Biomedical Engineering Reference
In-Depth Information
Preclinical Studies
Pharmacology and toxicology in animals
Apply for Approval for Human Testing
US: Investigational New Drug Application
EU: Investigational Medicinal Product Dossier
Clinical Trials
Phase I
Safety, pharmacology, &
dosing in small number of
patients or healthy
volunteers
Phase 2
Safety, efficacy, &
optimal dosing in
small number of
patients
Phase 3
Pivotal safety & efficacy
studies needed to support
marketing approval (enroll
large number of patients)
Apply for Marketing Authorization
US: New Drug Application
EU: Common Technical Document
US
One pathway
EU
Three pathways
Centralized
Single application
submitted to EMA
Mutual
Recognition
Apply to RMS only
Decentralized
Apply to several
countries at once
Reviewed by Center for
Drug Evaluation and
Research Scientists
(advisory board
optional)
Reviewed through
Committee for
Human Medicinal
Products
Reviewed through
RMS national
procedure
RMS reviews and
sends report to
other countries
If approved, can
seek further
approval from
other countries
who have agreed to
recognize RMS
decision rather than
conduct own
review
If approved, grants
authorization in all
countries to which
applied
If approved, grants
authorization in all
EU and EEA
countries
Fig. 1 Drug Development and Approval Process in the United States (US) and the European Union (EU). EMA:
European Medicines Agency; RMS: Reference member state; EEA: European Economic Area
2.1 Preclinical
Development
Worldwide, a candidate clinical therapeutic begins the drug devel-
opment process with extensive in vitro and in vivo testing in non-
human models. A successful preclinical development program
should provide all the information needed to determine if the
drug is appropriate for further testing in human subjects [
6
]. To
obtain approval for human testing in either the US or the EU,
preclinical testing should establish a detailed pharmacologic profile
of the drug, including pharmacokinetics, pharmacodynamics, and
mechanism of action [
6
,
7
]. It should also determine the acute
toxicity of the drug in at least two species of animals (usually one
