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Key Elements of a Phase 1 Clinical PK Study Protocol: Study Design

by Scientific Writing Team

Part 1: Study Design

The protocol is the most important document in a clinical study. A protocol’s study design outlines the specific objectives, study plan, procedures, & analysis methods. 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.

Questions Nuventra can help answer for a Phase 1, Clinical Pharmacology study:

  • What should I use for a phase 1 clinical pharmacology PK study design?
  • What clinical research unit (CRU)/Phase 1 unit/Phase 1 site should I use for my clinical PK study?
  • Should Phase 1 clinical studies have a placebo control (double-blind, placebo-controlled Phase 1 study)?
  • Should healthy volunteers remain in the clinical research unit for the entire Phase 1 study (inpatient study) or should a phase 1 study be conducted on an outpatient basis?
  • Do you need to collect ECGs in a Phase 1 study?
  • What are the disadvantages of collecting continuous cardiac conduction data via telemetry or holter monitoring in a Phase 1 study?
  • What is the correct PK/PD blood collection/sampling schedule for a Phase 1 PK study?
  • When should pharmacodynamic (PD) samples be collected in a Phase 1 PK/PD study?
  • How long does enrollment take for a Phase 1 clinical study?
  • Do I need to collect urine for PK evaluation in Phase 1 studies?
  • Should I look for metabolites in Phase 1?
  • Does PK data need to be assessed between interim cohorts in an escalating design PK clinical pharmacology study?
  • Do we need a full physical exam at Baseline upon admission to the Phase 1 CRU?
  • Should women of child bearing potential be enrolled in a First-Time-In-Humans (FTIH) or other clinical pharmacology studies in healthy volunteers?
  • What is my starting dose for a single-ascending dose clinical study or multiple ascending dose PK clinical study?
  • Can women of child bearing potential use oral or implantable birth control for Phase 1 PK studies such as First-Time-In-Humans (FTIH) or another clinical pharmacology study in healthy volunteers?
  • What are common inclusion/exclusion elements for a First-Time-In-Humans (FTIH), single dose, multiple ascending dose (MAD), drug-drug interaction, renal impairment, hepatic impairment, ADME, thorough QT, food-effect, bioequivalence (BE), or bioavailability (BA) clinical pharmacology Phase 1 clinical study?
  • Do I conduct all Phase 1 studies before Phase 2? When should certain Phase 1 studies be conducted…not all Phase 1 studies are conducted before Phase 2 or prior to Phase 3.

Be sure to read the next post in this series: Study Objectives and Inclusion/Exclusion Criteria

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

About the blog series: Key Elements of a Phase 1 Clinical PK Study Protocol

The 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/PK/PD investigations.  Key elements of a Phase 1 clinical protocol are described in 3 parts below:

[Note: This blog 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.]