in the condition being studied.

"So investigators will run into IRBs that don't truly understand the nature of the disease or the science behind what the investigator is proposing," she says.

International reach. Most studies in this field must be international endeavors to recruit enough subjects. Paulus says IRBs that want to make minor changes to protocols can end up causing serious delays.

"Changing a protocol that's been thoroughly reviewed by, let's say, the National Institutes of Health and multiple government agencies around the world, for minor issues really does hold up the research endeavor for these rare diseases," she says. "I'm a certified IRB professional, so I know where the IRBs are coming from, but they need to work with investigators to make sure that only really necessary changes to the protocol are made at the time of review. Other changes could really be held until the next amendment."

Paulus says that in her experience, the vast majority of IRBs understand this issue.

"They understand that this is a truly rare disease and that this is real progress being made by [NIH's] Office of Rare Diseases towards serving these patient populations," she says. "They're not willing to be bulldozed, nor should they be. But then there are one or two IRBs that don't quite understand how imperative it is for this to move forward without perhaps the level of bureaucracy that is standard with pharmaceutical studies."

Protecting subjects from unnecessary research. Paulus says IRBs she deals with often are concerned as to whether the research being proposed is truly of value.

"They're concerned with the protection of their local subject population," she says. "Because the diseases are so rare there is no standard of care. And is putting these families and these patients through this particular research endeavor really worth it, even if it's just a longitudinal study?"

As an example, she says an IRB may question whether it's necessary to ask extremely personal questions in a survey.

"They'll ask whether maybe the discomfort of asking this question may be inappropriate," Paulus says. "And it may be absolutely appropriate, because it speaks to the progression and history of the disease — it's a very important data point."

She notes that because there is limited funding for rare diseases research, experts in the field are careful to spend that money wisely.

"Much less with rare diseases research would you find a [study] that isn't really important to the cause of the disease," she says. "In rare diseases research, they're really focused on curative research or understanding the progression of the disease."

Recruiting a geneticist to the IRB

Because of the complexity of the diseases being studied, "the terminology becomes exponentially more technical," Paulus says. "The majority of rare diseases have a genetic basis, so you're talking a lot about genotypes and phenotypes."

Informed consent challenges. Paulus says IRBs could benefit from having a member who is a geneticist, to help sort through the scientific terminology and make sure informed consent is accurate and understandable.

She says much of the research is done on children, so IRBs also must carefully examine the consent/assent process for parents and their children.

"You have to make sure that you weigh the parents' eagerness against what the child would actually be willing to do, if they were of consenting age," Paulus says.

Although the diseases themselves are rare, there are so many of them that Paulus estimates that nearly every IRB should encounter at least one rare disease proposal at some point.

In addition to having a geneticist on board, she advises that IRBs learn where to go for specialized help should such a proposal come before them.

"They need to be aware of who are the leaders in the field," Paulus says. "They could approach a patient advocacy group — they will always know who the leading expert is. Or if it's one of our diseases [in the Rare Diseases Clinical Research Network] they could always come to us.

"There's nothing these researchers want more than to make sure that high-quality excellent research is being conducted on these areas where these populations are underserved."

Paulus says IRBs dealing with rare diseases research also should have a good understanding of certificates of confidentiality, which are issued by the NIH and other Health and Human Services agencies to protect identifiable research information from forced disclosure in civil or criminal legal actions.

"It's not an absolute catch-all — lawyers have been able to poke holes in it in the past, but it does provide some level of protection," she says. "It can provide a layer of assurance to investigators who may be reluctant to perform specific tests because of the risks to the patient. And we should use any tools at our disposal."