Phase II - Typically Therapeutic Exploratory

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Course:	Early Clinical Development
Book:	Phase II - Typically Therapeutic Exploratory

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Date:	Friday, 9 May 2025, 8:21 AM

Section Overview

1. Introduction
2. Selection of Doses for Proof of Concept (PoC) Studies
3. Dose-response

1. Introduction

(This section is organised in the form of a book, please follow the blue arrows to navigate through the book or by following the navigation panel on the right side of the page.)

After the successful completion of Phase I, the experimental medicine is next tested for efficacy (and safety) in Phase II clinical trials. If a significant portion of patients (afflicted with the disease or condition for which the medicine is developed) respond to the treatment, the treatment is judged to work or be ‘active’.

Phase II usually starts with studies in which the primary objective is to explore therapeutic efficacy and safety in patients. Patients are selected by strict selection (inclusion) criteria, leading to a relatively homogenous population, this is done in order to facilitate the interpretation of study results. Phase II studies typically involve:

Determining the dose(s) and regimen for Phase III trials - often dose finding designs are utilised to give an early estimate of dose response for a pursued indication. Confirmatory dose response studies may be conducted in Phase II or left for Phase III.
Exploratory analysis of multiple endpoints.
Exploratory analysis of therapeutic regimens including concomitant medications (medicines which are used at the same time or shortly after another).
Exploratory analysis of target populations (e.g. mild versus severe disease) for further study in Phase II or III.

Often surrogate endpoints are used (rather than clinical endpoints, the use of which occurs later) since the objective is to show some sign of efficacy (Proof of Concept (PoC)) rather than demonstrate efficacy as is done in confirmatory trials (Phase III). Phase II are typically fairly short, lasting several weeks (or months).

The objectives of the Phase II development are:

To explore therapeutic efficacy (and safety) in patients

Proof of concept (PoC): to determine the existence of activity or ‘response’ (often using surrogate endpoints) of a new treatment in a particular patient population.

To determine the dose(s) and regimen (schedule) for Phase III trials

Dose-range exploration: Finding the lowest effective dose and the optimal dose.

To explore potential trial endpoints, concomitant medications, and target populations (e.g. age, gender, disease stage/degree), and cumulative effects for subsequent studies, and provide the basis for confirmatory trial design.

Phase II studies are performed on large groups of patients (~100-500) usually seeing more than 30 patients per treatment group. When the development of a new medicine fails, it is often during phase II studies when the medicine is discovered not to work as expected, or to have unforeseen toxic effects in patients.

The outcomes of PoC should unambiguously be associated with clinical improvement. These outcomes and results must be considered which making a ‘go/no-go’ decision to progress to Phase III development.

2. Selection of Doses for Proof of Concept (PoC) Studies

As a rule, PoC is tested at the maximum tolerated doses (MTD), or maximal administered dose if MTD was not defined. This is to minimise false negative results, and to provide best test of hypothesis, as well as to maximise pharmacodynamics (PD) effect(s). The evaluation of several dose levels to assess dose response is preferred, but is not required. The assessment of dose response allows researchers to establish a minimum effective and optimal dose, to mitigate the risk of the MTD not being tolerated. Gathering these further data strengthens the weight of evidence, and guides dose selection for subsequent studies, however it increases the time required to complete phase II studies, and thus the cost.

3. Dose-response

Dose-response data is very important. In addition to formal dose-response studies, the sponsor of a clinical trial should look at the entire database of data for possible dose-response information (for example results from studies with fixed doses, blood concentration-response relationship from the variable concentrations attained in a fixed dose trial, etc.).

Dose-response studies are typically randomised parallel group studies which look at three or more dosage levels, one of which may be zero (placebo). It may also be useful to include one or more doses of an existing medicine as a control.

The information gained from dose-response studies:

Identify a reasonable starting (minimum effective) dose, ideally with specific adjustments.
Identify response-guided stepwise dose adjustment (titration) , and the intervals at which they should be taken.
Identify a dose, or a response (desirable or undesirable), beyond which titration should not ordinarily be attempted because of lack of further benefit or an unacceptable increase in undesirable effect.
Identify optimal dose