[Federal Register Volume 86, Number 168 (Thursday, September 2, 2021)]
[Notices]
[Pages 49334-49337]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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 
https://www.regulations.gov 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:

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     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
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 https://www.regulations.gov.
     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:
     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.
     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 https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday, 240-402-7500.
     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 https://www.regulations.gov. 
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: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov 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, 
Kevin.Fain@fda.hhs.gov.

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

[[Page 49336]]

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 https://www.fda.gov/media/126910/download. FDA 
updates guidances periodically. For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
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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 https://www.regulations.gov. 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


