Fact Sheet

Proof of Concept – Industry’s Perspective

The aim of this document is to help researchers understand what constitutes “proof of concept” (POC) from an industry perspective. The definition of “proof of concept” varies depending on context and the field of science, which has caused confusion and misconceptions. To add to the confusion, “proof of concept” is often used interchangeably or is closely associated with the terms “proof of principle” and “proof of mechanism.”


What is “proof of concept?”

In “Proof of Concept: A PhRMA Position Paper With Recommendations for Best Practice”, Cartwright et al. define POC as “the earliest point in the drug development process at which the weight of evidence suggests that it is ‘reasonably likely’ that the key attributes for success are present and the key causes of failure are absent.” (Cartwright et al. 2010) The interpretation of this definition, however, is context dependent.

For industry, POC almost always applies to clinical trials. POC studies are usually small and designed so as to provide early statistical evidence allowing drug developers to make the decision whether or not to proceed into larger, more expensive Phase 2b or 3 clinical trials.

To the academic researcher however, POC often represents the results of mechanistic in vitro studies, or at best, studies in an animal model. While the scientific rationale may be proved, other questions that are important in the broader drug development pipeline are often not addressed, such as safety, efficacy, dosing regime, cost of goods, and commercial and regulatory issues that could threaten the ultimate success of a novel drug.

It is critical that all parties involved in a drug development project agree on definitions at the beginning of any collaboration in order to ensure clarity and specificity. Often, researchers submit expressions of interest (EOI) for drug development programs under the impression that they have established POC for their project, but this is seldom seen as such by industry.

In short, for biomedical research and drug development, the definition of POC varies according to the developmental stage of the research. This leads to a wide range of the types of evidence needed to demonstrate the many different definitions of “proof of concept.”


What is needed to establish “proof of concept” in preclinical studies?

At the early stage of a program, human genetic evidence linking a proposed target to a disease provides powerful evidence supporting ‘proof of concept’. This can also assist in defining initial patient populations for study.

There are several elements needed to ensure “proof of concept” has been obtained in preclinical in vitro and in vivo studies. These involve the following areas:

Experimental design:

  • Ensuring experiments are performed rigorously (see Target Validation fact sheet) – no cherry picking, hypothesizing after results (also known as HARKing) or p-hacking
  • Subjective assays performed by blinded investigators
  • Having the appropriate controls (negative/vehicle and positive controls)
  • Experiments are repeated
  • All the data is shown and analysed
  • Appropriate statistical analysis
  • Using the appropriate tool molecule for testing (confidence in potency and selectivity; see Small Molecule Tool Compound Validation fact sheet)

In addition, in vivo studies require:

  • Randomisation of animals
  • Understanding pharmacokinetics [PK] (dose, schedule and exposure)
  • Delineating the pharmacokinetics and pharmacodynamics (PKPD) relationship
  • Ensuring a suitable formulation
  • Ensuring adequate sample size as determined by pre-specified power calculation
  • Ensuring there is adequate sampling (samples should also be taken for PK, tumour biomarker assessment and other tissue biomarkers)
  • Using the appropriate tool molecule for testing (confidence in potency and selectivity; see Small Molecule Tool Compound Validation fact sheet)

Considerations regarding choice of most appropriate in vivo preclinical model:

  • Model should be chosen based on the molecule’s mode of action and potential clinical indication
  • Model should be well characterised (gene expression, mutational analysis, immunophenotype)
  • The molecule required for “bench-marking”/differentiation has previously been examined in the chosen model
  • Will this therapy be developed as a monotherapy or part of a combination therapy?
  • When using human-drugs for testing or bench-marking in animal studies, have those reagents been demonstrated to be active and/or equi-potent on the target in the proposed test species as for the human target?
  • Testing targeted therapies require models demonstrated to be expressing relevant levels of the target of interest (e.g. cell line derived or patient-derived xenograft models)
  • Testing immune therapies require models with a functional immune system (e.g. syngeneic or humanised models)
  • The model of choice must be widely understood and accepted as having reliably predicted human clinical responses making it clear how to interpret and use the data generated

Although not directly related to POC, but critical to an emerging drug-development program, one aspect that is frequently overlooked is the manufacture of high-quality, clinical-grade material for toxicology and early clinical studies. This is referred to as “CMC” (Chemistry, Manufacturing and Controls). The lack of attention and investment in this area is one of the most common reasons for failure of drug-development projects within many small companies.


“Proof of concept” in clinical studies

Further along the drug development pipeline, POC has another, different definition. Here, POC refers to preliminary information gathered during the Phase I (“first-in-humans”) and Phase IIA stages of clinical trials. This is the definition that is more commonly recognised in industry.

This can be further segmented into “Exploratory Phase I” and “Confirmatory Phase I.” During Exploratory Phase I, the goal is confirmation of the mechanism of action (i.e., the drug ‘hits’ and ‘covers’ the target, with the desired downstream biochemical effect) in humans, as well as good quality data on the following:

  • Pharmacokinetics and pharmacodynamics
  • Safety and tolerability
  • Candidate selection
  • Dose and dosing regimen
  • Formulation and route
  • Critical interactions

Continuing on from this, in Confirmatory Phase I, the following should be established:

  • Drug interactions (PK and PD)
  • Specific target populations
  • Mass balance, bioavailability
  • New/alternative formulations special studies

As a result of Phase I studies, it is essential to have confirmation of mechanism of action, preliminary safety-data, and settled on the dose to be taken into Phase II studies.

Although not traditionally the goal of Phase I studies, increasingly there is a desire to generate preliminary efficacy data by focusing on select patient populations (using a patient stratification biomarker) most likely to respond to therapy.

In Phase IIa, the following should be validated:

  • Safety
  • Definition of study population
  • Validated biomarker
  • Availability of adequate formulation

Through these phases, the design of the study, the objective, the subjects (healthy volunteers or patients), the variables used to measure response (surrogate biomarkers) and the treatment regimen must be carefully considered in the context of the ultimate Phase III studies that will be required to achieve Regulatory Approval.

Only once this data has been obtained is POC established. Often, it is only at this stage that real value is added to a potential asset/drug/therapeutic. From here, decisions are made whether to progress the drug further through the development pipeline. By the establishment of an integrated POC from multiple disciplines and information sources, the drug developer is able to avoid inappropriate investment in a drug candidate that is unsafe, ineffective, or not commercially viable.


For further information on this, or any other topics related to the drug discovery and translation process, please email the BioCurate team on info@biocurate.com.

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