Highlights from the third OTAT Town Hall: Considerations for rare diseases


Feb. 08, 2023

At a Town-Hall style event held by FDA’s Office of Tissues and Advanced Therapies (OTAT) today, several members of the agency’s gene therapy regulatory team offered their perspectives on both philosophical and practical topics of interest to the development of gene therapies for rare diseases, including the design of studies and how to ensure the safety of clinical trial participants. AgencyIQ has key highlights from the 90-minute session focused on rare disease populations.

Quick overview:

  • The session featured insights from three members of the Division of Clinical Evaluation and Pharmacology/Toxicology (DCEPT): Melanie Blank, clinical team lead of DCEPT’s General Medicine Branch 1; Elizabeth Hart, chief of the General Medicine Branch 1; and Lei Xu, chief of DCEPT’s General Medicine Branch 2.
  • Town Hall-style sessions are basically verbal guidance documents, filled with advice for sponsors that is typically general and intended to address common developmental deficiencies. As a result, we’ve tried to capture much of what was said in verbatim quotes to avoid misinterpreting any of what was said.
  • We’ve condensed down the 90-minute session into bite-sized insights focused on what we thought were the points that regulatory professionals would most want to know.

Q: What factors should be considered when determining the study population for a gene therapy early-phase trial?

Melanie Blank: “In terms of the factors that should be considered, the two main principles are benefit-risk analysis, and also the ability for a patient to provide their consent. […] An adult is able to provide consent, whereas the pediatric population at best can provide assent.”

“When the disease affects the adult population, we always like to go first in adults and ensure there’s some preliminary safety before going into the children and if there are children affected, it’s best to go first into ones who can assent. The older before the younger. Unless the disease only affects the youngest children and then we have to adjust our thinking on that.

“In terms of benefit risk, we want to enroll a patient population who is most likely to benefit because in the early phase study, we don’t understand what the risk is going to be of the gene therapy. So we really want to make sure that those who are first enrolled will have the greatest potential benefit. We also like to ensure that they’re otherwise healthy because of the concerns about toxicity to make sure if there is a toxicity that is likely that we will be able to endure that toxicity.”

Q: What are the conditions under which it may be appropriate to allow single arm, externally controlled trial(s) to provide the primary evidence of effectiveness for approval for a gene therapy?

Lei Xu: The use of an external control may be appropriate under certain circumstances, and the FDA recently published guidance on this topic. Because the FDA prefers trials to be classically controlled – through placebo controls or active controls, as well as randomization – the agency asks that external controls be limited to “rare and serious conditions for gene therapy trials.”

“For example, if the disease which is studied has well understood underlying pathogenesis, the disease course is well documented, highly predictable and can be objectively measured and verified, the study population and external controls are suitably comparable and the treatment is self-evident,” then external controls might be acceptable, said Xu.

But there was a notable warning from Xu: “In many situations, however, the likelihood of demonstrating the effectiveness of a drug with external control is low. That’s why we recommend sponsors choose a more suitable design regardless of the prevalence of the disease.”

Q: What are general guidelines on determining the length of clinical trials that are designed to provide evidence of effectiveness in gene therapy trials?

Elizabeth Hart: “No product development will be the same because we’re dealing a bunch of different products and conditions. But in general, when feasible, we recommend from an efficacy perspective that clinical trials are designed to demonstrate a clinically meaningful effect in how patients feel, function or survive.”

“The duration needed to demonstrate this change, compared to the controls, will differ depending upon the condition and the product. In general, products that have a more rapid onset and for diseases that are more rapidly progressive, a shorter time will be needed to demonstrate efficacy compared to a disease that is more heterogeneous, has slower progression, where there might be a long latency period between treatments and the development of the specific symptoms that the product is intended to treat.”

Hart also noted that FDA recognizes differences for conditions that may be severe or life-threatening, and accepts surrogate or intermediate endpoints, such as validated or potentially valid biomarkers, which can also serve to shorten the duration of a trial.

Q: Would it be appropriate to enroll healthy volunteers in a gene therapy early-phase study?

Lei Xu: “Our thinking is that the study of healthy adult volunteers may be reasonable for an early-phase trial for a product with short duration of effect profiles. But for most gene therapy products, that is not the case. What we have encountered is that the risk of most gene therapy products include the possibility of extended or permanent effects along with the risks of any invasive procedures necessary for the product administration. Therefore, for most gene therapy trials, the benefit and the risk profile is not acceptable for healthy volunteers to be enrolled in the early phase study.” However, Xu noted that one historical exception has been in HIV trials “because of the community’s strong desire to find a cure” against HIV.

Q: Under what circumstances might it be appropriate to enroll pediatric patients in early-phase gene therapy clinical trials prior to testing a product in adults?

Melanie Blank: “If there’s no appropriate adult population in which to test the product first for safety – basically established proof of concept – and the prospect of benefit is solely reliant upon animal date, children may need to be the first early stage study subjects. [However], we prefer this not to be the case because they’re a highly vulnerable population. But what we do there, again, is we look to see can we enroll the oldest Pediatric population first. Because they can provide assent which is better than enrolling a vulnerable patient population, who really doesn’t understand what they’re going to be enduring.” The concern is really about toxicities, and first patients are most vulnerable, Blank added.

