The Basics of Phase 1 Clinical Trials and Clinical Pharmacology

The aim of Phase 1 studies is to determine the safety, pharmacokinetics/pharmacodynamics (PK/PD), and dosing range for your new drug product.

Phase 1 studies can also give preliminary signal of efficacy (or lack thereof) including patient/indication subsets that may be better responders to your drug. This can help inform the best patient subgroup to conduct your Phase II+ studies in (the studies that focus on drug efficacy).

A primary focus is identifying any dose-limiting toxicities (DLT) which defines the maximum tolerated dose (MTD) that a patient can take. MTD is designed around target probability of toxicities, which for oncology can be around 17% incidence of toxic events as defined by the FDA. 

Phase 1 trials are usually ~ 50 subjects or less (although this is highly dependent on the characteristics, incidence, prevalence of the disease). They can be conducted in healthy volunteers or patients. Drugs designed for non-life threatening diseases and with reasonable expected safety profile may conduct phase 1 studies in healthy volunteers; this is significantly cheaper and faster than an equivalent trial in patients. You may be able to ascertain preliminary pharmacodynamics information, e.g., for an antibody inhibiting a cell surface receptor, you may be able to assay the down-regulation of that receptor on the patient’s cells even if you do not expect a clinical readout from the binding & effect. For serious diseases with unmet need and more toxic drugs, it may not be ethical to use a placebo control or to use the product in healthy volunteers. For oncology, phase 1 is often run in  patients with advanced metastatic disease and various tumor types to assess tumor shrinkage (objective tumor response) and give preliminary signal on which subgroups may be the most responsive in further efficacy studies. 

Drug Behavior 101

Phase 1 trials primarily investigate the PK/PD, safety, dosing, and toxicities of a compound/drug. While completing the previous phase is generally necessary to proceed to the next, Phase 1 studies can be conducted alongside efficacy clinical trials.  The high level goal of PK/PD optimization - much of which begins in the preclinical research stage - is to minimize toxicities and maximize efficacy.

Pharmacodynamics (PD) is what the drug does to the body. 

The PD curve describes the effect of the drug relative to the concentration of the drug dosed. It is usually an S curve. The EC50 is the concentration needed to have the desired effect in half the cells/model organism/human, and is the center of the S curve.

Pharmacokinetics (PK) - what the body does to the drug (ADME)

Another definition of PK is the time and process of drug Absorption, Distribution, Metabolism, and Elimination (ADME) in the human body.

Absorption -

Distribution -

Metabolism -

Elimination -

The PK/PD profile of your drug can be affected by many variables, including:

• Product/formulation

• Administration route

• Organ (dys)function associated with the specific disease/patient

• Disease

• Concomitant medications

• Size

Phase 1 Clinical Trial Design & Structure

The design of a Phase 1 trial varies significantly depending on the type of drug, the expected safety profile, and the disease. Clinical trial designs can be broadly categorized into rule-based or model-based designs. Do note that Phase I trial design is a field in and of itself and I am giving a very high level summary of classical thoughts in the field!

Some phase 1 studies are single-dose, while later-stage or oncology phase 1 studies may use multiple doses. 

There are a number of ways to determine initial dosing, and it will vary significantly on the modality, mechanism, and delivery of your drug. Your preclinical, phase 1 enabling studies will be conducted at 50-100X concentrations of your initial dose. One rule of thumb for deciding your initial dose level is 1/10 - ⅓ of the mouse LD10 (the dose where 10% of the mice have a fatal toxicities).

Once you have your initial dose (d1), one method to set subsequent dosing levels is with a modified fibonacci multiplier: d1, d2=2d1, d3=1.67d2, d4=1.5d3. 

Rule- and model-based clinical trial designs

Rule-based designs follow pre-specified structures. Rule-based models are simple, which is both an advantage and a disadvantage. Model based designs use parametric or non-parametric statistical models to inform dose finding; these designs are more complicated but may offer more accurate models for dose allocation. A third, less common form of phase 1 design is interval-based design, which aims to be a hybrid between rule- and model-based design, adopting the simplicity and physician-friendliness of rule-based but the statistical rigour of model-based. 

