Small Molecule Orphan Drugs: Balancing Financial Incentives And Complex Challenges

Author: Kevin Kane, Global SME, Thermo Fisher Scientific

The orphan drug industry focuses on developing life-changing and potentially life-saving treatments for patients living with rare diseases. Previously, the needs of these patients often went unmet because of the prohibitively high costs of developing drugs for small populations. The Orphan Drug Act of 1983 ushered in an era of incentives, government support, and regulatory agency assistance, making the development of drugs for rare diseases financially feasible and changing the pharmaceutical landscape significantly. Nearly half of all drugs approved by the FDA in 2019 were orphan drugs, and the market value of this industry segment is anticipated to be $262 billion by 2024 (1). Achieving clinical and commercial success with orphan drugs requires overcoming numerous development and manufacturing challenges related to fast-tracked timelines, active pharmaceutical ingredient (API) supply lines, formulation scale-up, clinical trial establishment, and regional variation in legislation and regulatory policies. Meeting these challenges requires specialized skills, resources, and infrastructure, as well as agile supply-chain management with the flexibility to accommodate commercial needs. This whitepaper offers a roadmap for navigating the complexities of orphan drug development based on the following key features: close alignment of clinical and CMC teams; a continuous regulatory feedback loop;   predictive API modeling; a robust formulation development program; and an integrated, single-vendor strategy. Changing the lives of patients living with rare diseases requires collaboration, communication, and careful planning that incorporates regulatory, clinical, scientific, and commercial strategy. It also requires a commitment to advancing science to speed solutions.

The Orphan Drug Act (1983) was enacted to stimulate the development of drugs for rare diseases affecting small patient populations. The legislation provided financial incentives that included the waiver of FDA fees, market exclusivity for approved orphan drugs, tax incentives, and public diffusion of orphan innovation (1). Since its passage, more than 7,400 orphan drug designation requests have been submitted, and nearly 600 orphan drugs have been approved (2,3). Even with some of the financial and logistical barriers removed, designing orphan drug formulations for oral solid dose (OSD) presents several challenges related to the complexity of the substances, the need for novel and sophisticated synthetic routes and production methods, and accelerated timelines for getting these products to market. Specifically, sponsors face the difficulty of scaling up early-phase formulations for process validation, establishing clinical trials for small patient populations, managing geographically dispersed trial participants, and navigating complex regulatory environments of multiple countries. These obstacles can be overcome through careful planning and stakeholder collaboration, beginning with close alignment of clinical and chemistry, manufacturing, and control (CMC) teams.

Aligning clinical and CMC teams
Speed to approval of orphan drugs relies on accelerated clinical studies. However, with fewer patients involved in the early and later phases for orphan drugs than with traditional drug products, the result is relatively smaller batch sizes. Simple, phase-appropriate formulations are frequently used at this stage, but these are usually not scalable or suitable for process validation. These factors create challenges between the clinical team moving as quickly as possible, and the CMC team that must stay ahead and anticipate potential risks in scale-up. Robust coordination between these groups can help sponsors meet deadlines for clinical trial material (CTM) supply.

Unlike sterile drug products, where the difference between a Phase I and Phase III formulation might be more vials per batch, OSD forms are more complex and present additional CMC challenges. OSDs frequently change during clinical development due to patient requirements, release profile, or solubility issues. Moreover, formulation scale-up is heavily dependent on the physical properties of the drug substance, which can change when shifting from reaction vessels to support larger-scale synthesis of the API. Because CMC requirements often become critical path tasks on the submission timeline, CMC requirements should be initiated early and be aligned with the various clinical development phases throughout the program. This helps avoid pauses between activities that idles your staff and facility while overhead costs run unabated.

Shortening timelines and enabling early development and scale-up
Many sponsors preparing for first-in-human (FIH) trials can get distracted by the market image of their product before they’ve demonstrated safety and tolerability. This can be a bigger temptation with the accelerated timelines of orphan programs. Getting to FIH trials quickly will be for naught if…

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