Chapter 6: Gene Therapy and Viral Vectors: An Overview on Current Trends
52
are manufactured, and the evolving nature of the
field, using the traditional approaches developed
for small molecules and devices, for example,
may not be appropriate in the evaluation of
CGT products. Therefore, early engagement and
communication between sponsors and FDA
are encouraged. Products that meet the criteria
as a regenerative medicine advanced therapy
(RMAT) may qualify for expedited development
and review by CBER.23
Data from preclinical studies are needed to
not only support the safety of the CGT product,
but also to inform various aspects of the clinical
protocol, including dose, dosing regimen, route
of administration, inclusion/exclusion crite-
ria, and safety monitoring. Key suggestions or
recommendations for the design of these critical
studies are briefly outlined below:24
• Due to inherent lot-to-lot variations, it is
important that the specific lot of the product
be well characterized. Therefore, if possible,
the lot of CGT product to be administered
in humans should be the same as that used
in the in vitro and in vivo preclinical studies
in animals, with any differences discussed
in the IND. Please note that considerations
for the large-scale manufacture of viral
vector-based gene therapy products include
producing sufficient quantities to be used in
key preclinical studies as well as the planned
clinical studies.
• To derive pertinent information that can
guide the design of the clinical study,
appropriate animal species should be used
in preclinical studies. Test species that are
considered “non-standard” (e.g., transgenic
or large animals) may be used if an adequate
scientifically based justification is provided.
Specific animal models of disease or injury
also may be used in preclinical studies to
evaluate the mechanism of action, efficacy,
and safety of CGT products, as well as
inform the safety monitoring criteria in
clinical trials.
• Non-GLP proof-of-concept or pilot studies
may be conducted prior to definitive pre-
clinical studies. However, a comprehensive
safety assessment should be conducted in
preclinical, GLP toxicology studies. Key
design features of such pivotal studies
include the proposed clinical indication
appropriate animal species selected ade-
quate number of animals per gender for
each group evaluation of safety endpoints,
including mortality, body weights and his-
topathology and appropriate time points or
study duration. Findings from these studies
can provide a no observed adverse effect
level (NOAEL) to inform the selection of
the planned starting dose and dose-escala-
tion schedule.
In addition to the suggestions or recommen-
dations above, specific considerations for gene
therapy products include:25
• Safety concerns arising from the ex vivo
and in vivo administration of the investi-
gational GT product need to be addressed.
Study designs should include evaluations of
toxicities due to the route of administration,
any immune response towards the vector,
and mutagenic/oncogenic potential, to name
a few.
• The impact of the conditioning regimen
and expression profile of the transgene also
should be assessed as persistent expression
may lead to 1) overexpression, 2) accumu-
lation, or 3) abnormal immune response.
Note: Robust and sensitive quantitative
methods, such as RT-PCR, should be used
to determine transgene expression.
• Characterization of the biodistribution pro-
file of the vector after administration in vivo
is critical in determining its fate in target
and non-target tissues or fluids. The vector’s
persistence and clearance profile as well as
any histopathology findings can inform the
dosing schedule and safety monitoring.
Overall, considerations for the preclinical
assessment of CGT products for use in humans
require a systematic and comprehensive approach
to adequately determine their efficacy and safety
profile. To the extent possible, the study design
of preclinical studies should mimic the design of
the clinical trial.
52
are manufactured, and the evolving nature of the
field, using the traditional approaches developed
for small molecules and devices, for example,
may not be appropriate in the evaluation of
CGT products. Therefore, early engagement and
communication between sponsors and FDA
are encouraged. Products that meet the criteria
as a regenerative medicine advanced therapy
(RMAT) may qualify for expedited development
and review by CBER.23
Data from preclinical studies are needed to
not only support the safety of the CGT product,
but also to inform various aspects of the clinical
protocol, including dose, dosing regimen, route
of administration, inclusion/exclusion crite-
ria, and safety monitoring. Key suggestions or
recommendations for the design of these critical
studies are briefly outlined below:24
• Due to inherent lot-to-lot variations, it is
important that the specific lot of the product
be well characterized. Therefore, if possible,
the lot of CGT product to be administered
in humans should be the same as that used
in the in vitro and in vivo preclinical studies
in animals, with any differences discussed
in the IND. Please note that considerations
for the large-scale manufacture of viral
vector-based gene therapy products include
producing sufficient quantities to be used in
key preclinical studies as well as the planned
clinical studies.
• To derive pertinent information that can
guide the design of the clinical study,
appropriate animal species should be used
in preclinical studies. Test species that are
considered “non-standard” (e.g., transgenic
or large animals) may be used if an adequate
scientifically based justification is provided.
Specific animal models of disease or injury
also may be used in preclinical studies to
evaluate the mechanism of action, efficacy,
and safety of CGT products, as well as
inform the safety monitoring criteria in
clinical trials.
• Non-GLP proof-of-concept or pilot studies
may be conducted prior to definitive pre-
clinical studies. However, a comprehensive
safety assessment should be conducted in
preclinical, GLP toxicology studies. Key
design features of such pivotal studies
include the proposed clinical indication
appropriate animal species selected ade-
quate number of animals per gender for
each group evaluation of safety endpoints,
including mortality, body weights and his-
topathology and appropriate time points or
study duration. Findings from these studies
can provide a no observed adverse effect
level (NOAEL) to inform the selection of
the planned starting dose and dose-escala-
tion schedule.
In addition to the suggestions or recommen-
dations above, specific considerations for gene
therapy products include:25
• Safety concerns arising from the ex vivo
and in vivo administration of the investi-
gational GT product need to be addressed.
Study designs should include evaluations of
toxicities due to the route of administration,
any immune response towards the vector,
and mutagenic/oncogenic potential, to name
a few.
• The impact of the conditioning regimen
and expression profile of the transgene also
should be assessed as persistent expression
may lead to 1) overexpression, 2) accumu-
lation, or 3) abnormal immune response.
Note: Robust and sensitive quantitative
methods, such as RT-PCR, should be used
to determine transgene expression.
• Characterization of the biodistribution pro-
file of the vector after administration in vivo
is critical in determining its fate in target
and non-target tissues or fluids. The vector’s
persistence and clearance profile as well as
any histopathology findings can inform the
dosing schedule and safety monitoring.
Overall, considerations for the preclinical
assessment of CGT products for use in humans
require a systematic and comprehensive approach
to adequately determine their efficacy and safety
profile. To the extent possible, the study design
of preclinical studies should mimic the design of
the clinical trial.