Rare disease drug development varies from the pathways seen in more established indications. The sample sizes are often extremely small, and establishing a good base of clinical data can be difficult. Natural history studies help bridge the gap.
Per the FDA, the natural history of a disease can be defined as “the natural course of a disease from the time immediately prior to its inception, progressing through its presymptomatic phase and different clinical stages to the point where it has ended, and the patient is either cured, chronically disabled or dead without external intervention.” A natural history study effectively allows medical professionals to collect information about an indication.
What is a Natural History Study Protocol?
Natural history study protocols are designed to help researchers and clinicians understand a disease or condition better through observation in the natural environment. Natural History Studies can monitor how the disease progresses without intervention and follow the development of the condition through its resolution, be it some sort of remission or an individual’s death.
“The intent is to identify pathways for the treatment trials utilizing innovative treatments with unique mechanisms of action that may be applicable to other indications that share a similar pathology,” explains Jovana Vlajković-Josić, MD, Associate Medical Director at Pharm-Olam. “These studies can also calculate the prevalence of the disease, identify disease-specific centers of excellence, establish good practices in disease management worldwide, and, overall, find ways to improve patient care.”
Also called observational studies, natural history study protocols are designed to identify different demographics, genetic characteristics, and environmental factors then plot those variables against the condition itself to spot meaningful correlations. Natural history study designs can look at the disease in an untreated state or following the standard of care if there is one, as well as any treatments or medications that may be used to manage symptoms.
Applying a Natural History Study in Rare Disease
In rare diseases, natural history information is rarely available, but it plays several essential roles in clinical drug development. The Institute of Medicine calls the inclusion of natural history studies a “pillar of epidemiologic research on rare conditions.” Some conditions are so rare that they may not have been observed in a clinical setting often enough to draw reasonable conclusions about what the progression of the disease looks like or how it impacts the body.
“Treatment of rare indications has been slow to progress, primarily due to such low patient numbers complicated by a poor understanding of how the diseases progress,” continues Vlajković-Josić. "NH studies can provide historical data that can be used in a variety of ways to improve and fortify rare disease research."
Examination of Patient Profiles in Natural History Studies
Rare diseases often present with high amounts of heterogeneity because the population sizes are so small. When only a relative handful of people are impacted, finding true trends amongst those individuals is challenging. Natural history studies provide a way to collect that information and draw meaningful conclusions. In some cases, observing patients can help identify patient subgroups and rates of progression that could serve as the basis for inclusion or exclusion criteria in a future study.
Development of Clinical Outcomes in Rare Disease Research
Additionally, natural history studies can help identify physiologic changes or characteristics of the afflicted individuals that assist the medical community in understanding the progression of the disease. They record how these individuals function and survive their indications. This can include clinician-reported outcomes as well as observer reports, patient reports, and performance over time (e.g., vision, ability to walk).
Identification of Rare Disease Biomarkers
Natural histories also benefit rare disease drug development because they provide an opportunity for researchers to take a range of physiological measurements that could allow those professionals to identify biomarkers for the indication. Blood tests, as well as tissue samples, analyses of bodily fluids, measurements, genetic data, and so on, could provide a diagnostic for the indication in addition to acting as a prognostic for the condition.
Augmenting Placebo Arms for Efficient Study Design
Finally, natural history studies can serve or augment placebo arms in a study.
Jovana Vlajković-Josić explains, “If it can be proven that the NH study data can be comparable with data from an investigational drug trial, the placebo-controlled group can be reduced or eliminated, enabling more patients to receive the drug while lowering safety risks associated with a treatment trial as well as the overall costs.”
When there is a strong natural history study in place, rare disease researchers may be able to test their entire research group with an investigational product. They can then compare those results with that of the natural history study to expand the population size and ultimately draw more robust conclusions.
Collecting Data from Natural History Studies of Rare Disease
There is never a wrong time to start a natural history study, particularly where ultra-rare conditions are concerned.
“It should ideally start in parallel with the preclinical development of the drug, and it should be as similar as possible to the planned drug-intervention clinical trial in terms of planned study-related assessments,” said Vlajković-Josić. “In that way, besides collecting important historical and prospective data, you can also design and test endpoints and assessments that you plan to use in a future clinical trial.”
Natural history studies are both retrospective and prospective. They may collect data from living patients as well as those who are deceased, and information from future patients can be consolidated with previous observations. This expanded timeframe means that the NH study is continually being updated and fortified with new data. Many established clinical research organizations (CROs) maintain natural history databases that can be used to improve future research on an indication.
Work with an Expert Natural History Study CRO
Pharm-Olam has completed over a 125 rare disease studies and successfully supported numerous natural history studies in rare and ultra-rare diseases. With over 7,000 rare diseases in the world today, sponsors who are creating a new rare disease clinical development program must include the essential building block of a natural history study. Pharm-Olam is dedicated to helping create a healthier world, and our team is ready to support your natural history study today.