Moderna’s
messenger
RNA
influenza
vaccine
succeeded
in
two
pivotal
clinical
trials,
but
the
Food
and
Drug
Administration
is
refusing
to
even
review
the
application
seeking
regulatory
approval,
telling
the
company
that
the
comparator
in
the
studies
—
an
FDA-approved
vaccine
—
is
insufficient.
The
FDA’s
refuse-to-file
letter
did
not
identify
any
safety
or
efficacy
concerns
for
the
vaccine,
mRNA-1010,
Moderna
said
after
Tuesday’s
market
close.
The
agency
told
the
company
that
the
vaccine
lacked
an
adequate
and
well-controlled
study
and
the
comparator
does
not
reflect
standard
of
care.
Refuse-to-file
letters
inform
a
company
that
an
application
lacks
information
for
the
agency
to
conduct
a
review.
While
the
issue
may
be
resolved
by
submitting
additional
data,
it
can
also
mean
the
agency
wants
a
company
to
conduct
another
clinical
trial.
Refuse-to-file
letters
are
considered
confidential
communication
between
the
FDA
and
a
company,
and
are
not
typically
made
public.
But
Moderna
took
the
unusual
step
of
posting
this
letter
to
its
website.
It
was
signed
by
Vinayak
Prasad,
director
of
the
FDA’s
Center
for
Biologics
Evaluation
and
Research
(CBER).
“CBER
does
not
consider
the
application
to
contain
a
trial
‘adequate
and
well
controlled’
and
the
application
is
therefore,
on
its
face,
inadequate
for
review,”
Prasad
wrote
in
the
letter
dated
Feb.
3.
“This
is
because
your
control
arm
does
not
reflect
the
best-available
standard
of
care
in
the
United
States
at
the
time
of
the
study.
I
note
that
this
determination
is
consistent
with
FDA’s
advice
given
to
you
prior
to
your
study.”
Moderna’s
mRNA-1010
is
a
seasonal
flu
vaccine
that
uses
mRNA
to
get
the
body’s
protein-making
machinery
to
code
for
hemagglutinin,
a
protein
on
the
surface
of
the
influenza
virus.
This
protein
triggers
a
protective
immune
response.
The
company’s
submission
for
the
vaccine
candidate
was
based
on
Phase
3
studies
whose
designs
were
reviewed
by
the
FDA
before
their
start.
Moderna
noted
that
the
federal
rules
that
call
for
adequate
and
well-controlled
clinical
trials
make
no
reference
to
a
comparator
reflecting
“the
best-available
standard
of
care.”
According
to
the
company,
the
FDA’s
2024
written
guidance
stated
the
agency
agreed
a
licensed
standard
dose
influenza
vaccine
would
be
an
acceptable
comparator
for
the
pivotal
study,
but
“we
recommend
you
use
a
vaccine
preferentially
recommended
for
use
in
older
adults
by
the
ACIP
[Advisory
Committee
on
Immunization
Practices]
(i.e.,
Fluzone
HD,
Fluad
or
Flublok)
for
participants
>65
years
of
age
in
the
study.”
The
Centers
for
Disease
Control
and
Prevention
recommends
high-dose
flu
vaccines
for
older
adults
because
immune
responses
typically
diminish
with
age,
putting
this
age
group
at
higher
risk.
The
Moderna
flu
vaccine
met
pre-specified
efficacy
goals
for
the
study,
named
P303.
The
comparator
in
this
study
was
GSK’s
Fluarix,
a
standard-dose
quadrivalent
influenza
vaccine.
One
cohort
in
this
study
enrolled
participants
age
65
and
older
and
compared
the
Moderna
vaccine
to
Fluzone,
a
high-dose
influenza
vaccine
marketed
by
Sanofi.
Moderna
said
the
agency’s
written
feedback
asked
that
supportive
analysis
on
the
comparator
be
included
in
the
application
seeking
regulatory
approval.
The
company
said
it
provided
this
information,
including
data
from
a
separate
Phase
3
trial,
P304.
