The US Food and Drug Administration (FDA) recently issued a draft guidance describing the potential use of natural history studies across all phases of rare disease drug development.
The FDA defines a natural history study as a preplanned observational study intended to track the course of the disease. The goal of these studies is to identify demographic, genetic, environmental, and other variables, such as treatment modalities and concomitant medications, that correlate with disease development, the guidance explains.
“Rare diseases often have many unknowns associated with the progression, measurements of progression, and cause of the disease,” said Premier Research, vice president of patient and stakeholder engagement (PASE), Juliet Moritz.
“As companies are interested in developing treatments for rare diseases it is important to understand the disease progression, factors influencing progression, how progression is measured, current treatment modalities, and ultimately how to define efficacy measures for the development of future treatments,” Moritz told us.
The guidance addresses several topics important to rare disease clinical research, including the potential use of natural history data as external control group data.
Moritz said, “I think the discussion about natural history studies being an appropriate setting for the validation of disease-specific scales and functional assessments is quite significant, given the focus on therapeutic value as it relates to the approval and reimbursement of therapies for rare diseases.”
The guidance recommends using natural history studies to gain a better understanding of genotypic and phenotypic variations potentially influencing disease identification and progression factors, said Melanie Bruno, PhD, MBA, vice president, global project management and project coordination, CTI Clinical Trial and Consulting Services.
It also suggests using the studies to gain information about which types of clinical outcome assessment could be viable for disease evaluation, which biomarkers may be useful for treatment and progression evaluation, as well as what type of control groups might be available from retrospective studies, Bruno explained, noting that there are several benefits of natural history studies.
“These studies can contribute to a much better understanding of the course of the disease in the various stages, the influence of genetic and phenotype variability, and how the disease is currently being assessed or treated by physicians,” Bruno told us.
“With the aforementioned information, a company can design measures that may ultimately be included in clinical studies that can be supportive of new treatments for a particular rare disease.”
Additionally, Bruno said natural history studies may help identify potential patients for future studies.
Per the guidance: “The information about subtype signs and symptoms and rates and patterns of progression are useful in deciding the inclusion criteria, the stage of disease to treat, the duration of a trial, the frequency of data collection, and the specific endpoints.”
As for the challenges, Bruno said they are influenced by study design and include patient identification – a challenge for most clinical trials – as rare disease patients are often scattered across the globe.
She explained, “After determining the potential location of patients, the next challenge is working through the regulatory approvals to gain access to information at sites or physician practices particularly for retrospective trials.
“For prospective trials, identification of patients based on inclusion/exclusion criteria can be challenging and potentially the retention of patients for a longer study duration where travel is involved to centers for rare disease likely needs to be addressed.”
The benefits of natural history studies extend beyond drug development, per the guidance: “A natural history study may benefit patients with rare diseases by establishing communication pathways, identifying disease-specific centers of excellence, facilitating the understanding and evaluation of the current standard of care practices, and identifying ways to improve patient care.”
As part of the guidance, the FDA also is recommending consulting with patients and advocacy groups, which Moritz said is good news.
The agency is later this month holding a public meeting to obtain patients’ and caregivers’ perspectives on the effects of rare diseases on daily life.
Moritz said, “The goal is to ensure that the selected clinical outcome assessments are fit for regulatory use and constitute valid assessments of the relevant aspects of the disease.
“Anytime the FDA speaks to including patients and their caregivers in the design and execution of clinical research, that helps reinforce the message that clinical research should be happening with patients and their care networks — and not just to them — and that they are equal partners in the clinical development process.”
The FDA is accepting comments on the draft guidance until May 24, 2019.