Proposal To Refuse To Approve a New Drug Application for Sotagliflozin Oral Tablets, 200 Milligrams and 400 Milligrams; Opportunity for a Hearing, 12471-12473 [2021-04342]

Download as PDF Federal Register / Vol. 86, No. 40 / Wednesday, March 3, 2021 / Notices DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2021–N–0208] Proposal To Refuse To Approve a New Drug Application for Sotagliflozin Oral Tablets, 200 Milligrams and 400 Milligrams; Opportunity for a Hearing AGENCY: Food and Drug Administration, HHS. ACTION: Notice. The Director of the Center for Drug Evaluation and Research (Center Director) of the Food and Drug Administration (FDA or Agency) is proposing to refuse to approve a new drug application (NDA) submitted by Lexicon Pharmaceuticals, Inc. (Lexicon) for sotagliflozin oral tablets, 200 milligrams (mg) and 400 mg, in its present form. This notice summarizes the grounds for the Center Director’s proposal and offers Lexicon an opportunity to request a hearing on the matter. DATES: Submit either electronic or written requests for a hearing by April 2, 2021; submit data, information, and analyses in support of the hearing and any other comments by May 3, 2021. ADDRESSES: You may submit hearing requests, documents in support of the hearing, and any other comments as follows. Please note that late, untimely filed requests and documents will not be considered. Electronic requests for a hearing must be submitted on or before April 2, 2021; electronic documents in support of the hearing and any other comments must be submitted on or before May 3, 2021. The https:// www.regulations.gov electronic filing system will accept hearing requests until 11:59 p.m. Eastern Time at the end of April 2, 2021, and will accept documents in support of the hearing and any other comments until 11:59 p.m. Eastern Time at the end of May 3, 2021. Documents received by mail/hand delivery/courier (for written/paper submissions) will be considered timely if they are postmarked or the delivery service acceptance receipt is on or before these dates. jbell on DSKJLSW7X2PROD with NOTICES SUMMARY: Electronic Submissions Submit electronic comments in the following way: • Federal eRulemaking Portal: https://www.regulations.gov. Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to https:// www.regulations.gov will be posted to the docket unchanged. Because your VerDate Sep<11>2014 17:29 Mar 02, 2021 Jkt 253001 comment will be made public, you are solely responsible for ensuring that your comment does not include any confidential information that you or a third party may not wish to be posted, such as medical information, your or anyone else’s Social Security number, or confidential business information, such as a manufacturing process. Please note that if you include your name, contact information, or other information that identifies you in the body of your comments, that information will be posted on https://www.regulations.gov. • If you want to submit a comment with confidential information that you do not wish to be made available to the public, submit the comment as a written/paper submission and in the manner detailed (see ‘‘Written/Paper Submissions’’ and ‘‘Instructions’’). Written/Paper Submissions Submit written/paper submissions as follows: • Mail/Hand delivery/Courier (for written/paper submissions): Dockets Management Staff (HFA–305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. • For written/paper comments submitted to the Dockets Management Staff, FDA will post your comment, as well as any attachments, except for information submitted, marked and identified, as confidential, if submitted as detailed in ‘‘Instructions.’’ Instructions: All submissions received must include the Docket No. FDA– 2021–N–0208 for ‘‘Proposal to Refuse to Approve a New Drug Application for Sotagliflozin Oral Tablets, 200 Milligrams and 400 Milligrams; Opportunity for a Hearing.’’ Received comments, those filed in a timely manner (see ADDRESSES), will be placed in the docket and, except for those submitted as ‘‘Confidential Submissions,’’ publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240–402–7500. • Confidential Submissions—To submit a comment with confidential information that you do not wish to be made publicly available, submit your comments only as a written/paper submission. You should submit two copies total. One copy will include the information you claim to be confidential with a heading or cover note that states ‘‘THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.’’ The Agency will review this copy, including the claimed confidential information, in its consideration of comments. The second copy, which will have the claimed confidential information PO 00000 Frm 00062 Fmt 4703 Sfmt 4703 12471 redacted/blacked out, will be available for public viewing and posted on https://www.regulations.gov. Submit both copies to the Dockets Management Staff. If you do not wish your name and contact information to be made publicly available, you can provide this information on the cover sheet and not in the body of your comments and you must identify this information as ‘‘confidential.’’ Any information marked as ‘‘confidential’’ will not be disclosed except in accordance with 21 CFR 10.20 and other applicable disclosure law. For more information about FDA’s posting of comments to public dockets, see 80 FR 56469, September 18, 2015, or access the information at: https:// www.govinfo.gov/content/pkg/FR-201509-18/pdf/2015-23389.pdf. Docket: For access to the docket to read background documents or the electronic and written/paper comments received, go to https:// www.regulations.gov and insert the docket number, found in brackets in the heading of this document, into the ‘‘Search’’ box and follow the prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240–402–7500. FOR FURTHER INFORMATION CONTACT: Kevin Fain, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Rm. 6419, Silver Spring, MD 20993, 301–796–5842, Kevin.Fain@ fda.hhs.gov. SUPPLEMENTARY INFORMATION: I. Proposal To Refuse To Approve NDA 210934 Sanofi-aventis U.S. LLC (Sanofi), Lexicon’s predecessor-in-interest, submitted NDA 210934 for sotagliflozin oral tablets in 200 and 400 mg strengths on March 22, 2018, pursuant to section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(b)(1)). Sanofi proposed that sotagliflozin tablets be indicated as an adjunct to insulin therapy to improve glycemic control in adults with type 1 diabetes mellitus (T1DM). On March 22, 2019, the Office of Drug Evaluation II (ODE II) in the Office of New Drugs (OND) in FDA’s Center for Drug Evaluation and Research (CDER) issued a complete response letter to Sanofi under § 314.110(a) (21 CFR 314.110(a)) stating that NDA 210934 could not be approved in its present form, describing the specific deficiencies, and, where possible, recommending ways that Sanofi might remedy these deficiencies. The application in its present form is not approvable because the data submitted E:\FR\FM\03MRN1.SGM 03MRN1 jbell on DSKJLSW7X2PROD with NOTICES 12472 Federal Register / Vol. 86, No. 40 / Wednesday, March 3, 2021 / Notices do not show that the drug is safe under the proposed conditions of use. The deficiencies, which are summarized below, include the following: (1) The data demonstrated that the addition of sotagliflozin to insulin is associated with an increased risk of diabetic ketoacidosis (DKA), a serious and often life-threatening consequence of insulin insufficiency. a. In particular, the submitted clinical trial data showed a nearly 8-fold excess risk of DKA associated with sotagliflozin. Based on an FDA analysis of all three trials, an overall estimated hazard ratio (95 percent confidence interval) for DKA associated with sotagliflozin was 7.9 (3.2, 19.9). b. The majority of these cases required hospitalization and treatment in the intensive care unit, which underscores the seriousness of this risk. c. Although DKA is an inherent risk in T1DM, the magnitude of excess risk, severity of the cases, and characteristics of DKA (e.g., euglycemic DKA) associated with sotagliflozin treatment raised significant safety concerns, particularly because they occurred in a clinical trial setting, where patients are carefully selected for enrollment and receive more intensive safety monitoring than in clinical practice. d. Time-to-event analyses of the clinical trial data showed earlier development of DKA in sotagliflozintreated patients than in patients assigned to placebo, without evidence that the risk stopped increasing over time. e. The clinical trial data did not identify a patient group at lower risk of DKA, but instead showed the DKA risk was associated with sotagliflozin regardless of sex, age, duration of diabetes, method of insulin delivery, or body mass index. f. Overall, risk mitigation strategies used in the clinical trials were not sufficient to address the excess DKA risk observed in the clinical trials, as evidenced by the nearly 8-fold excess risk. g. Data analyses assessing the impact of risk mitigation strategies implemented during the course of the trials