Concept study phase

The filing of a full IND, with a formal coordinated writeup of all the supporting data, while necessary 40 years ago, is now an unnecessary requirement in the early-stage clinical programs of most large pharmas and CROs that do this work today. It is a barrier to the easy access to human studies that is needed for proof-of-concept studies (Phases 1 and 2a). There has been very little trouble in the past 20 years with early INDs filed by responsible individuals, corporations and institutions. The system can now be safety adjusted to recognise this fact, by scaling back the IND requirements for responsible entities, based on what has been learned in the past 40 years. 

Provided that field development is judged to be feasible, one development alternative is selected and further matured in the Concept study phase. The aim is to provide an adequate decision basis for investment approval to be made by the board of directors. The aims of the SHE activities in the first two phases are to ensure that the selected concept is feasible with respect to SHE and that the authorities and Norskoil s SHE goals and requirements are met in a cost-efficient way. It is not necessary to choose the best concept from a SHE point of view, but the rationale for making the selection has to be documented. 

Phase I studies evaluate the pharmacokinetics and safety of the drug in a small number (tens) of healthy volunteers. Phase I studies are sometimes conducted in a small patient population (Proof of Concept studies) with a specific objective such as the validation of the relevance of preclinical models in man. The purpose of these studies may be the rapid elimination of potential failures from the pipeline, definition of biological markers for efficacy or toxicity, or demonstration of early evidence of efficacy. These studies have a potential go/no-go decision criteria such as safety, tolerability, bioavailability/PK, pharmacodynamics, and efficacy. Dosage forms used in Phase I or Proof of Concept studies must be developed with the objectives of the clinical study in mind. 

Proof-of-concept studies in patients (Phase II) Preclinical support... 

It should be noted that our proposal goes considerably beyond the current proposal of FDA to create a looser Phase 0 stage for first-in-man pharmacokinetic and similar activities. Our proposal would cover all early human studies through clinical proof-of-concept, which usually occurs in Phase 2a. Only in the large pivotal studies (Phases 2b-3), when there is more assurance that the drug candidate has a solid chance of getting to an NDA submission, would the full formal IND filing be necessary. (These proposals are the opposite of what has been introduced by the EC Clinical trial Directive, see Chapter 17.)... 

Treatment effects on surrogate endpoints therefore do not necessarily translate into treatment effects on clinical endpoints and the validity of the surrogate depends not only on the variable itself but also on the disease area and the mode of action of the treatment. Establishing new valid surrogates is very difficult. Fleming and DeMets conclude that surrogates are extremely valuable in phase II proof of concept studies but they question their general use in phase III confirmatory trials. 

Typically these studies cost from 1.5 to 3 million to conduct. Based on the perceived probability of a significant QT interval effect (based on preclini-cal studies, class effects, and ECG data from phase 1 studies) a decision must be made whether to conduct the definitive QT study prior to proceeding with a proof-of-concept study in patients, or whether to delay this study until the proof of concept (POC) has been demonstrated. Of note, for many biophar-maceutical products it would not be possible nor ethical to dose to steady state in healthy volunteers, to dose at two to four times anticipated therapeutic exposures, or to use a crossover design with reasonable washout periods. Thus a QT study performed with a biopharmaceutical may need to vary from the usual design and the E14 guidance, and may present great challenges for subject or patient recruitment. 

The complex flow within an impactor can be studied by using the concept of phase trajectory analysis where the paths of particles with different initial locations and velocities are determined. By analyzing these paths, conclusions can be drawn about a particle s fate as it travels through an impactor. Because in this analysis ideal streamline flow conditions are assumed (which actually may not be the case), phase trajectory analysis helps show how predictions from ideal assumptions may be modified by real-world conditions. A fairly simple case is chosen to illustrate the method. 

In recent literature, the concept of surrogate endpoint has become inextricably linked to the term proof of principle or proof of concept study. There is nothing fundamentally new in this idea. It is an attempt by sponsors to design, execute and interpret small scale , preferably shortterm trials at the exploratory phase of development in which a selected surrogate (or surrogates) is determined as the go/no go decision point for... 

The activities in the projects have become increasingly creative and a specialized discipline of Early Phase Development was created here and there. With the challenging goal to become faster and to better predict the chance of success Proof of Concept studies meant to measure surrogate markers, biomarkers, results from functional imaging, creative early clinical readouts and endpoints have been... 

In Phase 2 the proof of concept study provides scientifically sound evidence supporting the postulated effect of the new drug, where the effect may be the relevant pharmacological action or a change in disease biomarkers, established surrogate endpoints, or clinical outcomes that may be beneficial and/or toxic in nature. The proof of concept is often used for go/no-go decisions and is therefore one of the most critical steps in the drug development process. 

In this chapter, we will provide a statistical overview of some important concepts, performance characteristics, and acceptance criteria related to analytical validation. We will also attempt to resolve the inconsistencies noted above and clarify the link between the performance criteria established during analytical validation and the required performance of the measurements during the routine use of the analytical method during the in-study phase. 

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