Regulatory Considerations for Developing Rare Disease Treatments

ART PODCAST | SEASON 3 | EPISODE 7

In this episode of Advancing Revolutionary Therapies, Mara Holinger, Senior Vice President of Regulatory Affairs at Veristat, talks to Robin Bliss, Vice President Strategic Consulting and John Kirk, Principal Regulatory Strategist, both also with Veristat to discuss key considerations for developing rare disease treatments.

In Season 3, Episode 1 of the ART podcast series, we discussed some of the challenges of developing products to treat rare diseases and orphan drug designations. In this episode, we dive deeper into those challenges, particularly for diseases that might be considered “ultra-rare”. Check out the full episode to learn more or read the summary below.

What Qualifies as a Rare Disease?

Robin Bliss: The FDA defines a rare disease as any condition affecting less than 200,000 people in the US and the EMA defines it as less than 5 cases in 10,000 people. However, neither Agency specifically defines an ultra-rare disease.  I have worked on programs where the case count was far lower than 200,000. Sometimes, the actual case count is unknown.  One that comes to mind has an estimated prevalence of somewhere between 1 in 1 million to 1 in 200,000 which translates to between 7,000 and 40,000 cases.

John Kirk:  One in ten Americans are affected by a rare disease. Overall, approximately 7,000 distinct rare diseases have been identified, 50% of rare diseases affect children, and most rare diseases affect fewer than 1 in 100,000 people. I am currently working on a program where the population is very small (200-250 known cases worldwide).

In other programs in the lysosomal storage space in particular, the prevalence I have seen is approximately 2,000-3,000 known cases. In March 2019, FDA issued a guidance on slowly progressive diseases, which says that lysosomal storage diseases are known to have prevalence rates of approximately a few thousand or fewer known cases in the U.S. Using this as a benchmark, an “ultra-rare disease” may be defined as one with prevalence that is under 5,000 cases in the U.S. It’s clear there is a massive unmet need, though it is a challenging process to develop a new product to treat any one particular rare disease

Accelerate Therapies for Rare and Ultra-Rare Disease Through Development to Approval

Robin Bliss: While a single disease may be rare, there are many people that are affected by rare disease, either as a patient or as a friend or family member of a patient. Thinking of 1 in 10 Americans having a rare disease emphasizes the importance of developing new therapies and taking a thoughtful, strategic approach early in the development process to ensure that not only are you, the researcher, on the right track scientifically, but that the pre-clinical and clinical studies are well-designed; that regulatory authorities are in agreement with your approach; and that there is an opportunity to positively impact patients by improving their quality of life, reducing the impact of disease on their everyday life, or even extending their life.

Challenges of Developing Rare Disease Products

Mara: What are some of the challenges associated with developing products intended to treat rare diseases?

John: There are thousands of unique rare diseases. Within a single disease, the individual patient experience can vary greatly from one person to another. Even if you know what the underlying genetic abnormality is, the expressed phenotype can be quite diverse. Therefore, it’s very important to engage with patients early on to gain an understanding of what symptoms are most troubling to patients.   

Robin: From a study planning perspective, understanding phenotypes of disease can be very informative to identify sub-populations that might be more likely to respond to a new therapy. To understand phenotypes of disease, sponsors need to determine the following:

• How do phenotypes of disease differ?
• Can those differences impact possible treatment or the reflection of the treatment effect? 
• Once these are established as being “different”, can the phenotypes be identified early, before disease progression? 
• Is there a genotype or set of genetic markers that might indicate one phenotype versus another?

Considerations for Planning Studies for Rare Diseases in the U.S. and Globally

Mara: If you can identify different subtypes of disease and are planning your early phase study, how will you know whether your new product is working? How do you decide what to measure?

Robin Bliss: A single endpoint may not reflect the same type of meaningful impact across all phenotypes of disease. This goes back to really understanding the phenotypes and their similarities and differences. When defining endpoints, we have to remember that our goal is to treat the disease, not the symptoms. We need to be able to define what are the characteristics of disease we can modify. We can then consider the following:

• What elements of disease in terms of patient function can be measured consistently and reliably?
• Which of these factors can be impacted or influenced by the novel therapy?

When these overlap, we have a potential endpoint. Remember that the progression or speed of disease progression might be unknown, it might be quite variable, or it might take a long time to progress. This needs to be considered when defining endpoints along with how and how often we can measure them. To emphasize, endpoints need to be measurable, quantifiable, and timely.

John Kirk: When considering that a particular rare disease progresses slowly from a clinical perspective, biomarkers of disease can be highly valuable for characterizing baseline severity, target engagement and confirmation of the mechanism of action. An ideal biomarker will respond to treatment in a shorter time interval compared to changes in a symptomatic clinical outcome. For regulatory utility as an approvable endpoint, biomarkers (or surrogate markers) must be shown as predictive of clinical benefit.  A good understanding of the underlying pathophysiology of the disease, the relevant clinical symptoms of the disease and the rate of disease progression are key to the development of a new treatment.

Mara: What are some expectations from the health authorities regarding programs that are developing therapies for the treatment of rare diseases? 

John: An important aspect to keep in mind is that the regulatory agencies generally take a flexible position when it comes to which nonclinical safety studies are required to assess the safety of a particular new product. Each rare disease must be supported by relevant studies, not simply "all" of the studies included in the guidelines. Most notable it is impossible to develop a safety database that meets the requirements in ICH E1 (i.e., 300 - 600 patients treated for 6 months and a minimum of 100 treated for one year). 

The nonclinical safety program should be a point of agreement with FDA as early in development as possible. It’s worth noting that FDA is not typically as flexible on GMP requirements. Also, recent experience in talking to FDA about development programs for rare diseases, the agency generally expresses a strong preference for placebo-controlled studies. However, for certain rare diseases it might be impossible or unethical to use a placebo-controlled design and substantial data may already exist from a registry or a natural history source. Agreement on study design should be a point of early discussion with FDA.

Robin Bliss: I would take a step back and raise the concept of Real World Evidence, which can be defined as evidence regarding disease progression and the potential benefits or risks of a therapy that is derived or supported by real world data. Natural history studies are one version of real-world evidence.  We have a few episodes in Season 2 of the ART podcast series that discuss some concepts surrounding natural history studies, and while these were developed in the context of cell and gene therapies, much of the information can be directly translated to other rare disease research areas.

Mara: We have discussed FDA and some of the specific considerations to have when planning studies for rare disease under U.S. regulations, but how might we consider planning studies for rare disease in the rest of the world?

John: It is important to keep in mind that the Agencies in the U.S. and across the globe take a serious public health attitude toward developing treatments for rare diseases. Given that it is a small population, you plan for the development program to extend not only within the U.S. but also across Europe, Asia, and the rest of the world according to where patients reside. You will probably need a global footprint to execute clinical trials that are powered based on the agreed endpoints. 

While you can start within the United States based on conversations with the FDA, you should also plan for similar conversations with the regulatory authorities in the global areas where you will be executing the studies and eventually applying for approval.  The importance of this is to find as much convergence on the single global development plan as possible.  While not all aspects may be viewed the same or of similar importance across different regions and authorities, gaining their respective experience and opinions will help to develop a robust development plan.

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