Notice2021-18928
Proposal To Refuse To Approve a New Drug Application for ITCA 650 (Exenatide in DUROS Device); Opportunity for a Hearing
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Published
September 2, 2021
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Director of the Center for Drug Evaluation and Research (Center Director) at the Food and Drug Administration (FDA or Agency) is proposing to refuse to approve a new drug application (NDA) submitted by Intarcia Therapeutics, Inc. (Intarcia), for ITCA 650 (exenatide in DUROS device) in its present form. This notice summarizes the grounds for the Center Director's proposal and offers Intarcia an opportunity to request a hearing on the matter.
Full Text
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<title>Federal Register, Volume 86 Issue 168 (Thursday, September 2, 2021)</title>
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[Federal Register Volume 86, Number 168 (Thursday, September 2, 2021)]
[Notices]
[Pages 49334-49337]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2021-18928]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2021-N-0874]
Proposal To Refuse To Approve a New Drug Application for ITCA 650
(Exenatide in DUROS Device); Opportunity for a Hearing
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Director of the Center for Drug Evaluation and Research
(Center Director) at the Food and Drug Administration (FDA or Agency)
is proposing to refuse to approve a new drug application (NDA)
submitted by Intarcia Therapeutics, Inc. (Intarcia), for ITCA 650
(exenatide in DUROS device) in its present form. This notice summarizes
the grounds for the Center Director's proposal and offers Intarcia an
opportunity to request a hearing on the matter.
DATES: Submit either electronic or written requests for a hearing by
October 4, 2021; submit data, information, and analyses in support of
the hearing and any other comments by November 1, 2021.
ADDRESSES: You may submit hearing requests, documents in support of the
hearing, and any other comments as follows. Please note that late,
untimely filed requests and documents will not be considered.
Electronic requests for a hearing must be submitted on or before
October 4, 2021; electronic documents in support of the hearing and any
other comments must be submitted on or before November 1, 2021. The
<a href="https://www.regulations.gov">https://www.regulations.gov</a> electronic filing system will accept
hearing requests until 11:59 p.m. Eastern Time at the end of October 4,
2021, and will accept documents in support of the hearing and any other
comments until 11:59 p.m. Eastern Time at the end of November 1, 2021.
Documents received by mail/hand delivery/courier (for written/paper
submissions) will be considered timely if they are postmarked or the
delivery service acceptance receipt is on or before these dates.
Electronic Submissions
Submit electronic comments in the following way:
[[Page 49335]]
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
<bullet> Mail/Hand delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
<bullet> For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2021-N-0874 for ``Proposal To Refuse To Approve a New Drug
Application for ITCA 650 (Exenatide in DUROS Device); Opportunity for a
Hearing.'' Received comments, those filed in a timely manner (see
ADDRESSES), will be placed in the docket and, except for those
submitted as ``Confidential Submissions,'' publicly viewable at <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday, 240-402-7500.
<bullet> Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Kevin Fain, Center for Drug Evaluation
and Research, Food and Drug Administration, 10903 New Hampshire Ave.,
Bldg. 22, Rm. 6419, Silver Spring, MD 20993, 301-796-5842,
<a href="/cdn-cgi/l/email-protection#a7ecc2d1cec989e1c6cec9e7c1c3c689cfcfd489c0c8d1"><span class="__cf_email__" data-cfemail="39725c4f5057177f585057795f5d581751514a175e564f">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Proposal To Refuse To Approve NDA 209053
Intarcia submitted NDA 209053 for ITCA 650 (exenatide in DUROS
device), a drug-device combination product intended to deliver the
active ingredient exenatide, a GLP-1 receptor agonist (RA), on November
21, 2016, under section 505(b)(1) of the Federal Food, Drug, and
Cosmetic Act (FD&C Act) (21 U.S.C. 355(b)(1)). Intarcia proposed that
ITCA 650 be indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus (T2DM).
