Final Decision on the Proposal To Refuse To Approve a New Drug Application for ITCA 650, 68168-68177 [2024-18898]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 89, Number 164 (Friday, August 23, 2024)]
[Notices]
[Pages 68168-68177]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-18898]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2021-N-0874]


Final Decision on the Proposal To Refuse To Approve a New Drug 
Application for ITCA 650

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is issuing an order 
under the Federal Food, Drug, and Cosmetic Act (FD&C Act) refusing to 
approve a new drug application (NDA) submitted by Intarcia 
Therapeutics, Inc., an i2o Therapeutics Business Unit, (Intarcia) for 
ITCA 650 (exenatide in DUROS device). FDA has determined that the 
approval criteria in the FD&C Act have not been met because Intarcia 
has failed to demonstrate that ITCA 650 is safe for its intended 
conditions of use.

DATES: This notice is applicable August 23, 2024.

FOR FURTHER INFORMATION CONTACT: Rachael Vieder Linowes, Office of 
Scientific Integrity, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 1, Rm. 4206, Silver Spring, MD 20993, 240-402-5931.

SUPPLEMENTARY INFORMATION:

I. Factual and Procedural Background

    ITCA 650 (exenatide in DUROS device) is a novel drug-device 
combination product for human patients intended to deliver the active 
ingredient, exenatide, a glucagon-like peptide-1 receptor agonist (GLP-
1 RA). 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. ITCA 650 is intended to provide continuous dosing of 
exenatide from an osmotic mini-pump implanted in the subdermal space of 
the abdomen for 3 months for initiation of therapy and every 6 months 
afterwards for maintenance therapy. ITCA 650 must be inserted and 
removed by a healthcare provider trained on the included placement tool 
and guide. ITCA 650 is proposed in two dosage strengths: 20 micrograms 
(mcg)/day for 3 months and 60 mcg/day for 6 months. The drug 
formulation used in ITCA 650 is a viscous, non-aqueous suspension. Each 
mini-pump of ITCA 650--20 mcg/day for 3 months and 60 mcg/day for 6 
months--nominally contains 2.56 milligrams (mg) and 14.05 mg of 
synthetic exenatide, respectively.
    On November 21, 2016, Intarcia submitted NDA 209053 for ITCA 650. 
In support of its NDA, Intarcia included three phase 3 clinical trials 
to establish substantial evidence of safety and effectiveness--CLP-103, 
CLP-105, and CLP-107. CLP-107, also known as FREEDOM, was a 
cardiovascular outcome trial (CVOT). On September 21, 2017, the Center 
for Drug Evaluation and Research (CDER) issued a complete response (CR) 
letter to Intarcia stating that the NDA could not be approved in its 
present form. On September 19, 2019, Intarcia resubmitted the NDA, and 
on March 9, 2020, CDER issued a second CR letter stating that the NDA 
could not be approved in its present form, describing specific 
deficiencies and, where deemed possible, recommending ways that 
Intarcia might remedy those deficiencies.
    On March 16, 2021, after pursuing formal dispute resolution, 
Intarcia submitted a request under 21 CFR 314.110(b)(3) for an 
opportunity for a hearing on whether there are grounds under section 
505(d) of the FD&C Act (21 U.S.C. 355(d)) for refusing to approve the 
NDA for ITCA 650. CDER subsequently published a notice of opportunity 
for a hearing (NOOH) regarding a proposal to refuse to approve the NDA 
(86 FR 49334

[[Page 68169]]

(September 2, 2021)). CDER highlighted six deficiencies with the NDA in 
the NOOH. CDER found that the clinical trial data raised concerns that 
ITCA 650 causes acute kidney injury (AKI), specifically that more 
subjects who received ITCA experienced AKI events than those who 
received the placebo. In addition to finding that those who experienced 
AKI events sometimes needed prolonged hospitalization, CDER also 
determined that ``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 reactions associated 
with exenatide therapy, supporting a causal relationship between ITCA 
650 and AKI'' (86 FR 49334 at 49335). Further, CDER concluded that 
Intarcia's proposed risk mitigation measures were inadequate and that 
``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.'' (86 FR 49334 at 49336).
    CDER's second deficiency noted that the cardiovascular risk 
assessment failed to provide sufficient assurances that ITCA 650 is not 
associated with excess cardiovascular risk. In particular, CDER stated 
that ``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.'' (86 FR 49334 at 49336). The other deficiencies 
related to concerns regarding the in vitro dose delivery performance 
data and drug-release specifications, delivery performance data and 
variability in daily in vitro drug-release (IVR) data, inadequate 
support of sterility assurance, and deficiencies regarding certain 
manufacturing practices. Key aspects of those deficiencies included 
that ``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,'' and that 
``failure rate data was inadequate to support the safety and 
effectiveness of the device constituent of ITCA 650'' (86 FR 49334 at 
49336).
    Intarcia, through counsel, timely requested a hearing and 
subsequently submitted data, information, and analyses in support of 
that hearing request. Intarcia further argued that the risks identified 
by CDER are in line with the risks of the product class, as opposed to 
unique to ITCA 650, and that, provided there are appropriate 
restrictions included in ITCA 650's labeling, the safety profile for 
ITCA 650 falls in line with the product class. Intarcia stated that 
ITCA 650's benefits, including the new dosage form for patients, 
outweighs its risks and allows for a positive benefit-risk ratio that 
supports approval.
    More specifically, Intarcia disputed CDER's determination that ITCA 
650 led to higher AKI events in a controlled clinical setting compared 
to other products in its class. In support of its contention, Intarcia 
submitted an analysis of publicly available clinical review documents 
for Wegovy, an approved drug with a similar active ingredient, i.e., a 
GLP-1 RA. Intarcia maintained that its analysis shows a comparable 
number of AKI events for Wegovy in the clinical trial setting but that 
FDA nonetheless approved Wegovy. Intarcia pointed to this analysis as 
evidence that ITCA 650's risks are in line with the drug product class 
risks and should also be able to receive approval, despite the AKI 
concerns. Intarcia made similar statements regarding adverse events 
(AEs) involving gastrointestinal (GI) issues stemming from AKI events 
in the clinical data for ITCA 650, in that their occurrence was in line 
with expectations for GLP-1 RA-containing drugs, including Wegovy.
    Regarding the cardiovascular risk, Intarcia stated that CDER 
previously acknowledged that, ``due to the limited size and duration of 
the preapproval CVOT, the hazard ratio for cardiovascular risk was not 
definitive and would not constitute sufficient grounds for denial of 
the NDA, as long as a postmarketing CVOT would be completed.'' Intarcia 
stated that, because CDER overstated the AKI risk for ITCA 650 and 
admitted that the cardiovascular risk is not grounds for denial, ITCA 
650 should be approved.
    In accordance with 21 CFR 314.200, CDER then submitted a proposed 
order denying Intarcia's hearing request on the proposal to refuse to 
approve ITCA 650. In the proposed order, CDER provided findings that 
Intarcia had not raised a genuine and substantial issue of fact 
justifying a hearing regarding CDER's proposal to refuse to approve NDA 
209053 in its present form. The proposed order found that the data and 
other evidence submitted in support of the NDA for ITCA 650 does not 
show the product to be safe under section 505(d)(2) of the FD&C Act:

    Intarcia's NDA fails to demonstrate that the novel combination 
of the DUROS pump device and exenatide (ITCA 650) is safe for use, 
in part because the IVR data do not demonstrate that ITCA is 
reliable and do not validate the limits of the dose delivery 
specifications for the device, the proposed acceptance criteria are 
too wide and would allow drug release that is not sufficiently 
controlled by the device to meet clinical needs, and the device 
hazards associated with failure modes have not been sufficiently 
addressed by new risk control measures.

