From Wikipedia, the free encyclopedia - View original article
|This article possibly contains original research. (October 2013)|
A proof of concept (POC) or a proof of principle is a realization of a certain method or idea to demonstrate its feasibility, or a demonstration in principle, whose purpose is to verify that some concept or theory has the potential of being used. A proof of concept is usually small and may or may not be complete.
The appearance of the terms in news archives suggests it might have been in common use as long ago as 1973.
One of the early definitions of the term "proof of concept" was by Bruce Carsten in the context of a "proof of concept prototype" in the column "Carsten's Corner":
Proof-of-Concept Prototype is a term that (I believe) I coined in 1984. It was used to designate a circuit constructed along lines similar to an engineering prototype, but one in which the intent was only to demonstrate the feasibility of a new circuit and/or a fabrication technique, and was not intended to be an early version of a production design.
Sky Captain and the World of Tomorrow, 300, and Sin City were all shot in front of a greenscreen with almost all backgrounds and props computer-generated. All three used proof-of-concept short films. In the case of Sin City, the short film became the prologue of the final film.
Pixar sometimes creates short animated films that use a difficult or untested technique. Their short film Geri's Game used techniques for animation of cloth and of human facial expressions later used in Toy Story 2. Similarly, Pixar created several short films as proofs of concept for new techniques for water motion, sea anemone tentacles, and a slowly appearing whale in preparation for the production of Finding Nemo.
In engineering and technology, a rough prototype of a new idea is often constructed as a "proof of concept". For example, a working concept of an electrical device may be constructed using a breadboard. A patent application often requires a demonstration of functionality prior to being filed. Some universities have proof of concept centers to "fill the 'funding gap'" for "seed-stage investing" and "accelerate the commercialization of university innovations". Proof of concept centers provide "seed funding to novel, early stage research that most often would not be funded by any other conventional source".
In the field of business development and sales, a vendor may allow a prospect customer to trial a product. This use of proof-of-concept helps to establish viability, to isolate technical issues, and to suggest overall direction, as well as providing feedback for budgeting and other forms of internal decision-making processes.
In these cases, the proof of concept may mean the use of specialized sales engineers to ensure that the vendor makes a best-possible effort.
In both computer security and encryption, proof of concept refers to a demonstration that in principle shows how a system may be protected or compromised, without the necessity of building a complete working vehicle for that purpose. Winzapper was a proof of concept which possessed the bare minimum of capabilities needed to selectively remove an item from the Windows Security Log, but it was not optimized in any way.
In software development, the term proof of concept often characterises several distinct processes with different objectives and participant roles: vendor business roles may utilise a proof of concept to establish whether a system satisfies some aspect of the purpose it was designed for. Once a vendor is satisfied, a prototype is developed which is then used to seek funding or to demonstrate to prospective customers.
Although not suggested by natural language, and in contrast to usage in other areas, Proof of Principle and Proof of Concept are not synonymous in drug development. A third term, Proof of Mechanism, is closely related and is also described here. All of these terms lack rigorous definitions and exact usage varies between authors, between institutions and over time. The descriptions given below are intended to be informative and practically useful.
The underlying principle is related to the use of biomarkers as surrogate endpoints in early clinical trials. See for example the introductory discussion on pages 3 to 9 of Downing's Biomarkers and surrogate endpoints: clinical research and applications. In early development it is not practical to directly measure that a drug is effective in treating the desired disease, and a surrogate endpoint is used to guide whether or not it is appropriate to proceed with further testing. For example, although it cannot be determined early that a new antibiotic cures patients with pneumonia, early indicators would include that the drug is effective in killing bacteria in laboratory tests, or that it reduces temperature in infected patients - such a drug would merit further testing to determine the appropriate dose and duration of treatment. A new antihypertension drug could be shown to reduce blood pressure, indicating that it would be useful to conduct more extensive testing of long-term treatment in the expectation of showing reductions in stroke (cerebrovascular accident) or heart attack (myocardial infarction). Surrogate endpoints are often based on laboratory blood tests or imaging investigations like X-ray or CT scan.
Proof of Mechanism or PoM relates to the earliest stages of drug development, often pre-clinical (i.e., before trialling the drug on humans, or before trialling with research animals). It could be based on showing that the drug interacts with the intended molecular receptor or enzyme, and/or affects cell biochemistry in the desired manner and direction.
Proof of Principle or PoP relates to early clinical development and typically refers to an evaluation of the effect of a new treatment on disease biomarkers, but not the clinical endpoints of the condition. Early stage clinical trials may aim to demonstrate Proof of Mechanism, or Proof of Principle, or both.
A decision is made at this point as to whether to progress the drug into later development, or if it should be dropped.
Proof of Concept PoC refers to early clinical drug development, conventionally divided into Phase I and Phase IIa.
Phase I is typically conducted with 10 to 20 healthy volunteers who are given single doses or short courses of treatment (e.g., up to 2 weeks). Studies in this phase aim to show that the new drug has some of the desired clinical activity (e.g., that an experimental anti-hypertensive drug actually has some effect on reducing blood pressure), that it can be tolerated when given to humans, and to give guidance as to dose levels that are worthy of further study. Other Phase I studies aim to investigate how the new drug is absorbed, distributed, metabolised and excreted (so-called ADME studies).
Phase IIa is typically conducted in up to 100 patients with the disease of interest. Studies in this Phase aim to show that the new drug has a useful amount of the desired clinical activity (e.g., that an experimental antihypertensive drug reduces blood pressure by a useful amount), that it can be tolerated when given to humans in the longer term, and to investigate which dose levels might be most suitable for eventual marketing.
A decision is made at this point as to whether to progress the drug into later development, or if it should be dropped. If the drug continues, it will progress into later stage clinical studies, termed "Phase IIb" and "Phase III".
Phase III studies involve larger numbers of patients treated at doses and durations representative of marketed use, and in randomised comparison to placebo and/or existing active drugs. They aim to show convincing, statistically significant evidence of efficacy and to give a better assessment of safety than is possible in smaller, short term studies.
A decision is made at this point as to whether the drug is effective and safe, and if so an application is made to regulatory authorities (such as the US Food and Drug Administration [FDA] and the European Medicines Agency) for the drug to receive permission to be marketed for use outside of clinical trials.
Clinical trials can continue after marketing authorisation has been received, for example to better delineate safety, to determine appropriate use alongside other drugs or to investigate additional uses.