Optimizing Clinical Trial Efficiency: The Power of Simplicity for First-in-Human Studies

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Bringing a new treatment to market is a complex process with many moving parts. It can take between 10 and 15 years on average, with associated costs of around $2.6 billion.¹ Only 12% of the new molecular entities (NMEs) that enter clinical trials gain FDA approval.¹ This is due to a demonstrated lack of efficacy for up to 50% of NMEs, toxicity for 30%, poor drug-like properties for between 10 and 15%, and inadequate commercial demands coupled with ineffective strategic planning for the remaining 10%.²

It is unsurprising, then, that demand for accelerated pathways to first-in-human (FiH) trials is growing across the pharmaceutical industry. Streamlining the path to Phase I can allow the acquisition of critical data regarding drug efficacy, safety, and toxicity early in the development process, providing insight into a potential drug product’s feasibility. This is vital to help accelerate development, all while de-risking scale-up and optimizing cost-effectiveness.

By simplifying formulation development approaches, such as dosing patients with capsules filled with the active pharmaceutical ingredient (API), developers can collect accurate clinical data to inform them whether a drug substance is worth pursuing before time and money are wasted.

Understanding demand for expedited FiH trials

FiH clinical trials represent the initial introduction of an investigational drug to human subjects. These studies primarily focus on safety assessments, closely monitoring adverse events and dose-limiting toxicities. Other data generated by FiH trials include insight regarding a drug’s real-world performance in the human body, such as:

• Absorption, distribution, metabolism, and elimination (ADME)
• Pharmacokinetic (PK) properties
• Pharmacodynamics (PD)

All of this is crucial in enhancing our understanding of the drug's interaction with the body, its effects, mechanism of action, and potential efficacy, and can help us determine optimal dosing regimens and administration schedules.

Often, FiH trials involve dose escalation to identify the maximum tolerated dose (MTD) and the recommended starting dose for subsequent trials. This information is essential in establishing safe dosage ranges as the drug progresses through clinical investigation. Early PK/PD data can significantly influence decisions regarding the drug's further development.

A growing number of pharmaceutical companies are seeking out increased time and resource efficiency in FiH trials—particularly those developing treatments for rare and orphan diseases. Developers in these areas face extra challenges due to small patient populations. This makes recruitment for clinical testing difficult and can affect decisions on the commercial viability of the drug. Therefore, reducing costs and time from traditional drug development as early as possible is imperative.

The data generated in FiH trials can support continued clinical development and provide valuable insights that mitigate risks throughout the process. Utilizing efficacy, safety, and toxicity data enables developers to make informed decisions regarding whether to proceed with drug development, especially in light of the increasing complexity of APIs.

Optimizing clinical trial efficiency: A streamlined formulation strategy

Key to addressing pharmaceutical companies’ demands for efficient FiH trials is to simplify formulation development.

One possible means of achieving this is to take a “blend in capsule” (BiC) approach—sometimes called “drug in capsule." This method involves filling a capsule with API directly, along with a limited number of excipients, if any are needed to ensure acceptable performance. BIC offers a number of benefits from an efficiency perspective:

• Minimized formulation development time by simplifying the formulation itself
• Acceleration of process from discovery to clinical trial
• Cuts development costs by allowing valuable FiH data to be obtained before investing time and money in more complex dosage forms

This approach still enables a drug to be manufactured in a good manufacturing practice (GMP) setting and administered to patients easily. It also reduces the costs associated with API synthesis and eliminates potential waste from manufacturing more material than is needed.

In BiC filling, specialized equipment plays a crucial role. Semi-automated and fully-automated capsule filling systems are available, which allow drug developers to microdose precise amounts of API into capsules. These systems offer flexibility in dosing, accommodating doses ranging from 0.1 mg to 100 mg. Moreover, they excel in rapidly encapsulating APIs with good flow and solubility properties, making them suitable for FiH trials. Additionally, fill-to-weight capsule filling machines are capable of handling complex formulations with poor properties and spray-dried powders, accommodating a diverse range of APIs. Furthermore, robotic capsule-filling systems that integrate check weighing and containment can be employed for the safe handling of highly potent APIs (HPAPIs).