were inadequate to provide reassurance that these strategies would be successful in reducing DKA risk postapproval. (2) The data demonstrated the significant DKA risk resulting from the addition of sotagliflozin to insulin was not justified by the drug’s modest clinical benefits. a. The data showed that sotagliflozin reduced HbA1c, a validated surrogate endpoint for clinical benefits expected due to improved glycemic control in the VerDate Sep<11>2014 17:29 Mar 02, 2021 Jkt 253001 treatment of diabetes mellitus, including T1DM. However, the effect on HbA1c in the sotagliflozin clinical trials was modest. b. In the three pivotal trials, addition of sotagliflozin to insulin resulted in statistically significant reductions in HbA1c at Week 24. The treatment difference relative to placebo was approximately ¥0.3 percent with sotagliflozin 200 mg and ¥0.4 percent with sotagliflozin 400 mg. c. In the extension of two pivotal trials to 52 weeks, the effect of sotagliflozin on HbA1c was smaller (¥0.23 percent and ¥0.33 percent HbA1c reductions with the 200 mg and 400 mg doses, respectively), and there are no longer term data to evaluate persistence of effect. The decrease in treatment effect from Week 24 to Week 52 is clinically relevant, as the major benefits to consider with sotagliflozin treatment are related to improved longterm glycemic control reducing the risk of microvascular complications. d. The improved HbA1c associated with sotagliflozin was not accompanied by an increased rate of hypoglycemia (defined as glucose ≤ 55 mg/dL) in the clinical trials, an adverse clinical effect that occurs with insulin therapy; however, this observation does not outweigh the increased rate of DKA. The data did not show sotagliflozin was associated with an overall decrease in the rate of severe hypoglycemia. e. In addition to improved glycemic control, other clinical benefits associated with sotagliflozin, small reductions in body weight and blood pressure, were not sufficient to outweigh the serious risk of DKA. f. The data did not show that sotagliflozin was associated with an effect on glycemic variability and timein-range that provided benefits distinct from reduced HbA1c. g. Patient reported outcome measures were not adequate in directly reflecting important aspects of the patient’s experience with T1DM and how sotagliflozin treatment affected these important aspects. The complete response letter stated that Sanofi is required either to resubmit the application, fully addressing all deficiencies listed in the letter, or take other actions available under § 314.110 (i.e., withdraw the application or request an opportunity for a hearing). Applicable regulations, including 21 CFR 10.75, also provide a mechanism for applicants to obtain formal review of one or more decisions reflected in a complete response letter (see FDA’s guidance for industry and review staff ‘‘Formal Dispute Resolution: Sponsor PO 00000 Frm 00063 Fmt 4703 Sfmt 4703 Appeals Above the Division Level’’ (May 2019)).1 Sanofi submitted a formal dispute resolution request (FDRR) on September 3, 2019, concerning the complete response letter issued by ODE II. Peter Stein, Director of CDER’s OND, denied the FDRR by correspondence dated November 29, 2019, based on his determination that the drug’s immediate, sustained, and substantial increase in DKA risk outweighed the modest benefit on glycemic control and any potential additional benefits (e.g., reductions in body weight and blood pressure). Sanofi submitted another FDRR on December 19, 2019, for review of the OND denial. On January 30, 2020, FDA was notified that NDA 210934 had been transferred from Sanofi to Lexicon. Robert Temple, Deputy Director for Clinical Science, CDER, denied the second FDRR on behalf of CDER by correspondence dated March 11, 2020, based on his determination that the drug’s DKA risk outweighed its benefits, reaffirming the reasoning in OND’s denial of the prior FDRR. On November 10, 2020, Lexicon submitted a request for an opportunity for a hearing under § 314.110(b)(3) on whether there are grounds under section 505(d) of the FD&C Act for denying approval of NDA 210934. II. Notice of Opportunity for a Hearing For the reasons stated above and as explained in further detail in the complete response letter and the November 29, 2019, and March 11, 2020, FDRR denials, notice is given to Lexicon and all other interested persons that the Center Director proposes to issue an order refusing to approve NDA 210934 on the grounds that the application fails to meet the criteria for approval under section 505(d)(2) of the FD&C Act because data submitted in the application do not show that the product would be safe under the proposed conditions of use.2 Lexicon may request a hearing before the Commissioner of Food and Drugs 1 Available at https://www.fda.gov/media/ 126910/download. FDA updates guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance web page at https://www.fda.gov/drugs/ guidance-compliance-regulatory-information/ guidances-drugs. 