t*******h
发帖数: 409 | 1 抛砖引玉
14Jan2014:
http://www.fda.gov/downloads/advisorycommittees/committeesmeeti
The primary reason to not recommend approval is the lack of sufficient
evidence of
efficacy. There is only one successful trial and it is well known that
random factors can
cause erroneous clinical trial outcomes. Patients with symptomatic
neurogenic
orthostatic hypotension are vulnerable and it is important to ensure their
safety b y
protecting them from exposure to drugs that may not be effective,
particularly drugs that
have a theoretical basis for causing cardiovascular safety issues, as this
drug has.
Additionally , the lack of evidence of durability is particularly concerning
. Patients should
not be exposed to a drug chronically unless benefit is established over a
reasonable
amount of time – at least three months. It is possible that there is a down
regulation of
NE receptors in the peripheral circulation after prolonged exposure to
droxidopa. If this
is the case, one might consider approval but would need to label the product
differ ently
than what is being currently proposed (long-term use). Durability of effect
should be
studied further so that proper instructions for use can be crafted. Finally,
the safety of
droxidopa is still poorly characterized and another properly designed trial
should be
conducted to evaluate it. This development program was not properly designed
to
evaluate safety because of three factors: 1) the absence of a pure placebo
group, 2)
most of the safety data were collected in open-label trials and 3) blood
pressure was
collected with the head of the bed tilted at 30 degrees. Vasoconstriction is
the
mechanism of action of droxidopa. Therefore, without a control group, it is
logical to
assume that the cardiovascular adverse events, and there were many, were
cause d by
droxidopa. There is also the concern of neuroleptic malignant syndrome.
Since there
were some Japanese postmarketing cases that were not explicable on the basis
of
other drugs known to cause the syndrome, one needs to be concerned that
droxidopa
may cause this sometimes fatal condition.
再对比 23Feb2012
http://www.fda.gov/downloads/advisorycommittees/committeesmeeti
没觉得有什么变化
如果approval，会比较surprise | g*******h
发帖数: 1327 | 2 approve也要看是否带条件的approve。 另外，这个公司接下来的资金是不是成问题？ | T******o
发帖数: 500 | 3 你引这个是上次的作为reference,当然跟上次没有任何不同
第二个reviewer当然意见也是negative的,但是至少跟上次不同了
【在 t*******h 的大作中提到】
: 抛砖引玉
: 14Jan2014:
: http://www.fda.gov/downloads/advisorycommittees/committeesmeeti
: The primary reason to not recommend approval is the lack of sufficient
: evidence of
: efficacy. There is only one successful trial and it is well known that
: random factors can
: cause erroneous clinical trial outcomes. Patients with symptomatic
: neurogenic
: orthostatic hypotension are vulnerable and it is important to ensure their
| t*******h
发帖数: 409 | 4 In the original application (9/28/2011), studies 301, 302 and 303 were
submitted to support effectiveness and, despite randomizing “enriched”
populations of responders, only study 301 met its primary endpoint, the
composite OHQ, as well as OHSA item-1 scores. While the Agency was concerned
about the lack of consistency with failed studies 302 and 303, the Agency
nonetheless considered study 301 as a single study to support effectiveness.
However, the reviewers’ confidence in study 301 was undermined by the
highly positive and unusually homogenous pattern of results in a single site
(Table 1 and Figure 2), along with this site’s disproportionate
contribution to the overall positive results. The Agency subsequently issued
a
Complete Response Action (3/28/2012).
The applicant submitted a dispute resolution request, which was denied;
however, the applicant was informed that Study 306B “has the potential to
serve as the basis for a resubmission of the NDA in response to the…request
for at least one additional adequate and well-controlled trialStudy 306B
met its amended primary endpoint, OHSA item-1 from baseline to Week 1, with
an effect size of -0.94 (p value =0.028) on an 11-point scale (see section 9
.2). Other Week 1 endpoints, such as OHQ, clinician and patient-reported CGI
-I and CGI-S, and standing systolic blood pressure (SBP), trended in a
consistent direction (i.e., favorable for droxidopa) (see Table 19, first
column, with an elevation in the lowest standing SBP [0-3 minutes] and
favorable reductions in all scores).
The results of study 306B, along with results of study 303, support a lack
of effect durability in this chronic condition. Study 306B met its primary
endpoint at Week 1 after dose titration; however, by Week 2, the next time
point, OHSA item-1 results for droxidopa and placebo appeared to merge
together (Figure 8).
A total of 27 deaths occurred across the applicant’s clinical studies, of
which 16 deaths were reported in the original NDA, one reported in the 90-
Day Safety Update and 10 newly reported deaths in the long-term uncontrolled
study 304 (one reviewed in the original clinical review and nine in this
review). There were no deaths in study 306. Cardiovascular serious events
can occur spontaneously in the elderly or in high-risk patients and it is
difficult to calculate the attributable risk without a comparator group.
However, since ABPM data demonstrated that droxidopa increases mean systolic
and diastolic BP, one can plausibly expect an increase in stroke and
cardiovascular risk; should droxidopa be approved, its use should be
discouraged in
patients with high cardiovascular risk.
306B trail是关键，看起来design的也不是很好，risk很大哟
真是一场赌局
愿赌服输
【在 T******o 的大作中提到】
: 你引这个是上次的作为reference,当然跟上次没有任何不同
: 第二个reviewer当然意见也是negative的,但是至少跟上次不同了
| t*******h
发帖数: 409 | 5 The results of study 306B, along with results of study 303, support a lack
of effect durability in this chronic condition. Study 306B met its primary
endpoint at Week 1 after dose titration; however, by Week 2, the next time
point, OHSA item-1 results for droxidopa and placebo appeared to merge
together (Figure 8).
这句话，应该是个killer了
即使是week 1, p = 0.028.也太靠近0.05了
其他人怎么看？
concerned
effectiveness.
site
issued
【在 t*******h 的大作中提到】
: In the original application (9/28/2011), studies 301, 302 and 303 were
: submitted to support effectiveness and, despite randomizing “enriched”
: populations of responders, only study 301 met its primary endpoint, the
: composite OHQ, as well as OHSA item-1 scores. While the Agency was concerned
: about the lack of consistency with failed studies 302 and 303, the Agency
: nonetheless considered study 301 as a single study to support effectiveness.
: However, the reviewers’ confidence in study 301 was undermined by the
: highly positive and unusually homogenous pattern of results in a single site
: (Table 1 and Figure 2), along with this site’s disproportionate
: contribution to the overall positive results. The Agency subsequently issued
| k******e
发帖数: 214 | 6 CHTP: Chelsea's Northera NDA reportedly approved, shares halted | k**********4
发帖数: 16092 | 7 it does not matter if it is less than 0.05, 0.028 is
good enough.
----Keystone0504, Ph.D.
【在 t*******h 的大作中提到】
: The results of study 306B, along with results of study 303, support a lack
: of effect durability in this chronic condition. Study 306B met its primary
: endpoint at Week 1 after dose titration; however, by Week 2, the next time
: point, OHSA item-1 results for droxidopa and placebo appeared to merge
: together (Figure 8).
: 这句话，应该是个killer了
: 即使是week 1, p = 0.028.也太靠近0.05了
: 其他人怎么看？
:
: concerned
|
|