    The proposed order further described how the inaccurate dosing 
``raises significant safety concerns because marked increases in [ ] 
exenatide increase the risk of gastrointestinal intolerability, AKI, 
and potentially MACE.'' In the proposed order, CDER noted how 
Intarcia's acceptance criteria for its dosing is ``unacceptably wide,'' 
indicating that the drug release is not well controlled and that, 
therefore, ITCA 650 is not safe for use under the proposed conditions.
    Regarding the AKI events, the proposed order included analysis of 
Intarcia's clinical trials and concomitant findings that serious 
adverse events of AKI occurred in 14 study participants (0.5 percent) 
who received ITCA 650 (all requiring hospitalization) and 4 (0.2 
percent) who received placebo. The proposed order found that this 
imbalance ``leads to an unfavorable benefit-risk assessment for ITCA 
650 based on the data and information contained in the NDA in its 
present form.'' According to the proposed order, even a reanalysis of 
the data in a manner that would be most favorable to Intarcia would 
still raise a concern regarding the number AKI events for ITCA 650, 
leading to an unfavorable benefit-risk balance, which would preclude 
approval. CDER's proposed order accounted for Intarcia's Wegovy 
discussion and concluded that ``the numeric imbalance in serious AKI 
adverse events in [FREEDOM] suggests that ITCA 650 causes AKI to a 
greater extent than other members of the GLP-1 RA class, which did not 
show numeric imbalances in large, randomized clinical trials, and that 
the available data set ITCA 650 apart from the class with regard to AKI 
risk.'' The proposed order further included a conclusion that the AKI 
risk indicated by the data offered in support of approval cannot be 
adequately mitigated with post-approval measures because the AKI events 
occurred in patients who did not have known risk factors and they 
occurred in both the initial and maintenance dosing.
    CDER's proposed order also addressed the cardiovascular risk, 
stating that the CVOT for ITCA 650, which was conducted in the 
population ``most

[[Page 68170]]

likely to reveal an adverse effect on MACE because of high baseline 
cardiovascular risk, had a hazard ratio (HR) for MACE alone of 1.24 (95 
percent confidence interval: 0.90, 1.70).'' According to the proposed 
order, the HR was in the higher range, and, coupled with the AKI 
concerns, does not support approval. Additionally, the proposed order 
addressed Intarcia's contention that ITCA-650's status as a new dosing 
option tips the benefit-risk balance in favor of approval. CDER stated 
that Intarcia has provided no evidence that its new method would 
increase adherence among patients.
    On October 10, 2022, Intarcia responded to CDER's proposed order. 
By letter dated February 7, 2023, the Office of the Commissioner (OC) 
provided Intarcia with an opportunity, pursuant to Sec.  12.32 (21 CFR 
12.32), to request a hearing under part 14 (21 CFR part 14) in lieu of 
a formal evidentiary hearing under part 12 (21 CFR part 12) and 
indicated that the Agency would conduct any such hearing before the 
Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC). On 
February 20, 2023, Intarcia requested a public hearing before the EMDAC 
in lieu of a formal evidentiary hearing. On March 24, 2023, OC granted 
Intarcia's request and explained that, under Sec.  12.32(f)(1), OC 
would treat the votes and discussion of the issues by the EMDAC as an 
initial decision under 21 CFR 12.120 and that both CDER and Intarcia 
could file exceptions to those votes and discussion pursuant to 21 CFR 
12.125. OC further indicated that it would render a final decision for 
the Agency based on the public record.
    On August 24, 2023, FDA published the notice of hearing before the 
EMDAC on the proposal to refuse to approve ITCA 650 and summarized the 
issues to be considered and addressed (88 FR 57958). CDER conducted the 
hearing before the EMDAC on September 21, 2023. After the EMDAC heard 
presentations from CDER, Intarcia, and the public participants, the 
EMDAC voted unanimously that, based on the available evidence, Intarcia 
had not demonstrated that the benefits of ITCA 650 outweigh its risks 
for the treatment of T2DM. The EMDAC members explained the reasoning 
behind their votes, which is summarized below. After the EMDAC meeting, 
Intarcia submitted timely exceptions to the EMDAC's votes and advice, 
and CDER responded to Intarcia's exceptions. Therefore, this matter is 
before the Principal Deputy Commissioner (PDC) on appeal under 21 CFR 
12.130.

II. Relevant Statutory Framework

    Pursuant to section 503(g) of the FD&C Act (21 U.S.C. 353(g)), for 
a combination product containing a drug and a device with a primary 
mode of action of a drug, Intarcia submitted an NDA for ITCA 650. Under 
section 505(d) of the FD&C Act, FDA may approve an NDA only if it 
contains, among other things, a demonstration of the safety and 
effectiveness of the product for the conditions prescribed, 
recommended, or suggested in the proposed labeling. FDA must deny 
approval if the evidence does not show that the drug is safe for use 
under the proposed conditions (section 505(d)(2) of the FD&C Act) or if 
there is insufficient information about the drug to determine whether 
it is safe for use under such conditions (section 505(d)(4) of the FD&C 
Act). In making these assessments, FDA ``implement[s] a structured 
risk-benefit assessment framework . . . to facilitate the balanced 
consideration of benefits and risks'' (section 505(d) of the FD&C Act).

III. Analysis

A. EMDAC's Votes and Discussion

    At the hearing under part 14, both CDER and Intarcia made 
presentations consistent with their previous submissions in this matter 
with respect to CDER's proposal to refuse approval of ITCA 650. At the 
close of the hearing, in light of those presentations and the 
presentations by public participants, the EMDAC then considered two 
discussion questions and voted on whether, based on the available data, 
Intarcia had demonstrated that the benefits of ITCA 650 outweigh its 
risks for treating T2DM. The discussion questions focused on the safety 
profile of ITCA 650 with respect to AKI, ``cardiovascular safety'' and 
``overall safety'' and the benefit-risk ``balance of ITCA 650 for the 
indication to improve glycemic control in patients with T2DM.''
    With respect to the discussion question regarding ITCA 650's safety 
profile, including the risk of AKIs and cardiovascular events, the 
EMDAC Chair summarized the views expressed by the committee as follows:

    [R]egarding whether the safety profile of [ ] ITCA 650 has been 
adequately characterized based on available data with respect to the 
AKI safety signal, what I heard is that panel members expressed 
concerns about the imbalance in AKI. Although some panel members 
also noted the low incidence, there were concerns expressed about 
this risk being increased while on metformin, or ACE [angiotensin-
converting enzyme] inhibitors, or ARBs [angiotensin receptor 
blockers], which are therapies that patients with [T2DM] are likely 
to be taking. * * * Regarding cardiovascular safety, there were a 
lot of comments about this, and I think, in general, the panel 
expressed a lot of concerns about the point estimate of 
cardiovascular risk being above 1 and felt that the cardiovascular 
safety signal needs to be further investigated before consideration 
for approval. * * * Then lastly, in terms of overall safety, the 
panel did have concerns. Some of the concerns expressed were related 
to, really again, AKI cardiovascular risk[,] but also all-cause 
mortality was mentioned. A few panel members expressed concerns 
about lack of information about glycemic excursions and rate of 
hyper- and hypoglycemia with concerns about variability in the 
release of the drug.

