» Can you explain the positions by the US Food and Drug Administration and the European Medicines Agency on microdosing? Is
microdosing under consideration by the International Conference on Harmonization?
In terms of toxicology requirements, in order to commence a microdosing study, FDA requires a single-dose, 14-day study in
both sexes of an appropriate mammalian species with interim sacrifice and histopathology. The intended route of human administration
should be used, and an 100-fold safety factor, taking into consideration allometric scaling for the species, should be used
to select the dose for the clinical trial. FDA does not require any genetic toxicology or safety pharmacology to be performed
EMEA requires a single-dose, 14-day study in both sexes of a justified mammalian species to include a control group. An interim
sacrifice and histopathology are required. IV, as well as the intended clinical route of administration is recommended. (If
the intended route is IV, then this route alone will suffice). Allometric scaling from animal species to man and using a safety
factor of 1000 should be used to set the dose limit. For genotoxicity studies, an abridged Ames test and abridged human lymphocyte,
chromosome aberrations, mouse lymphoma, or in vitro micronucleus test are sufficient (2).
For FDA and EMEA, the compound does not have to be GMP [good manufacturing practices] material but should come with a certificate
of analysis. Ideally, the same batch used for human microdosing should also be used for the toxicology studies.
At the current time, I am not aware of any consideration to harmonize microdosing by ICH. It would seem a next logical step
as the number of molecules tested this way continues to rise and the studies become more routine.
» What are microdosing's limitations and where does the industry stand in adopting microdosing?
The technique is most useful in candidate selection to rank the order of a lead compound against a number of backups. It is
also useful in situations where there may be conflicting animal data and the addition of early human data may significantly
aid the decision process. In addition, an IV microdose can provide data on the fundamental PK of a drug, not possible from
an oral dose alone. A current limitation is that we have too few data to form general views on which compounds or classes
of compounds the technique would be most useful.
Microdosing has been widely accepted by many companies as a way to get very early human data to increase confidence in taking
a drug forward into further development. It is one method of killing drugs with inappropriate PK properties and only advancing
the best drug candidates, thereby minimizing the risk of later-stage clinical failure. It is obvious that the industry needs
to change given the dearth of new chemical entities being approved and the increasing number of late-stage failures.
In our experience, it has been the small-to medium-sized pharmaceutical and biotechnology companies that have been the major
adopters of microdosing, but we are now starting to see a greater number of large pharmaceutical companies taking an interest
in the technology. The decision process tends to be much quicker in a small company, and I believe that microdosing provides
them with an edge whereby they can use scarce resources to really accelerate their programs by gaining early human data to
enable smarter decision-making.
In my opinion, the continued use and advancement of microdosing in drug development will most likely require:
Continued support of the methodology by regulatory agencies through programs such as FDA's Critical Path Initiative
Increasing the amount of data in the public domain with comparative results between microdose and pharmacological dose PK
across major classes of drugs. Xceleron coordinated the CREAM Trial in 2005–2006 and EUMAPP in 2007–2008 to do that. A similar
public–private partnership in North America could lend further support to the value of microdosing.
Improvements in the process such as on-line separation techniques coupling HPLC and AMS. Currently the separation is conducted
Greater general acceptance of the technology by the industry. Xceleron's service offerings in Phase 1 with META-ID and IV-PK
at pharmacologic doses and a microtracer of radioactivity have gained broad industry acceptance, and this, in turn, may bode
well for both the technology and its application in microdosing.