How are the Rare Disease Evidence Principles Reshaping Evidentiary Expectations?

The rare disease space has always been uniquely difficult for drug development, but recent regulatory developments are shaking things up. There have been signs of both positive and negative movement in this space. Laksheet Johari, an analyst for Lifescience Dynamics, spoke with Pharmaceutical Executive about these updates and how the industry is reacting.

Pharmaceutical Executive: How are the Rare Disease Evidence Principles (RDEP) reshaping evidentiary expectations?
Laksheeta Johari: This is a very exciting time in the rare disease space. We're seeing a lot of movement from regulators, including the RDEP. There is a lot more guidance coming from FDA that recognizes that rare disease is a unique space for sponsors to design clinical trials while addressing the unmet need for patients that often don't have any other alternative therapies available.

The guidance principles we are seeing from FDA recognizes this need and is allowing sponsors to be a little more flexible when it comes to the design, outcome measures, and what potentially could allow accelerated approval and development of these assets as well. In theory, there's a lot of excitement around these new guidelines from FDA. It's going to be interesting to see how this really translates into real world practice, when sponsors actually are able to design clinical trials, how the FDA is open to that trial design, to the data that comes out from these trials as well, and then how that's received in terms of approval for these assets as well.

PE: What impact is innovative CGT trial design having on sponsors?
Johari: It is very exciting that we are seeing the sponsors allowed a little more flexibility in the way they design their clinical trials across a lot of different indications, such as oncology, vaccines, immunology. We see a lot of larger clinical trials, very often either placebo-controlled or head-to-head against standard of care.

However, in rare diseases, we're working with very limited patient populations. It does often bring into question whether it's ethical to give a patient with such a rare disease a placebo. Allowing the sponsors that flexibility to use natural history data as the control arm in the trials is something that we have seen used to get accelerated approval (and then they are required to run a larger phase three trial to confirm those results as well).

That's one area of flexibility that we have seen previously, but we’re also seeing novel endpoints across clinical trials. We are also seeing biomarkers accepted as relevant endpoints that can then determine the efficacy of the asset at a later stage. FDA has also come up with the plausible mechanism pathway.

PE: How do recent actions from FDA provide insight to the agency's enforcement posture?
Johari: Things are changing almost every day within that space. In theory, there are good guidelines and guardrails that FDA has put into place to allow innovative development in the CTD and rare diseases.

One thing that is not missed across regulators and sponsors alike is that safety is paramount. We're often dealing with either very young patients or patients that have no other options. So, making sure that we're delivering a safe treatment is going to be the number one priority, as well as making sure it is efficacious and delivers on the benefit that the sponsors are promising.

On one hand, the guidelines are pushing towards that and promising additional hope for the sponsors. With the CRS that we're seeing come through, I think it's raising doubts as to how FDA is actually taking these guidelines and applying them into practice.

There have been comments made about the clinical trial design or the control arm used which might not always resonate with the guidelines that have been shared previously. That's where a lot of uncertainty is coming into play for the sponsors.

There is likely the need for more alignment across the regulators to ensure that the regular touch point meetings are conveying the message and the sponsors are able to act on it accordingly.

PE: How have recent regulatory actions impacted the rare disease space?
Johari: When we look at the rare disease space in general, we are seeing that rare disease is often explored by smaller companies that are working on maybe one or two assets in a very niche indication. They are really focused on those assets that they are developing for this large unmet need population.

However, we have seen recent changes in the past hinting that Big Pharma is also showing signs of interest with rare diseases. This might come through acquisitions of the smaller biotechs, but they're really looking for that proof-of-concept and making sure that in theory, the cell or gene therapy is delivering on the promise that they're showing.