Guest Column | January 26, 2024

FDA Draft Guidance On "Rare Diseases: Considerations For The Development Of Drugs And Biological Products"

By Raj Bandaru, Ph.D., Associate Director, Accenture Applied Life Science Solutions


The U.S. Food and Drug Administration (FDA) issued a draft guidance to industry in December 2023 that addresses “Rare Diseases: Considerations for the Development of Drugs and Biological Products.” Unlike previously issued industry guidance, this draft provides comprehensive regulatory considerations for the successful clinical development of small molecule- and biologics-based drug products for rare diseases. As per the National Organization for Rare Disorders (NORD), Genetic and Rare Diseases (GARD) Information Center, and Orphanet, the portal for rare diseases and orphan drugs in Europe, there are more than seven thousand rare diseases, and over 90% of them do not have an approved therapy or intervention. Though the science of rare diseases has evolved and advances in genetic testing have helped to reduce the time to diagnosis, more than thirty million Americans still live with rare diseases. There remains an unmet need for patients with rare diseases, as only 5% of rare diseases have an FDA-approved treatment.

FDA defines rare disease as a condition that affects less than 200,000 persons in the U.S., and many rare diseases commonly affect children. The statutory requirements for marketing authorization approval of drugs to treat rare and common diseases are the same, making it more difficult to develop drugs or biologics rapidly for rare diseases. In addition, limited medical and scientific knowledge, poorly understood natural history study data, sample size constraints, and lack of drug development experience impose an additional burden on the development of drugs or biologics for rare diseases. Though this draft guidance does not address all the general clinical developmental issues of rare diseases, it provides a comprehensive list of regulatory considerations as listed below for natural history, non-clinical, quality, and clinical development studies for rare diseases.

Considerations For Natural History Studies

Why do many orphan drugs often fail during clinical development? The answer to this question often points to the fact that natural history studies of rare diseases are either not clearly understood, or that available natural history study data and genetic testing are not adequate to ensure a successful rare disease drug development program. Although all drug development programs benefit from well-characterized natural history studies, it is especially important for rare disease studies, due to their prevalence in a limited number of patients and the often-heterogeneous nature of the rare disease (such as affecting multiple organs). Therefore, knowledge of a rare disease’s natural history study is important for planning any drug development program.

The natural history study of disease is traditionally defined as the course the disease takes in the absence of intervention in individuals with the disease, from the disease’s onset until either the disease’s resolution or the individual’s death. A natural history study is a preplanned or a prospectively conducted observational study intended to track the course of the disease. Its purpose is to identify demographic, genetic, environmental, and other variables (e.g., treatment modalities, concomitant medications) that correlate with the disease’s development and outcomes. Natural history studies are likely to include patients receiving the current standard of care and/or emergent care, which may alter some of the manifestations of the disease. Disease registries are a frequent platform to acquire data for natural history studies. Although the FDA does not mandate a natural history study for market authorization approval, the natural history of rare diseases is often poorly understood, and the need for prospectively designed, protocol-driven natural history studies initiated in the earliest stage of drug development planning cannot be overemphasized.

Therefore, information obtained from a rare disease natural history study can play a significant role in a majority of regulatory considerations listed in this draft guidance at every stage of orphan drug development, from drug discovery to the design of non-clinical, quality, and clinical studies intended to support marketing authorization approval of a drug and beyond into the post-marketing period.

Additional information including study planning, when to start a natural history study, information on retrospective as well as prospective natural history studies, finding a study site, and data collection including data storage and data dissemination can be found in the draft guidance for industry “Rare Diseases: Natural History Studies for Drug Development (March 2019).”

Considerations For Non-Clinical Studies

As stated above, the lack of natural history studies and natural history study data of rare diseases often imposes serious limitations on developing well-characterized and robust non-clinical study plan to support investigational applications to the FDA. The goal of the non-clinical study program consists of in vitro and/or in vivo safety studies to provide evidence that the drug is “reasonably safe to conduct the proposed clinical investigations in humans.” In addition, non-clinical studies can also contribute to a better understanding of the drug’s mechanism of action, metabolism, pharmacokinetics, pharmacodynamics, toxicology, and efficacy in animal studies. The data generated from non-clinical studies is important to the design of early-phase clinical investigations, particularly for selecting the starting clinical dose, dose escalation plan, dosing regimen, and route of administration. Non-clinical data may help to guide the selection of patient eligibility criteria and determine important safety monitoring procedures based on the observed toxicological profile of the drug in animals. However, there are no pharmacologically validated animal models readily available for rare diseases due to poor understanding of the diseases, and lack of pharmaco-genomic and established biomarkers of rare diseases. This guidance provides a full list of statutory non-clinical studies required to support investigational and marketing authorization applications.

In addition to statutory required non-clinical studies, this guidance also provides additional information related to the flexibility offered by the FDA for severely debilitating or life-threatening (SDLT) rare diseases. Investigational drugs for SDLT rare diseases often do not require extensive or full and single or repeat-dose GLP toxicology studies at the time of first-in-human IND application submission. Initial IND applications for SDLT rare diseases are often submitted with modifications to repeat-dose toxicology studies. FDA also offers the flexibility of full toxicology information of SDLT rare disease drugs submitted prior to initiation of the pivotal or confirmatory efficacy studies in humans. Similarly, safety information related to reproductive toxicology studies, juvenile toxicity studies in animals to support pediatric studies in children, and carcinogenicity study data are submitted at the time of market authorization application submission only.

