Phase 1 Clinical Trial Study Design – BioPharma Services

Clinical drug development progresses with the conduct of clinical trials, with different phases of clinical trials focusing on different aspects of the development process. Phase 1 clinical trials, including first-in-human studies, evaluate the safety and dose range of a New Chemical Entity (NCE) or an Investigational Medicinal Product (IMP). Next, clinical drug development proceeds with Phase 2 clinical trials, which provide additional safety data in patients with the disease of interest and initial efficacy data that inform further drug development. Phase 3 clinical trials, which are larger and longer in duration, deliver efficacy data and can help identify less common adverse events. After regulatory approval is obtained, Phase 4 trials can be employed for post-marketing monitoring of the safety and efficacy of the new drug. All phases of clinical trials are associated with inherent complexity, and both the volume of collected data and the number of employed procedures have shown a tendency to increase over time. 

Notably, Phase 1 clinical trials play a crucial role not only in establishing the safety, initial dose range, and pharmacokinetic profile of an NCE or IMP but also in laying out the groundwork for the success of later stages of clinical drug development. In addition to safety, dosing, and pharmacokinetic data, Phase 1 clinical trials can also deliver proof-of-concept pharmacodynamic information.

Clinical trial study design for Phase 1 trials should reflect their complexity and should collect information that can be used to design successful Phase 2 and 3 clinical trials. In addition, based on the characteristics of an NCE or IMP, potential concerns may already be identified and explored in Phase 1 trials. For example, for NCEs or IMPs that will require thorough QT (TQT) studies, determining their supratherapeutic dose in a Phase 1 trial can facilitate the design of the TQT study or QTc prolongation may already be confirmed in the Phase 1 clinical trial itself. In addition, information obtained in Phase 1 clinical trials can inform the design of human abuse potential (HAP) studies for NCEs that are expected to affect the central nervous system. 

To efficiently accomplish the clinical trial study design of complex Phase 1 studies, working with an experienced clinical research partner is of paramount significance. BioPharma Services is an experienced, full-service, Phase 1 clinical research organization (CRO) that has successfully completed over 2,000 clinical trials and has been acknowledged with over 20 awards and recognitions.

Objectives of Phase 1 Clinical Trials

Phase 1 clinical trials aim to collect important information regarding an NCE or IMP, including:

Safety Data – The primary goal of Phase 1 clinical trials is to assess the safety and tolerability of an NCE or IMP. 

Dose Range – The gathered information helps to determine the appropriate dose range for later-phase trials.

Pharmacokinetic Profile – Phase 1 clinical trials play a key role in elucidating the pharmacokinetic characteristics of an NCE or IMP, including their absorption, distribution, metabolism, and excretion. 

Proof-of-concept Pharmacodynamic Information – Even though the pharmacodynamic profiles of NCEs and IMPs are primarily elucidated in later-phase clinical studies, proof-of-concept pharmacodynamic information may already be collected during Phase 1 clinical trials.

Study Population

Clinical trials may be performed with normal healthy volunteers (NHVs), individuals from special populations, or individuals with the disease an NCE or IMP is being developed to treat. Most Phase 1 clinical trials are conducted with NHVs. However, in certain instances, such as in oncology trials, patients with the disease of interest are included already in Phase 1 clinical trials.

To ensure that the choice of the study population is aligned with the needs of the clinical trial, strict inclusion and exclusion criteria should be defined in the clinical trial study design.

Clinical Trial Study Design Elements

When designing a Phase 1 clinical trial, it is important to consider the characteristics of the investigated NCE or IMP and of the disease of interest. Key elements that should be reflected in the clinical trial study design include the study objective, study duration, cohort size, and statistical, regulatory, and ethical considerations. 

In Phase 1 clinical trials, both single ascending dose (SAD) and multiple ascending dose (MAD) studies are usually employed. First-in-human trials typically begin with a SAD study, with an initial dose selected based on preclinical toxicological data. The single dose of an NCE used in SAD studies can provide data on its safety and tolerability. Subsequently or simultaneously, a MAD can be conducted, involving the administration of multiple doses of an NCE, to provide safety, tolerability, pharmacokinetic, and (in some cases) pharmacodynamic data. 

Key Considerations for Clinical Trial Study Design

Randomization and Blinding – Randomization ensures that study participants have an equal chance of being assigned to the different intervention arms of a trial. Blinding renders the study volunteers and/or investigators unaware of which treatment is being administered to which study participant. Both randomization and blinding are commonly recommended as strategies to minimize bias in clinical trials, including early-phase clinical studies. However, in some instances, giving study sponsors access to unblinded data in early trials may help to accelerate drug development programs or terminate a trial early, if appropriate. In addition, blinding may be challenging in some Phase 1 clinical trials, especially for oral drug administration, due to the use of early formulations with distinctive tastes or colors, and the potential for participants to communicate and unblind each other.

