The Expanding Role of Natural History Studies in Drug Development

Natural history studies follow a group of people over time who have or are at risk of developing a specific disease. This type of study is an important tool in modern drug development and in assessing new health technologies by payers. This is especially true for rare diseases or diseases with high, unmet medical need where thousands of diseases still lack safe and effective treatments, and the populations available for clinical study could be small and heterogeneous.

The term “natural history of disease” theoretically restricts the population to one that has not been exposed to any intervention and where the disease has taken its natural course. However, this patient population rarely exists as some interventions, licensed or otherwise, would have been introduced for the patients at some stage of the disease. Hence, in practice, natural history studies often track patients who have failed earlier treatments and have no further recourse (high, unmet need patients).

Additionally, the regulators and payers are seeking opportunities to maximize the use of real-world evidence in drug development opening a channel for natural history studies. A natural history study can be submitted as a baseline that demonstrates the disease course for untreated patients along with data that charts the disease course of patients given the proposed therapy to show how the natural progression is changed or perhaps halted by the therapy.

FDA’s newly published guidance on the topic

Per the FDA, “Despite a recent wave of medical progress, most rare diseases still have no approved therapies. This presents a significant unmet public health need. One of the challenges we know innovators encounter developing therapies for rare diseases is the lack of natural history data to guide the design of successful clinical trials. Such data comes from observational studies that track how rare diseases develop and progress over time. Sometimes rigorous natural history models can help inform development programs, and even serve as comparator arms for studies where it may be impractical to randomize patients to placebo.”

On March 22, 2019, the FDA released its draft guidance, Rare Diseases, Natural History Studies for Drug Development. Specifically, this covered the strengths and weaknesses of various types of natural history study designs, common data elements and research plans, and a practical framework for the conduct of a natural history study. It provided considerations for aligning the study design with study objectives and for enhancing the interpretability of study results, patient confidentiality and data protection issues in natural history studies, and potential interactions with the FDA related to these studies.

Per the guidance, there are four key factors to identify when integrating natural history summaries in drug development:

  • Patient population – Variation in genotype and/or phenotype can affect the characterization, progression, and physiological changes of the disease in sub-groups which is valuable for understanding and developing clinical or other patient studies;
  • Clinical outcome assessments – Used during trials to assess both safety and efficacy, these assessments include clinic-reported, observer-reported, patient-reported, and performance outcomes. Natural history summaries can be used to evaluate the ability of a new or existing clinical outcome assessment to detect change or progression in a disease along with performance and reproducibility in the clinical investigation;
  • Development of biomarkers – A natural history study can be used to develop a biomarker strategy that can be diagnostic of the disease, prognostic of the disease course, predictive of treatment response, or useful in guiding patient selection and dose selection;
  • Use of natural history study data – Specific guidance on the use of externally-controlled studies. The guidance is detailed on this topic also highlighting the pros and cons of various controls contained in ICH guidance E10. The FDA has previously allowed many drugs to be assessed based on a single arm clinical trial but has also, in absence of a concurrent comparator, encouraged sponsors to design external control arms from patient registries or natural history cohorts. A recent example of this would be Brineura® (cerliponase alfa) for late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease where the sponsor submitted a retrospective comparator no-treatment arm designed from the DEM-CHILD registry.

Contents of a natural history study

A natural history study is a pre-planned observational study intended to track the course of the disease over time by identifying demographic, genetic, environmental, and other variables that correlate with the disease and outcomes in the absence of treatment. Natural history studies are likely to include patients receiving the current standard of care and/or emergent care, which may alter some manifestations of the disease. Natural history studies can be designed to collect data from case histories or ongoing clinical visits in a cross-sectional or longitudinal manner depending on the desired purpose.

The above guidance identifies two key types of studies:

  1. Retrospective and prospective (longitudinal) natural history studies – combining information from patient medical records, scientific literature reviews, and other existing sources of disease-specific information, retrospective studies can help fill critical knowledge gaps and set a course for future analysis. While more robust, prospective studies can greatly inform the development process, but require a longer time investment.

In longitudinal retrospective or prospective studies, data are collected over time, making them more suitable for use as an external control group.

  1. Cross-sectional studies – Cross-sectional studies collect patient data at a specific time point offering a snapshot of disease at particular time and are relatively cheap and quick to conduct. However, a ‘cause and effect’ relationship cannot be determined using cross-sectional design.

A mixed design, or hybrid approach combines elements from more than one study design type (e.g. cross-sectional and longitudinal).

Certara’s expertise in rare diseases and natural history studies

The more we know about how a rare disease progresses, the easier it is to evaluate the effects of investigational treatments and to measure whether a particular treatment changes disease progression or affects patients’ longevity or quality of life. Much of the information needed to understand disease progression can be derived from ‘natural history’ studies.

By supporting optimized drug development, leveraging our unique toolkit of modeling and simulation approaches, achieving global regulatory success, and advising on how to maximize a drug’s value and access, Certara has supported more than 100 rare drug programs over the past few years. Developing natural history summaries, performing cross-sectional and longitudinal studies, and advising on clinical trial protocols and selection of patient cohorts is part of our offering.

Rational, modern, and scientifically-based drug development requires understanding the disease pathophysiology. This understanding can be strengthened by natural history summaries.