Getting personal: a patient-centred approach to rare disease drug development

Published: 5-Dec-2023

In this article, Nazim Kanji, Executive Director, Pediatric Services at Quotient Sciences, explores the challenges associated with developing formulations to treat rare disease indications in diverse patient populations

Rare disease indications in the US are defined as affecting fewer than 200,000 people and, according to the EU definition, fewer than five in 10,000 people.1,2

Despite the low patient populations with rare indications, the large number of these conditions — approximately 7000 — means that they impact approximately 30 million people around the globe.3

A large proportion of these diseases affects the paediatric population, which makes navigating this patient group even more difficult; specific formulations, meticulous dosage precision and additional safety concerns must be addressed.

With restrictions on the available treatment options often in place, having an effective strategy to address patient needs and develop efficacious drug products (DPs) to treat rare diseases is critical. 

Getting personal: a patient-centred approach to rare disease drug development

Advancing rare disease treatments

Developing a DP is inherently complex, with several iterative improvement and optimisation steps required before the drug is ready for clinical use.

When this product is intended for rare diseases, many additional intricacies must be navigated — including the requirement for multiple DP formats to suit paediatric, adult and geriatric patients.

Plus, the fact that patient populations are small and distributed globally can result in a cost-inefficient process.

To overcome financial barriers and encourage businesses to invest in the development of orphan drugs, regulatory bodies have introduced certain incentives.

For example, organisations that produce a treatment for a rare disease are granted extended market exclusivity (7 years in the US and 10 in the EU).4 This is further extended by 2 years in the EU for medications intended for paediatric use.

Additionally, specialised regulatory designations can be provided that enable accelerated development and approval timelines to bring these essential products to patients at speed.

Despite these benefits, developing orphan drugs presents many chemistry, manufacturing and controls (CMC) challenges that must be overcome to reach the market successfully. 

Tackling CMC obstacles

The four major CMC challenges that orphan drug developers encounter include the following.

  • Developing patient-centric dosage forms: The DP has to be developed to suit a wide range of patient needs. Medication for a rare disease indication in children has additional complexities throughout development, requiring specialist knowledge to effectively develop a formulation that is palatable and suitable for paediatric patients. 
  • Accelerating progress to patient trials: to maintain a competitive market advantage and meet the growing demand for treatments, rapid optimisation and validation of DPs in humans before clinical trials are key. 
  • Navigating manufacturing and supply: Meeting manufacturing and supply demand is complex, but introducing a customised plan of the DP for patient trials can provide enhanced guidance. 
  • Forging long-term partnerships: Rare disease indications require low-volume production during development and commercialisation, with fast-changing demands; as such, finding a robust scale-up and manufacturing partner that can handle these demands is vital. 

Implementing a strategy to overcome these challenges remains vital for development, manufacturing and market success … and to meet diverse patient needs. 

The importance of formulation development to overcome these challenges

Having an effective development strategy starts with a comprehensive understanding of the active pharmaceutical ingredient (API). A characterisation programme that prioritises understanding the physicochemical and biopharmaceutical properties of the drug is essential.

One example of this is a developability classification system (DCS) assessment of the drug to identify potential dissolution and solubility risks further down the development pipeline.

From this, experts can recommend appropriate formulation strategies and excipient considerations for effective development. With this insight, timelines can be reduced — with data-driven decision making propelling DP development and maximising efficiency.

By considering the target product profile (TPP) at these early stages of development, organisations can start with the end in mind. This means that all steps are designed to balance accelerated development with downstream considerations such as scale-up and manufacturing. 

Harnessing formulation flexibility

Formulation development should extend to the first-in-human (FIH) trials, whereby inherent flexibility can enhance the process. This adaptability is driven by actionable insights drawn from patient data, allowing the formulation to be switched from “fit for phase” to a “patient-ready” format.

As a rapid development strategy, this FIH protocol enables precision during dose escalation, the screening of different formulation technologies and bridging from liquid to solid dose formulations.

Upon completion, the final formulation can be manufactured and supplied for the proof of concept study. 

Implementing manufacturing and supply chain solutions

Owing to the intermittent and slow recruitment of rare disease patients, navigating patient trial supply chains, which are often spread across multiple sites globally, can be complex.

Moving away from traditional large-batch manufacturing, having a global and flexible clinical trial supply plan that is tailored to the unique needs of the drug development programme is vital, providing the right product to the right patient at the right time. 

This approach prioritises small batch sizes, carefully considers API usage and takes into account dose flexibility to meet the needs of individual subjects (such as age and weight); it’s even more importance for paediatric populations.

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This means that the product is made on demand, reduces waste and costs, and enhances the likelihood of clinical success. In addition, considering the CPPs and CQAs at early development stages enables seamless scale-up from small to large batch manufacturing on demand, which is key for commercial success. 

The benefits of a long-term partnership

Navigating the challenges of the development, manufacture and commercialisation of an orphan drug can be eased when working with a specialist partner.

Forming an effective relationship provides insight and expertise for essential rare disease DP development and manufacture.

With the experience of handling low-volume manufacturing and supply chain solutions through to larger batch demands, DPs can be effectively formulated and produced to meet patient needs at accelerated rates. 



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