Biomedical Engineering Reference
In-Depth Information
rodent and one non-rodent species) chosen for similarities to
humans with regard to the organ system of interest and susceptibil-
ity to drug class (if known). The toxicity studies may range from
2 weeks to 3 months of drug exposure, depending on the proposed
duration of use of the drug in clinical studies [
6
,
7
].
It is important that the drug sponsor (drug developer seeking
to bring a drug to market) requests a meeting with the appropriate
contacts in either the FDA or the EMA before preclinical testing is
complete. There should be sufficient pilot data in hand to guide
decisions about further testing, but enough flexibility in the devel-
opment plan that modifications can be made if the agency requests
changes [
1
]. The drug sponsor should come to the meeting with a
list of questions about whether specific aspects of their develop-
ment plan and study designs are considered sufficient to support a
successful application to proceed with clinical testing. For example,
in the testing of intraocular implants it is common to use rabbits
and monkeys rather than rodents because of the need to use animal
models with large enough eyes to accommodate the implant.
Agency preapproval of this approach should always be obtained,
however, to ensure that the preclinical package is acceptable.
It is common knowledge that most candidate drugs never make
it out of this stage of development. Any sign of unfavorable phar-
macology, excessive toxicity, or other safety issues can and, in most
cases, should cause a drug to be removed from further development
activities; exceptions are drugs intended for conditions with a high
rate of morbidity/mortality for which there is no effective treat-
ment. If, however, preclinical testing has demonstrated that the
product is safe for initial use in humans and exhibits pharmacologi-
cal activity that justifies commercial development, the drug devel-
oper can apply for approval to proceed with human testing.
The vehicle through which a drug sponsor advances their product
to clinical testing in the US is called the Investigational New Drug
Application (IND) [
6
]. The IND does not specifically authorize
clinical trials to begin, but rather allows an investigational product
to be shipped across state lines to reach the appropriate clinical
investigational sites. After the IND is submitted, the sponsor
must wait 30 calendar days before initiating any clinical trials [
6
].
During this time, the Center for Drug Evaluation and Research
(CDER) at the FDA will review the IND for safety to assure that
research subjects will not be subjected to unreasonable risk [
6
].
If the CDER is not convinced that clinical trials can be conducted
without unreasonable risk to human subjects, they will initiate a
clinical hold (within the 30-day review period) to stop the clinical
trial. The sponsor must then address the issue(s) that the CDER
identifies as the reason for the clinical hold before the hold can be
lifted and clinical trials can continue [
6
].
2.2 Obtaining
Approval to Proceed
with Clinical Testing
in Humans