    A review of the transcript confirms the accuracy of this summary. 
Of note, multiple EMDAC members expressed concerns about the AKIs and 
cardiovascular risks given how little is known about the drug delivery 
and the variability of the delivery levels. In general, the EMDAC 
expressed a need for more data related to AKIs, cardiovascular risks, 
and overall safety to assess whether ITCA 650 is sufficiently safe for 
the indicated population.
    With respect to the discussion question regarding the benefit-risk 
balance of ITCA 650, the EMDAC Chair summarized the committee's stated 
views as follows:

    Regarding the panel's assessment of the benefit-risk balance of 
ITCA 650 for the indication to improve glycemic control in patients 
with [T2DM], what I heard was that, in general, panel members felt 
that the benefits of ITCA 650 didn't outweigh the risks. Panel 
members commented on the moving testimonies during the open public 
hearing. [T2DM] is a devastating disorder to live with. We need to 
do better with available therapies and other treatments, but right 
now there are other options for [T2DM] treatment, and several of 
them reduce cardiovascular risk and risk for kidney outcomes. * * * 
Furthermore, I heard the panel members talk about adherence being a 
very complex problem, and the management of [T2DM] is not just about 
taking a single medication; there are many other factors. Right now, 
we really don't have evidence for improved adherence or adequate 
data to alleviate the safety concerns. The benefit of [ ] lowering 
[blood sugar levels] is not enough for a [T2DM] medication 
necessarily now; we need to also be looking at cardiovascular 
benefits, heart failure, and kidney outcomes, among others.

    A review of the transcript again confirms the accuracy of the 
Chair's summary. Of additional note, several EMDAC members expressed 
concerns that variability in drug delivery by ITCA 650, as suggested by 
the data, could lead to patients receiving less reliable dosages of the 
drug on a regular basis than they would if they were using an

[[Page 68171]]

analogous drug regimen not delivered via an osmotic drug-delivery 
device.
    The hearing concluded with the EMDAC's consideration of a voting 
question: ``Based on the available data has the [sponsor] demonstrated 
that the benefits of the ITCA 650 drug-device combination product 
outweigh its risks for the treatment of T2DM?'' As noted above, the 
EMDAC members voted unanimously--by a vote of 19 to 0--that Intarcia 
had failed to make such a showing, and each provided a rationale for 
their vote. The Chair summarized the EMDAC members' stated rationales 
as follows:

    As you heard, none of the panel members voted yes[,] and all 19 
panel members voted no. What I heard is that panel members mentioned 
the uncertainty about AKI and cardiovascular safety, as well as the 
variability in drug delivery being the greatest concerns, and then 
whether or not this is the best version of the device was 
questioned. * * * I think, overall, the panel acknowledged the work 
that has gone into ITCA 650 and this innovative approach[ ] but felt 
that it would be a disservice to our patients to recommend approval 
with the safety and drug delivery concerns that exist, and panel 
members voiced their understanding of the negative impact of [T2DM] 
and the hope that the applicant can do [ ] additional safety studies 
because of the great potential for this device.

    Of note, the EMDAC consistently voiced safety concerns about ITCA 
650 based on the data presented at the hearing, including the potential 
for cardiovascular complications and AKIs and the variability of the 
dosages provided by the device component of the product. Several EMDAC 
members also observed that resolving these safety concerns before 
approval of ITCA 650 would be essential and that post-approval studies 
would be inadequate to ensure the safety of the product for patients.

B. Procedural Objections Raised by Intarcia on Appeal

    On appeal, Intarcia's arguments regarding the procedural aspects of 
the EMDAC hearing generally question the overall fairness of the 
proceeding. In general, Intarcia presented concerns related to the 
scope of the meeting and the voting question, specifically that the 
EMDAC did not focus solely on the issues identified in CDER's NOOH and 
that the considerations before the EMDAC were ``unjustly expanded'' 
beyond the scope of the NOOH. Furthermore, Intarcia states that the 
EMDAC Chair did not let Intarcia address certain ``inaccurate 
statements'' made by CDER and the EMDAC regarding: (1) the death 
narratives for certain subjects in the clinical studies of ITCA 650 and 
(2) a comparison of AKI events in the clinical data for ITCA 650 in 
relation to the clinical data for other products in the same class that 
received FDA approval. Intarcia also argues that CDER's presentation 
approach ``did not allow the EMDAC to engage in a fact-based and 
evidence-based deliberation and voting discussion that was supported to 
address the comparative GLP-1 safety assertions in CDER's proposed 
order under dispute.'' Where procedural objections and factual 
objections intertwine, the PDC addresses the core of the factual 
disputes below. Here, the analysis focuses on the overall fairness of 
the hearing.
    After considering Intarcia's procedural objections, the PDC finds 
that they are unfounded. When Intarcia requested the part 14 hearing in 
lieu of a formal evidentiary hearing under part 12, the PDC did not 
limit the scope of what would be reviewed by the EMDAC. CDER appears to 
have followed its standard processes for advisory committee meetings 
and presented its full assessment of Intarcia's NDA to enable the EMDAC 
to render an initial decision on whether the data offered in support of 
the NDA show that the benefits of ITCA 650 outweigh its risks. Intarcia 
received proper notice of the issues before the EMDAC, including the 
voting question. As was borne out at the EMDAC meeting itself, Intarcia 
had the opportunity to shape the issues for the advisory committee 
meeting through its briefing materials and presentation.
    As to Intarcia's contentions regarding the EMDAC Chair's meeting 
facilitation the PDC does not find any evidence of unfairness or 
prejudice against Intarcia after reviewing the EMDAC transcript. Both 
CDER and Intarcia had opportunities to present their views on the 
issues, ask clarifying questions of the other, and answer questions 
posed by the EMDAC. Intarcia argues that there were instances when the 
EMDAC Chair did not allow it to properly rebut certain assertions by 
CDER or the EMDAC members and when the EMDAC Chair made allegedly 
inaccurate statements. The PDC does not find that the inability to 
further respond to certain issues created an unfair hearing or any 
prejudice in this instance. The statements that Intarcia claims it was 
unable to rebut or challenge, namely statements regarding the death 
narratives for certain clinical study subjects and AKI rate reflected 
in the clinical data for ITCA 650 compared to the data for other 
products in the same class, were addressed in both CDER and Intarcia's 
presentations, as well as in the EMDAC's briefing documents. Intarcia 
had ample opportunity throughout the hearing to address both topics. 
Therefore, the EMDAC Chair's decision not to give Intarcia an 
additional opportunity to address either matter does not persuade me 
that the hearing was unfair. Further, as the PDC will explain in more 
detail below--after considering the additional information Intarcia 
presented on appeal, including statements on the death narratives and 
examples of what Intarcia states were ``inaccuracies''--the PDC does 
not believe that any of the procedural issues to which Intarcia points 
prejudiced it in a meaningful way or materially affected the advice and 
recommendations provided by the EMDAC. Perhaps more importantly, the 
PDC concludes that any alleged deficiency in the hearing process before 
the EMDAC would not affect her judgment with respect to the substantive 
issues discussed next.

C. Substantive Objections Raised by Intarcia on Appeal

    Intarcia's factual challenges center on three areas: the AKI 
discussion and conclusions, the necessity of a post-approval CVOT, and 
the IVR data and performance. Intarcia disputes numerous assertions and 
findings related to AKI events in the clinical data offered in support 
of approval, including: (1) whether the number of serious adverse 
events (SAEs) in the clinical studies cited by CDER was accurate, (2) 
whether the AKI events are a product-class issue, as opposed to an 
issue specific to ITCA 650, and (3) whether the GI-related events are 
also a drug-class issue related to the AKI events. Intarcia further 
disputes the EMDAC's findings on the necessity of another pre-approval 
CVOT, largely by suggesting that CDER's presentation on the issue was 
incomplete or misleading. Intarcia states that CDER misrepresented 
conclusions related to the necessity of another CVOT and that CDER 
presented conclusions conflicting with statements from its own dispute 
resolution process. Intarcia also asserts that there were multiple 
areas where CDER either did not provide proper context or provided 
false information regarding ITCA 650 and other products in the drug 
class. Regarding ITCA 650's device performance and dose variability, 
Intarcia claims that CDER's presentation was misleading in that it 
relied on hypotheticals while discussing the device.
    Beyond these specific challenges, Intarcia generally argues that 
the data provided in ITCA 650's NDA shows that the combination product 
would have a

