DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Silver Spring MD 20993

NDA 202788
MF 27320
REMS ASSESSMENT ACKNOWLEDGMENT
Insys Development Co.
c/o Insys Therapeutics, Inc.
1333 South Spectrum Blvd., Suite 100
Chandler, AZ 85286
Attention:

Stephen Sherman
Sr. Vice President, Regulatory Affairs

Dear Mr. Sherman:
Please refer to your New Drug Application (NDA) submitted under section 505(b) of the Federal
Food, Drug, and Cosmetic Act (FDCA) for SUBSYS (fentanyl) sublingual spray.
We also refer to your December 29, 2015, submission containing your assessment of the
Transmucosal Immediate-Release Fentanyl (TIRF) Products risk evaluation and mitigation
strategy (REMS).
After consultation between the Office of Surveillance and Epidemiology and the Office of New
Drugs, we found the REMS assessment to be complete with the following comments:
1.

After review of the 48 month (5th overall) REMS assessment report for the Transmucosal
Immediate-Release Fentanyl (TIRF) Products REMS, we conclude that it is not possible
to determine whether the overarching goal of the REMS - to mitigate the risk of misuse,
abuse, addiction, overdose, and serious complications due to medication errors is being
met.
a.
The first objective (prescribing and dispensing TIRF medicines only to
appropriate patients, which includes use only in opioid-tolerant patients) is not
being achieved. In the TIRF REMS Industry Group’s (TRIG’s) assessment of
opioid tolerance, approximately 42% of patients prescribed TIRF products were
not opioid tolerant. It is important that the TRIG further investigate this issue.
b.

Reference ID: 4012463

It is not possible to determine if the second objective (preventing inappropriate
conversion between TIRF medicines) is being met. Though no instances of
inappropriate conversions were submitted as a spontaneous report, the persistency
analysis provided indicates that the number of patients who may be exposed to
inappropriate conversion between TIRF medicines may be as high as 17.1-20.5%
of patients receiving TIRF medicines. Further assessment of these findings is also
warranted.

FDA_7702

 NDA 202788
MF 27320
Page 2

2.

c.

It is also not possible to determine if the third objective (preventing accidental
exposure to children and others for whom it was not prescribed) is being met. The
case reports for this metric remain quite low thus challenging the ability to assess
the impact of the REMS on this objective, particularly since the case reports do
not provide enough information to conduct a root cause analysis (RCA).

d.

The fourth objective (educating prescribers, pharmacists, and patients on the
potential for misuse, abuse, addiction, and overdose of TIRF medicines) is
partially being met. Overall, patients, prescribers, and pharmacists seem to have
an adequate understanding of most of the key risk messages related to preventing
inappropriate conversion, accidental exposure, and the potential for misuse,
abuse, addiction, and overdose of TIRF medicines; however, all groups had a
lower awareness of the need to only prescribe and dispense TIRF medicines to
appropriate patients.

In order to address the deficiencies outlined in 1a, b, c, and d, we have the following
comments:
a.

Regarding the assessment of opioid tolerance submitted in the 48 month
assessment, approximately 42% of patients prescribed TIRF products were not
opioid tolerant. The TRIG needs to further investigate this concerning finding. A
timeline for a plan to further evaluate this finding should be submitted with the
February 17, 2017, submission of the 60 month REMS assessment survey results.
At a minimum, further evaluation of this finding will include product-specific
assessment of opioid tolerance that each member sponsor will submit only to their
NDA or ANDA. Additional details regarding this evaluation will be
communicated in a separate letter.

b.