Consideration For Clinical Studies

This guidance provides extensive information related to clinical pharmacology, dose selection, identification, and use of biomarkers for rare diseases. FDA expects that routine clinical pharmacology assessments typically undertaken during drug development should be performed in rare disease drug development programs. The need for specific clinical pharmacology assessments may depend on factors such as what is known about the drug’s disposition, drug interaction potential with any concomitant medications, comorbidities, the anticipated safety profile of the drug, and the potential impacts of organ impairment on a drug’s pharmacokinetics. In rare disease drug development, given the limited number of patients, it is crucial to optimize all aspects of clinical investigation design and standardize the collection and management of data to ensure quality and interpretability. In general, increased measurement variability and inconsistency reduce data interpretability and confidence in the results. Therefore, standardized operating procedures, quality assurance, and quality control are essential.

This guidance also provides detailed aspects of clinical design including adaptive design, control selection, randomization schemes, endpoint selection, and clinical outcome assessments in rare diseases. Furthermore, it is important to consider the context-dependence of a clinical endpoint or clinical outcome assessment, and endpoints that might be appropriate for a few patients with a rare disease may not be appropriate for all patients with that rare disease, for patients with other rare diseases, or patients with common diseases.

Additional considerations for evidence-based clinical decisions about what is feasible in terms of rare disease drug clinical investigation enrollment depend on accurately estimated disease prevalence. Many rare diseases are genetic in origin and characterized by more than one phenotypic subtype (e.g., infantile, juvenile, adult). Many rare diseases severely affect children, for some diseases that affect both children and adults, sponsors should explore early inclusion of pediatric participants in clinical studies and discuss their plans for pediatric enrollment with the FDA during early stages of drug development, including pre-IND meetings.

According to estimates, about half of people affected by rare diseases are children. Therefore, conducting studies to evaluate drugs in pediatric patients is critical for determining the safety and efficacy of medications for many rare diseases. When preparing developmental plans, the sponsor should consider whether the rare disease affects children and adults or only children. The degree of overlap between the pathophysiology and similarity of clinical outcomes is an important consideration in pediatric development when a disease is seen across the lifespan. In general, sponsors should include pediatric patients with rare diseases in premarketing clinical studies to develop data on the full range of patients with the disease. FDA strongly encourages sponsors to study the drug in all relevant pediatric populations, from birth to younger than 17 years old, so that the drug can be properly and completely labeled for pediatric use.

FDA encourages the involvement of patients, their caregivers, and advocates in rare disease drug development. Patient input can provide important information about their experiences, perspectives, needs, and priorities that can be incorporated throughout the drug development process. This engagement can take many forms, such as providing solicited consultation on scientific issues (e.g., clinically meaningful treatment effects), working with industry sponsors as they design and conduct clinical investigations, and contributing to patient-focused drug development initiatives.

Quality Considerations

Many of the quality or CMC considerations for the drug substance and drug products of rare diseases are the same as established quality and CMC principles as described in IND, NDA, and BLA quality guidance documents. FDA may exercise some flexibility on the type and extent of manufacturing information that is expected at the time of submission and approval for certain components (e.g., stability data updates, process validation strategies, inspection planning, manufacturing scale-up, etc.,). The FDA can explore the level of flexibility on a case-by-case basis after considering factors such as (1) drug product characteristics, (2) the seriousness of the condition and medical need, (3) manufacturing processes, (4) the robustness of the pharmaceutical quality system, and (5) the strength of the sponsor’s risk-based quality assessment.

Considerations For Expedited And Accelerated Development Of Orphan Drugs

The FDA offers sponsors developing orphan drugs several accelerated pathways including Fast Track Designation (FTD), Breakthrough Designation (BTD), Orphan Drug Designation (ODD), Rare Pediatric Designation (RPD), and Pediatric Rare Voucher (PRV) programs, qualifying sponsors for incentives including tax credits for qualified clinical trials, exemption from user fees, or Orphan Drug Exclusivity which will allow seven years of market exclusivity after approval. In addition to traditional communications such as Type A, Type B, and Type C meetings with the FDA, the FDA recently extended CDER’s Critical Path Innovation Meetings (CPIM), Initial Targeted Engagement for Regulatory Advice on CBER/CDER Products (INTERACT), Accelerating Rare Disease Cures (ARC) and Rare Disease Endpoint Advancement (RDEA) etc.

In summary, the draft guidance of “Rare Diseases: Considerations for the Development of Drugs and Biological Products,” is very well written and provides useful information on regulatory considerations for non-clinical, quality, clinical studies, expedited and accelerated approaches for orphan drug development. Due to the complexity of orphan drug development for rare diseases, many sponsors will also need additional information from the agency on how to repurpose existing drugs and biologics through label extensions and information related to the combination of two or more investigational agents to treat rare diseases. Though the FDA has successfully implemented label extensions and a combination of two or more investigational drugs to treat cancers, such information is still lacking, which can help sponsors to speed up drug development for rare diseases.

About the Author

Raj Bandaru is a Senior Regulatory Affairs consultant on Quality and CMC in the Global Regulatory Affairs team at Accenture. Raj has an experience in the biopharmaceutical/ cell and gene therapy space, with a particular focus on manufacturing, CMC changes to CGT products and Healthy Authority strategy and communications for product development, and global regulatory submissions. Prior to joining Accenture, Raj worked for Enzon Pharmaceuticals, Inc., Girindus America, Valeant Pharmaceuticals International at Costa Mesa, CA, and Viventia Bio Inc., in Canada. Raj is currently serving in the advisory role in Regulatory Affairs for several CGT and biopharma companies at Accenture.