Editing Proof of concept (section)

=== Drug development===
{{Unreferenced section|date=March 2020}}
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.{{citation needed|date=February 2015}}

The underlying principle is related to the use of biomarkers as surrogate endpoints in early clinical trials.<ref>See for example the introductory discussion on pages 3 to 9 of: {{cite book|last=Downing|first=Gregory|title=Biomarkers and surrogate endpoints: clinical research and applications|year=2000|publisher=Elsevier|isbn=0-444-50316-1|url=https://books.google.com/books?id=QrN_TCCHJOQC&q=surrogate+endpoint+"proof+of+concept"&pg=PA3}}</ref> 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 anti-hypertension 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.{{citation needed|date=February 2015}}

* ''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.<ref>{{cite journal |doi=10.1016/j.eplepsyres.2005.09.019|pmid=16377153|title=Proof of principle studies|journal=Epilepsy Research|volume=68|issue=1|pages=48–52|year=2006|last1=Schmidt|first1=Bernd|s2cid=7277700}}</ref> 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'' or PoC refers to early clinical drug development, conventionally divided into the [[phases of clinical research]] Phase I ("first-in-humans") and Phase IIA.

Phase I is typically conducted with a small number of 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 (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 anti-hypertensive 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—commonly [[multicenter trial]]s—treated at doses and durations representative of marketed use, and [[Randomized controlled trial|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 authorization has been received, for example, to better delineate safety, to determine appropriate use alongside other drugs or to investigate additional uses.