Breaking Down The FDA Draft Guidance, "Rare Diseases: Considerations For The Development Of Drugs And Biological Products"

By Erin Harris, Editor-In-Chief, Cell & Gene
Follow Me On Twitter @ErinHarris_1

Back in January, Raj Bandaru, Associate Director in Regulatory Affairs and U.S. Regulatory Affairs Lead at Accenture, penned an article for Cell & Gene that took deep dive into the FDA Draft Guidance, “Rare Diseases: Considerations for The Development of Drugs and Biological Products.” Just recently, Raj and I talked more about the Draft Guidance and his article, and during our chat, he provided additional details and information that I believe you’ll find valuable. Here’s our conversation.

Back in January, you authored an article for publication on Cell & Gene titled, FDA Draft Guidance On “Rare Diseases: Considerations for The Development of Drugs and Biological Products,” which explains and breaks down the FDA’s Draft Guidance of the same name that was issued in December of 2023. Please provide some of the highlights it offers.

Raj Bandaru: To set the stage for the topic of rare diseases with high unmet need, we all understand that we have come a long way with the drug development for rare diseases despite several challenges. It is safe say to say that we still face lot of challenges during orphan drug development programs for rare diseases even though FDA has approved several orphan drugs for rare diseases, here are a few examples. I worked on these orphan drugs at Accenture for Duchenne Muscular Dystrophy (DMD), Hutchinson-Gilford Progeroid Syndrome (HGPS or Progeria), Spinal Muscular Atrophy (SMA) etc.

In addition, we must also acknowledge notable contributions of numerous non-profits, rare disease foundations/government organizations such as National Organization for Rare Disorders (NORD), Genetic And Rare Diseases (GARD), Orphanet, and many Patient Advocacy Groups such as Adrenoleukodystrophy or ALD Foundation for Lysosomal Disease Network listed here and other patient advocacy groups (PAG). These organizations continue to make considerable progress to advance orphan drug development programs for rare diseases worldwide.

Despite these advances and continuous global research, many rare diseases, for example, Infantile Tay-Sachs disease, have no treatment option available as of today. The prevalence of these diseases, however small they might be, highlights unmet therapeutic need and underscores what future efforts needed to develop drugs and biologics for many rare diseases.

FDA has recently published a guidance on “Rare Diseases: Considerations for the Development of Drugs and Biological Products.” It is extremely helpful guidance for orphan drug development. Also, it is especially important that sponsors of orphan drug development programs must always weigh in following regulatory considerations mentioned in the FDA guidance, such as:

Considerations for Natural History Studies, Non-clinical, clinical, and quality or CMC considerations, and Considerations for Accelerated Pathways.

One of the things you talk about in the article is considerations for natural history studies.

1. What are natural history studies and why they are important?

Raj Bandaru: Knowing the course of a given disease over time provides valuable information to drug developers on how the disease progresses in the absence of intervention, providing clues on how best to treat it. This information is obtained through what is known as a natural history study: an observational study that follows a group of people over time who have, or are at risk of developing, a specific medical condition or disease. These studies identify demographic, genetic, environmental, and other variables that correlate with the disease’s development and outcomes. Information obtained from a natural history study plays an essential role at every stage of product development, such as identifying the patient population and identifying or developing clinical outcome assessments and biomarkers.

Natural history studies are often part of disease registries, which significantly benefit research efforts by providing a centralized repository of patient data, supporting natural history studies and treatment evaluations, fostering collaborative research and biomarker identification, and raising disease awareness. Registries like AADCAware, for example, promote data sharing and standardization of research practices across institutions and countries for the rare disease aromatic l-amino acid decarboxylase (AADC) deficiency. Another example is the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS), which is the largest prospective natural history study performed in DMD to date.

2. Why are natural history studies conducted?

Raj Bandaru: Natural history studies have many purposes, chief among them the ability to provide information to help researchers and clinicians understand the disease course over time. Other important reasons they are conducted include the opportunities to:

• Better characterize the disease.
• Characterize the patient population and identify subgroups within the population.
• Understand the day-to-day effects of the disease on the lives of patients and their families from their perspective.
• Highlight areas of unmet medical need.
• Inform research priorities from patient and clinical perspectives.
• Establish diagnostic criteria.
• Develop clinical care guidelines.
• Identify biomarkers.
• Collect patient-reported outcomes and other clinical outcomes, which can be used to identify outcome measures to be used in clinical trials.
• Increase patient participation and retention in clinical trials.
• Compile data from the patient perspective that can be used by the FDA as part of their marketing review process.
• Amass data to advocate for expanded insurance coverage for therapies and services.

