First-in-man trials - Revision history

Lawrence: /* Conclusion */

2025-06-03T22:09:36Z

Conclusion

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	See also:		See also:
	* [[Phase 1 Trials]]		* Phase 1 Trials
	* [[Investigational New Drug (IND) Application]]		* Investigational New Drug (IND) Application
	* [[Data Safety and Monitoring Board]] (DSMB)		* [[Data Safety and Monitoring Board]] (DSMB)
	* [[Informed ~~Consent~~]]		* [[Informed consent]]
	* [[~~Clinical Trial~~ Ethics]]		* [[Ethics]]
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Lawrence: /* Conclusion */

2025-06-03T21:53:07Z

Conclusion

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 Regulatory submissions must be approved before human enrollment. In the U.S., an Investigational New Drug (IND) application must be submitted to the FDA. In Europe, a Clinical Trial Authorization (CTA) is required under EMA guidelines.
-Ethical oversight is critical. Participants must provide informed consent, with a clear understanding of the risks involved. Risk minimization strategies—such as dose staggering and intensive monitoring—are essential. Independent review by Institutional Review Boards (IRBs) or Research Ethics Committees (RECs) ensures that trials meet ethical standards.
+Ethical oversight is critical. Participants must provide [[informed consent]], with a clear understanding of the risks involved. Risk [[minimization]] strategies—such as dose staggering and intensive monitoring—are essential. Independent review by Institutional Review Boards (IRBs) or Research [[Ethics]] Committees (RECs) ensures that trials meet ethical standards.
 == Challenges and Risks ==
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 * [[Informed Consent]]
 * [[Clinical Trial Ethics]]

Lawrence at 14:10, 27 March 2025

2025-03-27T14:10:33Z

← Older revision		Revision as of 14:10, 27 March 2025
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	* [[Phase 1 Trials]]		* [[Phase 1 Trials]]
	* [[Investigational New Drug (IND) Application]]		* [[Investigational New Drug (IND) Application]]
	* [[Data ~~safety~~ and ~~monitoring board~~ (DSMB)]]		* [[Data Safety and Monitoring Board]] (DSMB)
	* [[Informed Consent]]		* [[Informed Consent]]
	* [[Clinical Trial Ethics]]		* [[Clinical Trial Ethics]]

Lawrence at 14:08, 27 March 2025

2025-03-27T14:08:17Z

← Older revision		Revision as of 14:08, 27 March 2025
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	* [[Phase 1 Trials]]		* [[Phase 1 Trials]]
	* [[Investigational New Drug (IND) Application]]		* [[Investigational New Drug (IND) Application]]
	* [[Data ~~Safety~~ and ~~Monitoring Board~~ (DSMB)]]		* [[Data safety and monitoring board (DSMB)]]
	* [[Informed Consent]]		* [[Informed Consent]]
	* [[Clinical Trial Ethics]]		* [[Clinical Trial Ethics]]

Lawrence: Created page with "= First-in-man trials = A '''First-in-Man (FIM) trial'''—also known as a '''First-in-Human (FIH) trial'''—is the first clinical study in which a new investigational drug, biologic, or medical device is administered to human participants. These trials follow extensive preclinical testing and are typically classified as Phase 1 trials. The primary focus of FIM trials is to assess safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) before proceeding..."

2025-03-27T14:06:54Z

Created page with "= First-in-man trials = A '''First-in-Man (FIM) trial'''—also known as a '''First-in-Human (FIH) trial'''—is the first clinical study in which a new investigational drug, biologic, or medical device is administered to human participants. These trials follow extensive preclinical testing and are typically classified as Phase 1 trials. The primary focus of FIM trials is to assess safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) before proceeding..."

New page

= First-in-man trials =

A '''First-in-Man (FIM) trial'''—also known as a '''First-in-Human (FIH) trial'''—is the first clinical study in which a new investigational drug, biologic, or medical device is administered to human participants. These trials follow extensive preclinical testing and are typically classified as Phase 1 trials. The primary focus of FIM trials is to assess safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) before proceeding to larger, more definitive studies.

