Download RESPONSE TO: COMMENTS TO THE SPONSOR IND 73,149 (R

RESPONSE TO: COMMENTS TO THE SPONSOR
IND 73,149
(R)-[11C]Rolipram
1) Part 1 and part 2 of the proposed study have different objectives (dosimetry and dynamic
brain imaging respectively) and will be performed sequentially. The data from part 1 (the
dosimetry study) will be useful in assessing the safety of part 2 of the study. We recommend that
you consider these to be separate studies and write separate protocols for each to avoid
confusion.
With NIMH IRB (Institutional Review Board) and the NIH RSC (Radiation Safety
Committee), we have developed a template protocol to test new PET ligands by performing
whole body and brain test retest studies. Because both of these studies are usually required to
perform initial tests of new PET ligands in humans, they are combined into a single protocol. By
doing so, duplicated reviewing procedures can be eliminated for whole body and brain imaging
studies. To make it clear that the brain imaging studies (part 2) will be initiated after completing
the whole body imaging studies (part 1), we have stated on page 6 of the protocol “Part 2 will be
initiated after completing part 1 and estimating radiation-absorbed doses from human data in part
1.” In addition, NIH RSC approves us to proceed to brain imaging only after confirming the
estimates of radiation-absorbed doses from all whole body imaging studies.
2) Please justify the need for arterial access and arterial blood sampling in this study.
In the quantification of PET brain imaging, the level of the ligand binding is measured by
calculating radioactivity ratios of [brain regions with specific binding]/[arterial plasma] or [brain
regions with specific binding]/[a brain region without specific binding] under equilibrium
conditions. Arterial blood sampling is not required to calculate the latter. However, a brain
region without specific binding (i..e. absence ofPDE4 is required for the calculation. From
literature, it is known that there is no brain region without PDE4, which is large enough to be
detected with PET.
3) We recommend that during the PET scan the patient be monitored with a single lead EKG
(rhythm strip) and pulse oximetry. Please confirm that the patient will be monitored for adverse
events, including injection site reactions.
Volunteer subjects will be monitored as recommended. They will be monitored for
adverse events, including injection site reactions.
Comments and questions related specifically to the dosimetry study (Part 1)
4) Please describe how time activity curves will be obtained from the dynamic PET scan data.
Please also specify which source organs and which target organs will be used in the dosimetry
calculations.
For each source organ, PET images at a couple of time points will be selected, which
visualize the organ well. On these images, a region of interest (ROI) will be drawn to obtain all
radioactivity of the organ. This ROI will subsequently be applied to PET data at all time points
to get time activity curves. Source organs will be determined based on the level of radioactivity
in the PET images but will not be determined beforehand without inspecting the PET images.
5) The time interval between the screening examination and PET scanning is too long. The
subject’s medical condition might change significantly in 4 months. We recommend that
screening evaluations occur no earlier than 30 days before imaging.
If the interval between screening and the PET scanning is going to be more than 30 days,
the blood and the urine tests will be repeated to make sure that the volunteer subject is still
healthy.
Comments and questions specifically related to the PET dynamic brain imaging study (Part 2)
6) Please explain the meaning and purpose of “test retest imaging”. If test retest imaging means
repeat imaging to assess reproducibility of results, the assessment would be valid only if the level
of PDE4 in the brain remains constant over time.
The purpose of the test retest brain imaging is to assess reproducibility of results. Healthy
subjects will be scanned twice without giving medication affecting brain neurotransmission
systems, and stable levels of PDE4 are expected.
7) If the object of the study is to determine the accuracy of 11C Rolipram PET scanning in
measuring PDE4 levels in the brain, the study must use some other method of measuring PDE4
levels in the brain as a “gold standard” comparator. Please provide information on the gold
standard that you will employ.
In our previous rat study (Fujita et al. NeuroImage 2005; 26:1201-1210), we confirmed
that specific binding of [11C]R-rolipram was measured by comparing PET measurement with and
without a blocking agent. There is no need to repeat a blocking study in humans. In addition, a
large mass dose of a blocking agent will cause pharmacological effects and impose risks to
volunteer subjects.
8) Please explain why PET scans and MRI scans will be obtained separately instead of obtaining
a single PET-CT scan. Using a PET-CT scanner insures that the patient position is identical for
both scans and co-registration of images is performed automatically by the device.
For the brain, MRI has much better tissue characterization (such as separation between
gray and white matter) than CT. Therefore, we will obtain MRI rather than CT.