Developing formulations for Phase 1 clinical trials

Phase 1 clinical trials, including first-in-human studies, bridge preclinical and clinical drug development by being the first stage in drug development programs during which a New Chemical Entity (NCE) or Investigational Medicinal Product (IMP) is evaluated in humans. Moreover, the safety, pharmacokinetic, and dose-range data obtained during Phase 1 clinical trials play a key role in go/no-go decisions regarding the continued development an NCE or IMP.

The collaborative efforts of experts from various scientific disciplines, including clinical pharmacologists, safety physicians, clinical development scientists, toxicologists, regulatory specialists, clinical operations specialists, and formulation scientists, are needed for the successful design and conduct of Phase 1 clinical trials. The role of formulation scientists in this process is to design and manufacture efficient and cost-effective formulations aligned with the specific requirements and challenges of early-phase clinical trials.

The Significance of Formulation Design for Phase 1 Clinical Trials

A thorough and balanced approach is required to design formulations for Phase 1 clinical trials. The selected formulation should enable the administered new chemical entity to reach sufficient bioavailability. Moreover, it should be possible to transform the early-phase formulation into a more complex and eventually commercialized formulation during the later stages of drug development. However, the process of formulation manufacture should also be sufficiently cost-effective and straightforward to enable the timely and efficient initiation and conduct of clinical trials.

What Types of Formulations are Used in Phase 1 Clinical Trials?

Various formulations, such as ready-to-use solutions or suspensions, drugs-in-capsules, powders-in-capsules, drugs-in-bottles, or formulated capsules or tablets, can be used in Phase 1 clinical trials. Some of them, including solutions, suspensions, drugs-in-capsules, and powders-in-capsules, are also known as “fit-for-purpose” or “platform” formulations. “Fit-for-purpose” formulations are often used in Phase 1 clinical trials, because they enable the generation of safety and pharmacokinetic data on a new chemical entity in a timely manner and at a relatively low cost.

Multiple formulations could be explored in Phase 1 studies, either in parallel (e.g., solution vs tablet) or through a stepwise approach (e.g. exploring immediate-release formulation then extended-release). This allows exploring the characteristics of the API and excipients, as well as finning the suitable formulations for further development stages.

Optimal Characteristics of Phase 1 Formulations

To facilitate the successful transition from preclinical to clinical studies, formulations for Phase 1 clinical trials should correspond to certain criteria:

• Dose flexibility – In Phase 1 clinical trials, the upper limit of the administered dose range is not known until toxicity data are generated in humans. To enable dose flexibility, formulations that can be delivered in a wide range of doses should be selected for Phase 1 trials.
• Potential to achieve sufficient bioavailability – The selected formulation should help ensure that the administered NCE will achieve sufficient systemic exposure. This, in turn, is a prerequisite for the generation of high-quality safety and pharmacokinetic data in Phase 1 clinical trials. It should be noted that for local-acting local-applied drugs the systemic exposure is rather for safety evaluation than a targeted achievement.
• Solubility – Poor solubility may interfere with the ability of NCEs to achieve sufficient bioavailability. Therefore, it is key to choose formulations with sufficient solubility or to adjust formulations to enhance their solubility.
• Stability – Formulations for Phase 1 clinical trials should comply with certain stability requirements, even though such requirements are typically less strict during early-phase than during late-phase clinical trials. In particular, formulations for Phase 1 clinical trials generally need to demonstrate stability for the duration of the study, whereas formulations for late-phase clinical trials should demonstrate long-term stability.
• Cost effectiveness – Keeping the manufacturing costs for drug formulations low facilitates the progression of an NCE into early-phase clinical trials. To ensure the cost effectiveness of a new formulation, a cost-benefit analysis should be conducted during its design.
• Composition – Drug formulations include an active pharmaceutical ingredient (API) and excipients. The specific combination of an API and excipients and their relative content in the dosage form should be selected carefully, as they influence the stability characteristics and release profile of the formulation, the safety and tolerability observed from formulations.
• Compliance with purity and quality specifications – All drug formulations developed for clinical trials should comply with certain purity and quality requirements, which may vary depending on the phase of the clinical trial.

How to Address Challenges in Phase 1 Formulation Development

Specific challenges associated with the development of drug formulations for Phase 1 clinical trials, including first-in-human studies, should be addressed to ensure successful formulation development and use: one of these approaches includes compounding for early-phase drug development, which allows for the preparation of customized formulations for new chemical entities whose physicochemical properties, solubility, and stability have not yet been optimized. This compounding method ensures that a safe and efficacious dose range is maintained, contributing to the overall success of Phase 1clinical trials. 