2 Section 505(d)(2) of the FD&C Act provides that FDA shall refuse to approve an NDA if ‘‘the results of . . . tests show that such drug is unsafe for use under [the] conditions [prescribed, recommended, or suggested in the proposed labeling] or do not show that such drug is safe for use under such conditions[.]’’ For the reasons explained in this notice, CDER has concluded that the data and information submitted in the NDA do not show that the drug is safe for use under the proposed conditions of use. E:\FR\FM\03MRN1.SGM 03MRN1 Federal Register / Vol. 86, No. 40 / Wednesday, March 3, 2021 / Notices (the Commissioner) on the Center Director’s proposal to refuse to approve NDA 210934. If Lexicon decides to seek a hearing, it must file: (1) A written notice of participation and request for a hearing (see the DATES section) and (2) the studies, data, information, and analyses relied upon to justify a hearing (see the DATES section), as specified in § 314.200 (21 CFR 314.200). As stated in § 314.200(g), a request for a hearing may not rest upon allegations or denials, but must present specific facts showing that there is a genuine and substantial issue of fact that requires a hearing to resolve. We note in this regard that because CDER proposes to refuse to approve NDA 210934 based on the multiple deficiencies summarized above, any hearing request from Lexicon must address all of those deficiencies. Failure to request a hearing within the time provided and in the manner required by § 314.200 constitutes a waiver of the opportunity to request a hearing. If a hearing request is not properly submitted, FDA will issue a notice refusing to approve NDA 210934. The Commissioner will grant a hearing if there exists a genuine and substantial issue of fact or if the Commissioner concludes that a hearing would otherwise be in the public interest (§ 314.200(g)(6)). If a hearing is granted, it will be conducted according to the procedures provided in 21 CFR parts 10 through 16 (21 CFR 314.201). Paper submissions under this notice of opportunity for a hearing should be filed in one copy. Except for data and information prohibited from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C. 1905, submissions may be seen in the Dockets Management Staff Office between 9 a.m. and 4 p.m., Monday through Friday, and on the internet at https://www.regulations.gov. This notice is issued under section 505(c)(1)(B) of the FD&C Act and §§ 314.110(b)(3) and 314.200. Dated: February 25, 2021. Patrizia Cavazzoni, Acting Director, Center for Drug Evaluation and Research. [FR Doc. 2021–04342 Filed 3–2–21; 8:45 am] BILLING CODE 4164–01–P jbell on DSKJLSW7X2PROD with NOTICES DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2020–N–1413] Michael Gurry: Final Debarment Order AGENCY: Food and Drug Administration, HHS. VerDate Sep<11>2014 17:29 Mar 02, 2021 Jkt 253001 ACTION: Notice. The Food and Drug Administration (FDA or Agency) is issuing an order under the Federal Food, Drug, and Cosmetic Act (FD&C Act) permanently debarring Michael Gurry from providing services in any capacity to a person that has an approved or pending drug product application. FDA bases this order on a finding that Mr. Gurry was convicted of a felony under Federal law for conduct that relates to the regulation of a drug product under the FD&C Act. Mr. Gurry was given notice of the proposed permanent debarment and an opportunity to request a hearing to show why he should not be debarred. As of October 22, 2020 (30 days after receipt of the notice), Mr. Gurry had not responded. Mr. Gurry’s failure to respond and request a hearing constitutes a waiver of his right to a hearing concerning this action. DATES: This order is applicable March 8, 2021. ADDRESSES: Submit applications for termination of debarment to the Dockets Management Staff, Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240–402– 7500, or at https://www.regulations.gov. FOR FURTHER INFORMATION CONTACT: Jaime Espinosa (ELEM–4029) Division of Enforcement, Office of Strategic Planning and Operational Policy, Office