[[Page 68172]]

positive benefit-risk profile if (1) the labeling included an AKI 
warning consistent with other products in its class and (2) Intarcia 
conducts a post-approval CVOT study. Intarcia presented a letter from 
12 experts stating that (1) ITCA 650 addresses an unmet need by 
promoting adherence to the therapy though its implant, (2) the AKI 
imbalance issue is well-known and there is no ``meaningful difference'' 
between ITCA 650's occurrences and others in the drug class, and (3) 
the cardiovascular data meet the requirements for approval with a post-
marketing study to ``further narrow the confidence interval around MACE 
events.'' Furthermore, Intarcia asserts that CDER made ``numerous 
misrepresentations of fact'' and that the EMDAC was given ``materially 
false and misleading information'' in the CDER briefing documents, 
which ``did not allow the EMDAC to engage in a fact-based and evidence-
based deliberation and voting discussion that was supported to address 
the comparative GLP-1 safety assertions in CDER's proposed order under 
dispute.'' \1\
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    \1\ After the EMDAC meeting, the PDC received comments from 
former Intarcia employees who claimed that CDER made misleading 
claims during the EMDAC meeting. These documents are available on 
the docket at https://www.regulations.gov, docket numbers FDA-2021-
N-0874-0081 and FDA-2021-N-0874-0082. Specifically, the individuals 
challenged hypothetical information that CDER provided the EMDAC 
related to device performance and CDER's failure to address certain 
analysis related to the IVR data. Consistent with the analysis 
included in this section, the PDC has considered the claims and, 
after reviewing information contained the public record, the PDC 
finds that CDER did not mislead the EMDAC by presenting to the EMDAC 
hypothetical information. CDER explicitly stated that the 
information provided was based on a hypothetical. Nor does the PDC 
find it problematic that CDER failed to address aspects of the IVR 
data submitted in support of the NDA for ITCA 650. CDER need not 
address all aspects of an NDA file to support its position; rather, 
CDER may determine what it feels are the key aspects underlying its 
determination and present on those topics accordingly.
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    Before addressing the specific factual challenges, the PDC first 
addresses the allegations that CDER made misrepresentations of facts 
and presented materially false and misleading information. In support 
of this position, Intarcia points to alleged inconsistencies in CDER's 
position during the review process and in its presentation to the 
EMDAC. For example, Intarcia states that CDER made misrepresentations 
related to the MACE data and the intersection of that data with the AKI 
imbalance by citing what it claims are differences in CDER's position 
in the formal dispute resolution process and the current process. In 
both the proposed order and its presentation to the EMDAC, CDER has 
consistently described its concerns with the MACE data and maintained 
that, taken together with its other concerns with ITCA 650, the data do 
not support approval because the benefit-risk profile presented by the 
clinical data offered in support of the NDA does not support approval. 
The documents associated with the prior dispute resolution process are 
not part of the record before the PDC in this proceeding. Nevertheless, 
even if Intarcia's allegations of inconsistency are accurate, a mere 
evolution in thinking by CDER, including statements in previous 
decisions by specific officials within CDER, would not establish that 
CDER misled the EMDAC.
    In support of its position that CDER misled the EMDAC, Intarcia 
also includes a list of allegedly inaccurate claims that misled the 
EMDAC, including but not limited to the number of AKI-related deaths, 
the AKI imbalance calculation, and hypothetical device graphs used 
during CDER's discussion of the IVR concerns. Intarcia's disagreement 
with CDER's assessments do not even approach establishing that CDER 
made an effort to mislead the EMDAC, and a review of Intarcia's 
arguments and the underlying record bears out that Intarcia merely 
disagrees with CDER's interpretation of the evidence in many instances.
    Regarding the AKI disputes, the differences in interpretation of 
the data regarding AKI events were central to the presentations by 
Intarcia and CDER, and their divergent views do not establish an effort 
by CDER to mislead the EMDAC. The PDC addresses the disputes regarding 
AKI events in the clinical data in detail below but finds nothing in 
the record before her to indicate that CDER misled the EMDAC or 
included inaccurate information in its briefing materials for or its 
presentation to the EMDAC. As to the IVR dispute, CDER affirmatively 
disclosed that its presentation used hypothetical graphs, negating the 
argument that the data used in those hypothetical graphs were 
inaccurate or misleading. CDER appears to have presented those graphs 
to demonstrate the effect of inconsistent dose delivery in hypothetical 
devices as a means of providing context and enabling a fuller 
understanding of the clinical data presented. While the PDC does not 
explicitly address each aspect of Intarcia's claims that CDER misled or 
misrepresented the evidence or data to the EMDAC, the record before her 
establishes that Intarcia's arguments along those lines reflect 
disagreement with CDER's interpretation of the data and do not show 
that the CDER's presentation to the EMDAC or its briefing materials 
were misleading or inaccurate. Further, as previously discussed, 
Intarcia had ample opportunity to challenge CDER's interpretation of 
the data and frame the scientific issues for the EMDAC.
    After reviewing the information presented by Intarcia on appeal and 
documents contained in the public record, the PDC finds that CDER's 
presentation, while at odds with Intarcia's own interpretation of the 
underlying data, contained appropriate conclusions. As to the allegedly 
inaccurate statements by the EMDAC Chair, a review of the evidence and 
the meeting transcript supports that the EMDAC's overall assessment was 
amply reasoned and supported based on the underlying record. In short, 
the PDC finds that the data presented and evaluated by the EMDAC 
regarding the safety of ITCA 650 precludes a finding that the drug is 
safe for use under the proposed conditions.
    Intarcia urges FDA to consider ITCA 650's NDA based on a comparison 
to approved drug products, rather than on its own standalone merits. 
The PDC finds that the benefit-risk profile of ITCA 650, as reflected 
in the data and other information presented at the hearing, is 
inadequate to support approval. In so finding, the PDC is aligned with 
the conclusions of the EMDAC, whose stated views on the safety of ITCA 
did not, to any meaningful degree, hinge on comparisons to the benefit-
risk profile of other therapies. The evidence presented to the EMDAC 
highlights serious safety concerns that have not been adequately 
addressed by the information contained in ITCA 650's NDA. Based on the 
multiple safety concerns addressed below, the NDA in its present form 
does not support a determination that ITCA 650 is safe within the 
meaning of section 505(d)(2) of the FD&C Act. As discussed in more 
detail below the PDC has further concluded, based on the data, 
information, and arguments presented to the EMDAC, that Intarcia has 
failed to show that the benefit-risk profile of ITCA 650 compares 
favorably to drug products currently on the market.
    The PDC now addresses each area of concern identified by Intarcia 
with respect to EMDAC's conclusions regarding the clinical data offered 
to support approval of ITCA 650, namely issues related to concerns 
expressed by CDER with respect to AKI and cardiovascular events and 
variability in the dosing provided by the product.

