On January 16th, FDA issued a revised draft guidance outlining a number of common issues and challenges that many Sponsors face during the process of developing an orphan product. Though the regulatory requirements and approval process is the same for both common and rare diseases, there is often limited medical and scientific knowledge, natural history data, and drug development experience available for rare diseases, making these issues more difficult to address.
The original draft guidance was published in August 2015 and addressed a number of important aspects, stating that Sponsors were more likely to have a productive meeting with the FDA if they were addressed efficiently and adequately. The revised document includes:
In a recent statement, Scott Gottlieb, M.D., FDA Commissioner, stated that many of the updates were made directly in response to the feedback the FDA received on the initial draft. For example, Gottlieb notes that the Agency “updated the section describing the use of information about natural history as clinical comparators and added more information on the use of historical controls and early randomization.”
All drug development programs benefit from a firm scientific foundation, which includes an awareness of the disease’s natural history. In rare diseases, this history is often poorly understood, and “the need for prospectively designed, protocol-driven natural history studies initiated in the earliest drug development planning stages cannot be overemphasized.” Although FDA does not require natural history studies, a comprehensive understanding of the disease can help Sponsors define the disease population, which is even more important when seeking approval of a product indicated for the treatment of a rare disease.
“Natural history study designs can be characterized as (1) retrospective or prospective and (2) cross-sectional or longitudinal.”
The Agency suggests making data from these studies publicly available to help promote rare disease drug development.
Information pertaining to a disease’s pathophysiology and clinical manifestations is frequently incomplete for rare diseases. This knowledge can help contribute “to the successful development of a treatment, for example, by:
Nonclinical studies demonstrate that the drug is “reasonably safe to conduct the proposed clinical investigations,” and are a required by the FDA. Data obtained at this stage is important to the design of early phase clinical trials and can help identify the drug’s possible efficacy, mechanism of action, pharmacokinetics, and metabolism. The data can guide the selection process of patent eligibility criteria, and “will often determine important safety monitoring procedures based on the observed toxicologic profile.”
As long as guarantees for a drug’s safety and effectiveness are not compromised, FDA regulations state that the Agency may exercise flexibility when applying statutory standards for drugs indicated for the treatment of rare diseases. “This flexibility includes determining the nonclinical data necessary to support clinical development programs. Factors that FDA evaluates when determining areas of nonclinical flexibility include the pharmacological and chemical characteristics of the drug, the design and objectives of the proposed clinical investigations, the anticipated risks to humans, and the existing accumulated nonclinical toxicology and human data. When determining the relevance of existing data, a sponsor may consider factors such as drug product constituents, dosage form, route of administration, dose levels, and dosing regimen plan.”
Well characterized efficacy endpoints are not available for many rare diseases; however, they are crucial for a clinical trial. For Sponsors to define a trial endpoint, FDA recommends selecting “a patient assessment to be used as an outcome measure and define when in the trial the patient would be assessed.”
Endpoint selection for a clinical trial involves understanding the following:
Due to the limited number of patients, it is crucial for orphan Sponsors to standardize data collection and handling of data to ensure quality and interpretability. An adequate and well controlled investigation will provide substantial evidence that the drug will have its claimed effect. A safety evaluation during drug development can characterize the drug’s safety profile in a reasonable number of patients over a reasonable duration of time.
Drug manufacturing should undergo development simultaneously with clinical development. In an attempt to decrease the potential for delays in a drug’s development or approval, Sponsors are encouraged to discuss pharmaceutical quality development plans in early-phase and throughout the drug development process.
FDA recommends that Sponsors carefully assess any planned changes to the drug substance at any phase of development to determine if the changes could affect the safety or effectiveness of the product. Manufacturing changes should be made as early as possible to ensure there is time to evaluate potential effects on the drug’s safety and effectiveness.
Feedback from FDA may result in more effective drug development; therefore, Sponsors are encouraged to meet with the relevant drug review division throughout the development process. FDA will also provide advice on “specific matters relating to an IND, including advice on the adequacy of data to support an investigational plan, the design of a clinical trial, and whether proposed investigations are likely to produce the data and information needed to meet requirements for a marketing application”.
The FDA announced plans to hold a public meeting to obtain the perspective of patients’ and caregivers on the impact rare diseases has on their day to day life. The Agency hopes that their experiences may develop a future understanding which will help guide the development for treatments for rare diseases potentially through the creation of novel endpoints or trial designs that focus on commonalities across a variety of rare diseases.
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