1. Please discuss
the available data regarding the potential cardiovascular (CV) risk for the
non-selective and COX-2 selective NSAIDs.
Please discuss whether the available data support a conclusion that increased
CV risk is a class effect for all NSAIDs, the COX-2 selective NSAIDs only, or
only for certain agents within the class.
Also, please discuss the possible mechanism(s) of action for an
increased cardiovascular risk with these agents.
2. Please discuss
the contributions and limitations of the currently available observational
studies to the assessment of CV risk for the non-selective and COX-2 selective
NSAIDs. In particular, please discuss
the role of such observational studies in informing regulatory decisions about
post-marketing safety issues.
3. Please discuss
the available data regarding the potential benefits of COX-2 selective NSAIDs
versus non-selective NSAIDs and how any such benefits should be weighed in
assessing the potential benefits versus the potential risks of COX-2 selective
agents from a regulatory perspective.
Approved
products
Three
COX-2 selective NSAIDs are currently approved for marketing in the
Although
Merck voluntarily withdrew Vioxx from marketing worldwide on
Based on the data presented in the background package and
during the committee meeting, please address the following questions regarding
the approved COX-2 selective NSAIDS.
1. Celecoxib
a.
Do the available data support a conclusion that celecoxib
significantly increases the risk of cardiovascular events?
b.
Does the overall risk
versus benefit profile for celecoxib support marketing in the
c.
If yes, please describe the patient population(s) in which
the potential benefits of celecoxib outweigh the potential risks and what
actions you recommend that FDA consider implementing to ensure safe use of
celecoxib.
2. Valdecoxib
a.
Do the available data support a conclusion that valdecoxib
significantly increases the risk of cardiovascular events?
b.
Does the overall risk versus benefit profile for valdecoxib
support marketing in the
c.
If yes, please describe the patient population(s) in which
the potential benefits of valdecoxib outweigh the potential risks and what
actions you recommend that FDA consider implementing to ensure safe use of
valdecoxib.
Questions (cont.)
3. Rofecoxib
a.
Do the available data support a conclusion that rofecoxib
significantly increases the risk of cardiovascular events?
b.
Does the overall risk versus benefit profile for rofecoxib
support marketing in the
c.
If yes, please describe the patient population(s) in which
the potential benefits of rofecoxib outweigh the potential risks and what
actions you recommend that FDA consider implementing to ensure safe use of
rofecoxib.
4. If the
available data support a conclusion that one or more COX-2 selective agents
increase the risk of cardiovascular events, please comment on the role, if any,
of concomitant use of low-dose aspirin in reducing cardiovascular risk in
patients treated with COX-2 selective NSAIDs.
5. What
additional clinical trials or observational studies, if any, do you recommend
as essential to further evaluate the potential cardiovascular risk of
celecoxib, rofecoxib, and valdecoxib?
What additional clinical trials or observational studies, if any, do you
recommend as essential to further evaluate the potential benefits (e.g.,
reduced gastrointestinal risk) of celecoxib, rofecoxib, and valdecoxib? Please be specific with regard to which COX-2
selective agent to study, trial design, patient populations, control groups, endpoints,
duration, sample size, etc.
There
are more than 20 non-selective NSAIDs currently approved for marketing in the
6. Do you
recommend that the labeling for these products include information regarding
the absence of long-term controlled clinical trial data to assess the potential
cardiovascular effects of these drugs?
If so, please describe how you recommend that information be conveyed
(e.g., warning, precaution).
7. What
additional clinical trials or observational studies, if any, do you recommend
as essential to further evaluate the potential cardiovascular risk of
the non-selective NSAIDs? Please be
specific with regard to which non-selective NSAIDs (i.e., all or only selected
agents), trial design, patient populations, control groups, endpoints,
duration, sample size, study drug etc.
Questions (cont.)
Standards for
approval of new NSAIDs (non-selective and COX-2 selective agents)
The
information that has accumulated about the safety and effectiveness of COX-2
selective NSAIDs since their approval, including the potential for increased
cardiovascular risk, must be considered as FDA determines the standards for
data to be submitted in support of approval of new non-selective and COX-2
selective NSAIDs. In addition, the
experience with the approved COX-2 selective agents will help inform benefit
versus risk assessments that will need to be made by FDA in evaluating pending and
future applications for new NSAIDs.
Based on the data presented in the background package and
during the committee meeting, please address the following questions regarding
the approval of new non-selective and COX-2 selective NSAIDs.
8. With regard to
evaluation of cardiovascular risk, what studies do you recommend as essential
to be completed and reviewed prior to approval of new NSAIDs? With regard to the evaluation of the
potential benefits (e.g., reduced gastrointestinal risk), what studies do you
recommend as essential to be completed and reviewed prior to approval of
new NSAIDs? Please be specific with
regard to trial design, patient population, control groups, endpoints,
duration, sample size, safety monitoring and patient protections, etc.
9. If the
pre-approval studies recommended as essential in question 8 do not demonstrate
an increased risk of cardiovascular events for a new NSAID, please comment on
how FDA should handle the issue of cardiovascular risk in labeling. For example, would the absence of a
cardiovascular risk signal in the pre-approval database preclude the need for
any warnings or precautions in the labeling for the new product? Alternatively, should all future NSAIDs carry
a “class” warning or precaution about cardiovascular risk even in the absence
of a signal of increased risk in the pre-approval database? If yes, please describe your recommendations
for the “class” labeling regarding cardiovascular risk with particular
attention to whether you recommend it apply to all NSAIDs or only COX-2
selective NSAIDs.