[[Page 68173]]

1. AKI Events
    As described above, the EMDAC highlighted concerns related to AKI 
events reflected in the data, including the number of AKI events 
observed in the clinical data and the likelihood that the AKI risk 
would increase if the patient were also taking common T2DM therapies 
while using ITCA 650. The EMDAC also expressed concerns about the 
number of reported AKI events in the clinical data even with a low 
proportion of participants with significant chronic kidney disease. The 
EMDAC expressed concerns about how the AKI rates would translate in a 
real world setting when the indicated population would likely have 
higher, or more serious, rates of chronic kidney disease.
    CDER has stated that, based on the evidence included in the NDA, 
clinical trial subjects who received ITCA 650 had more AKI events than 
the control group. CDER, relying on individual and pooled analyses of 
the three ITCA 650 phase 3 clinical trials and the resulting analyses, 
found a numeric imbalance in serious AKI events:

    Baseline eGFR category was coded as mild renal impairment 
(baseline eGFR 60 to 89 mL/min/1.73m2) for 9 subjects and moderate 
renal impairment (baseline eGFR 30 to 59 mL/min/1.73m2) for 5 
subjects who had AKI SAEs in the ITCA 650 treatment arm. As shown in 
Table 30 (Section 5.2) among these 5 subjects categorized as 48 
moderately renally impaired at baseline, two subjects had baseline 
eGFRs of 57 and 58 mL/min/1.73m2, respectively, and no subject had 
baseline eGFR. . . . Only a limited number of subjects with chronic 
kidney disease (CKD) stage 3 or worse were enrolled in any of the 
trials, including FREEDOM: as previously noted, only one subject in 
CLP-103 had a baseline eGFR under 60 mL/min/1.73m2, fewer than 5% of 
subjects in CLP-105 had a baseline eGFR under 60 mL/min/1.73m2, and 
fewer than 10% of subjects in CLP-107 had a baseline eGFR under 60 
mL/min/1.73m2 at baseline. The AKI signal in FREEDOM was observed in 
a population less susceptible to AKI I, whereas no AKI signal was 
observed in the other [GLP-1 RA] CVOTs which studied populations 
more susceptible to AKI . . . further indicating that the risk of 
AKI associated with use of ITCA 650 is greater than the risk of AKI 
associated with currently marketed [GLP-1 RAs].

    The crux of Intarcia's argument related to the AKI events reflected 
in the clinical data for ITCA 650 is that AKI concerns expressed by 
both CDER and the EMDAC are a drug-class risk and no worse for ITCA 
650. Intarcia points to data from various other drug products to 
support its assertions. Intarcia also disputes the number of AKI events 
presented by CDER, claiming that there are 11 AKI events instead of the 
14 counted by CDER.
    In its presentation to the EMDAC, CDER discussed a key concern 
contained within the data--namely, an increase in AKI events in trial 
subjects who received the drug, particularly in Intarcia's largest 
study, FREEDOM, which had a relatively low proportion of subjects with 
significant chronic kidney disease:

    All but one serious AKI event and all but 4 nonserious AKI 
events occurred in Study CLP-107 (FREEDOM), the largest study with 
the longest median follow up time. Baseline eGFR is associated with 
risk of AKI events (Grams et al. 2010); e.g., patients with eGFR 
below 60 mL/min/1.73m2 have greater risk than patients with higher 
eGFR. Only a limited number of subjects with chronic kidney disease 
(CKD) stage 3 or worse were enrolled in any of the trials, including 
FREEDOM: as previously noted, only one subject in CLP-103 had a 
baseline eGFR under 60 mL/min/1.73m2, fewer than 5% of subjects in 
CLP-105 had a baseline eGFR under 60 mL/min/1.73m2, and fewer than 
10% of subjects in CLP-107 had a baseline eGFR under 60 mL/min/
1.73m2 at baseline. The AKI signal in FREEDOM was observed in a 
population less susceptible to AKI, whereas no AKI signal was 
observed in the other [GLP-1 RA] CVOTs which studied populations 
more susceptible to AKI (see Table 21)--further indicating that the 
risk of AKI associated with use of ITCA 650 is greater than the risk 
of AKI associated with currently marketed [GLP-1 RAs].

    The EMDAC appears to have agreed with this analysis.
    Having a low proportion of participants with significant chronic 
kidney disease would lead to the expectation that there is a lower 
baseline risk for AKI events. Renal impairment is common for those with 
T2DM. Therefore, if an AKI safety concern is present for those who do 
not have significant renal concerns, it raises serious questions 
regarding the potential AKI risk to those in the patient population for 
ITCA 650 that Intarcia has proposed. The indicated population would 
generally have underlying renal impairment concerns. The higher risk 
observed in the clinical data for ITCA 650 raises issues about the 
potentially greater risk in the postapproval setting. In the monitored 
setting of a clinical trial, some AKI events may be prevented or 
mitigated, but doing so is more difficult in the real world. As 
explained in CDER's proposed order, ``sufficient risk mitigation 
approaches could not be identified for the AKI risk, particularly 
because serious AKI events occurred in participants who did not have 
known risk factors, could occur at unpredictable times, and were 
observed with both the initial (20 mcg/day) and maintenance dose (60 
mcg/day) of ITCA 650'':

    [T]here is no evidence to support Intarcia's assertion that the 
AKI events occurred in ``well-defined windows'' of treatment 
initiation and dose escalation. Although some of the AKI events in 
the treatment group occurred proximate to implantation and dose 
escalation, others occurred at unpredictable time points thereafter. 
The unpredictable timing of these events makes it impossible to 
adequately warn providers as to when patients may be most likely to 
experience serious AKI. Accordingly, the clinical trial data support 
CDER's conclusion that the AKI risk cannot be adequately mitigated 
through labeling.

    The PDC further finds that, if serious AKI events are occurring in 
individuals without significant renal concerns and at variable times, 
there is insufficient reason to believe that the potential for AKI 
events stemming from ITCA 650 can be addressed through risk mitigation 
measures, such as labeling or patient monitoring, because healthcare 
providers would not have adequate information to identify patients 
requiring additional monitoring or education.
    Additionally, throughout the process, CDER also responded to 
Intarcia's contentions that the increase in AKI events was observed in 
those in the study who were also using metformin. As CDER and the EMDAC 
correctly noted, metformin usage is a first line treatment for patients 
with T2DM, and therefore this signal would apply to the majority of the 
intended patient population for ITCA 650. Given that metformin is not 
believed to be associated with an increased AKI risk, the increase in 
AKI events for ITCA 650 for those patients being treated with metformin 
simply reinforces the conclusion that ITCA 650 poses an increased AKI 
risk, especially for those in the intended patient population. Indeed, 
as CDER explained in its briefing materials for the EMDAC, study 
subjects in both the control and test groups were often taking 
metformin:

    Study CLP-105 was a multicenter, randomized, double-blind 
(subjects randomized to ITCA 650 and placebo pill or to sitagliptin 
and placebo ITCA 650 device), active comparator trial that compared 
efficacy, safety, and tolerability of ITCA 650 to sitagliptin, both 
as add-on to metformin.

    Regardless of the AKI risk associated with approved products whose 
active ingredient is a GLP-1 RA, the evidence underlying the NDA for 
ITCA 650 highlights a concerning AKI risk arising in subjects that did 
not have significant renal impairment. The PDC notes that neither in 
its recommendations nor its underlying reasoning, did the EMDAC

[[Page 68174]]

address the risk comparisons that Intarcia included in its 
presentation. The EMDAC's focus in those recommendations on the data 
for ITCA 650--as opposed to comparisons of the data underlying ITCA to 
that for GLP-1 RA-containing products--effectively conveys the EMDAC's 
view that it is not necessary to reach such comparisons to conclude 
that ITCA 650 is not safe for its intended use. Indeed, the PDC agrees 
with the EMDAC's overall conclusions that the AKI events observed in 
the clinical data are a significant safety concern regardless of 
comparisons to other available therapies.
    Additionally, even if the PDC was to view Intarcia's arguments 
regarding the number of AKI events in its favor and find that there 
were only 11 AKI events for subjects being treated with ITCA 650, it 
would still not address the overriding concern of the AKI risk 
appearing in a subject population with low significant chronic kidney 
disease. Regardless of which count is used, although the number of AKI 
events in the ITCA 650 Phase 3 trials was small, there is an overall, 
and serious, increase in AKI events for ITCA 650.
    Separately, despite the concerns just described, were the PDC to 
consider Intarcia's arguments regarding ITCA 650's risk relative to the 
risk of similar products with an analogous indication, the evidence 
presented to the EMDAC supports that ITCA 650 in fact presents a higher 
risk than approved drug products containing GLP-1 RA as an active 
ingredient. After analyzing the CVOTs for other products in the class, 
CDER summarized its findings in its EMDAC briefing materials:

    CDER interrogated the CVOTs of the approved [GLP-1 RA] products 
with the same censoring schemes, [standardized MedDRA queries] 
(SMQs), and [FDA MedDRA queries] (FMQs) as were applied to FREEDOM. 
. . . CDER notes that the imbalance in AKI seen in FREEDOM (labeled 
ITCA in Figure 12) was not observed in other CVOTs in the [GLP-1 RA] 
class. This imbalance in AKI was observed despite FREEDOM enrolling 
a lower proportion of subjects with baseline moderate-to-severe 
renal impairment compared with other CVOTs in the [GLP-1 RA] drug 
class, such that the FREEDOM population would be expected to have 
lower baseline risk for AKI events (Table 21).

