Regulation of Regenerative Medicines: A Global Perspective
53
Long-Term Follow-up Studies
In January 2020, CBER provided updated recom-
mendations on the design of long-term follow-up
studies (LTFU) following administration of gene
therapy products in humans.26 While a follow-up
period is typically described in the main clinical
study protocol, long-term follow-up studies are
intended to obtain longitudinal adverse event
data from patients after the primary follow-up
period has ended adverse events that occur in
this timeframe are referred to as delayed adverse
events. Figure 6-1 is adapted from FDA’s assess-
ment process.27 The risks associated with delayed
adverse events are largely founded on the bio-
logical characteristics of the vectors used in gene
therapy products and informed by the extensive
preclinical and clinical experience gained to date.
These characteristics include the following:28
• The capability of vectors to integrate
non-specifically to the host genome
• Prolonged or sustained expression of the
therapeutic gene of interest may promote
unchecked cell growth or latency
• Replication competent viruses and bac-
teria-based vectors may lead to persistent
infection in immunocompromised patients
Note: According to the LTFU guidance, FDA
advises observation of subjects for 15 years
after exposure to the highest-risk gene therapy
products (e.g., integrating viral vectors such
as lentivirus), with a minimum of five years of
annual examinations and 10 years of annual
in-person queries or questionnaires of the study
subjects.29
Figure 6-1. Framework to Assess the Risk of Gene Therapy-Related Delayed Adverse Events
Gene therapy products
Genome-editing technology used? Clinical protocols should include
long term follow-up observations
Is the vector used only for ex
vivo modification of cells?
Do preclinical study results show
persistence of the product?
Are the vector sequences
integrated or is the human genome
otherwise genetically altered?
Does the product have the potential
for latency and reactivation?
Low risk of product-related delayed
adverse events. Long term follow-up
observations may not be needed.
Clinical protocols should include
long term follow-up observations.
No
No
No
No
Yes
Yes
No
Yes
Yes
Note: Please see FDA guidance for industry: long term follow-up after administration of human gene therapy products for
nonbinding recommendations and additional considerations for products that may integrate or were designed to facilitate
integration this guidance also includes recommendations on how to perform clinical long-term follow-up observations.
53
Long-Term Follow-up Studies
In January 2020, CBER provided updated recom-
mendations on the design of long-term follow-up
studies (LTFU) following administration of gene
therapy products in humans.26 While a follow-up
period is typically described in the main clinical
study protocol, long-term follow-up studies are
intended to obtain longitudinal adverse event
data from patients after the primary follow-up
period has ended adverse events that occur in
this timeframe are referred to as delayed adverse
events. Figure 6-1 is adapted from FDA’s assess-
ment process.27 The risks associated with delayed
adverse events are largely founded on the bio-
logical characteristics of the vectors used in gene
therapy products and informed by the extensive
preclinical and clinical experience gained to date.
These characteristics include the following:28
• The capability of vectors to integrate
non-specifically to the host genome
• Prolonged or sustained expression of the
therapeutic gene of interest may promote
unchecked cell growth or latency
• Replication competent viruses and bac-
teria-based vectors may lead to persistent
infection in immunocompromised patients
Note: According to the LTFU guidance, FDA
advises observation of subjects for 15 years
after exposure to the highest-risk gene therapy
products (e.g., integrating viral vectors such
as lentivirus), with a minimum of five years of
annual examinations and 10 years of annual
in-person queries or questionnaires of the study
subjects.29
Figure 6-1. Framework to Assess the Risk of Gene Therapy-Related Delayed Adverse Events
Gene therapy products
Genome-editing technology used? Clinical protocols should include
long term follow-up observations
Is the vector used only for ex
vivo modification of cells?
Do preclinical study results show
persistence of the product?
Are the vector sequences
integrated or is the human genome
otherwise genetically altered?
Does the product have the potential
for latency and reactivation?
Low risk of product-related delayed
adverse events. Long term follow-up
observations may not be needed.
Clinical protocols should include
long term follow-up observations.
No
No
No
No
Yes
Yes
No
Yes
Yes
Note: Please see FDA guidance for industry: long term follow-up after administration of human gene therapy products for
nonbinding recommendations and additional considerations for products that may integrate or were designed to facilitate
integration this guidance also includes recommendations on how to perform clinical long-term follow-up observations.