Background and Definitions:
The natural history of a disease is the natural course of a disease from the time immediately prior to its inception, progressing through its pre-symptomatic phase and different clinical stages to the point where the disease has ended without external intervention.
Natural History Studies track the course of disease over time, identifying demographic, genetic, environmental, and other variables that correlate with its development and outcomes in the absence of treatment. Thorough understanding of disease natural history is the foundation upon which a clinical development program for drugs, biologics, medical foods or medical devices is built.
Rare Diseases, as defined in the US Orphan Drug Act (ODA), are diseases or conditions with a prevalence of fewer than 200,000 persons in the US. Though individually rare, together there are ~30 million Americans affected by 7,000 known rare diseases.
Unlike common diseases, there is little existing knowledge on the natural history of most rare diseases, which makes natural history studies of particular importance for rare diseases product development. In January 2014, the FDA organized a Public Workshop on Complex Issues in Developing Drugs for Rare Diseases. During the workshop, the lack of natural history studies was reconfirmed by all stakeholders (patients, industry, researchers and the FDA) as one of the most common and urgent issues that hinder treatment development for rare diseases. The need for natural history studies was also emphasized in the recently published (August 17, 2015) draft FDA Guidance for Industry, Rare Diseases: Common Issues in Drug Development.
Types of Natural History Studies:
Retrospective Study: data have already been generated prior to study initiation. Retrospective studies are most commonly reviews of medical records, such as patient charts.
Prospective Study: data are generated after study initiation. Prospective studies allow implementation of a predefined and consistent data collection, up-to-date medical terminology and standard of care and the flexibility to collect additional data as the study evolves.
Survey Study: collects and analyzes natural history data through questionnaires answered by patients, primary caregivers, and/or others. Survey studies typically do not involve clinical visits and provide a quick overview of the disease population.
The goal of FDA's Orphan Products Natural History Grants Program is to support studies that advance rare disease medical product development through characterization of the natural history of rare diseases/conditions, identification of genotypic and phenotypic subpopulations, and development and/or validation of clinical outcome measures, biomarkers and/or companion diagnostics.
Applicants must include in the application's Background and Significance section:
- documentation to support the estimated prevalence of the orphan disease or condition (or in the case of a vaccine or diagnostic, information to support the estimates of how many people will be administered the diagnostic or vaccine annually)
- an explanation of how the proposed study will either help support product approval or provide essential data needed for product development
- the landscape of the disease including what the current treatment options and standard of care options are for this rare disease, what is being done in terms of product development currently for this rare disease, what competing natural history studies are ongoing, and how this study will progress the existing knowledge
The protocol and the informed consent form should be submitted in the application and included as an appendix.
Additional information may be required upon request.
For additional requirements and criteria the application will be scored on, please see the detailed RFA.
OOPD intends to commit approximately $2 million and award 2-5 grants in Fiscal Year 2017 (October 1, 2016-September 30, 2017).
- Prospective Natural History Studies:
Maximum of $400,000 in total cost per year for up to five years
- Retrospective Natural History Studies or Survey Studies:
Maximum of $150,000 in total cost per year for up to two years
The program project officer will oversee grantees' activities periodically. The oversight may be in the form of telephone conversations, e-mails, or written correspondence between the project officer/grants management officer or specialist and the principal investigator. Information including, but not limited to, information regarding study progress, enrollment, problems, changes in protocol, and study oversight activities will be requested. OOPD may conduct periodic site visits to grantees to ensure extramural funded studies, which involve human subjects, are consistent with grant agreement terms and human subjects’ protection requirements.
When multiple years are involved, awardees will be required to submit the Non-Competing Grant Progress Report (PHS 2590) annually with financial statements. The grantee organization must comply with all special terms and conditions of the grant, including those which state that future funding of the study will depend on recommendations from the OOPD project officer. The scope of the recommendations will consider the following: (1) progress toward enrollment, based on specific circumstances of the study; and (2) compliance with applicable FDA and HHS regulatory requirements for the natural history study.
The grantee must file a final program progress report, financial status report, and invention statement within 90 days after the end date of the project period as noted on the notice of grant award.