Key Elements of a Phase 1 Clinical PK Study Protocol

Key Elements of a Phase 1 Clinical PK Study ProtocolThe protocol is the most important document in a clinical study.  A clinical protocol outlines the specific objectives, study plan, procedures, and analysis methods for studies.  Protocols also specify the type of patient population included in the clinical study and describe safety procedures for the study.  Each clinical study is different but Phase 1 studies have many elements that are common and can be applied to varying types of clinical pharmacology and PK/PD investigations.


[Note: This post relates to a generic Phase 1/Phase I study design for a single-ascending dose study that could be modified for use in a First-Time-In-Humans (FTIH) study or for a multiple-ascending dose (MAD), drug-drug interaction, renal impairment, hepatic impairment, ADME, thorough QT, food-effect, bioequivalence (BE), or bioavailability (BA) clinical pharmacology Phase I study design.  The Phase 1 study design also could be modified in numerous ways, including changing to open-label, unblinded, cross-over designs and for use in patients with disease (e.g., oncology Phase 1 study designs), healthy elderly, pediatrics, ESLD (end-stage liver disease), Child Pugh Class A, B, and C hepatic impairment subjects, etc.]

Part 1: Phase 1 Study Design

Phase 1 Clinical Study Protocol Element #1 - Study DesignSingle Ascending Dose, First-time-in-human (FTIH), IND-enabling Phase 1 Clinical Study Protocol and Study Design

This is a Phase 1, single-ascending dose (SAD), placebo-controlled, double-blind, clinical study to evaluate the pharmacokinetics, safety, and tolerability of drug X in healthy volunteers.

Subjects will be enrolled into escalating dose cohorts (N=X) and randomly assigned in a 3:1 ratio to receive either Drug X (n=X) or placebo (n=X) at one of six dose levels (Dose A, B, C, D, E, or F mg of Drug X).  Pharmacokinetic and safety data will be reviewed by a Medical Review Committee (MRC), composed of the Investigator and Medical Monitor, following the completion of each dose level.  The MRC will make recommendations to the sponsor regarding escalation to the next planned dose level, repeating a prior dose, or investigating other dose levels (i.e., intermediate or lower doses) until the maximum tolerated dose (MTD) is identified.  The MTD is defined as the dose level prior to a dose where there were unacceptable safety parameters.  

[Of note, many studies have requirements for specific safety thresholds to enable dose escalation. For example, there cannot be certain numbers of moderate or severe adverse events to allow for dose escalation to proceed.]

Subjects will be screened within 28 days (Day -28 to -1) prior to admission to the Clinical Research Unit (CRU) on Day 0 (the day prior to dosing) for Baseline assessments.  On Day 1, following final pre-dose qualifications and pre-dose collection of blood for PK, subjects will receive a single dose of Drug X at time zero.  Blood for PK analysis will be collected at a, b, c, d, e, f, g, h, i, j, and k hours after dosing.  Subjects will remain in the CRU from admission (Day 0) through the final post-dose blood collection at ‘k’ hours and will be thereafter discharged if safety parameters are acceptable to the Investigator.  Safety parameters will be collected pre-dose and at intervals specified in the schedule of procedures and Time & Events table.  Common safety parameters for a Phase 1 study include ECG, vital signs, clinical laboratory panels, physical exam, urinalysis, adverse events, concomitant medications, etc.  A follow-up visit will be conducted for final safety assessments between 3 to 5 days after discharge from the CRU.

Click here to speak with a clinical pharmacology/PK expert to help with your Phase 1 study from a scientific, operational, regulatory, clinical pharmacology, and pharmacokinetic perspective.

Part 2: Phase 1 Study Objectives and Inclusion/Exclusion Criteria

Phase 1 Clinical Study Protocol Element #2 - Objectives, Inclusion and Exclusion CriteriaPhase 1 Study Objectives

The objectives of this study are:

  • To evaluate the pharmacokinetics and safety of DRUG X in healthy volunteers
  • To identify the maximum tolerated single dose (MTD)


Phase 1 Clinical Study Inclusion/Exclusion Criteria

Inclusion Criteria

  1. Signed and dated Institutional Review Board-approved informed consent is obtained prior to the conduct of any study activities
  2. Subject is between 18 and 45 years of age, inclusive
  3. Female subjects are non-pregnant, non-lactating, and practicing an acceptable method of birth control, or be surgically sterile or post-menopausal
  4. Subject has a body mass index between 18 and 32 kg/m2, inclusive
  5. Negative urine drug screen
  6. Negative Screening assessment for human immunodeficiency virus or viral hepatitis (Hep B or Hep C) or has a history of HIV infection/acquired immune deficiency syndrome
  7. Subject agrees to ABSTAIN from using tobacco or nicotine-containing products, consuming alcohol, grapefruit, or grapefruit juice, or taking any prescription drugs, dietary supplements or non-prescription drugs (unless approved by the Investigator and Medical Monitor) from CRU admission through follow-up
  8. Subject is able to communicate effectively with study personnel and is willing to comply with protocol requirements


