Date: 01/05/2022

Collaborating With The FDA For Rare Disease Clinical Trial Success: Our Experiences

Clinical Leader

By Zachary Rome, chief operating officer, Timber Pharmaceuticals

Team workGettyImages-955768228

If you are familiar with rare diseases, you know there are unique challenges associated with conducting clinical trials to evaluate potential new treatments for small patient populations. These populations are typically study naïve, meaning there has not been a large amount of research to help understand the baseline characteristics of their disease or its progression. Patients and their families often spend years bouncing from one specialist to the next seeking a proper diagnosis and might be skeptical of the healthcare system as a result. They often must travel great distances to find anyone willing and able to help. These challenges can make designing and enrolling clinical trials for rare diseases very difficult.

When we set out to design our Phase 2b CONTROL study evaluating an investigational topical treatment for a rare dermatologic condition called congenital ichthyosis (CI), we knew we would need a plan to tackle these challenges. CI is a group of rare, genetic keratinization disorders that lead to dry, thickened, and scaling skin. People living with CI may have limited range of motion, chronic itching, an inability to sweat, and a high risk of secondary infections.

Importantly, there has never been a drug approved by the FDA for the treatment of CI, meaning we had no precedent for which study endpoints to evaluate. We also needed a plan for dosing – CI patients can have up to 90 percent of their body surface area affected by the condition, so there is a high degree of variability in how much drug each patient needs based on how much of their skin needs to be treated. And as in any topical dermatology study, we needed to account for the potential of relatively high vehicle response rates. In dermatology, there is no such thing as a true placebo, as anything you put on the skin may have some effect and simply moisturizing the skin can improve certain conditions to a certain degree.

Creative Solutions Require Out-Of-The-Box Thinking

Thinking about how to overcome these challenges was a learning process that unfolded over several years. In 2018, the FDA awarded us a $1.5 million grant to support our Phase 2a and Phase 2b clinical trials through its Orphan Products Clinical Trials Grant program. This opened the door to more consistent quarterly communication with the agency. After consulting with a variety of experts including key opinion leaders, ex-FDA consultants, and the leading patient advocacy organization in CI, as well as statisticians and regulatory and clinical design experts, we created our own Investigator's Global Assessment (IGA) scale to assess a wide variety of signs and symptoms associated with CI that was useful in measuring results of the Phase 2a study.

We began thinking about the Phase 2b study design as soon as we completed our Phase 2a study, and, in 2019, we had a Type C meeting with the FDA to begin formal discussions. The meeting focused on the proposed patient population, entry criteria, and efficacy outcome measures. Our orphan drug designation covered the broad category of CI, but the FDA suggested we further define our indication for continued clinical development. There is significant genetic and phenotypic heterogeneity within CI, and we began to focus on the moderate to severe cases, known as X-linked recessive and lamellar ichthyosis. While these subtypes originate from different genetic mutations, they result in a similar phenotype of thickened, scaling skin. It was also helpful to have clear guidance from the FDA on managing a trial during the COVID-19 pandemic. The agency’s guidance for industry helped us amend the trial protocol to allow for remote, virtual visits with clear rationale.

From there, we turned our attention to our strategy for engaging contract research organizations (CRO). This took some out-of-the-box thinking. Our goal was to take advantage of favorable research and development programs offered in different regions around the world and specifically in Australia. While this offered many advantages and incentives, it also made operations more complicated. The time difference alone meant we could not work with our research partners in real time on our own. So, we elected to move forward with two CROs – one based in the U.S. and the other in Australia. We developed algorithms for how to assess patient drug needs and implemented just-in-time shipping, which allowed each patient to receive the specific amount of drug they needed no matter their location.

In the end, we had a well-designed Phase 2b study that was randomized, double-blind, and vehicle controlled. It assessed the efficacy and safety of two concentrations of our drug, in two distinct subtypes of CI. Our primary endpoint was determined by a reduction in the validated Visual Index for Ichthyosis Severity (VIIS) scaling score, which garnered a lot of attention in the CI community. The FDA encouraged us to correlate the VIIS score with our original IGA scale, which was used for our secondary endpoints. Both scales were considered clinically relevant and provided the information we needed to support future development. We are now planning for an end-of-Phase 2 meeting with the FDA and expect to begin a Phase 3 study next year.

For any clinical trial evaluating a new treatment for a rare disease, it is important to open lines of communication with the FDA to assess potential endpoints and understand the appropriate measurement tools. This clarity up front ensures that a study’s design will ultimately meet the scientific goals of a clinical program. Flexibility and the ability to create customized solutions are also key. It takes some courage to implement and adapt solutions that have not been tried before and environmental challenges often require creative thinking. You must have top-notch leadership in trial management who can quickly overcome new and unprecedented hurdles such as a global pandemic.


A clinical trial should not be designed as a single study in isolation of a broader development program. If there are key questions that need to be addressed to support a potential new drug application, it is important to find ways to incorporate as many of those components as early as possible in a development program to help regulators address potential questions. Finally, keeping all stakeholders in mind is essential. The more unique perspectives on how to approach a study, especially regarding complex and multifaceted rare diseases, the better. It is essential to understand the target patient population and embrace their journey. A sponsor’s ability to do so will greatly impact participation in rare disease clinical trials.

About The Author:

Zachary Rome is the cofounder and chief operating officer of Timber Pharmaceuticals. He is also a partner at TardiMed Sciences, a life sciences company creation firm. At TardiMed, he has helped to form several life sciences companies that span multiple therapeutic areas and stages of development. Previously, he was the cofounder and president at Patagonia Pharmaceuticals, a privately owned specialty pharmaceutical company developing treatments for rare dermatologic diseases. He was the lead inventor on all of Patagonia’s technologies and oversaw their development from concept through Phase 2 studies. He has a BS in marine science and biology from the University of Miami and an MST in adolescent science biology from Pace University.

Share This Page: