Regulatory Issues: Down to the Bare Bones - Engineered Bone: Tissue Engineering Intelligence Unit - page 208

Unfortunately innovative therapies were already shown to carry potential unwanted effects,
besides being sometimes unclear regarding the benefits gained by the patients as already tragi-
cally experienced in the case of gene therapy. 4-7 Furthermore, few preclinical data have been
published and toxicological evaluations are seldom found in the literature for the ancillary
substances that may still contaminate the final product. Nontissue components, even though
to a lesser extent, could also represent means of unwanted effects. It should be stressed that
tissue-based products that are intended for therapeutic use, that contain synthetic or mechani-
cal components and that achieve their primary mode of action by means other than metabolic
or systemic action are regulated as devices, including combination products. In the United
States, their evaluation should therefore be carried out by the Center for Device and Radiologi-
cal Health (CDRH) of the FDA. 8 Premarket investigations and clinical trials would be re-
quired under investigational new drugs (IND) or investigation new device exemptions (IDE),
as appropriate.
Composite products for tissue-engineering of skeletal tissues are comprised of two or more
regulated components, i.e., drug/device, biologic/device, drug/biologic or drug/device/biologic
that are physically, chemically or otherwise combined or mixed and produced as a single en-
tity. 9 Composites such as a biomaterial associated to bioactive molecules (growth factors,
cytokines, etc.) may ultimately be considered as devices exerting their action as a drug, and
therefore be regulated by the Center for Drug Evaluation and Research (CDER) of the FDA.
Other composites, such as a porous ceramic associated to autologous osteogenic cells, would
obviously fall under two categories. Wisely the FDA has recognized the possible overlaps of
competence in the evaluation process of these new therapeutic agents. In the same document,
therefore, a clear statement was made to sustain the setting of a Tissue Reference Group, com-
posed of six members, three of the CBER and three of the CDRH, to assist in making jurisdic-
tional decisions and applying consistent policy to these products. 8 The bottom line is that the
mode of action of the combination product, once defined, dictates which FDA branch will
review applications and draw the rules for the therapeutic use.
In the “Proposed approach to regulation of cellular and tissue-based products” issued by the
FDA it is also stated that “...for combination products with synthetic or mechanical compo-
nents (which comprise the largest class of combination products), clinical trials and marketing
applications must address the clinical safety and effectivness of the overall product, as well as
the function and compatibility of the synthetic or mechanical components. The agency princi-
pal concerns are that they function correctly, that they last a predictable and adequate length of
time and that they are compatible with surrounding tissues...”. 8
Thus the real challenge for national and international regulatory boards is how to step into
a guideline and law proposal strategy that grants efficiency and at the same time sufficient
flexibility to meet the patients' needs and rights, the scientific innovations and the
market-oriented enterprises.
The Backbone of the Current Regulatory Frameworks
for Cell Therapy Products
This section is a summary of most recent and updated guideline for design/manufacturing
of a tissue engineered product to be used for cartilage/bone repair. It should be noted that any
nation may have considered or may be considering to introduce, apply and enforce additional
regulatory requirements.
In this overview, we will not encompass the current issues that rule the procedures used to
manipulate whole organs or minimally-manipulated bone marrow (both of which are under
the Health Resources and Service Administration in the US), or the transfusable blood prod-
ucts (i.e., whole blood, red blood cells, platelets and plasma) which are ruled separately. We will
not deal also with the current framework for tissue-related products, such as those derived from
animals, with products used in the propagation of cells or tissues, or products that are secreted
from cells or tissues, (such as human milk, collagen or growth factors).