This
study
compared
mRNA-1010
to
Fluarix,
whose
FDA
approval
covers
adults
age
65
and
holder.
Moderna
said
many
other
countries
do
not
preferentially
recommend
high-dose
influenza
vaccines
over
standard-dose
flu
vaccines
for
those
age
65
and
older.
The
company
added
that
based
on
the
FDA’s
prior
feedback,
there
was
no
indication
the
agency
would
refuse
to
review
the
application.
“It
should
not
be
controversial
to
conduct
a
comprehensive
review
of
a
flu
vaccine
submission
that
uses
an
FDA-approved
vaccine
as
a
comparator
in
a
study
that
was
discussed
and
agreed
on
with
CBER
prior
to
starting,”
Moderna
CEO
Stéphane
Bancel
said
in
a
prepared
statement.
“We
look
forward
to
engaging
with
CBER
to
understand
the
path
forward
as
quickly
as
possible
so
that
America’s
seniors,
and
those
with
underlying
conditions,
continue
to
have
access
to
American-made
innovations.”
The
Trump
administration’s
justifications
for
some
of
its
health
policies
has
been
to
bring
the
U.S.
in
line
with
other
countries.
When
the
CDC
cut
the
list
of
recommended
vaccinations
from
17
to
11
last
month,
the
agency
said
the
move
makes
the
U.S.
consistent
with
peer
nations.
That
was
also
one
of
the
justifications
for
the
FDA
changing
its
Covid-19
recommendations,
emphasizing
vaccination
for
older
adults
and
at-risk
groups.
In
an
article
published
in
the
New
England
Journal
of
Medicine
last
May,
Prasad
and
FDA
Commissioner
Marty
Makary
pointed
out
this
approach
is
consistent
with
Europe
and
other
high-income
nations.
Like
other
manufacturers
of
Covid-19
vaccines,
Moderna
has
been
dealing
with
declining
revenue
from
these
shots
amid
falling
vaccination
rates.
But
the
Trump
administration’s
policy
shifts
effectively
shrink
the
market
for
Moderna’s
top
source
of
revenue,
putting
pressure
on
the
company
to
grow
revenue
from
other
products.
Some
of
these
efforts
have
been
also
been
stymied
by
the
Trump
administration.
Last
year,
the
Department
of
Health
and
Human
Services
terminated
Moderna’s
$590
million
contract
to
develop
a
vaccine
for
avian
influenza.
Moderna’s
flu
vaccine
is
currently
under
regulatory
review
in
Europe,
Canada,
and
Australia,
and
the
company
plans
submissions
in
more
countries
this
year.
But
securing
U.S.
approval
will
be
key
for
meeting
revenue
goals.
Investment
bank
William
Blair
had
projected
mRNA-1010
sales
could
top
$1
billion
in
what
is
a
$5
billion
annual
market.
Moderna
is
also
developing
mRNA-1083,
a
Covid-19/influenza
combination
vaccine.
In
a
Wednesday
research
note,
William
Blair
analyst
Myles
Minter
wrote
that
the
refuse-to-file
letter
for
mRNA-1010
casts
doubt
on
the
future
of
the
combination
shot.
“We
remain
curious
as
to
the
specific
control
arm
CBER
is
requesting,
particularly
given
its
stated
preference
for
placebo-controlled
studies
in
its
previously
published
Covid-19
vaccine
guidance,”
Minter
said.
“Moderna’s
quotations
taken
from
FDA
meeting
minutes
acquired
prior
to
the
Phase
3
program
initiation
suggest
the
company
did
utilize
a
recommended
comparator
vaccine
in
the
P303
and
P304
studies
and
appear
to
directly
contradict
Vinayak
Prasad’s
statement
in
the
RTF
letter
that
his
‘determination
is
consistent
with
FDA’s
advice
given
to
you
prior
to
your
study.”
Moderna
has
requested
a
meeting
with
the
FDA
to
discuss
the
refuse-to-file
letter.
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appledesign,
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