Regarding the persistency analysis submitted by the TRIG, these data indicate that
the number of patients who may be exposed to “inappropriate conversion between
TIRF medicines” is not insignificant. Thus these TIRF product switches need to
be further assessed by the TRIG and a protocol developed to assess the starting
doses of the TIRF products that existing TIRF patients switch to in order to
ascertain what proportion of these switches are conducted as per products’
labeling. In addition, if the data system used has outcome data, this would be
informative as to whether or not any switch marked as “inappropriate” resulted in
any adverse sequelae. Limitations of the databases and/or approaches used are to
be included in the protocol. Please submit this protocol with the February 17,
2017, submission of the 60 month REMS assessment survey results; if additional
time for protocol development is needed, please request an extension.

c.

We would like to schedule a meeting to discuss opportunities for obtaining
additional data on accidental exposure to children and others for whom TIRF
products are not prescribed, as well as to discuss possible ways to address the low

Reference ID: 4012463

FDA_7703

 NDA 202788
MF 27320
Page 3

awareness of the need to prescribe and dispense TIRF medicines to appropriate
patients.
3.

Additional comments on the 48 month assessment:
a.

In the FDA’s 36-month REMS Assessment Acknowledgement Letter (date
August 3, 2015), the TRIG was asked to “Conduct outreach to a representative
sample of those health professionals and pharmacies who did not re-enroll in the
TIRF REMS Access Program so as to ascertain their reasons and report the results
in your next Assessment Report. We are concerned about potential patient access
issues.”
In the 48 month assessment report, the TRIG responded that: “Based
on…analysis, there is no barrier to patient access and further outreach is
unwarranted.” The TRIG states that 516 prescribers (8.6%) chose to not re-enroll
and that these prescribers had an average of no more than four prescriptions total
over the course of the reporting period. However, the reasons why these
prescribers withdrew from the program are unknown as are the reasons why 1,134
prescribers had their enrollment expire this reporting period and remain expired.
Additionally, the reasons why 412 pharmacies chose not to re-enroll are not
presented.
It is therefore important that the TRIG proceed with conducting an “…outreach to
a representative sample of those health professionals and pharmacies who did not
re-enroll in the TIRF REMS Access Program so as to ascertain their reasons…
(w)e are concerned about potential patient access issues.” Submit a timeline for
the plan to conduct this outreach in the February 17, 2017, submission of the 60
month REMS assessment survey results.

b.

There continues to be a steady increase in mean and median prescription
processing times during this reporting period versus the previous periods. The
TRIG was previously asked to investigate this finding, but did not do so, instead
stating that this finding may be due to a lower number of prescriptions with at
least one initial REMS-related rejection this reporting (1,735) period as compared
to the 36-month report (3,738). These differences cited by the TRIG do not appear
to be so large as to account for some sort of number skewing induced by a small
sample size. The TRIG needs to investigate and identify the causes of these
increasing delays in prescription processing as these are potential indicators of
access barriers.

c.

The TRIG Protocol for Corrective Actions for Instances of Non-Compliance
contains few concrete criteria or decision trees as to how to deal with episodes of
non-compliance. Thus it is unclear to us what types of non-compliance actions
would reliably lead to suspension or deactivation. The TRIG should add

Reference ID: 4012463

FDA_7704

 NDA 202788
MF 27320
Page 4

increased specificity to the Non-Compliance Review Team (NCRT) protocol as
well as to the Supporting Document of the REMS.
In addition, it is concerning that the TRIG’s criteria for an incident of an
individual prescriber non-compliance with Patient-Prescriber Agreement Form
(PPAF) requirements needs to involve at least “5 or more patients enrolled by the
prescriber without a complete PPAF on file, with each patient having greater than
10 working days lapse from initial enrollment date.” These criteria would appear
to potentially lead to an under-reporting of PPAF non-compliance. The TRIG
should explore mechanisms to capture lower levels of non-compliance.
d.

Regarding the three instances where a non-closed system pharmacy dispensed a
TIRF product after a TIRF REMS rejection, all three reports were brought to the
attention of the TRIG only after the pharmacy contacted the REMS. The TRIG
should develop a more active mechanism by which to identify and prevent such
occurrences.

e.

