Rare diseases, by their very nature, don’t fit the mold—so neither should the trials for therapies designed to treat them nor the regulatory process to approve them. This was the tone set during a recent panel discussion where Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, argued that non-randomized, single-arm trials could be the best option when testing certain gene therapies for rare diseases.

“There are many rare diseases affecting dozens to a few hundred individuals in the United States where the concept of trying to do a randomized trial is very challenging at best and impossible at worst,” Marks told BioSpace. When it comes to trialing gene therapies, it’s not possible to efficiently enroll sufficient numbers of patients, either because there aren’t enough patients or because those patients won’t agree to be randomized, he explained. “It’s a situation where you can’t get the job done.”

While single-arm trials may seem like an efficient path to approval of therapies for diseases with high unmet need, experts told BioSpace that this approach is not always appropriate. As they explained, there are several variables to consider when deciding whether having a control arm is important.


When Single-Arm Trials Can Work

There is no typical trial design for rare disease gene therapies, according to Suyash Prasad, a genetic medicine consultant and former chief medical officer in the biotech industry.

He told BioSpace that for a single-arm trial to be effective, certain parameters need to be met. These include significant clinical efficacy in a reasonable number of patients, a non-heterogeneous patient population with a consistent disease progression and a mechanistic or biological endpoint.

“If you have those three things in position, then . . . I think a single-arm study is fine,” he said, but added that the converse is also true. “If you have a subtle improvement, if you see only the improvement in one or two endpoints . . . if there’s a very heterogeneous disease population, then it becomes much harder to run a single-arm study.”

Marks concurred, saying that one of two conditions needs to be met for CBER to consider approval of a gene therapy based on a single-arm trial. “The treatment has to create a large enough effect that it is apparent to a non-statistician that something has happened significantly to those individuals, such that having a control group is not necessary,” he explained, or measurement tools must show that “a parameter has changed enough so that we feel comfortable that it is reasonably likely to predict that something good down the line is going to happen.”


Biomarkers in Question

Marks has long been a proponent of regulatory flexibility and has overseen drug approvals in this vein. In June 2023, the FDA granted Accelerated Approval to Sarepta Therapeutics’ Elevidys, the first gene therapy for Duchenne muscular dystrophy (DMD). This followed a narrow 8-6 advisory committee vote in favor of Elevidys and FDA briefing documents that questioned evidence of “a pharmacologic effect on a biomarker in the pathway of the disease.”

The FDA’s Accelerated Approval pathway allows for the approval of medicines for serious or life-threatening diseases based on surrogate endpoints that are reasonably likely to predict clinical benefit. Marks said this pathway provides a way to get around the need for randomization in gene therapy trials.

If a gene therapy is targeting a disease where a protein is deficient, and it’s possible to test for increases in protein production, that can act as a biomarker, he explained. Patients essentially act as their own controls, Marks said, as investigators look for the affected protein to reach levels thought to allow “normal or near normal function.”

There is some question, however, both inside and outside of regulatory circles, about the scientific rigor of certain biomarkers.

Holly Fernandez Lynch, assistant professor of medical ethics at the University of Pennsylvania’s Perelman School of Medicine, pointed to dystrophin in DMD as an example. The FDA in 2016 greenlit Sarepta Therapeutics’ Exondys 51 under Accelerated Approval based on a dystrophin increase in skeletal muscle observed in some patients treated with the drug.

“Seven years after the first approval on the basis of that endpoint, we still don’t know whether that endpoint actually is supporting clinical benefit that is meaningful in patients’ lives,” Fernandez Lynch said.

She stressed that she supports Accelerated Approval but believes confirmatory trials should be underway before it is granted—something the FDA is taking strides toward. However, she said, “This question about what counts as an acceptable surrogate, I think still needs more refinement.”

Particularly in the case of subtle changes, Marks said biomarkers would ultimately need to be connected to a clinical endpoint in a post-approval study.

Using biomarkers in this way gets the ball rolling ahead of a confirmatory trial, he said. “Honestly, for parents of children with very serious diseases . . . it’s a way of intervening with something that is well scientifically justified and where the chances are it’s reasonably likely to predict that they will have clinical benefits,” he said.


Getting Gene Therapies to Patients

One approach for these types of studies is to run a trial with both clinical and biomarker endpoints. Menlo Park, Calif.-based Grace Science recently received FDA clearance for an open label, single-arm Phase I/II/III trial for GS-100, an AAV9 gene replacement therapy for NGLY1 deficiency, a rare metabolic disease.

This trial’s co-primary endpoints are change in motor subdomain on the Bayley Scales of Infant and Toddler Development and change from baseline in a disease-specific pharmacodynamic biomarker of enzymatic activity, the molecule GNA. GNA accumulation is directly linked to the absence of functional NGLY1, according to a 2021 article published in The Journal of Biochemistry and co-written by Grace Science co-founder and CEO Matt Wilsey.

Wilsey told BioSpace in an email that this trial design was “absolutely essential given the severity of NGLY1 Deficiency as well as the rarity. We had to create a trial that used a small number of patients to select the highest safe dose.”

For Wilsey, the ideal trial design for an ultra-rare pediatric disease is “a study with no placebo control that leverages a disease-specific biomarker and allows a sponsor to dose as young as two years old as quickly as possible.”

Prasad shared that at his former employers, Taysha Gene Therapies and Audentes Therapeutics, he argued for just one single-arm trial for approval of therapies for ultra-rare diseases with an unmet need where a clinically significant improvement is expected. However, he said, “Most of the time, I have ended up in a compromise situation,” with randomization between immediate and delayed treatment arms.

Ultimately, Prasad continued, disease prevalence and availability of other treatments should factor into the trial design decision.

“When you’ve got a very rare disease where there’s only a hundred or a few hundred patients, and the patients are dying at the age of three, four or five years of age, for example. . . then there’s much more urgency.”

Marks echoed that sentiment. It’s important, he said, “not to be hamstrung in trying to move things forward. We’re here to try to alleviate suffering of kids with bad diseases. Will we get it right all the time? Probably not. But as long as we get it right 90 or 95% of the time, I think that’s plenty good.”

Check out our AAV CDMO service to expedite your gene therapy research
About PackGene

PackGene Biotech is a world-leading CRO and CDMO, excelling in AAV vectors, mRNA, plasmid DNA, and lentiviral vector solutions. Our comprehensive offerings span from vector design and construction to AAV, lentivirus, and mRNA services. With a sharp focus on early-stage drug discovery, preclinical development, and cell and gene therapy trials, we deliver cost-effective, dependable, and scalable production solutions. Leveraging our groundbreaking π-alpha 293 AAV high-yield platform, we amplify AAV production by up to 10-fold, yielding up to 1e+17vg per batch to meet diverse commercial and clinical project needs. Moreover, our tailored mRNA and LNP products and services cater to every stage of drug and vaccine development, from research to GMP production, providing a seamless, end-to-end solution.

Related News

Related Services

Plasmids GMP Services

Multiple scales & grade of solutions of various kind of plasmids suitable for multiple treatments in a fast and cost effective way.

AAV GMP Services

Ranging from small-scale AAV production, to large-scale AAV cGMP manufacturing for animal studies.
aav icon

Technology Platforms

PackGene’s proprietary π-Alpha™ 293 AAV High-yield Platform increases AAV production by 3 to 8 times that of traditional platforms.