Scientific Director’s Corner: What is a Natural History Study?
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When I say ‘Natural History Study’ what are your first thoughts? ‘I’ve heard the phrase but I’m not sure what it means’, ‘I think I’ve already taken part in a natural history study’, or ‘History, I hated history in school’. For this blog post I’m going to discuss what a natural history study is, and isn’t, and why these types of studies are important, especially for rare diseases like STXBP1.
A natural history study is simply a medical study that looks at how a disease changes over time in a patient population. The goal of a natural history study is to gain a better understanding of the disease process and the disease burden on the patient to help develop better treatments.
The name ‘natural history’ refers to how a disease progresses over time without any treatment or intervention. I want to note that most natural history studies allow participants to continue using their prescribed medications, such as anti-seizure medications.
A natural history study is not a medical study where a new drug or other type of therapy is tested. So if you are asked to enroll your child in a natural history study they would not receive any drugs, other than those they currently may take.
Natural history studies are especially important for rare diseases like STXBP1 because patients tend to have varied symptoms and the patient population is small, so performing a natural history study may be the only way for researchers and physicians to obtain a good understanding of the disease.
Natural History Study vs Patient Registry
You may think you have taken part in a natural history study because you have signed up for a patient registry. Though natural history studies and patient registries have some things in common, they tend to have distinct roles, especially in terms of clinical drug development.
A patient registry is an organized system for collecting, storing, and disseminating information about people who have a disease. While registries may collect medical information about people, they tend to be broad in scope and are important resources for pharmaceutical companies to recruit patients.
A natural history study, on the other hand, has a very specific goal, to track the progress of a disease over time. Some patient registries also function as natural history studies, depending on the type and depth of information that they collect on the patient.
What type of information does a natural history study collect?
A natural history identifies demographic, genetic, environmental, and other factors that are associated with a disease’s development, progression, and eventual outcome. It does this by collecting a range of information on patients including, symptoms, test results, physical signs, imaging, age, genetics, quality of life, etc, over a specific period of time.
How are natural history studies conducted?
Natural history studies can be conducted using pre-existing data for a patient, for example, by reviewing their medical records; this type of study is called a retrospective natural history study.
Another type of natural history study is called a prospective study. In this type of study new data is collected from patients over a period of time. It is not uncommon for some natural history studies to collect both past medical data and future medical data, i.e. collecting both retrospective and prospective data.
The period of time covered by a natural history study can vary and usually depends on the disease being studied. A study may start before the disease begins and continue until the disease stabilizes or becomes chronic.
For most diseases, including STXBP1, it is very difficult to follow a single individual during their entire lifetime. Because of this, cohorts of patients, grouped by age, symptom, or disease progression, can be followed during a shorter period of time, say a couple of years, and all the collected data put together to paint a more complete picture of the totality of the disease. You can think of this as putting together a panoramic picture from several smaller snapshots. Alternatively, you can take data generated from several separate natural history studies that may have been conducted on certain subsets of patients (again, based on age or symptom for example) to put together the larger panoramic picture. In the case of pharmaceutical companies, it is not uncommon for them to restrict a natural history study to the subset of patients they initially intend to treat in a future clinical trial. This would usually be a period when a potential drug could have its greatest impact, for example during the earliest stage of the disease.
Figure 1 outlines a basic natural history study.
Figure 1. Conceptual framework for a natural history study. Adapted from Palmer et al, Neurotherapeutics,18:1432.
How are natural history studies used?
Even though natural history studies do not test any new drugs or therapies, they are very important in helping scientists and physicians design future medical studies that will test new drugs or therapies. They do this providing 4 important types of information.
First, they can help identify patient populations that can be used to test a new drug. For example, patients that have specific disease symptoms might be better candidates for a particular drug than patients who do not have the specific symptom. If you were going to test that drug you would want to include only the subset of patients with that symptom. Natural history studies are often used to help determine which patients should be included in a drug trial.
Second, natural history studies are important in identifying what are called ‘clinical outcomes measures.’ Clinical outcome measures are used in a drug trial to determine if a drug is effective. These are basically the ‘tests’ or ‘observations’ that are made concerning the patient. For STXBP1, these might include improvements in communication, movement, or behavior as reported by the physician, caregiver, or by formal testing.
The third important type of information that can be obtained from natural history studies is the identification of what are known as ‘biomarkers’. A biomarker is something that can be measured in a patient and used to help monitor the progression of a disease or a response to a drug or therapy. Common biomarkers that you might be familiar with are blood pressure and cholesterol. High blood pressure or high levels of cholesterol in the blood are associated with heart disease. Someone may take drugs to reduce their chance of developing heart disease and the effectiveness of these drugs can be monitored by keeping track of the person’s blood pressure and cholesterol. For STXBP1 an important biomarker may be EEGs.
Fourth, the data collected in a natural history study can be used as the ‘control’ data in a drug trial. In clinical drug trials patients are usually divided into two groups, one group gets the drug, and the other group gets a placebo; this group is known as the control group. By comparing what happens to the group that gets the drug compared to the control group, you can determine if the drug is having an effect.
In certain instances, it may be unethical to give a placebo to a group of patients. For example, in rare diseases, like STXBP1, where the number of patients is small and there are no current effective treatments, including a placebo group in a drug trial is considered a wasteful as the placebo group would be denied a potentially life-altering therapy. Similarly, for certain types of gene therapy a placebo group cannot be used because immune responses to the placebo would prohibit the patient from eventually getting the drug. In these cases, the data obtained in a natural history study can be used as the ’control group’.
I hope this blog post helped you better understand what natural history studies are, what they entail, and why they important. Moreso, I hope it has encouraged you to participate in a natural history study if you have not already done so. We are on the cusp of developing several therapeutic drugs for STXBP1 and natural history data is going to be extremely important when evaluating these potential drugs in the future
James Goss