To date, the 3+3 model is the most common oncology phase 1 design and is a rule-based design. The most common model-based design the continuous reassessment model. 

Examples of clinical trial designs:

Rule-based: 3+3

Interval model: mTPI, mTPI-2, cumulative cohort design (CCD), Bayesian optimal interval design (BOIN)

Model based: continuous reassessment

The term “Bayesian framework” or model is often used - this refers to trials that, as more evidence is available, update the probability of the hypothesis (the hypothesis being the MTD or DLT). This is not seen in rule-based designs. 

3+3 Design

The 3+3 design is the classic rule-based phase 1 design for dose-finding in oncology trials - 98% of phase 1 studies from 1991 to 2006 used this design.. 

Successive cohorts of patients, n=3 each cohort, are given the first, fixed, lowest dose of the drug. If there are no DLTs observed in these 3 participants, then a new cohort of 3 is enrolled in the next dosing level.

If one of the three has a DLT, then a new cohort of 3 is enrolled at the same dose level. If two or less of this group show a DLT, then a new cohort at a new dose level is initated. This pattern is continued until the DLT dose is found (at least 2 in a cohort of 3 or at least 3 in a cohort of 6 showing DLT). 

A common critisism of this method is that a number of patients are treated at sub-therapeutic doses. This method may be sub par for molecularly targeted agents. 

Below is a classic SAD trial design. Cohorts are given either placebo or the drug product. New cohorts are established for each increasing dose level. 

Continuous Reassessment Model

CRM is the classic model-based phase 1 clinical trial design. This is a dose-responsive flexible plan design, meaning that the dosing levels are informed by the previous level’s quantitative response. Before starting the study, the target DLT rate fixed. 

The aim of the CRM is to find a dose given a target DLT; focus is not on the dosing toxicity curve. As described in the classic paper describing this method, the context for the type of drug this is applicable to is:

1. The patients are at a very high risk of death in the short term

2. The new drug product will have severe, potentially fatal toxicities

3. Low doses of the drug are not expected to show much benefit

4. Little is known about the efficacious and safe dosing range. 

In very severe patients, the seemingly safest route (slow dose escalation) may actually put the patient at most risk of death. CRM has been shown to be more accurate in finding the MTD that the canonical 3+3 method, while also allowing as many patients as possible near the MTD (where higher dose = better). This is important for clinical trials of drug products indicated for serious or fatal diseases where the risk of death from disease is of same or higher concern that potential risk of death due to toxicity.

Another important aspect of cancer clinical trial design is the rolling nature of patient enrollment. Therefore, earlier patients’ response to the drug should be used to continuously adjust the dosing for the next patient; CRM allows and takes advantage of this. 

Aims of Phase 1

In the exploratory phase, you will conduct your first-in-man (FIM) study to evaluate gross toxicity and find the dosing range and MTD. Once the dosing range in humans is better understood, there are a number of confirmatory, ADME studies necessary to better characterize and de-risk your drug product. These include:

• Relative/absolute bioavailability

• Dose linearity - as you increase dosing, does toxicity or effect increase linearly? 

• Food, age, gender effect - does your drug work differently in populations with different diets, different ages, different genders?

• Drug-drug interactions - does your drug effect the metabolism of other drugs, or otherwise modified or is modified itself by another drug? 

• Special populations (renal, hepatic impairment) - are there populations with known variant metabolism of drugs that you need to independently characterize your drugs PK/PD in?

• Imaging/biomarker studies - if relevant

• ECG, phototoxicity, abuse liability - effect of your drug on cardiac, liability of patients developing a dependency

• QTc - corrected QT interval heart rate 

• Bioequivalence - if you are developing a drug with the same active ingredient as another approved drug

• Proof of mechanism (POM) - does your drug actually do what it says, target engagement

Terms & Clinical Trial Types

Placebo-concurrent control - Test drug compared with inactive formulation that closely resembles drug

Dose-comparison concurrent control - Compare two different doses of the same drug

No treatment concurrent control - When no anticipation of a placebo effect, no comparison/control

Active treatment concurrent control - Compared to a known effective therapeutic - usually used in situations where no treatment/placebo would not be ethical. 