On September 21, 2017, the former Division of Metabolism and
Endocrinology Products (DMEP), Office of Drug Evaluation II (now the
Division of Diabetes, Lipid Disorders, and Obesity, within the Office
of Cardiology, Hematology, Endocrinology and Nephrology (OCHEN)) in the
Office of New Drugs (OND) in FDA's Center for Drug Evaluation and
Research (CDER), issued a complete response letter to Intarcia under
Sec. 314.110(a) (21 CFR 314.110(a)) stating that NDA 209053 could not
be approved in its present form, describing the specific deficiencies
and, where possible, recommending ways that Intarcia might remedy these
deficiencies. On September 9, 2019, Intarcia resubmitted the NDA under
section 505(b)(1) of the FD&C Act. On March 9, 2020, the former DMEP
issued a second complete response letter stating that NDA 209053 could
not be approved in its present form, describing the specific
deficiencies and, where possible, recommending ways that Intarcia might
remedy these deficiencies. These deficiencies, which are summarized
below, include the following:
1. The clinical trial data demonstrated that ITCA 650 causes acute
kidney injury (AKI).
a. A signal of AKI was evident in the pivotal phase 3 trials of the
ITCA 650 clinical development program. A standardized Medical
Dictionary for Regulatory Activities query for acute renal failure
identified reports of AKI serious adverse events in 14 subjects (0.6
percent) who received ITCA 650 versus 4 subjects (0.2 percent) who
received placebo.
b. The magnitude of the AKI risk was greater for ITCA 650 than for
the marketed exenatide products or for other members of the GLP-1 RA
class. Although other drugs in the GLP-1 RA class have a risk of AKI,
this information is based on spontaneous postmarketing adverse event
reports. The risk of AKI was not detected in the clinical trials that
supported the approval of these drugs. In contrast, the risk of AKI was
clearly identified in the ITCA 650 clinical trial data. This AKI risk
for ITCA 650, compared to other members of the GLP-1 RA class, is
particularly concerning because it was identified from these adequate
and well-controlled clinical trials, which constitute stronger evidence
for assessing a drug's safety than spontaneous postmarketing adverse
event reports.
c. AKI events experienced by participants who received ITCA 650
sometimes resulted in prolonged hospitalization; complications observed
in association with AKI events included dialysis and death.
d. A majority of the serious AKI events in participants randomized
to ITCA 650 appeared to be associated with vomiting, diarrhea, and
dehydration, which are known adverse
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reactions associated with exenatide therapy, supporting a causal
relationship between ITCA 650 and AKI.
e. Intarcia's proposed risk mitigation measures were inadequate and
sufficient risk mitigation approaches could not be identified for the
AKI risk identified in the clinical trial data, particularly because
serious AKI events occurred in participants who received ITCA 650 who
did not have known risk factors (moderate to severe renal impairment or
use of concomitant medications that increase the risk of AKI) and
serious AKI events were observed with use of both the nominal initial/
reduced dose ITCA 650, 20 micrograms (mcg)/day, and the nominal
maintenance dose ITCA 650, 60 mcg/day.
2. The cardiovascular risk assessment failed to provide sufficient
assurance that ITCA 650 is not associated with excess cardiovascular
(CV) risk. Rather, the clinical trial data suggested that ITCA 650 may
be associated with an increased risk for major adverse cardiovascular
events (MACE), defined as myocardial infarction, nonfatal stroke, and
cardiovascular death.
a. A prespecified meta-analysis incorporated the data from clinical
trials CLP-103, CLP-105, and CLP-107, and included 181 MACE and
unstable angina (UA) events. An unfavorable point estimate of 1.12 was
observed [hazard ratio (HR) for MACE + UA; 1.12 (95 percent confidence
interval (CI): 0.83, 1.51)].
b. Furthermore, estimates of CV risk from the meta-analysis were
notably higher and nominally statistically significant in the subgroup
of participants 65 years of age or older [HR for MACE + UA; 1.67 (95
percent CI: 1.02, 2.71)]. Subgroup analyses also suggested an
interaction between CV risk and baseline renal function, where the HR
estimates trended higher with worse renal function.
c. The CV risk analyses from trial CLP-107 augmented the concern
that the drug is associated with a higher risk for MACE. CLP-107 was a
randomized, double-blind, placebo-controlled cardiovascular outcomes
trial (CVOT) conducted in a patient population at high risk of MACE.
