Regulatory Issues: Down to the Bare Bones - Engineered Bone: Tissue Engineering Intelligence Unit - page 209

Cell Therapy Products
In the USA, the Center for Drug Evaluation and Research (CDER) has been assigned as the
FDA component that has the primary jurisdiction for the regulation and the premarket ap-
proval of the products derived from autologous cells manipulated ex vivo (MAS cells). Clinical
investigations of MAS cell products should be performed in accordance with the requirements
for investigation of new drugs and they are subject to licensure as biological products. The
current Good Manufacturing Practice regulations (GMPs) will apply, although FDA intends
to consider on a case-to case basis alternative approaches to specific regulations, when these
may be impractical or unnecessary to assure safety, purity and efficacy of the product. 10
Establishments engaged in the manufacture of the MAS cell products should register as a
drug manufacturer, and should be subjected to inspections on a biannual basis by a representa-
tive of the CBER and by an investigator from the closest FDA District Office.
European or Asian nations will refer to the European Agency for the Evaluation of Medici-
nal Products (EMEA) or to national authorities for regulatory jurisdiction and similar control-
ling actions. It should be stressed that US officials will not allow marketing within the USA of
MAS cell products manufactured in a plant outside USA, unless directly approved by the FDA
or unless evaluated through a FDA-approved review process.
Whether the MAS cell product will be applied by public institutions or sponsored by pri-
vate companies, investigative clinical studies will be required. The FDA guidance on “Applica-
tions for products comprised of living autologous cells” also state that “...Prospective random-
ized clinical studies traditionally have been the best way to demonstrate safety and efficacy.
However, where studies of MAS cells without internal patient controls provide evidence of
effective structural repair which substantially and clearly represents improvements in outcomes
compared to patients in an appropriate historical databases, this may be sufficient to demon-
strate efficacy...”. 10
To follow the proper guidance for clinical trials, early contacts of the proponents with the
relevant authorities are strongly recommended. Previous to any activity, the structures where
the tissue engineered products will be manufactured and clinical experimentations will be car-
ried out need to be credited and certified by the competent authorities. 11,12 Within the term
“structure” several items are included, such as room and building requirements, hardware re-
quirements, as well as legal and clinical/scientific responsible officers.
In several European countries, Ethical Committees within hospitals have the power to ap-
prove or refuse clinical trial proposals on the basis of the risk assessment for the patient. They
also are the proper administrative body to overview adherence to international and national
law requirements including the existence of adequate manufacturing structures. If the use of a
new drug/device/biologic is suggested and the risk evaluation is undetermined or unclear, as in
most cases of tissue engineered products, the appointed committee may directly request the
Ministry of Health and/or national health institutions approval. In the case of Italy, for ex-
ample, this is the proper role of the Istituto Superiore di Sanita'. 13 The Istituto Superiore di
Sanita' would require, in turn, immediate interaction with the proponents to establish a con-
trolled phase I clinical study, according to all the GMPs, law and guidance recommendations.

Manufacturing Facilities
Following are some specific points to be considered before proposing a clinical study to
prove safety and efficacy of a tissue engineered product.

General Room/Building and Hardware Requirements
•

all cultures for tissue engineering purposes will have to be performed aseptically and by
using sterile instruments;

• source tissue harvesting and cell culturing must be performed in GMP approved rooms.

Whenever necessary, as for gene therapy applications or as decided on a case-to-case basis
by the appropriate authority, in biosafety containment level 3 rooms (BL3; the rooms must