Historical control - Compared to historical data 

Randomized - Patients randomly allocated to one group or another

Open-label - Both the patient and the physician/data analyst know which treatment they are receiving 

Blinded - The patient does not know if they are in the control or treatment group

Double-blinded - Both the patient and the physician/data analyst do not know which group they are in

Cross-over study - Single patient is on comparable and new drug, allows within-patient comparison, each serves as their own control; increased time and potential carryover effect of previous treatment. 

Patient 1: drug A <washout period to ensure the drug is out of the patient’s system> drug B 

Patient 2: drug  B <washout> drug A

Two-stage study - Usually used in phase II. A small preliminary group is first enrolled; if outcomes are sufficient then a larger secondary group is

Matched pair study - Study participants are grouped by some factor in a pair and then act as an internal control for the drug and placebo. 

Sequential design - The number of patients is not fixed in advance - instead, as data is received and evaluated from initial cohorts, the study is continued or stopped if it hits a predefined stopping rule once results are statistically significant.

Parallel design - Subjects randomly assigned to one group or another, only receive one treatment 

Target toxicity level - the target percentage of patients with dose-limiting toxicities

Maximum tolerated dose - the maximum dose that gives a toxicity rate below the target toxicity level.

Recommended phase II dose = MTD (unless in Europe/Japan - where the recommended Phase II dose is one dose level below the MTD)

Therapeutic index - dosages of a drug which have a certain level of toxicity over the dosage that gives desired efficacy (tox dose/effective dose)

A Classical Version of an Ideal Small Molecule Drug

*Biopharmaceutics Classification System (BCS)

Classing system for molecule dissolution, solubility, intestinal permeability

Class 1 - High solubility - high permeability ← can be exempt from some BE/BA studies

Class 2 - Low solubility - high permeability

Class 3 - High solubility - low permeability

Class 4 - Low solubility - low permeability

A few more details on the Phase 1 studies….

ADME study

• Understand clearance of drug + metabolites 

• Single dose in healthy males (n=4-6), radiolabeled 

• Amt of radioactivity in plasma, urine, feces

• Relative concentration of parent and metabolites 

Bioavailability (BA)/Bioequivalence (BE) studies

• Evaluate the rate (Cmax - max concentration, Tmax - time to max) and AUC of absorption of the drug

• Bioavailability - rate and extent to which the active ingredient is absorbed from the product and becomes available at the site of action. Fraction of a dose that is absorbed into systemic circulation. 

• Bioequivalence - comparison of two pharmaceutical equivalents. Studies are conducted to establish BE 

• Considerations for BA studies:

  • fasted/fed

  • Generally single-dose

  • Usually crossover 

  • Measure metabolites and parent drug 

  • Biofluids mainily plasma, blood

• For BA, measure active metabolites and ingredient in biofluids. 

• Total exposure studies, which are usually single-dose - use area under plasma, serum, or blood concentration time curve, from time 0 to time t (AUC0-t), where t is [c]=0

Food effect study

To assess the effect of food on rate, extent of drug absorption

Fed a specific FDA high-fat, high-calorie meal 

Effect of food on the bioavailability of oral drugs

For labeling - whether to give the drug on an empty stomach or not

Study design

• Single dose

• Crossover

• Two treatment (fed vs fasted)

• Highest strength

• Healthy patients 

Drug Interaction Studies

• To evaluate whether the drug is (ant)agonist/substrate of metabolizing enzymes

• Crossover design unless too long a half life 

• Healthy patients 

Thorough QT/QTc Study

• Identify drugs which prolong the QT

• These drugs may modify cardiac function and therefore require ECG monitoring 

• Completed prior to phase 3

• Single dose in healthy patients