CLP-107 contributed 174 of the 181 total MACE + UA events observed in
the CV risk meta-analysis. In CLP-107, the assessment of product-
related CV risk yielded an HR for MACE of 1.24 (95 percent CI: 0.90,
1.70).
d. This CV risk resulting from ITCA 650 use is particularly
concerning when compared to the beneficial effect of other drugs in
this class on CV outcomes. In contrast to the unfavorable CVOT results
for ITCA 650, some other GLP-1 RA products carry indications for MACE
risk reduction in patients with T2DM based on favorable results of
CVOTs. The MACE HR observed in a CVOT conducted for another formulation
of exenatide was 0.91 (95 percent CI: 0.83, 1.0). The lower bound of
the CLP-107 confidence interval (0.90) nearly excludes the point
estimate for MACE risk observed with this other product (0.91),
suggesting a true difference in MACE risk between the products.
3. The data provided to validate the limits of the in vitro dose
delivery specifications did not support the safe and effective use of
the device constituent of ITCA 650.
a. The device design validation data did not support the proposed
daily, weekly, and biweekly in vitro drug-release specifications as
appropriate for the intended use.
b. The in vitro device performance data demonstrated inconsistent
day-to-day drug delivery and did not support that weekly and biweekly
in vitro drug-release testing is adequate to ensure controlled in vivo
drug release by the device constituent of ITCA 650.
4. The data provided, inclusive of delivery performance data and
failure analyses, did not demonstrate adequate device reliability
associated with in vitro dose delivery to support safety and
effectiveness for the intended use.
a. Variability in the daily in vitro drug-release data did not
support the use of weekly and biweekly averages to calculate device
failure rates.
b. The failure rate data was inadequate to support the safety and
effectiveness of the device constituent of ITCA 650.
c. The sponsor provided inadequate mitigation strategies to reduce
device failures.
5. The information provided, including the following, was
inadequate in support of sterility assurance for ITCA 650:
a. The container-closure integrity test data provided to support
integrity of a container-closure system used for sterile intermediate
storage of sterile components of ITCA 650.
b. Information regarding the product-contact filling equipment used
for commercial manufacturing of ITCA 650.
c. Information provided to support the routine depyrogenation
process for components of the primary container-closure system for ITCA
650.
d. The method suitability data provided to support the proposed
routine endotoxins test method with ITCA 650.
6. An FDA inspection of the Intarcia manufacturing facility
identified deficiencies with the manufacturing practices for ITCA 650
that were not adequately addressed.
a. Controls were inadequate to ensure empty devices would not be
included in the final release of ITCA 650.
b. Qualification of the filling line with an original or new
manifold was not performed.
c. The results and reports of the process simulation test, used to
demonstrate the effectiveness of preventing microbiological
contamination of ITCA 650, were not provided.
The complete response letters issued on September 21, 2017, and
March 9, 2020, both stated that to address the clinical deficiencies,
Intarcia should address all the specific device and product quality-
related deficiencies and provide additional clinical data that
adequately address the clinical risks and establish that ITCA 650 is
safe and effective for the intended use. The complete response letters
stated that Intarcia is required either to resubmit the application,
fully addressing all deficiencies listed in the letter, or take other
actions available under Sec. 314.110 (i.e., withdraw the application
or request an opportunity for a hearing). Applicable regulations,
including 21 CFR 10.75, also provide a mechanism for applicants to
obtain formal review of one or more decisions reflected in a complete
response letter (see FDA's guidance for industry and review staff
``Formal Dispute Resolution: Sponsor Appeals Above the Division Level''
(November 2017)).\1\
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\1\ Available at <a href="https://www.fda.gov/media/126910/download">https://www.fda.gov/media/126910/download</a>. FDA
updates guidances periodically. For the most recent version of a
guidance, check the FDA guidance web page at <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents">https://www.fda.gov/regulatory-information/search-fda-guidance-documents</a>.
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Intarcia submitted a formal dispute resolution request (FDRR) on
June 5, 2020, concerning the complete response letter issued on March
9, 2020, by the former DMEP. Ellis Unger, Director of OND's OCHEN,
denied the FDRR by correspondence dated July 30, 2020, based on his
determination that the drug's unexpected numeric imbalance in cases of
serious AKI, the MACE observed in the CVOT, and device-related
deficiencies regarding exenatide release rates over the life of the
product outweighed the benefit in reductions in Hemoglobin A1c.
