It is well-known that going from drug discovery to commercialisation takes, on average, 10–15 years and poses significant costs – approximately $2.6 billion when R&D, materials, manufacturing, and related expenses are added up.1 In this challenging landscape, drug developers are under ever-increasing pressure to deliver effective therapies to patients faster and without compromising drug safety or quality. This has increased the industry’s need to find ways to improve first-in-human (FiH) clinical trial pathways for nearly all indications.
The US Food & Drug Administration (FDA) has defined four ways a pharma or biotech may accelerate through development and approval to meet the goal of getting to patients earlier. The FDA’s designations for priority review, breakthrough therapy, accelerated approval, and fast track status each have their own set of requirements.2 A drug that has been designated as fast track, for example, must fill an unmet need and provide therapy where none exists or that has a significant advantage when compared with the available therapy.2 Similarly, the European Medicines Agency (EMA) may recognise a drug with a PRIME status, which grants similar benefits to the FDA fast-track designation. Conducting FiH trials more efficiently can benefit both developers and patients but, this can be challenging and costly particularly for emerging pharmaceutical companies or biotechs with limited resources.
Adding to the pressure, development challenges faced at the clinical stage can ultimately lead to a bleak future for a molecule. Only 12% of the new molecular entities (NMEs) entering clinical trials gain U.S. Food and Drug Administration (FDA) approval.1 Lack of efficacy and drug toxicity remain the leading reasons why an NME may fail at the clinical stage.3 One potential way to progress forward is to leverage simplicity in formulation by directly filling capsules with the active pharmaceutical ingredient (API). This approach allows for a faster path to the clinic, where drug efficacy, safety, and toxicity data can be obtained early in development.
In this article, Martin Wing-King, Vice President and General Manager at Quotient Sciences -Reading explores the demand for accelerated FiH trials and outlines how simple formulations can be leveraged for a faster way to progress through early clinical studies.
What is Driving the Demand for Accelerated FiH Trials?
FiH clinical trials are the first instance where an investigational drug is introduced to human subjects. A primary focus of these studies is a safety assessment, which monitors adverse events and dose-limiting toxicities. Data about a drug’s absorption, distribution, metabolism, and elimination (ADME) are essential for determining optimal dosing regimens and administration schedules. Additionally, FIH trials provide crucial
pharmacokinetic (PK) and pharmacodynamics (PD) data that support a better understanding of how the body interacts with the drug and its impacts on the body, mechanism of action, and potential efficacy.
FiH trials often involve dose escalation to identify the maximum tolerated dose (MTD) and the recommended starting dose for subsequent trials. This information is vital in determining safe dosage ranges for the drug as it moves forward in clinical investigation. In all instances, early PK/PD data can influence decisions about the drug’s further development.
Increased efficiency in FiH trials is in demand across nearly all indication areas but in rare and orphan diseases in particular, the benefits are clear. In these cases, developers are faced with small patient populations that are both hard to recruit for clinical testing and equally as challenging when it comes to deciding the commercial viability of a drug downstream. Removing costs and time from traditional drug development is imperative to do as early as possible.
The data generated may support continuing clinical development and provide insight that de-risks the process. Using efficacy, safety, and toxicity data can allow developers to decide whether or not to continue developing a drug, especially when it comes to addressing challenges with the increasing complexity of APIs.
Enhancing Efficiency in Clinical Trials with a Simple Formulation Approach
Simplifying formulation development can streamline FiH trials and enable developers to obtain crucial clinical data. A “drug in capsule” approach, also known as “blend in capsule” or filling a capsule directly with API and limited (if any) excipients, is a dosage form that requires minimal development and can be used to simplify formulation and accelerate FiH trials. This approach enables developers to get their API into the clinic and obtain FiH data before investing in more complex dosage forms, such as dry powder inhalers.
API-filled capsules can reduce the need for complex formulation development while still enabling the drug to be manufactured in a GMP setting and administered to patients easily. This approach improves the time to reach the clinic while significantly reducing the costs associated with API synthesis and the potential waste of manufacturing excess material.
Specialised equipment that can help with API drug-in- capsule filling includes semi-automated and fully-automated capsule filling systems that microdose a precise amount of API into capsules. With choices in equipment that can handle doses ranging from 0.1 mg to 100 mg, drug developers have flexibility in dosing with rapid encapsulation of APIs with good flow and solubility properties for their FIH trials. Additionally, fill-to- weight capsule filling machines that can accommodate a wide range of APIs make it possible to handle complex formulations with poor properties and spray-dried powders. Using a robotic capsule filling system that integrates check weighing and containment can also be beneficial for the safe handling of high-potency APIs (HPAPI).
