Regulatory Issues: Down to the Bare Bones - Engineered Bone: Tissue Engineering Intelligence Unit - page 207

Tissue-Engineered Products: Drugs, Biologics or Devices?
Cell and gene therapies represent new approaches not feasible only a few years ago. They are
focused on the patient, in many cases the human subject being the source of his/her own means
of cure (autologous cell therapies). The first worldwide authority organization to recognize the
need of appropriate guidelines for this type of therapies was the American Food and Drug
Administration. It is of relevance that the US attention to the issue came as a direct conse-
quence of the vital framework that interconnects the industry and the academic world in the
North American scientific community. Presently several national and international public of-
fices deputed to drug regulation, among which the Center for Biologics Evaluation and Re-
search (CBER) of the american Food and Drug Administration (FDA) and the European Agency
for the Evaluation of Medicinal Products (EMEA), are developing rules and guideline for the
manufacturing and use of tissue engineering products.
Initial regulations in the field were derived from the interim rule for banked human tissue
promulgated in the American federal register on December 14 th , 1993, entitled “Human tissue
intended for transplantation”. 1 In this document banked human tissue products are defined as
“…derived from a human body which: (1) is intended for administration to another human
for the diagnosis, cure, mitigation, treatment or prevention of any condition or disease; (2) is
recovered, processed, stored, or distributed by methods not intended to change tissue function
or characteristics; (3) is not currently regulated as a human drug, biological product, or medi-
cal device; (4) excludes kidney, liver, heart, lungs, pancreas, or any other vascularized human
organs; (5) excludes semen or other reproductive human tissues, human milk and bone mar-
row…”. In addition, recognizing that the sponsors of the developing tissue and cell based
therapies were willing to render their products commercially available, another note was issued
on the federal register within the same year, defining the somatic cell therapy products as
“…autologous (self ), allogenic (intra-species), or xenogenic (inter-species) cells that have been
propagated expanded, selected, pharmacologically treated, or otherwise altered in biological
characteristics ex vivo to be administered to humans and applicable to the prevention, treat-
ment, cure, diagnosis, or mitigation of diseases or injuries…”. 2 In this document a relevant
statement was promulgated by the FDA, and widely accepted by the international scientific
community: the definition of “manipulation of cells” was described as the ex vivo propagation,
expansion, selection, or pharmacological treatment of cells or other alteration of their biologi-
cal characteristics. 2 Clear emphasis was posed on the need to precisely frame a “biological
characteristic” (unique and identified by any specific technical means) and its “normal” or
“altered” condition.
Nonetheless these regulations were insufficient for a higher scale exploitation of the tech-
nology and for its transfer to the market, mainly for the temporary absence of reference stan-
dards, of product quality assessments and of lot release controls. Instead, the required screening
of the starting material was already partially regulated, taking advantage of the issues dedicated
to the transplantation of human tissues. 1
Thus the industrial and the private investments world were looked upon as proponent
counterparts by the regulatory boards. On the contrary the academic world hardly interfaces
with the legislator, traditionally focusing on basic research as a primary goal. Academic scien-
tists may often be applying an innovative approach that clinically works but that was never
screened nor approved by any official board and/or national commission. 3 It should be stressed
that, as a consequence, these therapeutic approaches have grown to the status of “possible
marketable products” either from only partially controlled clinical trials or directly off the
bench of academic institutions. In this respect, therapies that take advantage of autologous cell
culturing often derive the culture conditions directly from the optimizations run on the labo-
ratory benches. Usually several media are tested, with different self-made modifications, in-
deed needed for specific cell types or for particular growth conditions. Nonetheless, ancillary
products, such as growth factors, cytokines or chemicals in the culture media, not intended to
be part of the final product, might affect its quality, effectiveness, or safety.