== Key Objectives ==

The primary goal of a First-in-Man trial is to evaluate the safety profile of a novel intervention. Researchers aim to identify any dose-limiting toxicities and determine the maximum tolerated dose (MTD). Close monitoring of adverse events is essential at this stage.

Another key objective is to characterize the drug’s pharmacokinetics—how it is absorbed, distributed, metabolized, and excreted. This is typically assessed through blood samples, urine collection, and other biomarker studies.

Pharmacodynamic assessments measure the biological effect of the drug on the body. These may include evaluating target engagement, biomarker changes, and physiological responses.

A critical part of FIM trial planning involves defining a safe starting dose, often based on preclinical toxicology data. Regulatory guidance (e.g., from the FDA or EMA) recommends deriving the starting dose from the no observed adverse effect level (NOAEL) in animals—usually beginning at one-tenth of the NOAEL.

== Trial Design ==

First-in-Man trials are commonly structured as randomized, placebo-controlled, dose-escalation studies. The two main formats are:

* '''Single Ascending Dose (SAD)''': Participants receive a single dose of the investigational product, with subsequent groups receiving increasing doses.
* '''Multiple Ascending Dose (MAD)''': Participants receive multiple doses over time to assess accumulation and repeated exposure effects.

The trials typically begin with healthy volunteers, especially for low-risk drugs. However, when safety risks are high—such as in oncology or gene therapy—patients with the target condition may be enrolled directly.

The intended clinical route of administration (oral, intravenous, subcutaneous) is usually used from the outset. Participants are closely monitored, and trial conduct is overseen by a Data Safety Monitoring Board (DSMB). Predefined stopping rules are implemented to mitigate risk.

== Regulatory and Ethical Considerations ==

Before initiating a FIM trial, extensive preclinical safety assessments are required. These include toxicology studies in at least two animal species, as well as evaluations for genotoxicity, reproductive toxicity, and carcinogenicity (when applicable).

Regulatory submissions must be approved before human enrollment. In the U.S., an Investigational New Drug (IND) application must be submitted to the FDA. In Europe, a Clinical Trial Authorization (CTA) is required under EMA guidelines.

Ethical oversight is critical. Participants must provide informed consent, with a clear understanding of the risks involved. Risk minimization strategies—such as dose staggering and intensive monitoring—are essential. Independent review by Institutional Review Boards (IRBs) or Research Ethics Committees (RECs) ensures that trials meet ethical standards.

== Challenges and Risks ==

One of the greatest challenges in FIM trials is the unpredictability of human responses. Despite extensive preclinical testing, a drug may behave differently in humans. A well-known example is the TGN1412 trial in 2006, where healthy volunteers experienced life-threatening immune reactions after receiving a monoclonal antibody.

Another challenge is dose selection. Choosing a dose that is too high may cause toxicity, while starting too low may delay development due to a lack of observable effects.

There are also ethical concerns, particularly when enrolling healthy volunteers. Ensuring informed consent, fair compensation, and adequate risk disclosure are all essential components of ethical trial conduct.

== Examples of First-in-Man Trials ==

* '''mRNA COVID-19 Vaccine Trials''': The first human trials of the Pfizer-BioNTech and Moderna vaccines began in 2020 and provided critical safety and dosing information.
* '''CAR-T Cell Therapy Trials''': First-in-human studies evaluated genetically engineered T-cells in patients with leukemia and lymphoma.
* '''CRISPR Gene Editing Trials''': Early FIM trials explored genome editing for conditions such as sickle cell disease and inherited blindness.

== Conclusion ==

First-in-Man trials are a cornerstone of medical innovation. They represent the first step in translating scientific discovery into clinical application. Due to the high level of uncertainty and potential risk, FIM trials require robust design, regulatory compliance, and a strong commitment to participant safety. With careful planning and ethical oversight, these trials can pave the way for transformative advances in health care.

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See also:
* [[Phase 1 Trials]]
* [[Investigational New Drug (IND) Application]]
* [[Data Safety and Monitoring Board (DSMB)]]
* [[Informed Consent]]
* [[Clinical Trial Ethics]]