3. Why participate in a natural history study?

Raj Bandaru: Due to the small numbers of people affected by rare diseases, many rare diseases have incomplete natural history data. Therefore, there are unique challenges in understanding the disease and drug development for these conditions. Participating in a natural history study can be beneficial to the community for many reasons:

The data from a natural history study can:

• Be used in FDA review of new therapies for rare disease, resulting in regulatory approval and making the therapy accessible to those with the rare disease.
• Be used as evidence with government policy makers when expressing the needs of people with rare diseases.
• Help with the development of clear diagnostic criteria or clinical management guidelines by considering patient/caregiver burden.
• Support the development of clinical trials by helping to design better study criteria.
• Raise awareness of disease in medical, academic, and pharmaceutical communities
• Provide your patient community with a sense of momentum and increase interest in participation in research.
• It can lead to the development of more effective, safe treatments or potentially a cure for the disease.

4. Why do many drugs fail in the clinic due to lack of natural history studies for rare diseases?

Raj Bandaru: We need to discuss the importance of Natural History Studies, Patient/or Rare-Disease Registries and Real-World Evidence (RWE) data often required for NDA/BLA approvals at FDA. Natural history study data, data from patient registries and real-world evidence (RWE), is not obtained from so called FDA established gold-standard randomized clinical trials (or RCTs). We know very well that this data is generated often outside of Randomized Controlled Trials, such as Natural History Studies, Patient Registries and Real-World Evidence data.

Also, we know very well, many investigational drugs for rare diseases often fail during clinical development due to lack of thorough understanding of natural history study data including incidence, prevalence and outcomes of disease and characteristics of the patient population etc. It is important to note that FDA does not mandate natural history study data for a marketing authorization approval in the USA.

Explain non-clinical studies for rare diseases and why they’re a mandated part of drug development.

Raj Bandaru: Non-clinical studies are a mandated part of drug development. The goal of the non-clinical program, which consists of in vitro and/or in vivo studies, is to provide evidence that the drug is “reasonably safe to conduct the proposed clinical investigations.” Non-clinical studies can also contribute to a better understanding of the drug’s mechanism of action, metabolism, pharmacokinetics, pharmacodynamics, and efficacy. The data generated from non-clinical studies are 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. The non-clinical data may help guide the selection of patient eligibility criteria and will often determine important safety monitoring procedures based on the observed toxicological profile.

Internationally accepted guidelines discuss the general design of non-clinical safety studies and the timing of such studies relative to the conduct of a clinical development program. 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 severity of the targeted disease (including the rate of progression to death or irreversible morbidity), adequacy of other available therapies, and the anticipated risks to humans based on the accumulated non-clinical toxicology and human data. When determining the relevance of existing data, a sponsor can consider factors such as drug 108 product constituents, dosage form, route of administration, dose levels, and dosing regimen plan.

The sponsor should design the pivotal toxicology studies considering the biology of the disease, expected pharmacology of the drug, existing proof-of-concept (POC) data, proposed population to be studied (e.g., adult versus pediatric), and proposed clinical investigation design(s) for the clinical indication sought. Healthy animals are the test system used in traditional toxicology testing and, in most circumstances, would be the test system used to support initiation of clinical investigations. When an animal model of the disease is available, pharmacology and safety studies may contribute to understanding the actions of the drug on disease pathophysiology, inform safety in the context of that disease, and guide plans for measuring biological effects in patients. Combined POC and safety studies in animal models of human

We understand often lack of validated animal model or a genetic testing or a pharmaco-genomic biomarker is a serious limitation for the drug development of rare diseases. In addition, animal models for rare diseases often do not accurately predict progression of disease due to heterogenic nature (i.e., pediatric population to adults and eventual multiorgan failure etc.). We are aware that FDA offers some flexibility for the conductance of non-clinical studies for Severely Debilitating or Life Threatening (SDLT) rare diseases at the IND and NDA approval stages.

FDA and NIH are offering many research grants for Natural History Studies of rare diseases. These research grants from the NIH were also used to develop validated animal models for many rare diseases. Though industry may have some reservations of animal models developed at research labs in the universities or by the academicians, this certainly seems to me a path forward to speed up orphan drug development and develop initial animal models to support non-clinical data package for many rare diseases.