    CDER concluded:

    The higher risk observed in the preapproval database for ITCA 
650 raises concern about the potentially greater risk versus other 
[GLP-1 RA] products in the postapproval setting: in the monitored 
setting of a clinical trial, some AKI may be prevented or mitigated, 
while this may not consistently occur in clinical practice. 
Moreover, the number of patients exposed to the ITCA 650 product 
would be much higher postapproval, and both of these factors 
differentiate the preapproval from the postapproval setting.

    CDER reiterated in its presentation to the EMDAC that ``no approved 
[GLP-1 RA-containing] product had an AKI imbalance in their premarket 
or postmarket clinical trials.'' In response, Intarcia points to the 
AKI warning included in Wegovy's labeling, which it claims refutes the 
notion that no AKI imbalances occurred in the clinical trials for GLP-1 
RA products. Intarcia's argument conflates AKI occurrence with an AKI 
imbalance. CDER does not claim that AKI events never occurred in GLP 1- 
RA related clinical trials, but rather that the number of events that 
occurred in FREEDOM led to an imbalance that was not seen for any other 
GLP-1 RA products in a randomized clinical trial. The relative number 
that occurred in FREEDOM distinguishes ITCA 650 from the other clinical 
trials for approved products containing a similar active ingredient, 
which may have had instances of AKI events but in a smaller proportion 
than ITCA 650 in the preapproval setting.
    Intarcia specifically points to Wegovy as an example of another 
GLP-1 RA product that had an AKI imbalance in its randomized clinical 
trials and still received approval; however, that argument is not borne 
out by the data. As explained in CDER's proposed order:

    Intarcia asserts that there was an imbalance in serious AKI 
events during titration in both Wegovy arms (1.0 mg and 2.4 mg) in 
Trial 4374 (STEP 2). Intarcia states that the percentage of 
participants with serious AKI for each arm in STEP 2, and in STEP 2 
overall, was ``identical'' to the percentage of treatment-emergent 
serious AKI in [FREEDOM]. The STEP 2 trial demonstrated a rate of 
serious AKI adverse events of 0.5% for both the 2.4 mg and 1 mg arms 
(2 participants with serious AKI events per arm), and 0.2% for the 
placebo arm (1 participant with serious AKI events). Although 
Intarcia claims these percentages are comparable to the AKI risk 
demonstrated in [FREEDOM], there are too few events (i.e., just two 
versus one event) for a meaningful analysis, in contrast to the 
larger serious AKI imbalance observed in the ITCA 650 development 
program.

    The PDC agrees with CDER's analysis. Indeed, considering that ITCA 
650 showed an AKI imbalance in a preapproval trial, where no others in 
the class presented similar concerns, the PDC finds that ITCA 650 
presents a higher risk than approved products containing a GLP-1 RA.
    GI-related issues. Intarcia makes additional arguments on appeal 
relating to the incidence of GI events in the study subjects using ITCA 
650 and again focuses on how the GI events are a drug-class risk and 
whether the GI events observed for ITCA 650 in the clinical data are 
comparable to those observed for other products in the class in the 
clinical data or otherwise. Intarcia includes arguments surrounding the 
GI events and dose titration and contends that, after dose escalation, 
the number of GI events decreased. As stated, the pivotal question here 
is whether the data offered in support of the NDA for ITCA 650 yields a 
positive benefit-risk profile adequate for a finding of safety.
    CDER described the connection between GI events to AKI occurrence 
in its briefing materials, stating that ``CDER's review of the 
narratives of serious AKI events that occurred in the ITCA 650 
treatment arms revealed 11of 14 events described GI symptoms (e.g., 
nausea and vomiting) and dehydration that preceded development of 
AKI.'' Intarcia does not contest CDER's findings that serious AKI 
events in FREEDOM were preceded by GI symptoms. Given the concerns 
outlined in the AKI discussion, the PDC finds that these GI events and 
the connection to the AKI risk are yet another indication that ITCA 
650's NDA has not provided enough evidence and data to show a benefit-
risk profile that would support a finding that ITCA 650 is safe within 
the meaning of section 505(d)(2) of the FD&C Act. Regarding the 
relationship between dose titration and GI events, as the PDC will 
discuss in the IVR-related section, the PDC finds that the wide 
variability in dose accuracy does not support that the GI issues would 
necessarily be adequately controlled after the initial titration 
period.\2\
---------------------------------------------------------------------------

    \2\ Insofar as Intarcia argues that the GI issues associated 
with ITCA 650 compare favorably to approved products containing a 
GLP-1 RA, Intarcia ties those arguments to the occurrence of AKI and 
cardiovascular events in the clinical data for the products at issue 
(including ITCA 650). Thus, the PDC finds that the analysis in the 
previous and next sections adequately addresses those arguments.
---------------------------------------------------------------------------

2. Cardiovascular-Related Issues and the Necessity of a Pre-Approval 
CVOT
    Both CDER, and later the EMDAC, expressed concerns regarding 
cardiovascular safety. Specifically, the EMDAC felt that, after looking 
at the various data analyses, the CVOT did not adequately exclude the 
possibility that ITCA 650 is associated with an excess risk of 
cardiovascular harm. The EMDAC disagreed with Intarcia's view that, 
because its CVOT met the primary end point requirements and conformed 
to FDA guidance, those findings are sufficient alone to support 
approval of ITCA 650. The EMDAC concluded that,

[[Page 68175]]

given the MACE point estimate was above one, the cardiovascular safety 
signal should be further investigated before ITCA 650 receive approval. 
Some members of the EMDAC found that, regardless of point estimates or 
HRs, a concerning cardiovascular signal in a preapproval trial is 
itself enough to warrant further investigation before approval. 
Further, in addressing the discussion question on the cardiovascular 
risks, the EMDAC found that the current data, as a whole, did not 
establish that ITCA 650 was sufficiently safe to warrant approval and 
recommended that Intarcia perform another pre-approval CVOT.
    On appeal, Intarcia contests both the need for another pre-approval 
CVOT, stating that its original pre-approval CVOT meta-analysis met 
CDER's primary end point requirements, and the comparison of its CVOT 
results to post-approval CVOTs for other products. Intarcia also 
contends that CDER's current analysis conflicts with previous 
statements. Lastly, Intarcia states that a ``larger, longer, post-
approval CVOT is warranted and would be performed.''
    Intarcia does not, however, dispute that the CVOT showed an HR 
estimate of 1.12, with a 95 percent confidence interval. Moreover, 
Intarcia does not challenge the number of MACE incidents or contend 
that collecting additional CVOT data is warranted. But the fundamental 
question is whether the data submitted with the NDA show a benefit-risk 
profile sufficient to establish the safety of ITCA 650 for approval. 
Whether, if ITCA 650 were approved, FDA would require a postmarketing 
CVOT is a separate issue. In the PDC's view, the cardiovascular data 
for ITCA 650 are troubling and do not characterize the risks associated 
with the product, including the cardiovascular risk, in a manner 
adequate to support the finding of safety necessary for approval.
    Additionally, were the PDC to consider Intarcia's CVOT comparisons 
to other GLP-1 RA products, the PDC still finds that the ITCA 650 data 
does not adequately characterize the cardiovascular risks associated 
with ITCA 650. CDER analyzed FREEDOM in its EMDAC briefing materials 
and summarized its findings:

