CRO Perspectives on Changes in Rare Disease Studies

The CRO industry continues to find ways to diversify and expand on the expertise it brings to clinical trials. More CROs are specializing in the rare disease space, especially now with new technologies and regulations surrounding gene therapies. In this interview, Lisa Dilworth, as VP, Rare and Orphan Diseases at Synteract, will discuss common challenges with rare disease studies, how to encounter them, and how the rare disease space is evolving.

Moe Alsumidaie: What are the leading challenges with rare and orphan disease studies?

Lisa Dilworth: There are unique challenges to rare disease studies, with the primary challenges having a large impact on enrollment. The problem is how to enroll a study when patients are not diagnosed correctly. It is also challenging finding a homogenous population and obtaining clean data within rare diseases, which have a high level of phenotypic heterogeneity. Another issue in rare diseases is that they are usually genetic in nature. A parent with a disease may have multiple children with that disease, but not all children may be eligible, which makes it emotionally tough to decide whether some children will have access to a trial. Carrier guilt is also an issue in rare diseases because there can be a denial to accept the genetic state of a parent’s child, which can become another barrier to enrollment and accessing care. We also struggle to validate endpoints in under-researched diseases where we do not understand the natural history of the disease. Coming up with a clinically meaningful endpoint means something different to a regulator, versus a clinician, versus a patient. We have to ensure that the trial is a valuable experience for the patient.

MA: How do you overcome the recruitment challenge? 

LD: That is part of the evolution of the rare disease space. There is a big push for companion diagnostics. Patients often do not know they have the disease, and we are not testing for these diseases routinely, so how do we find the patients? Pharmaceutical companies and biotechs, often through partnering with CROs and advocates in the patient community, are learning that an essential part of their drug development program is to co-develop a companion diagnostic with their potential treatment to help diagnose the patients and bring them in. In addition to helping diagnose new patients, you need a strategy to connect with previously diagnosed patients and their families. There are over seven thousand rare diseases; therefore, you must thoroughly understand the specific patient community. There needs to be a tailor-made strategy unique to each disease that fits the needs of the patient population. For example, if you are looking at a neurodegenerative disease of the elderly population, they are not on social media. Therefore, a Facebook or Twitter campaign is not going to be helpful in connecting with the patients, whereas a social media campaign can be very valuable in other diseases.

MA: How are clinical trials for rare and orphan diseases evolving? 

LD: Some of the most exciting advancements include precision medicine. There is excellent promise for rare genetic diseases where there is much work with CRISPR Cas9 and gene therapy. Regulations are evolving in this space with the new draft guidance, and I think we are going to see more evolution in that space for rare diseases. Equally exciting are adaptive design capabilities in our rare disease studies, as companies are more willing to invest necessary resources in adaptive study designs. We can have either an umbrella design, a platform trial, or a basket trial to allow more patients to be enrolled, and there is less likelihood of being exposed to placebo.

MA: What is the status of rare and orphan disease drug development?

LD: Rare disease studies have been under-researched and under-utilized for a long time overall. But for those of us who came into the industry with the desire to provide a service and give hope to patients with unmet medical needs, the rare disease area is the most exciting place to be. 

At Synteract, we have conducted over 135 trials in the last five years. In 2018, we made a decision to point to this experience due to market need and customer demand, and thus, our Center of Development was established based on this foundational experience.

I think we are at the forefront of innovation and technology within the rare disease space because we are continually being challenged and are looking at using new endpoints, novel data collection techniques, and rejecting outdated paradigms. Patients are still facing barriers to enrollment, so it is an exciting space to challenge yourself and to continue to get ahead of the curve and overcome those challenges in order to bring trials to patients. It is also rewarding because you get to work closely with patient communities. We have been incorporating patient-centric models by meeting with patients and advocates and making sure our trials work into their lives, rather than forcing the patient to build their life around a clinical trial. We also recognize that rare disease trials are competitive, as these patients have options, and on a day-to-day basis, the patients and caregivers understand the disease better than anyone. To not tap into patient and caregiver expertise would be a lost opportunity, and it is exciting to be a part of a dedicated group where we can engage patients, and put them at the center of our processes. 

MA: What do you see as a successful patient centric process?

LD: It starts with understanding that for our clinical trial subjects, enrolling in a clinical trial is often times a life-changing decision. But in the rare disease area, because we do not understand the natural history of the disease, companies want to throw all kinds of endpoints into a trial. That makes for a long day for patients and their families, and at the completion of the study visit we have worn the patient out, and how reliable can that data be? Not to mention that the socioeconomic impact of alienating these patients for extensive amounts of time while requesting they complete psycho-modulated assessments. At Synteract, we are transparent and closely scrutinize protocols with the patient in mind. We are willing to give feedback, even if it is not easy to hear. We try to come up with solutions, such as, leveraging artificial intelligence capabilities, creating technology apps to increase engagement, or using devices for event-based sampling when passive assessments aren’t suitable. It is also vital for a patient to buy in on a protocol and give their honest feedback before it is finalized. If it does need to be that long of a day on site, we often will break up the visit into blocks and educate sites on the highest priority items. It helps to standardize our data because mandating the sequence of events limits the variability introduced through fatigable assessments at the site level. 

Moe Alsumidaie, MBA, MSF is Chief Data Scientist at Annex Clinical, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.