of Regulatory Affairs, Food and Drug Administration, 12420 Parklawn Drive, Rockville, MD 20857, 240–402–8743, debarments@fda.hhs.gov. SUPPLEMENTARY INFORMATION: SUMMARY: I. Background Section 306(a)(2)(B) of the FD&C Act (21 U.S.C. 335a(a)(2)(B)) requires debarment of an individual from providing services in any capacity to a person that has an approved or pending drug product application if FDA finds that the individual has been convicted of a felony under Federal law for conduct relating to the regulation of any drug product under the FD&C Act. On January 13, 2020, Mr. Gurry was convicted as defined in section 306(l)(1) of the FD&C Act when judgment was entered against him in the U.S. District Court for the District of Massachusetts, after a jury verdict, on one count of racketeering conspiracy in violation of 18 U.S.C. 1962(d). The pattern of racketeering activity he was convicted of included engaging in multiple acts of mail fraud (18 U.S.C. 1341) and wire fraud (18 U.S.C. 1343). The factual basis for this conviction is as follows: Mr. Gurry held executive PO 00000 Frm 00064 Fmt 4703 Sfmt 4703 12473 management positions, to include Vice President of Managed Markets, of Insys Therapeutics Inc. (Insys), a Delaware Corporation, with headquarters in Chandler, Arizona. Insys developed and owned a drug called SUBSYS, a liquid formulation of fentanyl to be applied under the tongue. FDA approved SUBSYS for the management of breakthrough pain in adult cancer patients who are already receiving and are already tolerant to opioid therapy for their underlying persistent cancer pain. From early 2012 and continuing through 2015, Mr. Gurry participated in a conspiracy whereby employees of Insys bribed medical practitioners in various states to get those practitioners to increase prescribing SUBSYS to their patients, many of whom did not have cancer. Mr. Gurry, along with his coconspirators, measured the effect of these bribes on each practitioner’s prescribing habits and on the revenue that each bribed practitioner generated for Insys. Mr. Gurry, along with his coconspirators, reduced or eliminated bribes paid to those practitioners who failed to meet the minimum prescription requirements or failed to generate enough revenue to justify additional bribes. To further this conspiracy, Mr. Gurry and his coconspirators misled and defrauded health insurance providers to ensure those providers approved payment for SUBSYS. Insys achieved this goal by establishing the ‘‘Insys Reimbursement Center’’, which was designed to shift the burden of seeking prior authorization for SUBSYS from practitioners to Insys. This allowed Insys to determine what medical information was presented to insurers. Mr. Gurry and his coconspirators directed Insys employees to mislead insurers to obtain payment authorization. As a result of this conviction, FDA sent Mr. Gurry, by United Parcel Service, on September 21, 2020, a notice proposing to permanently debar him from providing services in any capacity to a person that has an approved or pending drug product application. The proposal was based on a finding, under section 306(a)(2)(B) of the FD&C Act, that Mr. Gurry was convicted of a felony under Federal law for conduct relating to the regulation of a drug product under the FD&C Act. The proposal also offered Mr. Gurry an opportunity to request a hearing, providing him 30 days from the date of receipt of the letter in which to file the request, and advised him that failure to request a hearing constituted an election not to use the opportunity for a hearing and a waiver of any contentions concerning this E:\FR\FM\03MRN1.SGM 03MRN1

Agencies

[Federal Register Volume 86, Number 40 (Wednesday, March 3, 2021)]
[Notices]
[Pages 12471-12473]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-04342]



[[Page 12471]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2021-N-0208]


Proposal To Refuse To Approve a New Drug Application for 
Sotagliflozin Oral Tablets, 200 Milligrams and 400 Milligrams; 
Opportunity for a Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Director of the Center for Drug Evaluation and Research 
(Center Director) of the Food and Drug Administration (FDA or Agency) 
is proposing to refuse to approve a new drug application (NDA) 
submitted by Lexicon Pharmaceuticals, Inc. (Lexicon) for sotagliflozin 
oral tablets, 200 milligrams (mg) and 400 mg, in its present form. This 
notice summarizes the grounds for the Center Director's proposal and 
offers Lexicon an opportunity to request a hearing on the matter.

