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A Detailed Technical Overview: 

The Phase 1 Clinical Trial Process for a Novel Pharmaceutical

A new drug's path from the lab to the clinic is a methodical and strictly controlled process. Transitioning from animal (pre-clinical) research to human subject testing is the first crucial step. Phase 1 clinical trials are the term used to describe this first stage of human testing. Phase 1's main goals are to address basic concerns regarding the medication's use in humans rather than to demonstrate if it prevents a disease: 



  • Is it secure? 
  • How does the body process it?                        
  • What dosage is acceptable? 



The development program for the breakthrough anti-HIV medication KP-1461 from Koronis Pharmaceuticals offers a clear, practical example to analyze this process, especially the typical partition of Phase 1 into Phase 1a and Phase 1b stages.

1. The Foundational Step: Experimental Compound Data Submission

Sponsors create a comprehensive data submission that covers the formulation procedure, molecular characterization, and preclinical examination before experimental substances move on to subsequent research stages.

 Before more extensive research starts, this phase makes sure that all scientific and technical components are accurately recorded and prepared for review.  

1.1.Purpose and Rationale of the IND

The IND's primary goal is to reassure the FDA that:

  • When given to people for the first time, the medication is fairly safe.
  • Product quality is ensured by the drug's constant and regulated chemical composition and manufacturing procedure.
  • The suggested clinical trial design is morally sound and won't put participants at needless risk.

1.2.KP-1461 Case Study - IND Timeline

  • Koronis Pharmaceuticals formally submits its IND for KP-1461 to the FDA on August 4, 2004. All of the pre-clinical data was included in this submission, including findings from both in vivo (animal) and in vitro (test tube) investigations that showed the drug's unique mechanism of action (Viral Decay Acceleration) and its safety profile in animal models.
  • November 17, 2004: The FDA approves Koronis to start clinical testing on humans. The FDA did not impose a clinical hold during the 30-day review period following submission, thereby permitting the trials to move forward. According to the release, "The clinical trial will begin later this month."
2. Phase 1a: Initial Experimental Evaluation

2. Phase 1a: Initial Experimental Evaluation

The Phase 1a trial represents the very first time a new chemical entity is administered to human beings. It is a cautious, deliberate, and closely monitored process.

Primary Objectives of Phase 1a:

Safety and Tolerability: To describe the drug's acute safety profile following a single dosage. While keeping an eye out for any indications of toxicity, investigators carefully record every adverse event.

Pharmacokinetics (PK): To comprehend how the medication is absorbed by the body. Important PK parameters that are measured include:

  • C~max~: The maximum concentration of the drug in the bloodstream.
  • T~max~: The time it takes to reach C~max~.
  • AUC (Area Under the Curve): A measure of the total exposure to the drug over time.
  • Half-life (t~1/2~): The time it takes for the concentration of the drug in the plasma to reduce by half, indicating how quickly it is eliminated.




Study Design: Single Ascending Dose (SAD) :

A Single Ascending Dose (SAD) study, which is often carried out in a specialized clinical research center, is the typical design for a Phase 1a trial.  

 
  • Cohort Structure: Participants are enrolled in small groups, called cohorts, typically consisting of 3 to 8 individuals.
  • Dose Escalation: The first cohort receives a very low, sub-therapeutic dose, predetermined from animal studies to be safe. These participants are monitored intensely for a predetermined period.
  • Sentinel Dosing: Often, the first one or two subjects in a cohort are dosed first ("sentinels"). If no immediate safety concerns arise, the remainder of the cohort is dosed.
  • Dose Escalation Committee: A independent committee reviews all safety and PK data from one cohort before granting permission to escalate the dose for the next cohort. This process continues until a pre-defined stopping criteria is met, often related to the emergence of predefined adverse events or a pharmacokinetic benchmark.


KP-1461 Case Study - Phase 1a Execution:

November 30, 2004: Koronis starts testing KP-1461 in Phase 1a.

Koronis announces the project's complete completion on March 18, 2005. The business stated that "The Phase 1a trial of KP-1461 has successfully completed enrollment of all subjects, the data locked, the trial unblinded and the data analyzed." The main results were:

  • Safety: "No consistent toxicities were noted." This means no adverse events were repeatedly observed across subjects that could be attributed to the drug.
  • Pharmacokinetics: "The pharmacokinetics were as predicted by our animal studies." This is a crucial positive finding, confirming that the animal models were predictive of human metabolism, validating the pre-clinical work.




3.The Transition: From Phase 1a to Phase 1b

A Phase 1a trial's successful conclusion is an important milestone. It offers the fundamental information needed to plan the subsequent, more intricate investigation. Once single-dose safety and PK have been proven, attention turns to comprehending the consequences of repeated dosing.

  • Protocol Finalization: Designing the detailed Phase 1b study protocol.
  • Regulatory Engagement: "FDA guidance has already been received for this trial." (March 18, 2005). This indicates Koronis had productive discussions with the FDA about the Phase 1b design, ensuring alignment on endpoints and safety monitoring.
  • Site Selection and Activation: "Evaluation of prospective investigators for the phase 1b is underway." (March 18, 2005). This involves selecting clinical trial sites, training investigators, and obtaining approval from Institutional Review Boards (IRBs) to protect participants' rights and welfare. "Seven clinical sites have been selected... currently in the process of seeking IRB approvals." (May 27, 2005).

4. Phase 1b: Multi-Stage Evaluation in the Target Study Group

The results of Phase 1a are directly expanded upon in Phase 1b. It serves as a vital link between early safety and more advanced efficacy investigations.


  • Safety and Tolerability with Repeated Dosing: To assess the safety profile of the drug when administered multiple times. This can reveal side effects that do not appear after a single dose.
  • Steady-State Pharmacokinetics: To understand how the drug accumulates in the body with multiple doses and to confirm the dosing interval. The goal is to see if a stable concentration ("steady state") is achieved.
  • Preliminary Assessment of Drug Activity: To gather initial, exploratory evidence of biological or clinical effect in the intended patient population.

The standard design for a Phase 1b trial is a Multiple Ascending Dose (MAD) study.

  • Patient Population: Unlike Phase 1a, which may use healthy volunteers, Phase 1b is almost always conducted in the target patient population (e.g., HIV+ patients for KP-1461).
  • Dosing Regimen: Cohorts of patients receive the drug multiple times over a defined period (e.g., twice daily for 14 days). The dose escalation principle remains, starting with a dose deemed safe from Phase 1a.
  • Expanded Endpoints: In addition to safety and PK, the protocol includes exploratory endpoints for drug activity. This is not a formal test of efficacy but can provide early signals.

  • May 27, 2005: Koronis files an amendment to its IND to begin Phase 1b, finalizing the protocol.
  • October 12, 2005: Koronis publicly announces the beginning of the Phase 1b trial.
  • Trial Design Details: The announcement and previous filing provide specific technical details:
    • Duration: "A 14-day multi-dose, dose escalation trial."
    • Population: "In HIV+ patients."
    • Sample Size: "Forty patients will be accrued to the protocol." This is a larger sample size than a typical Phase 1a, necessary for assessing variability in a patient population.
    • Endpoints: "PK, tolerability and drug activity." The inclusion of "drug activity" is the key differentiator from Phase 1a, marking the first look at potential therapeutic effect in patients.