Designing Effective First in Human Studies for New Therapies

First in Human (FIH) studies are a critical early step in the clinical development of new therapies. These studies mark the transition from preclinical research to the first administration of a drug in humans. The primary goal of First in Human Studies is to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the new therapy. Given the unknown risks associated with administering an investigational drug to humans for the first time, designing effective and safe FIH studies requires careful planning and a comprehensive understanding of the therapy in question.

This article will explore key considerations in designing effective FIH studies, highlighting best practices and strategies to ensure safety, robust data collection, and regulatory compliance.

Key Objectives of First in Human Studies

FIH studies are typically Phase I clinical trials, focused on collecting critical information that will shape the future development of the drug. The primary objectives of these studies include:

1. Assessing Safety and Tolerability: The primary concern in FIH studies is the safety of the participants. This involves closely monitoring for adverse effects and understanding the drug’s tolerability in a controlled, small-scale environment.
2. Determining Pharmacokinetics (PK): FIH studies provide essential PK data, including how the drug is absorbed, distributed, metabolized, and excreted by the human body. This information helps determine dosing regimens for future studies.
3. Evaluating Pharmacodynamics (PD): PD studies assess the drug’s biological activity, including its mechanism of action and the dose-response relationship. These data are crucial for understanding the drug’s potential efficacy.
4. Identifying a Safe Starting Dose: One of the most critical aspects of FIH studies is determining the appropriate starting dose based on preclinical data, ensuring that it is both safe and likely to elicit a therapeutic effect.
5. Exploring Dose Escalation: Most FIH studies use a dose-escalation design, where increasing doses are administered to successive cohorts of participants to identify the maximum tolerated dose (MTD).

Designing Effective First in Human Studies

Designing an effective FIH study involves multiple factors, including preclinical data interpretation, study design, participant selection, and regulatory compliance. Below are key components that must be considered.

1. Leveraging Preclinical Data for Dose Selection

Accurate and safe dose selection is one of the most crucial elements in FIH study design. Preclinical studies, conducted in animals and in vitro systems, provide the foundation for estimating an appropriate starting dose. This includes:

• No Observed Adverse Effect Level (NOAEL): The NOAEL, obtained from animal toxicology studies, is typically used to determine the starting dose in humans.
• Allometric Scaling: Mathematical models that scale the dose from animals to humans help account for physiological differences between species.
• Safety Margins: Safety factors, often between 10 and 100 times the NOAEL, are applied to ensure that the starting dose is well below potentially harmful levels.

2. Choosing the Right Study Design

The design of an FIH study must balance the need to collect essential data with the safety of the participants. Some common study designs include:

• Single Ascending Dose (SAD) Design: In SAD studies, a single dose of the investigational drug is administered to a small cohort of participants, followed by monitoring for adverse effects. Subsequent cohorts receive progressively higher doses.
• Multiple Ascending Dose (MAD) Design: MAD studies involve administering multiple doses over a period of time to assess the drug’s safety, pharmacokinetics, and pharmacodynamics during repeated exposure.
• Sentinel Dosing: Sentinel dosing involves administering the drug to one or two participants first, followed by close monitoring. If no significant adverse effects occur, the remaining participants in the cohort receive the drug. This strategy helps mitigate risks when testing a new therapy in humans for the first time.

3. Safety and Risk Mitigation

Ensuring participant safety is the top priority in FIH studies. Several strategies are employed to mitigate risk:

• Careful Participant Selection: FIH studies are often conducted in healthy volunteers, unless the drug has significant toxicity (e.g., oncology drugs), in which case patients with the target disease may be enrolled. Selecting the right participants helps reduce unnecessary risk.
• Rigorous Monitoring: Close monitoring of participants, especially during dose escalation, is essential. This includes regular assessments of vital signs, laboratory tests, and adverse event reporting.
• Adaptive Trial Design: An adaptive design allows for modifications based on real-time data from the study. If significant adverse effects are observed, the trial can be modified, paused, or terminated to protect participants.

4. Dose Escalation Strategies

Dose escalation is a key part of FIH studies, helping researchers identify the maximum tolerated dose (MTD) and the therapeutic dose. Escalation strategies include:

• Cohort Dose Escalation: Each cohort of participants receives a higher dose than the previous cohort. Careful attention is given to safety data between dose escalations to ensure participant safety.
• Pharmacokinetic Guidance: PK data from earlier cohorts can help guide dose escalation. If the drug is cleared more quickly than expected or shows limited bioavailability, the dose may need to be adjusted.

5. Pharmacokinetic and Pharmacodynamic Considerations

Understanding the PK and PD properties of the drug in humans is critical for determining its potential efficacy and safety. Key considerations include:

• PK Profiling: Collecting PK data at multiple time points helps create a comprehensive profile of the drug’s absorption, distribution, metabolism, and elimination in humans. This data can be compared with preclinical models to ensure consistency.
• PD Analysis: PD data is used to assess the drug’s effect on the body, including biomarker changes or target engagement. This helps confirm that the drug is working as expected at the molecular or cellular level.

6. Regulatory and Ethical Compliance

FIH studies must comply with stringent regulatory and ethical guidelines to ensure participant safety and scientific integrity. Key regulatory considerations include:

• Investigational New Drug (IND) Application: Before starting an FIH study in the U.S., a sponsor must submit an IND application to the FDA, which includes preclinical data, the proposed study design, and safety monitoring plans.
• Ethics Review: Institutional Review Boards (IRBs) or Ethics Committees (ECs) review and approve FIH study protocols, ensuring that participant rights are protected and the study is ethically sound.

7. Participant Safety and Adverse Event Monitoring

FIH studies place a strong emphasis on real-time monitoring of participants for adverse events. This includes:

• Regular Safety Assessments: Continuous monitoring of vital signs, laboratory values, and adverse event reports allows researchers to detect potential safety issues early.
• Stopping Rules: Predefined stopping rules are established to halt the study if certain safety thresholds are crossed, such as the occurrence of serious adverse events or dose-limiting toxicities.

8. Data Collection and Analysis

Efficient data collection is crucial for FIH studies, as the data generated will inform decisions about the future of the drug development program. Considerations include:

• Biomarkers and Surrogate Endpoints: In some cases, biomarkers or surrogate endpoints can be used to assess the drug’s activity in early-phase trials, reducing the need for large participant numbers or long trial durations.
• Interim Analysis: Regular interim analyses of safety and PK/PD data enable researchers to make informed decisions about dose escalation, cohort expansion, or trial modifications.

Challenges in First in Human Studies

Despite careful planning, FIH studies face several challenges:

• Unpredictable Human Response: Human responses to new therapies can be unpredictable, even with robust preclinical data. Adverse effects that were not observed in animal models may arise, requiring rapid adaptation and participant protection.
• Translational Gaps: Differences between animal models and human physiology can lead to discrepancies in how a drug is metabolized or tolerated. Bridging these translational gaps requires careful interpretation of both preclinical and clinical data.
• Ethical Concerns: Ensuring that the risks to participants are minimized, especially in the context of healthy volunteers, is an ethical challenge. Clear communication of potential risks and thorough informed consent processes are vital.

Conclusion

Designing effective First in Human (FIH) studies is a critical step in the development of new therapies. These studies provide essential data on the safety, tolerability, pharmacokinetics, and pharmacodynamics of a drug in humans for the first time. By carefully selecting doses, employing risk mitigation strategies, and adhering to regulatory guidelines, researchers can conduct FIH studies that protect participants while generating the data necessary to advance promising therapies.

The success of FIH studies lays the foundation for later-stage clinical trials and ultimately, the approval of new, life-saving therapies.