DATES: Submit either electronic or written requests for a hearing by 
April 2, 2021; submit data, information, and analyses in support of the 
hearing and any other comments by May 3, 2021.

ADDRESSES: You may submit hearing requests, documents in support of the 
hearing, and any other comments as follows. Please note that late, 
untimely filed requests and documents will not be considered. 
Electronic requests for a hearing must be submitted on or before April 
2, 2021; electronic documents in support of the hearing and any other 
comments must be submitted on or before May 3, 2021. The https://www.regulations.gov electronic filing system will accept hearing 
requests until 11:59 p.m. Eastern Time at the end of April 2, 2021, and 
will accept documents in support of the hearing and any other comments 
until 11:59 p.m. Eastern Time at the end of May 3, 2021. Documents 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are postmarked or the delivery 
service acceptance receipt is on or before these dates.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2021-N-0208 for ``Proposal to Refuse to Approve a New Drug 
Application for Sotagliflozin Oral Tablets, 200 Milligrams and 400 
Milligrams; Opportunity for a Hearing.'' Received comments, those filed 
in a timely manner (see ADDRESSES), will be placed in the docket and, 
except for those submitted as ``Confidential Submissions,'' publicly 
viewable at https://www.regulations.gov or at the Dockets Management 
Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Kevin Fain, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 22, Rm. 6419, Silver Spring, MD 20993, 301-796-5842, 
[email protected].

SUPPLEMENTARY INFORMATION: 

I. Proposal To Refuse To Approve NDA 210934

    Sanofi-aventis U.S. LLC (Sanofi), Lexicon's predecessor-in-
interest, submitted NDA 210934 for sotagliflozin oral tablets in 200 
and 400 mg strengths on March 22, 2018, pursuant to section 505(b)(1) 
of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 
355(b)(1)). Sanofi proposed that sotagliflozin tablets be indicated as 
an adjunct to insulin therapy to improve glycemic control in adults 
with type 1 diabetes mellitus (T1DM).
    On March 22, 2019, the Office of Drug Evaluation II (ODE II) in the 
Office of New Drugs (OND) in FDA's Center for Drug Evaluation and 
Research (CDER) issued a complete response letter to Sanofi under Sec.  
314.110(a) (21 CFR 314.110(a)) stating that NDA 210934 could not be 
approved in its present form, describing the specific deficiencies, 
and, where possible, recommending ways that Sanofi might remedy these 
deficiencies. The application in its present form is not approvable 
because the data submitted

[[Page 12472]]

do not show that the drug is safe under the proposed conditions of use. 
