Natural history studies ‘essential’ for rare disease drug development
For rare disease drug development, Jovana Vlajković-Josić, MD, CCRA, PMP, associate medical director, Pharm-Olam, called natural history (NH) studies “essential.”
To this point, the US Food and Drug Administration (FDA) published a draft guidance addressing the potential uses of NH studies in the development of drugs for rare diseases.
These studies help researchers gain a better understanding of a disease’s progression, how it is managed by clinicians, and what unmet needs exist. This is especially important for rare and orphan disease where there are limited patients and treatment options.
“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,” Vlajković-Josić told us.
Read more: CROs comment on FDA's new draft guidance for conducting natural history studies
Additionally, patients with known risk factors or biomarkers can be followed to help better understand the timing and potential of disease occurrence. Environmental factors, which could complicate disease progression, also can be identified during an NH study, helping researchers identify targets for drugs that could prevent the disease.
“Researchers can also determine the ideal time to treat a patient,” added Vlajković-Josić, noting that NH studies may be used to create a “more efficient drug development pathway” by characterizing the outcomes of the standard of care.
Registry study vs. natural history study
“Registry study” and “natural history study,” while sometimes used interchangeably, have differences.
Mainly, a registry study is typically non-interventional, collecting data for purposes such as patient identification, establishing standard of care, for health economics analysis, or post-marketing commitment.
“A registry study is not always done for a rare disease indication; sometimes people with a certain predisposition for a condition, or preexposure to a certain pathogen are involved,” explained Vlajković-Josić.
“For that reason, registry studies may or may not need comparison groups, and, if there is a comparison group, it may be internal, external, or historical.”
Data from registry studies can augment NH studies and possibly eliminate the need for the collection of some data points or patient population identification, she added.
Still, NH studies, while essential for rare disease research, do more than support drug development, said Vlajković-Josić.
“Especially for rare disease research, it is amazing what a well-designed and promoted NH study can do to raise disease awareness,” she said. “These studies can also calculate 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.”
Said Vlajković-Josić, “Unfortunately, the 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.”
Clinical trial design: Augmenting placebo arms
The main challenge to conducting an NH study is the design, which Vlajković-Josić explained must serve as a solid foundation for the drug-interventional clinical trial. Ideally, an NH study could even replace the placebo arm of a clinical trial, so all patients are able to receive the drug.
As Vlajković-Josić explained, diseases in some cases have progressed to a point where severe debilitation or death is expected within a couple of years, in which case it is not ethical to put patients in a placebo-controlled trial “if there is a clear unmet medical need and no relevant control treatment.”
For these reasons, NH trial design must be “broad in a way to collect data from patients with the same disease, but also to serve as a testing ground for assessments, biomarkers, and endpoint measurements in future drug-intervention studies.”
Nevertheless, proceeding to an open-label treatment is not guaranteed and must be planned and discussed with regulators. While the US Food and Drug Administration (FDA) recognizes historical control data, acceptance depends on actual historical data collection, Vlajković-Josić explained. “Biases need to be prevented, and the control group should be similar to the treatment group,” she said.
“Some assessments should be performed in patients who are similar to the patients planned in the control trial, so, for example, similar patient-reported outcomes can be collected,” she added.
“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.”
Data collection: Looking to the past and the future
A natural history study is most useful if it is both retrospective and prospective, collecting past data from living or deceased patients, as well as data in the future.
“Since rare/orphan populations are so small, the acquisition of historical data from deceased patients is extremely valuable to the characterization of the disease but difficult to obtain,” said Vlajković-Josić.
However, the case in which a deceased patient was misdiagnosed, the data is usually lost, she said.
While collating deidentified data from electronic medical records (EMRs) is a possibility, due to the rarity of the disease, Vlajković-Josić said finding correctly coded data in an EMR is a challenge in and of itself.
“As our use of EMRs continues to improve and EMR vendors’ ability to aggregate data evolves, I expect the use of this data to contribute to hybrid NH studies greatly,” she said. “Unfortunately, right now we are not quite there.”
Ultimately, Vlajković-Josić stressed that it is never too early – especially in ultra-rare diseases – to start an NH study.
“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,” she said. “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.”