Exclusion Criteria

  1. Subject has a current acute or chronic disease
  2. Subject has any clinical significant laboratory value (per Investigator judgment) outside the normal range at Screening
  3. Subject has clinically significant abnormal findings from physical examination conducted at Screening and CRU admission
  4. Subject has a clinically important history of a medical disorder that would compromise subject safety or data quality (per Investigator’s judgment)
  5. Subject has a history of anaphylaxis, a documented hypersensitivity reaction, or a clinically important reaction to any drug
  6. Subject has donated blood or plasma within 30 days prior to CRU admission
  7. Subject has received another investigational drug or has participated in an investigational drug or device study within the 30 days prior to CRU admission
  8. Subject has a history of drug abuse within 6 months prior to Screening or exhibits evidence of drug abuse at Screening or CRU admission
  9. Subject currently uses tobacco and nicotine-containing products or has used such products within 60 days prior to the CRU admission
  10. Subject has consumed any dietary supplements or non-prescription drugs within 3 days prior to CRU admission or has consumed any prescription drugs with 14 days prior to CRU admission
  11. Subject has consumed alcohol within 3 days prior to CRU admission
  12. Subject has consumed grapefruit or grapefruit juice within the 14 days prior to CRU admission


Click here
 to speak with a clinical pharmacology/PK expert to help with your Phase 1 study from a scientific, operational, regulatory, clinical pharmacology, and pharmacokinetic perspective.

Part 3: Phase 1 Study Procedures

Phase 1 Clinical Study Protocol Element #3 - ProceduresScreening (Day -28 through Day -1)

  • Obtain a signed informed consent form from the subject
  • Obtain a relevant medical history and document subject demographics
  • Assess vital signs and subject height/weight
  • Record prior medications
  • Conduct 12-Lead ECG (could be done in triplicate)
  • Obtain blood for serum pregnancy test
  • Collect blood for clinical laboratory analysis and analysis for HIV, hepatitis B, and hepatitis C analysis
  • Collect urine for urinalysis
  • Conduct a urine drug test
  • Conduct a physical examination
  • Confirmation of eligibility (inclusion/exclusion criteria)


CRU Admission (Day 0)
– BASELINE

  • Confirmation of eligibility (review inclusion/exclusion criteria)
  • Conduct physical examination (could be a reduced or abbreviated exam if needed)
  • Assess vital signs and subject weight
  • Collect blood for clinical laboratory analysis and urine for urinalysis
  • Obtain urine for urine pregnancy test
  • Conduct 12-Lead ECG
  • Conduct a urine drug test
  • Assess for prior medications


Procedures Prior to Dosing

  • Confirmation of eligibility (review inclusion/exclusion criteria)
  • Collect Pre-dose blood and urine for PK analysis
  • Assess vital signs and subject weight
  • Collect blood for clinical laboratory analysis and urine for urinalysis
  • Conduct 12-Lead ECG
  • Assess for prior medications
  • Randomization to treatment group (active or placebo)


Procedures for Dosing Subjects

  • Administer study drug with a specified amount of water (either 120 mL or 240 mL of water).  Subjects can consume more water if needed for compliance with the full dose of study drug.  Additional water use for study drug administration will be documented.


Post-Dose Procedures

  • Collect venous blood for PK analysis at [X, etc.] hours post-dose
  • Collect and pool urine at X-hour intervals after dosing (e.g., 0-X, X-X, X-X hour etc., intervals through X hours post-dose)
  • Collect vital signs at [X, etc.] hours post-dose
  • Collect venous blood for clinical laboratory analysis and urine for urinalysis at X hours post-dose
  • Collect 12-Lead ECG at X hours post-dose
  • Assess for AEs and concomitant medications


Discharge Procedures

  • Collect venous blood for PK analysis at [X, etc.] hours post-dose
  • Collect vital signs
  • Collect venous blood for clinical laboratory analysis and urine for urinalysis
  • Conduct 12-Lead ECG
  • Assess for AEs and concomitant medications
  • Conduct physical examination including assessment of weight
  • Discharge from CRU

Speak with a clinical pharmacology/PK expert to help with your Phase 1 study from a scientific, operational, regulatory, clinical pharmacology, and pharmacokinetic perspective.

 

Part 4: Phase 1 Time and Events Table or Schedule of Procedures

 

Phase 1 Clinical Study Protocol Element #4 - Schedule of Procedures

Time and Events Schedule for a Phase 1/Phase I Clinical Study Protocol (Clinical Pharmacology Study Protocol)

 

 

 

 

 

Click here to speak with a clinical pharmacology/PK expert to help with your Phase 1 study from a scientific, operational, regulatory, clinical pharmacology, and pharmacokinetic perspective.