Notice2024-18898
Final Decision on the Proposal To Refuse To Approve a New Drug Application for ITCA 650
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
August 23, 2024
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
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.
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[Federal Register Volume 89, Number 164 (Friday, August 23, 2024)]
[Notices]
[Pages 68168-68177]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>, 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
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</html>Indexed from Federal Register on August 23, 2024.
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