It is unlikely IRBs will see many studies with one enrolled participant (the N=1 study design), but they should be prepared for this type of protocol.

The single-subject study design can be applied to chronic conditions like cystic fibrosis or to ultra-rare diseases.

“Like many emerging techniques, this will find a niche, but it will be fairly small,” says Jonathan Kimmelman, PhD, professor and interim director of the biomedical ethics unit at McGill University in Montreal.

These types of trials are expensive. They involve niche conditions that typically are treated by rare diseases specialists, Kimmelman adds.

In one type of N=1 trial, the study participant starts as his or her own control in a randomized trial. The participant is randomized to either the treatment or control for a set number of weeks. Then, there is a period in which the treatment/control is washed out before the participant crosses over to the opposite arm, and this is repeated.

“N=1 designs have been used in clinical practice for a long time, and it’s a great way to do care for individual patients and for certain kinds of clinical decisions,” Kimmelman says. “When you do a N=1 study, you assume the drug will rapidly leave the system and its affects won’t carry over to the next block.”

Another N=1 study approach involves a protocol in which a patient is monitored before and after receiving a bespoke therapy, like a personalized antisense oligonucleotide (ASO).

“It’s just like a regular clinical trial with no crossover and only one patient,” Kimmelman says. “Patients get the treatment, you look at how they respond, and you make inferences about how other patients with similar, but not identical, genetic diseases might respond to a similar treatment.”

This type could apply to drugs that are used in common mutations to determine whether they will work in uncommon mutations, he says.

One ethical concern in reviewing this type of study is the participant will experience much longer exposure to research, more cycles of placebo, longer periods on an unproven drug, and more frequent clinic visits. All of these add to the participant’s burden.

“What goes on with N=1 studies is the number of patients experiencing this burden is going down, but those patients are experiencing much more burden,” Kimmelman adds. “You’re spreading risk differently with these N=1 studies.”

IRBs should ask these questions of the N=1 study:

  • How much extra burden is on this vs. the standard of care?
  • Has the consent process been explained adequately?

One recent example of a study using the N=1 design is a trial in which investigators developed a personalized ASO for a 6-year-old girl with neuronal ceroid lipofuscinosis 7, a form of Batten disease. Researchers discussed how the N=1 study of the treatment for a particular girl could be a possible template for the rapid development of patient-customized treatments.1

Thirty million Americans are affected by rare diseases. More than 7,000 distinct conditions exist, which creates research and drug development challenges.1

Another ethical challenge is how these studies are funded. “These are often patient-funded clinical trials,” Kimmelman says. “I and others have written about the issues of patient-funded clinical trials.”

For instance, these trials are expensive, and patients sometimes raise money through crowdfunding campaigns. “It misaligns the incentives for research with goals of high-quality science, they are not fully peer-reviewed, and are not having a proper evaluation of merit,” Kimmelman says. “They are highly susceptible to fraud and misinformation.”

These trials also might be unfair and inequitable. “It’s unfair in that people with a lot of social capital and with cuter children and broader networks are more successful in raising that support,” he says. “It has many features of fundraising that are setting one up for misalignment of merit and access.”

Skilled researchers are a scarce resource and valuable commodity. There is an ethical question of whether this type of research is the best use of experts, he adds.

The trials might not be registered through ClinicalTrials.gov, although any research study should be registered.

“Because people have this mental picture that this [research] is purely desperate, treating children with rare illnesses, it frustrates the ability for people to think through the ways this is research and what you need to do differently in delivering these treatments because it is research,” Kimmelman says.

REFERENCE

  1. Kim J, Hu C, Moufawad El Achkar C, et al. Patient-customized oligonucleotide therapy for a rare genetic disease. N Engl J Med 2019;381:1644-1652.