Want to learn about scientific topics without needing a PhD? Check out the Science Simplified blog from TESS Research Foundation! Dr. Tanya Brown, PhD, works with researchers to make science accessible and empower rare disease community members with scientific knowledge. Dr. Brown has over a decade of experience in neurodevelopmental research and is currently the Scientific Director for TESS Research Foundation. Please reach out to her at [email protected] if you have questions or comments.

Thank you to Tanya Brown, PhD, Research Program Manager, for writing this article about natural history studies This article was edited by Emily Hsu, Operations Manager, and Kim Nye, Executive Director at TESS Research Foundation.

What is a Natural History Study?

Rare diseases have small patient populations and a big need for new therapeutics. SLC13A5 Epilepsy fits in this category as a rare disease with a significant need for treatment options. One way TESS Research Foundation is striving to find treatment options is by sponsoring a Natural History Study (NHS). An organized and well-executed Natural History Study prepares groups for clinical trials by characterizing the course of a disease from start to finish. It helps clinicians, scientists, the FDA, and patients understand the course of a specific disease.

Figure 1. Natural History Studies build the foundation for clinical trials. This figure was modified from FDA.gov.

A Natural History study is truly a team effort and requires massive collaboration. This article will walk through the purpose of an NHS, who participates, how a NHS can be useful to help drive clinical trials, and how this is relevant for SLC13A5 Epilepsy.

What is the purpose of a Natural History Study?

The goal of a Natural History Study is to learn about the course of a disease. This involves learning about how the disease develops, who is affected by the disease, and how the disease is treated.

Some of the basic questions a NHS may answer are:

• What does a disease look like over time?
• Does the disease change with age?
• Are there markers that predict whether a disease will improve or worsen?
• What are the specific biomarkers (indicators) of the disease?
• Who is the patient population?

How is the information from a Natural History Study used?

Well-executed Natural History Studies are useful for many different reasons. A NHS can:

• Open up new communication pathways between the patients, clinicians, and researchers
• Identify standard of care practices for patients and clinicians
• Identify excellent locations for patient care and research
• Helps drive clinical trials

One way a NHS can be used is for a comparison group in a clinical trial. This is particularly important for rare disease patient populations, which are often small groups of patients. For example, instead of having a placebo-controlled clinical trial study where some participants receive treatment and some receive a placebo, all patients could receive a treatment! Clinicians and scientists could compare the treatment group to the natural course of the disease, as described in the Natural History Study.

Figure 2. This is an example of how information from a NHS could be used as a comparison arm in a clinical trial.

For the information from a NHS to be used as a comparison group in a clinical study, the NHS must have:

• High patient participation and engagement
• Information collected in a standardized manner
• Thorough and comprehensive analysis of the information collected

This will provide a detailed understanding of the course of the disease and hopefully identify biomarkers (indicators) of the disease. If a biomarker is identified, it may indicate the presence or absence of a disease, or potentially the severity of a disease. A biomarker may also be used in clinical trials to measure whether or not a treatment is working (i.e. researchers and clinicians could measure whether the disease biomarker had changed or been affected, after the patient received the treatment).

For example, researchers are asking whether the level of citrate correlates with the severity of SLC13A5 Epilepsy symptoms. If citrate was an accurate biomarker for SLC13A5 Epilepsy, a citrate test could be used in a clinical trial to indicate whether a treatment was improving or worsening SLC13A5 Epilepsy symptoms.

What are the different types of NHS?

A retrospective study collects information from the past. This may include medical records, published scientific literature, information from disease experts, or other information collected from patients. This can be useful because past information can tell a lot about the medical journey without requiring additional tests or doctor visits.

A prospective study collects information moving forward. This could include patient information gathered from in-person and/or telehealth medical visits. Prospective studies generally take a longer time to collect information than retrospective studies do.

Who participates in a Natural History Study and what do they do?

A NHS is a big undertaking that requires everyone working together. Some of the types of participants and their involvement include:

• Patients and their families: These are the people volunteering their time to participate. This may involve doctor’s visits, lab tests, providing medical records, and/or filling out questionnaires.
• Research team: The research team is led by the principal investigator. The principal investigator designs and executes the research study. Other members of the research team include clinical staff, who identify what information needs to be collected and organize patient visits, and the scientific staff, who analyze and interpret the information collected. The results of the study will be shared with the broader scientific community through peer-reviewed publications, announcements, and conferences.
• Clinical team: These are the doctors, nurses, clinical coordinators, and administrators who all collect information from patients by conducting in-person visits, sending out surveys, or collecting medical records. Sometimes the clinical team and the research team overlap.
• Sponsor: The group who initiates, manages, and/or funds the study.
• Institutional Review Board (IRB): A specific review body established to protect the rights and welfare of people recruited to participate in scientific research.

SLC13A5 Epilepsy has an ongoing Natural History Study!

TESS Research Foundation is sponsoring a Natural History Study for SLC13A5 Epilepsy. The goal of this study is to establish a thorough understanding of SLC13A5 Epilepsy by collecting information in a standardized manner. The study is broken up into 3 parts.

Figure 3. The 3 parts of the SLC13A5 Epilepsy Natural History Study.

Medical Collections NHS: To collect medical records, we are partnering with Ciitizen. The Medical Collections NHS will analyze medical records to learn what SLC13A5 Epilepsy looks like, starting from birth. This will describe the symptoms of SLC13A5 Epilepsy and how SLC13A5 Epilepsy changes over time. This includes English-speaking patients from both the US and other countries.

Remote NHS: The remote study is using telehealth visits, video recordings, and questionnaires to collect information about SLC13A5 Epilepsy. This study includes SLC13A5 Epilepsy patients of all-ages, all over the world.

In-person NHS: This involves clinic visits over 2 years. This will help determine the clinical characterization of SLC13A5 Epilepsy and how it changes over time. This will also use lab tests to identify biomarkers that can be used in future clinical trials. This study involves patients of all ages in the United States.

Together, these studies will provide a comprehensive understanding of SLC13A5 Epilepsy and help us prepare for future clinical trials. If you have questions or want to learn more, please email Dr. Tanya Brown at [email protected].

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