Since having crafted your article, what other information have you and your team unveiled or reviewed regarding regulatory considerations for non-clinical, quality, clinical studies, expedited and accelerated approaches for orphan drug development?

Raj Bandaru: At Accenture we provide RA consulting and submission services to our clients. We have ~30 to 40% of clients at any given time developing drugs for rare diseases. We often work with number of clients who have been developing drugs for rare diseases. We understand every program is different with nuances. We provide regulatory advisory, intelligence, knowledge-based drug development information especially how to address regulatory issues early in the drug development so that developmental program would achieve success eventually. We relay the available regulatory information related to natural history studies, non-clinical/clinical, CMC and advise our clients suitable or available accelerated programs at FDA. In addition, we number of services related to accelerated pathways such as ODD, RPD, RPV, RMAT, Breakthrough and fast drug designation. In addition, we also liaison or agent services to promote interactions between rare disease clients and FDA or EMA or Health Canada etc.

For the back half of 2024 and as we look to 2025, what is your advice to CGT biotech companies and innovators when it comes to regulatory affairs?

Raj Bandaru: Prior to CGTs many of the rare diseases are always studied with small molecule drugs or biologics or enzyme replacement therapies. Obviously, CGTs are the fastest growing number of clients for many rare diseases. We also thank the University of Pennsylvania, which is helping with groundbreaking research in gene therapies and manufacturing such as AAV vectors and T-Cell receptor targeting especially for immune-oncology rare genetic cancers.

Gene therapy is a type of medical treatment that involves adding, removing, or changing a person’s genetic material—also known as their DNA. Gene therapies are being studied in patients with serious or life-threatening rare diseases because they focus on correcting the root cause of the disease rather than just treating the symptoms. As a result, gene therapies offer patients a better chance at long-term improvements in how their bodies function and their quality of life. Several gene therapies have been approved by the U.S. Food and Drug Administration (FDA) and many others are currently being evaluated in clinical trials.

In recent years, gene therapy has been raising hopes toward viable treatment strategies for rare genetic diseases for which there has been exclusively supportive treatment. We here review this progress at the pre-clinical and clinical trial levels as well as market approvals within diseases that specifically affect the brain and spinal cord, including degenerative, developmental, lysosomal storage, and metabolic disorders.

The field reached an unprecedented milestone when Zolgensma® (onasemnogene abeparvovec) was approved by the FDA and EMA for in vivo adeno-associated virus-mediated gene replacement therapy for spinal muscular atrophy. Shortly after EMA approved Libmeldy®, an ex vivo gene therapy with lentivirus vector-transduced autologous CD34-positive stem cells, for treatment of metachromatic leukodystrophy. These successes could be the first of many more new gene therapies in development that mostly target loss-of-function mutation diseases with gene replacement (e.g., Batten disease, mucopolysaccharidoses, gangliosidoses) or, less frequently, gain-of-toxic-function mutation diseases by gene therapeutic silencing of pathologic genes (e.g., amyotrophic lateral sclerosis, Huntington's disease).

In addition, the use of genome editing as a gene therapy is being explored for some diseases, but this has so far only reached clinical testing in the treatment of mucopolysaccharidoses. Based on the substantial number of planned, ongoing, and completed clinical trials for rare genetic central nervous system diseases, it can be expected that several novel gene therapies will be approved and become available within the near future. Essential for this to happen is the in-depth characterization of short- and long-term effects, safety aspects, and pharmacodynamics of the applied gene therapy platforms.

In conclusion, we expect that gene therapy will become increasingly relevant for rare brain and spinal cord diseases in the coming future. Considering that many medical treatments available for diseases that offer merely symptomatic alleviation without targeting the underlying pathological etiology, approval of more gene therapies by regulatory authorities could become game changers for patients affected by rare diseases. This also highlights the potential of a change in thinking where we move from symptomatic alleviation to disease modification and even cure.

About Raj Bandaru:

Raj Bandaru is Associate Director in Regulatory Affairs and U.S. Regulatory Affairs Lead at Accenture. He has been with the company for the past 11 years. Before joining Accenture, he had 20 plus years of industry experience in pharma and biopharma companies. He worked on several therapeutic areas including orphan drug development for rare diseases. He is a Subject Matter Expert (SME) for Chemistry, Manufacturing, and Controls (CMC). As a Senior Regulatory Affairs Consultant at Accenture, he provides regulatory strategy and advisory services to the company’s client programs.