A real-world example of the power of drug in capsule formulation

A biotechnology company based in the EU focused on developing oncology therapies, needed a solid dose formulation for first-in-patient (FIP) trials. This first-in-class molecule was designated as an FDA "fast track" for different oncology indications. However, the availability of the API was limited, potentially hindering the company’s ability to conduct the study and move into the potential treatment phase if patients responded positively to the drug.

A program to initiate human trials with a simplified formulation that maintained the API was designed. It involved developing a BiC formulation with flexible manufacturing capabilities that allowed for the production of batches up to 3 kg. Over three years, more than 30 small product batches using a semi-automated capsule filling system were produced, with over 100 product shipments packaged and labeled. To support larger patient trials, the BiC formulation was scaled up to 10 kg batches while ensuring API conservation and providing patients with custom-labeled products on demand. In parallel, an ICH stability program was developed and managed to extend the product’s shelf life. This approach aimed to move the formulation to larger patient trials while maintaining product quality and regulatory compliance.

Once the simple BiC formulation was deemed effective in patient trials, the biotech was supported in transitioning to a patient-friendly, commercial-ready tablet drug product. The dry blend composition for the formulation remained the same for the tablets and included excipients that would support a dry granulation process. A film coat for taste masking was also applied to the tablet. The tablet was used in continuing Phase II and III patient trials and is currently being scaled up for registration batches and commercial supply.

The benefits of simplified formulation

Specialized capsule-filling technology and a simpler approach to formulation have the potential to shave months off the drug development process by significantly reducing development timelines and eliminating the need for repeated stability studies. By simplifying the formulation process and utilizing advanced capsule-filling technology, drug development timelines can be drastically reduced, eliminating the need for repeated stability studies. This approach has the potential to accelerate the drug development process by several months, bringing life-saving treatments to patients faster.

Moreover, streamlined formulations, such as BiC, can demonstrably optimize consumption of API, which often has limited availability, all while meeting the needs of a clinical study. In addition, configuring an “on-demand” GMP manufacturing solution by providing flexibility in batch size can offer the opportunity to proactively defer API scale-up investment until post-POC, or reactively manage programs where there is little API available.

Working together with experts is key to accelerating FiH trials

The success of FiH trials relies on partners who appreciate the importance of reaching clinical milestones within tight timelines. Their extensive experience and specialized equipment are pivotal in this endeavor. Utilizing simple formulation methods at an early stage can help prevent unnecessary expenditures on compounds that might later prove ineffective or hazardous.

Moreover, underestimating the complexity of technology transfer can be a costly mistake. Conducting development and manufacturing within the same provider network, particularly within the same facility, can significantly streamline the process. A dedicated project management team ensures seamless coordination, timely communication, and adherence to timelines and budgets, ultimately benefiting both drug developers and patients.

Strategic collaborations with experienced partners who offer integrated drug development and manufacturing services can further optimize the process. This approach enables efficient technology transfers and project management. By leveraging simplified formulation methods, such as capsules filled with APIs, drug developers can accelerate their path to the clinic. These strategies collectively pave the way for early collection of FiH data, facilitating successful drug development, and ultimately benefiting patients.

Martin Wing-King, vice president and general manager, Quotient Sciences

References

1. Research and Development, accessed May 28, 2024, from: https://phrma.org/policy-issues/Research-and-Development-Policy-Framework
2. Sun, D., Gao, W., Hu, H., & Zhou, S. (2022). Why 90% of clinical drug development fails and how to improve it? Acta pharmaceutica Sinica. B, 12(7), 3049–3062. https://doi.org/10.1016/j.apsb.2022.02.002