gene and other biotechnology therapies in princi-
ple, there is often greater complexity associated
with the former. These complexities include uncer-
tainties with preclinical toxicology and the poten-
tial for germ cell line incorporation.
Firstly, the toxicology of any gene therapy needs
to be considered as a combination of three pro-
ducts: the construct, nongenetic elements in the
construct (e.g.pharmaceutical adjuvant-stabilizing
materials) and thirdly the vector.
Secondly, there is a need to test in animals the
possibility of incorporation of the therapeutic gene
into the germ cell line. Many constructs contain
multiple genes: not only is the therapeutic gene
present, but also genes to assist in manufacturing,
for example those conferring antibiotic resistance
to the microorganism that is being used for produc-
tion, or a gene for a marker enzyme. All these genes
require toxicological assurance that they do not
incorporate into the germ cell line, and thus will
not be replicated in the offspring of the treated
patient. This is a special field of toxicology that is
still in its infancy; in some cases clinical trials have
to be restricted to surgically sterile patients in the
absence of this information.
Regulatory issues specific
to gene therapies
In the United States and Europe gene therapy pro-
tocols attract an additional degree of regulatory
review. Not only must an IND be approved by the
US FDA, but also the protocol must be approved by
the Recombinant DNA Advisory Committee of the
National Institutes of Health (the ‘RAC’). To date,
many dozens of such protocols have been approved,
withthe largest groupfor therapies that are designed
to increase production of a specific cytokine in a
specifictissuelocation. In Europethereisno equiva-
lent to the RAC, and regulatory requirements are
handled within the national regulatory authorities
reviewing research protocols for investigational
agents. There is no anticipation of product licence
applications in Europe. Gene therapies are also
exempt from the time limits that usually apply to
the review of clinical trial protocols by national
competent authorities in Europe.
22.9 Cell and tissue products
There are various clinical conditions where admin-
istration of cultured whole cells or tissue may be
desirable. The sources of these tissues are as
diverse as the disease targets. For example, cul-
tured fibroblasts from human prepuces are being
developed as ‘artificial skin’ for the treatment of
leg ulcers and burns (Advanced Tissue Sciences,
La Jolla, California; Smith and Nephew, Romford,
UK). Other companies are developing implantable
pancreas generated from isolated pancreatic islet
cells. Unlike matched transplantations, such thera-
pies may involve treatment of large numbers of
patients from a limited or sole initial human source
or may be autologous albeit after someex vivo
manipulation and culturing of the cell mass before
reimplantation.
Ex vivotherapeutic strategies may take different
forms. Chronic lymphocytic leukemias have been
treated for long periods of time by using cell
separators to reduce the burden of lymphocytosis,
and to permit red cell transfusion. Laser-directed
cell sorters may be used to select appropriate sub-
populations of lymphocytes, which are then trans-
fected with an appropriate gene productex vivoand
returned to the patient, where these cells will hope-
fully target some diseased tissue such as widespread
melanoma. Expense, availability of therapy and the
duration and specificity of effect currently limit the
widespread application of these approaches.22.10 General ethical issues
The modern advances of biotechnology create
numerous ethical issues. Care should be taken in
relating directly the therapy type and the ethical
issue. Moreover, ethical standards vary among
highly respected ‘experts’. Indeed, it can be said
that, to some extent, everyone is an ethicist, and
those involved in biological product development
certainly should be.
It is easy for those without technical training
to extrapolate thatallbiological products have
the same range of ethical issues which actually
only affectsomeof these therapies and because288 CH22 BIOTECHNOLOGY PRODUCTS AND DEVELOPMENT