Phase I Trial

Purpose of Phase I Trials

Primary Objectives

Objective	Key Questions
Safety	What side effects occur? What’s tolerable?
Tolerability	What doses can people handle?
Pharmacokinetics	How is the drug absorbed, distributed, metabolized, excreted?
Pharmacodynamics	What does the drug do to the body?
Dosing	What’s the maximum tolerated dose (MTD)?

What Phase I Does NOT Determine

• Whether the drug treats disease effectively
• Long-term safety profile
• Efficacy compared to other treatments
• Optimal therapeutic dose (only maximum safe dose)

Phase I Trial Design

Participant Selection

Population	When Used	Rationale
Healthy volunteers	Most Phase I trials	Assess drug effects without disease confounding
Patients	Cancer drugs, serious conditions	Ethical concerns about exposing healthy people
Special populations	Later Phase I	Elderly, renal/hepatic impairment effects

Dose Escalation Strategies

3+3 Design (Traditional):

Start at low dose (3 participants)
        |
        v
If 0/3 have toxicity --> Escalate dose
If 1/3 has toxicity --> Add 3 more
If 2+/3 have toxicity --> MTD found
        |
        v
Continue until MTD determined

Accelerated Titration:

• Single participant per dose initially
• Faster escalation with safety monitoring
• Switches to 3+3 at first toxicity sign

Key Measurements

Parameter	How Measured	Why Important
Cmax	Peak blood concentration	Predicts intensity of effect
Tmax	Time to peak	Onset of action
Half-life	Time to 50% elimination	Dosing frequency
AUC	Total drug exposure	Overall effect prediction
Clearance	Elimination rate	Dose adjustment needs

Phase I in Peptide Development

GLP-1 Agonist Phase I Examples

Early Semaglutide Studies:

• Tested single and multiple doses
• Established weekly dosing feasibility
• Identified GI side effects as dose-limiting
• Determined pharmacokinetic profile enabling once-weekly administration

Tirzepatide First-in-Human:

• Explored dual GIP/GLP-1 mechanism safety
• Established dose range for Phase II
• Characterized unique PK profile

Common Phase I Findings for Peptides

Finding	Implication
GI tolerability limits	Informs dose titration strategy
Injection site reactions	Formulation optimization needed
Half-life determination	Supports dosing schedule
Immunogenicity signals	Monitors for anti-drug antibodies

Duration and Scale

Typical Phase I Parameters

Aspect	Typical Range
Participants	20-100
Duration	Several weeks to months
Sites	Usually single center
Cost	$1-5 million
Success rate	~65% proceed to Phase II

Single vs Multiple Ascending Dose

Single Ascending Dose (SAD):

• One dose per participant
• Tests acute safety
• Determines initial safety range

Multiple Ascending Dose (MAD):

• Repeated doses over days/weeks
• Tests accumulation
• Mimics real-world use patterns

Safety Monitoring

Adverse Event Tracking

Severity	Description	Action
Mild	Noticeable but not problematic	Continue, document
Moderate	Interferes with activities	Assess continuation
Severe	Significantly impairs function	Likely dose-limiting
Life-threatening	Immediate risk	Stop dosing, intensive monitoring

Data Safety Monitoring

• Independent committee reviews safety data
• Can recommend dose modifications
• Authority to halt trial if needed
• Protects participants in real-time

Frequently Asked Questions

Why do Phase I trials use healthy volunteers?

Healthy volunteers provide a clean baseline to understand drug effects without disease complications. This isolates the drug’s pharmacology from disease-related changes. However, cancer drugs and treatments for serious conditions often use patients because it would be unethical to expose healthy people to potentially harmful agents with no personal benefit.

What happens if Phase I shows safety problems?

Development may stop entirely, or researchers may modify the drug, formulation, or dosing strategy. Sometimes safety issues at high doses are acceptable if therapeutic doses remain safe. The drug may also pivot to a different patient population or indication where the risk-benefit balance is more favorable.

Can Phase I trials show if a drug works?

Phase I focuses on safety, not efficacy. However, researchers often include exploratory efficacy endpoints (biomarkers, early clinical signals) to guide Phase II design. For peptides, early weight changes or glucose improvements might be observed, providing preliminary evidence while safety remains the primary focus.