    Notably, Table 21 [,which compared baseline subject 
characteristics across CVOTs in the GLP-1 RA class,] demonstrates 
that at baseline, a smaller proportion of subjects enrolled in 
FREEDOM had moderate or severe renal impairment than the trial 
populations of any other CVOT in the class, and the proportion of 
subjects with baseline [cardiovascular] disease was lower relative 
to most of the other [GLP-1 RA] CVOTs. This observation is reflected 
in the lower incidence of MACE in the placebo arm of the trial 
compared to the placebo arms of the other trials (Table 22). As 
noted above, imbalances in MACE events unfavorable to ITCA 650 were 
most pronounced in susceptible subgroups (i.e., subjects >=65 years 
of age, and subjects with baseline moderate to-severe renal 
impairment), as interventions that increase risk of MACE cause the 
greatest harm among the highest-risk populations.

    CDER concluded:

    The primary and secondary endpoint analyses and all other 
prespecified analyses of CV risk, regardless of pooling or censoring 
strategy utilized, support the same conclusion: the results of 
FREEDOM, a dedicated CVOT which enrolled patients with T2DM at high 
CV risk, do not adequately exclude the possibility that ITCA 650 is 
associated with excess risk of CV harm.

    On appeal, Intarcia merely dismisses CDER's analyses as 
scientifically unsound and reiterates that a postapproval CVOT is 
warranted because the preapproval CVOT met the primary endpoint 
requirements. However, the PDC agrees with CDER's analysis regarding 
comparisons between the preapproval clinical data offered in support of 
approved GLP-1 RA products and the data presented in support of ITCA 
650 in this proceeding.
    Diabetes is associated with an elevated risk of cardiovascular 
disease. The PDC finds that, while the original CVOT met the primary 
end point requirements, the PDC agrees with CDER's and EMDAC's concerns 
that the HR, especially in light of the other findings, does not 
provide adequate assurance that ITCA 650 is not associated with an 
increase in cardiovascular risk. Contrary to Intarcia's assertions, 
meeting the primary endpoints in the original CVOT is not sufficient, 
standing alone, to show that the existing clinical data adequately 
characterizes the cardiovascular risks associated with ITCA 650 to 
conclude that the product is safe. Meeting the primary endpoints is 
merely one data point in the overall assessment of the overall benefit-
risk assessment of a medical product. As described by CDER in the 
briefing materials to the EMDAC and highlighted through tables 20-22 in 
those materials, the primary and secondary endpoint analyses, 
regardless of pooling strategy, supports that the data generated by 
FREEDOM, the only CVOT conducted thus far, do not adequately exclude 
the possibility that ITCA 650 is associated with excess risk of 
cardiovascular harm. As described in CDER's briefing materials to the 
EMDAC, ``imbalances in MACE events unfavorable to ITCA 650 were most 
pronounced in susceptible subgroups (i.e., subjects >=65 years of age, 
and subjects with baseline moderate to-severe renal impairment), as 
interventions that increase risk of MACE cause the greatest harm among 
the highest-risk populations.'' Intarcia's concession that a postmarket 
CVOT is warranted aligns with the PDC's view that more data is 
necessary to adequately characterize the cardiovascular risk associated 
with ITCA 650 for a full assessment of the product's benefit-risk 
profile and a determination of safety. The question is when that CVOT 
should occur, and the PDC agrees with CDER and the EMDAC that the data 
available for ITCA 650 does not satisfy the requisite threshold for 
safety under section 505(d)(2) of the FD&C Act. Therefore, discussion 
of a postmarket study is premature.
3. IVR-Related Concerns
    Finally, in considering whether the benefits outweigh the risks for 
ITCA 650, the EMDAC also expressed concerns about the variability in 
drug delivery and the device itself. CDER's review of the data found 
that the IVR ranges for ITCA 650 are unacceptably wide, leading to 
concerns with dose accuracy. On appeal, Intarcia's states that its 
daily IVR testing meets the acceptance criteria and necessary 
confidence intervals and offers comparisons to other products on 
pharmacokinetic variability. Focusing on the issue of variability, the 
PDC finds that Intarcia has not presented adequate information to 
ensure that ITCA 650 would be safe for the proposed indication.
    In its previous submissions, and in its appeal, Intarcia lists its 
proposed IVR range for each dosage target: for the 20 mcg/day device, 
from days 0 to 14, the proposed IVR range is 2 to 40 mcg/day, which 
represents 10 percent to 200 percent of the target dose. From days 14 
to 91, the IVR range is 10 to 36 mcg/day, which represents 50 percent 
to 180 percent of the target dose. For the 60 mcg/day device, the IVR 
range for days 0 to 28 is 2 to 120 mcg/day, which represents 3.3 
percent to 200 percent of the target dose. The IVR range for days 28 to 
182 is 25 to 110 mcg/day, which represents 50 percent to 180 percent of 
the target dose. Intarcia states that these ranges are within a 95 
percent confidence interval with 80-90 percent reliability, but they 
nonetheless reflect very wide acceptance criteria. For both the 20 mcg/
day device and the 60 mcg/day device, after day 14, a patient could 
receive anywhere from 50 percent to 180 percent of the exenatide dose, 
which could also result in rapid shifts

[[Page 68176]]

between either end of the spectrum on a daily basis. A device that 
might deliver 3.3 percent, 10 percent, or 200 percent of the target 
dose would be expected to cause clinical adverse events related to 
irregular daily dosing when administering exenatide. As noted by CDER 
in its proposed order,

    Such wide acceptance criteria would allow for daily exenatide 
release that is not controlled sufficiently by the ITCA 650 device 
to safely meet clinical needs for the proposed indication. For 
example, because in steady state both ITCA 650 devices can deliver 
on a daily basis anywhere from 50% to 180% of the target dose of 
exenatide, rapid shifts in exenatide exposure could result. 
Increasing exposures to exenatide are known to result in 
gastrointestinal adverse reactions such as vomiting and diarrhea 
leading to dehydration, decreased intravascular volume, and AKI.

    Intarcia argues that the GI concerns lessen after dose titration 
and escalation, but such a wide dosing range undermines that position. 
If patients are never assured of how much exenatide they are receiving, 
if they receive too little or too much, there is always an elevated 
risk of GI events with ITCA 650 in its present form.
    In general, applicants propose acceptance criteria, and FDA may 
agree or disagree with the proposal, depending on the data. The data 
submitted by Intarcia are intended to show that the device meets the 
proposed acceptance criteria to a specific confidence interval. Even if 
the specific ITCA 650 performance data submitted are within a tighter 
range than the acceptance criteria proposed by Intarcia, those 
acceptance criteria are inappropriate because they would allow for 
manufacture of the device with unacceptably wide criteria. As stated in 
CDER's proposed order, ``[t]he wide acceptance criteria specifications 
for both the 20 mcg/day and the 60 mcg/day devices would allow for drug 
release that is unreliable and not controlled sufficiently by the 
device to meet clinical needs.'' The IVR acceptance criteria proposed 
by Intarcia are very wide and thus indicate that drug release is not 
well controlled by the device.
    Additionally, given that the IVR ranges are so wide, the confidence 
interval and reliability percentages are low for ITCA 650. As CDER 
described in its proposed order,

    CDER typically recommends that dose accuracy requirements are 
met with 95% confidence and 95% reliability. In this context, 
reliability is the probability that the device will perform 
satisfactorily for a specified period of time for the intended use. 
Because ITCA 650 is an implantable device that does not communicate 
device failures to the end user (e.g., device occlusion, free flow, 
etc.), an even higher level of reliability is expected (>99%).