• Transitioning between preclinical and clinical formulations – Drug formulations used in first-in-human studies often differ from those employed in preclinical in vivo experiments, which may render predictions regarding the pharmacokinetics of an NCE in first-in-human studies even more challenging. These differences in the formulations should be considered when selecting doses and dosing schedules for single ascending dose (SAD) and multiple ascending dose (MAD) studies in Phase 1 clinical trials.
• Assessing formulation effects – As formulations can influence the bioavailability of NCEs, awareness of potential formulation effects in early-phase clinical trials is important and may facilitate decision-making regarding the later stages of clinical drug development. The evaluation of formulation effects typically requires a cross-over design and can be incorporated in SAD studies, when dose escalation has reached a potentially therapeutically relevant level. It is especially important to assess formulation effects for NCEs with nonlinear pharmacokinetics, as revealed by preclinical in vivo or incoming clinical pharmacokinetic data.
• Overcoming solubility challenges – The solubility of the administered formulation is important to ensure that the NCE will achieve sufficient bioavailability; however, many compounds have poor solubility. Various strategies, including the use of solubilizing agents, solid dispersions, or pH alterations, can be employed to increase solubility.
• A pathway to commercialized dosage forms – One of the key considerations when designing early-phase drug formulations is ensuring that there is a pathway to their transition into more complex and eventually commercialized dosage forms during the later phases of drug development. This requires advance and careful planning already during the early phases of clinical trials.
• Employing an adaptive strategy for formulation development – Emerging data from Phase 1 clinical trials may indicate that a drug formulation requires modifications. Employing an adaptive strategy for formulation development enables formulation adjustments based on incoming clinical trial data. This, in turn, can help to optimally adjust the formulation to the characteristics of the NCE and the specific needs of the study.

Requirements for the Manufacturing of Phase 1 Formulations

The manufacturing process for Phase 1 formulations should be straightforward and with fast turnaround to enable the prompt and cost-effective initiation and conduct of early-phase clinical trials. However, the possibilities for scaling up the manufacturing process during later phases of clinical drug development should also be considered.

The Role of Compounding in Phase 1 Clinical Trials

In Phase 1 clinical trials, compounding can be used to prepare customized formulations of NCEs. In compounding, ingredients are combined and mixed by a licensed pharmacist or physician to prepare a medication that is aligned with the needs of the individual patient. This approach enables the preparation of formulations for NCEs whose physicochemical properties, solubility, and stability have not yet been optimized, while maintaining a safe and efficacious dose range.

Compounding plays a particularly important role in human abuse potential (HAP) studies that investigate NCEs with abuse potential. By incorporating chemical or physical barriers, abuse-deterrent formulations (ADFs) are designed for NCEs with abuse potential to reduce the risk of drug tampering. Compounding can simulate methods that recreational drug users may employ to overcome ADFs and can thus provide insight into the abuse potential of an NCE.

Regulatory Requirements for Formulation Development

Manufacturing processes for drug formulations should comply with certain regulatory requirements, which may evolve as a clinical drug development program progresses. Moreover, good manufacturing practices may become more rigorous during more advanced stages of clinical drug development. To comply with these requirements, the production of salts or conjugates as well as the incorporation of additives, solvents, and release matrices may be implemented during clinical drug development.

BioPharma’s Expertise in Formulation Development for Phase 1 Trials

Collaborating with a proficient clinical partner with know-how in drug formulations can help address the complex challenges associated with formulation development for Phase 1 clinical trials. BioPharma Services is a full-service, award-winning contract research organization (CRO) that offers its clients expertise in all aspects of drug formulation:

• A team of multidisciplinary experts who can bring a breadth of perspectives to all aspects of the design and conduct of Phase 1 clinical trials, including formulation development
• A proficient team of pharmacists and physicians with extensive experience in compounding
• Extensive know-how in the design and conduct of HAP studies, including compounding for ADFs

If you want to collaborate with a proficient, multidisciplinary team who can competently support all aspects of your clinical drug development program, including the design and manufacture of drug formulations for Phase 1 clinical trials, schedule a discovery call with BioPharma Services today.

BioPharma Services, Inc., a HEALWELL AI and clinical trial services company, is a full-service Contract Clinical Research Organization (CRO) based in Toronto, Canada, specializing in Phase 1 clinical trials 1/2a, Human Abuse Liability(HAL) and Bioequivalence clinical trials for international pharmaceutical companies worldwide. BioPharma Services conducts clinical research operations from its Canadian facility, with access to healthy volunteers and special populations.