One of my Colleagues Dr Anthony Lockett recently attended a presentation by David R. Jones an expert scientific assessor (Pharmacotoxicologist) at the MHRA who gave a very useful update on the area of safety testing with regard to Phase I studies.

One of the topics under discussion was Microdosing in Phase 1 clinical trials.

There is a new section of the ICH M3 guidelines, – EXPLORATORY CLINICAL STUDIES

It has been recognised that in some cases insight on human physiology / pharmacology, knowledge of drug candidate characteristics and therapeutic target relevance to disease are benefited by earlier access to human data. This new section in the guidance hopes to provide an avenue to meet this end.

The rational is that if you screen drugs early in man, you enable better drug candidate selection, which means less overall exposure to man and reduced animal “wastage”, which in tern is good for the industry and good for the public. Even where you only have one drug candidate you can get an earlier decision on future development potential.

These exploratory clinical studies are intended to be conducted very early on in phase I, involve limited human exposure, there can be no therapeutic or diagnostic intent (this is very important) and maximum tolerated dose (MTD) style designs will not be accepted, these are strictly PK/PD studies.  Its not a free for all, some appropriate characterisation of pharmacology using in-vivo and/or in-vitro models is needed  to support dose selection. (the EMEA document of interest is EMEA/CHMP/SWP/28367/07 Guideline on strategies to identify and mitigate risks for first-in-man clinical trials with investigational medicinal products).

These new rules apply to all new chemical and biological IMP’s (investigational medicinal products) with the exception of gene and cell therapy products. The guidlines provides a detailed requirement for supporting non-clinical work and provides designs for the conduct of the trials.  (these should be read before any CTA is submitted). There are 5 approaches described, but other justifiable approaches can be discussed with the regulators. the Key feature is that non-clinical requirements are much reduced when compared to “traditional” exploratory studies in man.

1. The first (microdosing) is limited to not more than a total of 100ug that can be divided among up to five doses in any subject
2. The second (microdosing) is limited to 100ug per subject per administration to up to a total of 500ug
3. Single dose study at sub-therapeutic or into anticipated therapeutic range studies. Maximum allowable dose is half the NOAEL
4. 14 days of clinical dosing into the therapeutic range – PK/PD only not MTD
5. 14 days of clinical dosing into the therapeutic range – PK/PD only not MTD – different designs

The non-clinical requirements are laid out in the guidance for these studies and are much reduced compared to what has been required in the past.

If you would like any assistance with these new guidelines or how you can use them to mange the risks in your programme or accelerate your development programme don’t hesitate to get in touch.

Click Here to Access – ICHM3 Expert Services – Click Here

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology), we work with our clients to define a development target, define a development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch using the contact form or email Damien at damien.bove@idaconsultants.com