ISSUE NO. 17 — Maximizing Drug Formulation for First-in-Human Trials

The main objective of first-in-human (FIH) trials is to determine the starting dose of a new drug, one that is low enough to provide minimal to no safety and toxicity risks and allows the highest dosage/benefit for the intended trial.

The manufacture of the drug product for clinical trials is of critical importance, as the formulation, manufacturing, and assessment of a drug candidate during FIH trials can be contributing factors in whether the drug safely provides the correct dosage and, ultimately, gains regulatory approval. Decisions made during early phase development, when the compound is being used in a clinical research setting, provide significant learnings for its progression through later phase research. Integration is key — ensuring that information gathered at the clinic is efficiently incorporated into the manufacturing process is a major contributor to the goal of achieving marketing approval.

In Issue 17 of The Altascientist, we review:

• the role of formulation in drug development
• the impact of formulation on subject safety
• meeting regulatory requirements
• Pharmacy case study: Supporting Regulatory Approval
• Manufacturing case study: Mission Impossible to Possible

The Importance of Drug Formulation in First-in-Human Trials

The first step on the pathway to FIH clinical trials is formulation development. Generally, it is advisable to develop a dosage form that can be produced efficiently and cost effectively, to established quality specifications; simpler dosage forms like oral liquids, powders, tablets, or capsules are favored. Among the favored dosage forms, there are advantages and disadvantages to each. For example, tablets can have a longer shelf life and can accommodate a higher dose of active ingredient than capsules, while capsules are fast acting and can provide a higher drug absorption rate. Some advanced drug delivery systems, such as nanoparticles, require more complex formulations and manufacturing processes, and thus involve increased manufacturing costs, particularly in later development stages and commercialization.

Many of the drugs that enter development fail, even if they make it through FIH studies. Some of the high attrition rate can be attributed to the fact that key performance characteristics — such as solubility and bioavailability — are easily achieved in simple FIH formulations but challenging to replicate in more complex dosage forms for late-stage trials and commercial use. When creating a FIH formulation, it is important to keep in mind the rigors of later stage development and eventual market availability.

The Impact of Drug Formulation on Subject Safety in First-in-Human Trials

Subject safety is always a primary concern in planning clinical studies, and particularly with novel drug products entering FIH trials. The use of single ascending dose (SAD) and multiple ascending dose (MAD) cohorts, as well as the employment of adaptive protocols and sentinel dosing are part of the established safety protocols for Phase I studies.

If the candidate drug is considered high risk based on data from preclinical trials, it is preferable to formulate for intravenous administration. A slow intravenous infusion can easily be stopped if serious/severe adverse reactions occur. Likewise, dose escalation needs to be considered during manufacturing to fit the planned dose levels in the FIH study and the data gathered from sentinel dosing. If adjustments are needed based on data from the initial dose plan between cohorts, it is important to be prepared with a plan to titrate dosage, or reformulate the product to ensure maximum effectiveness with minimal safety concerns.

How Altasciences Can Help With Drug Formulation for Your First-in-Human Trials

Significant benefits can be realized with Altasciences’ Proactive Drug Development approach of integrating Good Manufacturing Practice (GMP) manufacturing and clinical testing. Shorter timelines, reduced costs, and improved flexibility are achieved with real-time drug product manufacture, as the development team can evaluate and optimize new formulations in the clinic, based on human data. When clinical trial teams work closely with those involved in formulation and manufacturing process development, collaboration and data sharing minimize risk and help reduce delays. Product development can be started when a quality active pharmaceutical ingredient (API) is ready, the clinical study can start as soon as regulatory approvals are received, and the product is released.

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