FIH Studies

Estimating the first in human (FIH) dose is one of the initial steps in the clinical development of any molecule that has successfully gone through all of the hurdles in preclinical evaluations. It is an important parameter in the FIH clinical trials, since a high starting dose may cause serious toxicity in volunteers, while a low starting dose could prolong the dose escalation/optimization, leading to unnecessary delay in the clinical programs. Conversion of animal data into human equivalent doses (HED) is therefore essential. In 2005, the US Food and Drug Administration (FDA) issued guidance on estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers, which provided a framework to carry out the estimation. The process of calculating the MRSD should begin after the toxicity data have been analyzed. Note that the European Counterpart, the European Medicine Agency (EMA), has a comparable approach, but there as some differences. One of the main difference is that the FDA centralizes the No-observed adverse effect level (NOAEL). In other words, dosing is very heavily dependent on calculations based on the toxicology of the compound, and exceptions may be possible. The EMA, on the other hand, also recommends the use of NOAEL, but also includes more explicitely the approach of the minimum anticipated biologic effect level (MABEL). In other words, which dose shows pharmacological acitivity. Below you find several definitions of all these terms.

There is a discussion on dosing in humans is allowed with only a proper indication on toxicology data, without any information of pharmacological effect levels. The issue is that when only looking at toxicology levels, one risk that healthy volunteers are exposed to doses that are already well beyond the level necessary for a clinical effect.  So there is no need to increase the dose any further, since clinical effects will already occur at a lower dose range. However, when the maximum tolerated dose (MTD) is not yet reached in healthy volunteers, this could still be a reason to increase the dose since no toxicological indications appear. Nowadays, there's a debate whether dose ascending studies to find the MTD should take place at all, particularly if there is no scientific rationale for a further dose increase. 

Definitions

• Maximum recommended starting dosage (MRSD): maximum dose in which a clinical trial should start. The classical calculation only considers the NOAEL to obtain this value
• Level: Refers to the dose or dosage, generally expressed as mg/kg or mg/kg/day. 
• No Observed Adverse Effect Level (NOAEL): The highest dose level that does not produce a significant increase in adverse effects.
• No Observed Effect Level (NOEL): Refers to any effect, not just adverse ones, although in some cases the two might be identical.
• Minimal Anticipated Biological Effect Levels (MABEL): The lowest dose that is associated with any biological effect, whether it be toxicity or a desired pharmacological effect
• Human Equivalent Dose (HED): The quantity of a chemical that, when administered to humans, produces an effect equal to that produced in test animals by a smaller dose. 

  More extensive information can be found at: https://www.slideshare.net/RamakanthGadepalli/first-in-human-dose