Although results for both governmental (Veteran’s Health Administration and
Department of Defense) and closed-pharmacy systems appear to have improved
from the 36-month audit, they continue to be unsatisfactory. The 36-month REMS
Assessment Acknowledgement Letter requested that the TRIG “Re-evaluate
whether a novel authorization process is warranted or technically feasible at this
time for the closed system pharmacies and report your conclusions with your next
Assessment Report.” The TRIG has issued the following response: “The TRIG
has determined that the current prescription authorization volume for closedsystem pharmacies is less than 1% of all TIRF prescriptions and due to the
absence of complaints with the current process, no changes are warranted at this
time.” An absence of complaints does not necessarily mean that a closed
pharmacy system process is functioning optimally. These audits are likely one of
the best sources of information regarding the performance of these closed-system
pharmacies in meeting the REMS requirements. If the TRIG does not favor a
novel authorization process for all of the closed-system pharmacies solely due to
the poor performance of the governmental entities, the TRIG should propose an
outreach to these programs to improve compliance. In addition, the TRIG should
be sure to include both governmental entities in the 60-month audit so that their
performance in the REMS can continue to be monitored.
Lastly, the TRIG presents the process times for prescriptions that have
experienced at least one REMS-related rejection. However, data on the overall
processing time of a prescription that does not meet with any rejections is unclear.
Given that one of the pieces of information solicited during the closed-system
audits is “Date and time of each prescription transaction,” this is an excellent
opportunity for the TRIG to assess prescription processing times for prescriptions
that do not experience any REMS-related rejections. The TRIG should add this
component to their closed-system audits.

Reference ID: 4012463

FDA_7705

 NDA 202788
MF 27320
Page 5

4.

f.

For the Inpatient Pharmacy audits, six inpatient pharmacies either did not respond
to the audit request or decided not to participate. In the current inpatient
pharmacy enrollment form, the pharmacy only agrees to have their training
audited. We are considering revisions to this enrollment form to allow for process
audits so as to increase the potential pool of inpatient pharmacies in the audit and
will communicate any required modifications during the review of the next
REMS assessment.

g.

The TRIG reports a number of instances where prescribers were either unaware of
requirements to submit a PPAF or chose not to do so. It is important that the
TRIG investigate mechanisms to reinforce to prescribers the necessity of timely
completion of PPAFs.

h.

For subsequent submissions of Researched Abuse, Diversion and AddictionRelated Surveillance (RADARS) data that contain CII opioid comparators,
expand the CII immediate-release opioid category to include
oxycodone/acetaminophen, oxycodone/aspirin, and oxycodone/ibuprofen.

i.

The Agency has increasing concerns about the use of RADARS data to assess
some of the outcomes outlined in the TIRF REMS. Given the limitations of
RADARS, the Agency believes that additional data sources that can track adverse
outcomes of interest associated with the TIRF products are necessary, and the
TRIG must study intermediate objectives more closely related to the REMS
intervention. The FDA proposes a meeting with the TRIG to discuss and explore
new approaches to assessing this REMS with the goal of gathering useful
information to better understand the impact of the REMS and to improve the
program going forward.

We refer to the July 21, 2016, FDA electronic communication in which comments on the
patient, prescriber, and pharmacist surveys were conveyed based upon the 48 month
REMS assessment results. We acknowledge the subsequent agreement between the
Agency and the TRIG that the survey results for the 60 month TIRF REMS assessment
will be submitted to the Agency on February 17, 2017.

Reference ID: 4012463

FDA_7706

 NDA 202788
MF 27320
Page 6

If you have any questions, call Mark Liberatore, PharmD; Safety Regulatory Project Manager, at
(301) 796-2221.
Sincerely,
{See appended electronic signature page}
Judith A. Racoosin, MD, MPH
Deputy Director of Safety
Division of Anesthesia, Analgesia,
and Addiction Products
Office of Drug Evaluation II
Center for Drug Evaluation and Research

Reference ID: 4012463

FDA_7707