    It is even more imperative that ITCA 650 doses reliably because it 
does not communicate device failures to the user. As explained by CDER 
in its briefing materials,

    A patient may only discover that a device failure occurred 
during use due to the onset of symptoms related to the device 
failure. This lack of user awareness regarding the status of drug 
delivery necessitates a high degree of device reliability to ensure 
that use of the device is safe in patients.

    Intarcia's analysis does not support its claims related to dose 
accuracy, given the low reliability percentages as well as the wide IVR 
specification ranges. The wide acceptance criteria specifications for 
both the 20 mcg/day and the 60 mcg/day devices would allow for drug 
release that is unreliable and not controlled sufficiently by the 
device to meet clinical needs. Given the rates of adverse events in the 
clinical trials for ITCA 650, as discussed above, it is reasonable to 
interpret those safety signals as potentially flowing from dosing 
variability. In short, the data do not support that the intended 
patient population would receive an accurate dose of exenatide each 
day, thereby leading to adverse health events.
    Intarcia on appeal compares ITCA 650's IVR data to other products' 
data. The PDC does not find Intarcia's arguments regarding such 
comparisons to be persuasive. On appeal, Intarcia references another 
exenatide product, Byetta, which it says, ``is known to have large 
swings in pharmacokinetic variability.'' As noted in the proposed 
order, however, ``Byetta is not an implanted device. Byetta (exenatide) 
is a twice daily injection indicated as an adjunct to diet and exercise 
to improve glycemic control in adults with type 2 diabetes mellitus.'' 
CDER, in the proposed order, further explained, ``The timing of the 
injections is specific and clearly outlined in the prescribing 
information. In contrast, as discussed in detail above, Intarcia's 
proposed IVR acceptance criteria are very wide and as such would allow 
for drug release that is not sufficiently controlled by the device.'' 
Similarly, Bydureon, which Intarcia points to as an example of an 
exenatide product with comparable pharmacokinetic variability, is also 
not an implantable device but instead is a weekly injectable. CDER 
compared ITCA 650 and Bydureon's variability in its briefing materials 
and summarized the findings:

    Quantification and comparison of within-subject variability 
(WSV) in pharmacokinetics is challenging for a few reasons. First, 
clinical trials do not typically collect frequent pharmacokinetic 
samples, particularly in time periods relevant to detect rapid 
concentration excursions. Secondly, the estimate of variability is 
sensitive to the nature of the chosen time window (duration of 
window, time between samples). Lastly, even if ideal data were 
available, within-subject variability does not quantify infrequent 
but dramatic spikes, but rather average variability (e.g., the 
``spread'' of the data over a specified sampling window). In other 
words, WSV reflects usual variability, but is insensitive to 
infrequent abrupt concentration increases. Nonetheless, CDER 
reanalyzed the PK data from Study CLP-109 and CLP-103SS and 
estimated the WSV in individual exenatide concentrations collected 
over 24 hours (i.e., within-day WSV) as well as the between-day WSV 
in individual exenatide concentrations data collected across 
multiple days proximal to each other [i.e., within 72-hours of each 
other and compared to the WSV of Bydureon (from Studies 104 and 
105)]. The results of the within-day WSV and between-day WSV are 
summarized below in Table 5. These values reported in Table 5 for 
ITCA 650 are similar to the WSV of 65% (using individual 
concentrations over 24 hours in Study CLP-109) reported by the 
Applicant in their Summary of Clinical Pharmacology Studies. In 
comparison, Bydureon showed a lower estimated within-day and 
between-day WSV of 20% and 30%, respectively.

    Even if the PDC was to consider these other products, which are not 
implantable devices like ITCA 650, the PDC agrees with CDER and the 
EMDAC that the evidence and data presented in this proceeding suggests 
that ITCA 650 raises concerns with drug delivery variability that 
compare unfavorably to approved products with a similar or identical 
active ingredient.
    The studies supporting ITCA 650's NDA, which were conducted in a 
controlled environment to measure drug delivery rates, demonstrated 
that the ITCA 650 does not provide an accurate and predictable release 
of exenatide. Given the information discussed above, the PDC finds that 
Intarcia's IVR data does not support the safety of the product given 
the wide IVR acceptance ranges and lower reliability percentages.
4. Potential Benefits of ITCA 650
    Having already addressed the safety-related concerns, the PDC will 
turn briefly to the benefits of ITCA 650. Intarcia states that the 
benefits of ITCA 650 include (1) an extended maintenance therapy 
option, (2) a dosing option with ``unequivocal sustained efficacy with 
6-month dosing,'' and (3) safety in-line with other GLP-1s. Intarcia 
presented a letter signed by 12 experts in support of its arguments 
related to the benefits of ITCA 650.

[[Page 68177]]

    The main benefits that Intarcia highlights relate to its position 
that ITCA 650 is a valuable new dosing option because it may increase 
medication adherence. Intarcia has not provided data in support of its 
argument but instead bases this assertion on the fact that ITCA-650 is 
an implantable device that lasts for 3 or 6 months. However, the 
evidence offered in support of approval undermines Intarcia's position. 
As previously discussed, ITCA 650 has dose reliability and variability 
issues. As previously outlined in the EMDAC discussion summary, 
multiple EMDAC members expressed concern that the drug delivery 
variability issue could lead to patients receiving less reliable drug 
doses than if they were using an analogous drug regimen that was not 
delivered via an implanted osmotic pump. Therefore, if ITCA 650 does 
not provide the proper dose, a patient would become nonadherent to 
their medication, regardless of the patient's intentions. The PDC 
therefore disagrees with Intarcia and its experts that the mode of drug 
delivery inherently equates to medication adherence. Furthermore, as 
found by CDER in its proposed order, ``Intarcia has provided no 
evidence that demonstrates patients prescribed ITCA 650 are more likely 
to continue the treatment than patients prescribed other approved 
treatments for type 2 diabetes.'' Given the lack of concrete 
information to support its theoretical argument, the PDC gives little 
weight to this benefit in the overall assessment of whether the 
benefit-risk assessment supports approval of ITCA 650 in its present 
form.

D. Conclusion

    While Intarcia correctly points out in its appeal that more 
therapies are needed for patients with T2DM, FDA will only approve NDAs 
when the data shows that the benefits outweigh the risks. After 
reviewing the information contained in the public record, the PDC finds 
that the benefits of ITCA 650 do not outweigh its risks. The PDC agrees 
with the EMDAC's conclusions and find that there are too many 
unanswered questions regarding risks associated with ITCA 650 to find 
that it has a positive benefit-risk profile and is safe under section 
505(d)(2) of the FD&C Act. For the reasons described above, Intarcia 
has not presented adequate evidence to show that the drug is safe for 
use under the proposed conditions; therefore, the PDC cannot approve 
the NDA for ITCA 650.

IV. Findings and Order

    For the reasons described above, FDA finds that the record shows 
that the approval criteria set forth in section 505(d)(2) of the FD&C 
Act have not been met, as ITCA 650's risks outweigh its benefits; 
therefore, Intarcia has not demonstrated that ITCA 650 is safe for its 
intended use. Therefore, under section 505(d) of the FD&C Act, FDA 
hereby denies approval to Intarcia's NDA in its current form.

    Dated: August 16, 2024.
Namandj[eacute] N. Bumpus,
Principal Deputy Commissioner.
[FR Doc. 2024-18898 Filed 8-22-24; 8:45 am]
BILLING CODE 4164-01-P