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0:00
Hi, everyone. I'm
Avery McIntosh,
and I'm very glad to be
with you here today.
This talk is on
long-term follow-up
of gene therapy
trial participants:
practical and statistical
considerations.
0:15
Health authorities such as
the US Food and Drug
Administration,
European Medicines Agency and
Chinese regulatory
bodies require
subjects administered
gene therapy
to be followed for 5-15 years.
The reason for this is that
the long-term safety profile
of these products
is still evolving.
Sponsors such as
pharmaceutical companies
may also be interested in
quantifying the length
of durability since
gene therapies are one-time
administration drugs.
We also want to understand
the adverse event profile,
which could include
viral reactivation,
immune reactions, and
off-target effects.
This is really an
unprecedented length
of follow-up and
engagement with patients.
So there's a substantial
risk in this paradigm
to loss to follow-up
and potentially lack
of protocol adherence.
There are a number of
innovative solutions
to the complexity of
long-term follow-up
that have been proposed,
including platform trials
and master protocols,
which I'll talk about
a little bit here,
innovative statistical
techniques,
use of real-world data
and patient registries,
and decentralized
trial elements.
1:26
Now, we'll talk briefly
about the history of
long-term follow-up
for trial participants
administered a gene
therapy product.
The first published
human gene therapy trial
to introduce a therapeutic
gene was in the 1970s.
So quite a long time ago.
That same decade,
the US National
Institutes of Health
Recombinant Regulatory
Considerations in
the Development of
Gene Therapy Products
DNA Advisory Committee
was formed to reduce risks
associated with gene
transfer clinical protocols.
In 1988, the NIH RAC
officially approved the
first clinical protocol
to introduce a foreign
gene into humans.
By the 1990s, the US Food
and Drug Administration
and institutional review
boards assumed authority
to carry out
regulatory review of
gene therapy study protocols.
Prior to 2000,
the FDA required
long-term follow-up
only for clinical trial
participants who received
gene therapy products
containing retroviral vectors.
But a tragic event
with a subject
who ultimately died
after receiving
an investigational product
with an adenoviral vector
led regulators and industry
to reassess those guidelines.
After a series of
workshops in 2006,
the Food and Drug
Administration released
the final guidance on
observing subjects for
delayed adverse events,
and they recommended 15 years of
long-term follow-up
for participants
receiving investigational
gene therapy products,
of which the first five years,
subjects were to be
assessed through
clinical examination and for
10 more years through
questionnaires.
The guidance on this has
become a bit more specific
based on the mechanisms
of action of
the particular gene
therapy product.
Guidelines on the
long-term follow-up of
