Bringing new treatments to market is a complex and costly endeavor, often taking over a decade and billions of dollars. Streamlining the path to Phase I, particularly first-in-human (FiH) trials, is increasingly vital for acquiring early data on drug efficacy, safety, and toxicity.
Expediting First-in-Human Trials
FiH trials mark the initial introduction of an investigational drug to humans, focusing on safety assessments, monitoring adverse events, and determining dose-limiting toxicities. These trials also provide insights into a drug's absorption, distribution, metabolism, and elimination (ADME), as well as pharmacokinetic (PK) and pharmacodynamic (PD) properties. This information is crucial for understanding the drug's interaction with the body, its mechanism of action, and potential efficacy, ultimately guiding optimal dosing regimens.
Many pharmaceutical companies, especially those developing treatments for rare and orphan diseases, seek increased efficiency in FiH trials due to the challenges of small patient populations and recruitment difficulties. Data from FiH trials supports continued clinical development and helps mitigate risks, enabling informed decisions about whether to proceed with drug development.
Optimizing Efficiency with Simplified Formulation
Simplifying formulation development is key to meeting the demand for efficient FiH trials. One approach is the "blend-in-capsule" (BiC) method, where the active pharmaceutical ingredient (API) is directly filled into a capsule, often with minimal excipients. This offers several benefits:
- Minimized formulation development time
- Accelerated transition from discovery to clinical trial
- Reduced development costs by obtaining valuable FiH data early
BiC allows for GMP manufacturing and easy administration to patients while reducing API synthesis costs and minimizing waste. Specialized capsule-filling systems, including semi-automated and fully automated options, enable precise microdosing of API into capsules, accommodating doses from 0.1 mg to 100 mg. These systems can handle APIs with good flow and solubility, while fill-to-weight machines manage complex formulations and spray-dried powders. Robotic systems with check weighing and containment are available for highly potent APIs (HPAPIs).
Real-World Application: Oncology Therapy Development
A European biotechnology company developing oncology therapies utilized a BiC formulation for first-in-patient (FIP) trials. The molecule received FDA "fast track" designation, but limited API availability threatened the study. A program was designed to initiate human trials with a simplified formulation, producing batches up to 3 kg using a semi-automated capsule filling system. Over three years, more than 30 small batches were produced, with over 100 product shipments packaged and labeled. The BiC formulation was scaled up to 10 kg batches for larger patient trials, maintaining API conservation and providing custom-labeled products. An ICH stability program was also developed to extend the product's shelf life.
Following successful patient trials with the BiC formulation, the company transitioned to a commercial-ready tablet. The dry blend composition remained the same, with excipients supporting a dry granulation process and a film coat for taste masking. The tablet is now used in Phase II and III trials and is being scaled up for registration batches and commercial supply.
Benefits of Simplified Formulation
Specialized capsule-filling technology and simplified formulation can significantly reduce drug development timelines, potentially shaving months off the process and eliminating the need for repeated stability studies. Streamlined formulations like BiC optimize API consumption, especially when availability is limited. An "on-demand" GMP manufacturing solution provides flexibility in batch size, allowing for proactive deferral of API scale-up investment until post-POC or reactive management of programs with limited API.
Strategic Partnerships for Accelerated Trials
The success of FiH trials depends on partners who understand the importance of meeting tight timelines. Utilizing simple formulation methods early can prevent unnecessary expenditures on ineffective or hazardous compounds. Conducting development and manufacturing within the same provider network streamlines the process, with a dedicated project management team ensuring seamless coordination and adherence to timelines and budgets.
Strategic collaborations with experienced partners offering integrated drug development and manufacturing services can further optimize the process, enabling efficient technology transfers and project management. By leveraging simplified formulation methods, drug developers can accelerate their path to the clinic, facilitating early collection of FiH data and ultimately benefiting patients.
