Regulatory agencies, whether the FDA or EMA, offer expedited programs for drugs that meet specific criteria. For instance, a drug granted FDA fast-track designation must either meet an unmet medical need or offer a substantial improvement over available treatments (1). Similarly, the EMA employs a comparable approach with its PRIME designation, which supports the generation of robust data for medicines targeting unmet needs (2). These initiatives are designed to accelerate the drug development process, which can traditionally take over a decade to complete when considering R&D, clinical trials, manufacturing, and other related processes and their expenses.
The demand for accelerated first-in-human (FiH) trials spans nearly all therapeutic areas, but the advantages are evident in orphan drugs to treat rare diseases. Developers in these areas face small patient populations that are difficult to recruit for clinical trials, making it challenging to assess a drug's commercial viability. This makes reducing the costs and time associated with the traditional drug development process even more relevant.
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The low success rate of clinical trials further complicates development. Only 12 percent of new molecular entities (NMEs) gain FDA approval, with failure often linked to efficacy or toxicity concerns (3). FiH trials are a crucial milestone in providing pharmacokinetic (PK) and pharmacodynamic (PD) data to enhance the understanding of the drug and its interactions with the human body. To determine safe dosage ranges, dose escalation is used to identify the maximum tolerated dose and establish the recommended starting dose for future trials. Absorption, distribution, metabolism, and elimination studies further inform optimal dosing regimens and administration schedules.
A fit-for-phase approach to get to FiH
Early PK and PD data can be invaluable to inform decisions about the drug's continued development. The data generated can offer insights that de-risk the process or lead to decisions on whether to pursue further development, which is especially pertinent when dealing with increasingly complex APIs.
Even with support from the FDA and EMA, the complexity of FiH trials must be addressed through creative approaches to formulation development. Sometimes, this means going back to basics. One strategy to accelerate early development involves simplifying drug formulation by directly filling capsules with the API to rapidly generate early clinical data. Streamlining formulation development in FiH trials, when the API allows for this kind of approach to be done, can significantly reduce the time and cost associated with collecting early-stage clinical data. A drug-in-capsule or blend-in-capsule approach can achieve this, which involves directly filling capsules with the API and minimal or no excipients.
This simplified formulation method offers several advantages. It enables rapid entry into FiH trials so developers can gather crucial data on safety, efficacy, and toxicity before committing resources to more complex dosage forms. API-filled capsules can be manufactured in a GMP-compliant setting, ensuring quality and patient safety. Specialized equipment, such as semi-automated and fully-automated capsule-filling systems, can be used to support these approaches. Precise filling of capsules with varying doses of API from 0.1 mg to 100 mg provides the flexibility to rapidly encapsulate APIs with good flow and solubility. The versatility of fill-to-weight capsule filling machines also allows for the handling of diverse APIs, including complex formulations with suboptimal characteristics and spray-dried powders. In the later stages of drug development, parallel tracking of formulations with more complex dosage forms is an additional important consideration.
Leveraging simplified formulation approaches allows developers to eliminate the need for repeated stability studies, and gain greater flexibility in managing API resources, optimizing inventory and potentially deferring API scale-up investments until later stages. This is especially beneficial where API availability is limited. A drug development partner with integrated contract research, development, and manufacturing services that understand the benefits of collecting FiH data early in development and offer integrated drug product formulation development and manufacturing services can further streamline the process.
Ultimately, adopting simplified formulation strategies, such as the drug-in-capsule approach, combined with specialized capsule-filling technology and strategic collaborations, can significantly enhance the efficiency of FiH clinical trials. This approach not only accelerates the drug development timeline but also reduces costs and optimizes resource utilization, benefiting both drug developers and patients alike.
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References
- FDA, “Fast Track”. Available at: https://bit.ly/4eEso4R
- EMA, “PRIME: priority medicines”. Available at: https://bit.ly/4h1ktQQ
- D Sun et al, “Why 90% of clinical drug development fails and how to improve it?” Acta Pharmaceutica Sinica B, 12(7), 3049–3062. (2022) DOI: 10.1016/j.apsb.2022.02.002