Intarcia submitted another FDRR on August 14, 2020, for review of the
OCHEN denial. Robert Temple, Senior Advisor to OND, denied the second
FDRR on behalf of OND by correspondence dated October 30, 2020,
[[Page 49337]]
based on his determination that the drug's clinical risks, device-
related deficiencies, and product quality and manufacturing
deficiencies had not been satisfactorily resolved, reaffirming the
reasoning in OCHEN's denial of the prior FDRR. Intarcia submitted a
third FDRR on November 27, 2020, for review of the OND denial and
requested an advisory committee meeting. Douglas Throckmorton, Deputy
Director for Regulatory Programs, CDER, denied the third FDRR and the
request for an advisory committee meeting on behalf of CDER by
correspondence dated February 12, 2021, based on his determination that
the drug's clinical risks and device-related deficiencies had not been
satisfactorily resolved, reaffirming the reasoning in OND's denial of
the prior FDRR, and determined that an advisory committee would be
premature because of these unresolved safety issues.
On March 16, 2021, Intarcia submitted a request for an opportunity
for a hearing under Sec. 314.110(b)(3) on whether there are grounds
under section 505(d) of the FD&C Act for denying approval of NDA
209053.
II. Notice of Opportunity for a Hearing
For the reasons stated above and as explained in further detail in
the March 9, 2020, complete response letter and the February 12, 2021,
November 27, 2020, and July 30, 2020, FDRR denials, notice is given to
Intarcia and all other interested persons that the Center Director
proposes to issue an order refusing to approve NDA 209053 on the
grounds that the application fails to meet the criteria for approval
under section 505(d) of the FD&C Act, including the following: (1) Data
submitted in the application do not show that the product would be safe
under the proposed conditions of use (section 505(d)(2) of the FD&C
Act) and (2) the methods used in, and the facilities and controls used
for, the manufacture, processing, or packing of the product are not
shown to be adequate to preserve its identity, strength, quality, and
purity (section 505(d)(3) of the FD&C Act).
Intarcia may request a hearing before the Commissioner of Food and
Drugs (the Commissioner) on the Center Director's proposal to refuse to
approve NDA 209053. If Intarcia decides to seek a hearing, it must
file: (1) A written notice of participation and request for a hearing
(see the DATES section) and (2) the studies, data, information, and
analyses relied upon to justify a hearing (see the DATES section), as
specified in Sec. 314.200 (21 CFR 314.200).
As stated in Sec. 314.200(g), a request for a hearing may not rest
upon mere allegations or denials, but must present specific facts
showing that there is a genuine and substantial issue of fact that
requires a hearing to resolve. We note in this regard that because CDER
proposes to refuse to approve NDA 209053 based on the multiple
deficiencies summarized above, any hearing request from Intarcia must
address all of those deficiencies. Failure to request a hearing within
the time provided and in the manner required by Sec. 314.200
constitutes a waiver of the opportunity to request a hearing. If a
hearing request is not properly submitted, FDA will issue a notice
refusing to approve NDA 209053.
The Commissioner will grant a hearing if there exists a genuine and
substantial issue of fact or if the Commissioner concludes that a
hearing would otherwise be in the public interest (Sec.
314.200(g)(6)). If a hearing is granted, it will be conducted according
to the procedures provided in 21 CFR parts 10 through 16 (21 CFR
314.201).
Paper submissions under this notice of opportunity for a hearing
should be filed in one copy, except for those submitted as
``Confidential Submissions'' (see ``Written/Paper Submissions'' and
``Instructions''). Except for data and information prohibited from
public disclosure under 21 U.S.C. 331(j) or 18 U.S.C. 1905, submissions
may be seen in the Dockets Management Staff Office between 9 a.m. and 4
p.m., Monday through Friday, and on the internet at <a href="https://www.regulations.gov">https://www.regulations.gov</a>. This notice is issued under section 505(c)(1)(B)
of the FD&C Act and Sec. Sec. 314.110(b)(3) and 314.200.
Dated: August 27, 2021.
Jacqueline Corrigan-Curay,
Principal Deputy Center Director, Center for Drug Evaluation and
Research.
[FR Doc. 2021-18928 Filed 9-1-21; 8:45 am]
BILLING CODE 4164-01-P
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