Safety Monitoring and Adverse Event Reporting – As Phase 1 clinical trials are the first stage of drug development, during which an NCE or IMP is administered to humans, ensuring the safety of study participants is of utmost importance. Accordingly, Phase 1 clinical trials require the development of stringent protocols for close monitoring of study volunteers, state-of-the-art clinical facilities, and an expert medical team. NCEs or IMPs, for which preclinical data indicate a narrow therapeutic window, pose a particular challenge with respect to safety monitoring. 

Innovative Clinical Trial Study Designs – Incorporating adaptability and flexibility in clinical trial protocols can help address the complex challenges posed by clinical trials. Adaptive clinical trial study designs allow for pre-planned protocol changes based on the incoming data of the trial and interim analyses. Such changes may include alterations of the sample size or dosing as well as an early termination of the trial. Seamless study designs consolidate two or more phases of a clinical trial in a single, adaptive clinical trial design. They may enhance the efficiency of a clinical trial but require careful consideration and planning. Biomarker-driven clinical trial study designs can help advance biomarker-based precision medicine strategies based on data obtained using molecular profiling. In decentralized clinical trials, activities are at least partially performed at a location different from a traditional clinical trial site, such as the study participant’s home or a local healthcare facility.

Biomarker Identification – Even though the pharmacodynamic properties of an NCE or IMP are typically elucidated in later phases of a clinical trial, collecting preliminary biomarker data in Phase 1 clinical trials can help identify appropriate target patient populations and gather preliminary evidence of target inhibition.

Ethical and Regulatory Considerations

One of the important ethical challenges associated with Phase 1 clinical trials is the fact that they are commonly performed on NHVs. Study participants should be informed regarding all aspects of the clinical trial, including the potential risks associated with participation, and should provide written informed consent prior to the initiation of the study.

Phase 1 clinical trials should adhere to strict principles for ethical conduct and should comply with the regulatory requirements of the United States Food and Drug Administration (FDA) or other relevant regulatory authorities. In addition, regulators should be informed about the limits of the clinical trial study design that will potentially be assessed without further regulatory review and approval. 

A prerequisite for the initiation of a Phase 1 clinical trial in the United States is the approval of an Investigational New Drug (IND) application by the FDA. Conducting a Phase 1 clinical trial in Canada is an alternative strategy that can enable investigators to initiate their first-in-human study faster and to shift IND-related interactions with the FDA until after early-phase clinical data have been collected.

Data Collection and Analysis

Data on the safety of an NCE or IMP, its pharmacokinetic properties, treatment response, and biomarkers are collected during Phase 1 clinical trials. Standardized tools should be used for data collection to maintain the consistency of the data. 

A detailed statistical analysis plan (SAP) should be designed in alignment with the specific objectives of the study. The cohort size should be selected to ensure that the clinical trial will have sufficient power. Finally, the statistical analysis of the data should be performed by expert biostatisticians. 

Challenges and Solutions for Phase 1 Clinical Trial Study Design

Recruitment and Retention – Challenges with the recruitment and retention of study participants may lead to study delays. Therefore, a comprehensive recruitment and retention strategy should be developed. It should be aligned with the needs of the specific clinical trial and may involve active outreach to potential study volunteers and measures to facilitate their access to study participation.

Variability – Clinical trials are associated with the risk of data variability, which can occur at any stage, including sampling, study conduct, and measure collection. To reduce variability in clinical trials, it is important to standardize all conducted procedures. 

Translational Challenges – Phase 1 clinical trials are the initial stage of clinical drug development. This transition from preclinical to clinical studies is associated with challenges, as data from animal models cannot directly be translated to humans. Therefore, Phase 1 clinical trials require careful planning and close safety monitoring.

Why Choose BioPharma Services for Your Next Drug Development Project?

Well-designed Phase 1 clinical trials can provide valuable safety, pharmacokinetic, dosage, and biomarker data that set the groundwork for later stages of clinical drug development. Thus, the information collected during Phase 1 clinical trials informs decisions regarding the future fate of a drug development program. 

Clinical trial study designs should take into consideration the specific needs of each study and challenges related to its conduct and recruitment, regulatory, and ethical aspects. Implementing innovative clinical trial designs, developing proactive strategies to address challenges, and working with an experienced Phase 1 CRO can help increase the efficiency of Phase 1 clinical trials and accelerate drug development.

BioPharma Services is a full-service Phase 1 CRO with extensive expertise in early-phase clinical trials that is based in Toronto, Canada. Its expert multidisciplinary team operates a state-of-the-art Canadian facility and has access to a large database of healthy volunteers and special populations.

If you want to learn more about the services that BioPharma offers, schedule a Discovery Call below 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.