Q: How can biomarker endpoints be best used in gene therapy clinical trials?

Melanie Blank: “This depends on how well the biomarker tracks the disease process; how confident we are that this will be a clinically meaningful improvement and how confident we are in the assay or imaging technique used to measure the biomarker. Scientific data are needed and understanding the natural history of the disease through a natural history study is the best way to explore the clinical utility of biomarkers.”

“That’s why at the beginning of a clinical development program, when you’re even thinking about studying gene therapy for a disease, it’s really important to start your natural history study so you can decide what would be some good biomarkers to follow to be able to track disease activity and the affect of your product on that disease activity. Some biomarkers, as Dr. Hart said, are validated and established and we use them all of the time for approvals.

Q: When testing new gene therapies in rare diseases, should only safety be tested at first, or should efficacy endpoints also be incorporated into Phase 1 studies?

Melanie Blank: “Sponsors should carefully design their early phase studies. Although Phase I studies are primarily geared toward evaluating dose exploration, efficacy should also be evaluated to help inform the design of later studies and enable the phase two and three studies. So furthermore, it’s important to follow all Phase I study subjects in long-term studies where clinical outcomes measuring not just safety should also be assessed. Clinical outcome measures can also provide confirming evidence of efficacy. That’s another reason, these are the first subjects that are treated often and so that they will be followed the longest and so their efficacy data is very informative for our final decision regarding approval.”

Q: Can you address what is needed for short-term safety monitoring in gene therapy trials?

Lei Xu: Because therapies are administered only once, sponsors need to quickly capture any safety signals through intensive safety monitoring and frequent follow-up. Patients should be closely evaluated clinically during the first several weeks. Sponsors also need good stopping rules in place.

Q: How do we justify the risk of prophylactic or chronic immunosuppression in a placebo population?

Melanie Blank: “Generally we don’t. When we think about a patient population that is the control group in a clinical trial, we want to try to preserve their safety as much as possible. Immunosuppressant therapy is sometimes required for the active arm to prevent autoimmune hepatitis but then we’re stuck in terms of having a blinded study. We can sometimes have a sham arm for the placebo where they’re given immunosuppressive therapies, but occasionally that may not be possible and then we have to have an open label study, which is still better than not having any internal control. But we do like to have a controlled study, as we’ve mentioned before and blinding is preferable but sometimes there are situations where that can’t be done. The answer is, basically I can’t think of a situation where we would give immunosuppressive therapy to a patient who is going to be receiving placebo.”

Q: Considerations for intra-subject control design when we are discussing single arm trials?

Lei Xu: Patients may be followed for a period of time before being enrolled into an interventional study and this pretreatment follow-up period will be considered or will be used as the control to compare the effect following the gene therapy treatment. In general, regarding when it is appropriate to use an external control, to me, I still consider this as a single-arm open label externally controlled study. Patients know that they didn’t receive the product.” Pre-treatment period may not be able to predict disease progression. “In many situations we still don’t think this kind of intrasubject control is appropriate.”

Melanie Blank: We use baseline controls, but it’s really not a control. Our regulations don’t list any way for a patient to be its own control. It’s really an external control. “I think that terminology should not be used.”

Q: What are the different strategies for optimizing dose finding in gene therapy clinical studies?

Elizabeth Hart: “I want to start by saying dose exploration is so important. We recommend it happen as early as possible. As far as dose selection, it should be based on preclinical data as well as clinical data from similar products.”

“The specific plans for dose escalation should consider the risks in activity associated with the change in dose within the clinical dose escalation studies. It’s important to identify the maximum tolerated dose within the therapeutic target range. Usually clinical outcomes are delayed, so toxicity and biomarkers can be helpful in dose selection and subsequent product development.”

Q: How to incorporate diversity in small studies?

Elizabeth Hart: “When you’re dealing with a smaller disease, you have a limited population. It really is about what you think the product is going to be designed to treat. If you think that the product is designed to benefit the entire disease population, as the product advances through the different stages of development, it would make sense to really work to enroll as much of the population as you can such that it makes sense and it’s feasible. If you are dealing with a population where it only makes sense to treat the early phases of the disease, well then, you know, you should focus on just that subset, or if you have a product that is targeted to a specific manifestation.”

Q: Is there an appropriate use of a sham administrative procedure?

Lei Xu: “I think the purpose of including a sham control as a concurring control is to try to maintain the blinding as much as [possible]. I have to acknowledge, it is unlikely to maintain a perfect blinding, [but] hopefully appropriate enough to allow more reliable data collection regarding those efficacy assessments.”

With respect to the sham control, Xu recommends it be “as minimally invasive as possible,” such as the sham group receiving sedation instead of anesthesia, or only receiving partial penetration of the skin. In addition, sponsors should “not ask the patients in the control arm to receive immunosuppressants. Again, although it may not be perfect blinding, but with some level of blinding – also with incorporation of the randomization – we think it will be helpful to generate more interpretable data to support the effectiveness and also as a comparison for the safety.

To contact the author of this synopsis, please email Alec Gaffney ( [email protected])

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