The deficiencies, which are summarized below, include the following:
    (1) The data demonstrated that the addition of sotagliflozin to 
insulin is associated with an increased risk of diabetic ketoacidosis 
(DKA), a serious and often life-threatening consequence of insulin 
insufficiency.
    a. In particular, the submitted clinical trial data showed a nearly 
8-fold excess risk of DKA associated with sotagliflozin. Based on an 
FDA analysis of all three trials, an overall estimated hazard ratio (95 
percent confidence interval) for DKA associated with sotagliflozin was 
7.9 (3.2, 19.9).
    b. The majority of these cases required hospitalization and 
treatment in the intensive care unit, which underscores the seriousness 
of this risk.
    c. Although DKA is an inherent risk in T1DM, the magnitude of 
excess risk, severity of the cases, and characteristics of DKA (e.g., 
euglycemic DKA) associated with sotagliflozin treatment raised 
significant safety concerns, particularly because they occurred in a 
clinical trial setting, where patients are carefully selected for 
enrollment and receive more intensive safety monitoring than in 
clinical practice.
    d. Time-to-event analyses of the clinical trial data showed earlier 
development of DKA in sotagliflozin-treated patients than in patients 
assigned to placebo, without evidence that the risk stopped increasing 
over time.
    e. The clinical trial data did not identify a patient group at 
lower risk of DKA, but instead showed the DKA risk was associated with 
sotagliflozin regardless of sex, age, duration of diabetes, method of 
insulin delivery, or body mass index.
    f. Overall, risk mitigation strategies used in the clinical trials 
were not sufficient to address the excess DKA risk observed in the 
clinical trials, as evidenced by the nearly 8-fold excess risk.
    g. Data analyses assessing the impact of risk mitigation strategies 
implemented during the course of the trials were inadequate to provide 
reassurance that these strategies would be successful in reducing DKA 
risk post-approval.
    (2) The data demonstrated the significant DKA risk resulting from 
the addition of sotagliflozin to insulin was not justified by the 
drug's modest clinical benefits.
    a. The data showed that sotagliflozin reduced HbA1c, a validated 
surrogate endpoint for clinical benefits expected due to improved 
glycemic control in the treatment of diabetes mellitus, including T1DM. 
However, the effect on HbA1c in the sotagliflozin clinical trials was 
modest.
    b. In the three pivotal trials, addition of sotagliflozin to 
insulin resulted in statistically significant reductions in HbA1c at 
Week 24. The treatment difference relative to placebo was approximately 
-0.3 percent with sotagliflozin 200 mg and -0.4 percent with 
sotagliflozin 400 mg.
    c. In the extension of two pivotal trials to 52 weeks, the effect 
of sotagliflozin on HbA1c was smaller (-0.23 percent and -0.33 percent 
HbA1c reductions with the 200 mg and 400 mg doses, respectively), and 
there are no longer term data to evaluate persistence of effect. The 
decrease in treatment effect from Week 24 to Week 52 is clinically 
relevant, as the major benefits to consider with sotagliflozin 
treatment are related to improved long-term glycemic control reducing 
the risk of microvascular complications.
    d. The improved HbA1c associated with sotagliflozin was not 
accompanied by an increased rate of hypoglycemia (defined as glucose <= 
55 mg/dL) in the clinical trials, an adverse clinical effect that 
occurs with insulin therapy; however, this observation does not 
outweigh the increased rate of DKA. The data did not show sotagliflozin 
was associated with an overall decrease in the rate of severe 
hypoglycemia.
    e. In addition to improved glycemic control, other clinical 
benefits associated with sotagliflozin, small reductions in body weight 
and blood pressure, were not sufficient to outweigh the serious risk of 
DKA.
    f. The data did not show that sotagliflozin was associated with an 
effect on glycemic variability and time-in-range that provided benefits 
distinct from reduced HbA1c.
    g. Patient reported outcome measures were not adequate in directly 
reflecting important aspects of the patient's experience with T1DM and 
how sotagliflozin treatment affected these important aspects.
    The complete response letter stated that Sanofi is required either 
to resubmit the application, fully addressing all deficiencies listed 
in the letter, or take other actions available under Sec.  314.110 
(i.e., withdraw the application or request an opportunity for a 
hearing). Applicable regulations, including 21 CFR 10.75, also provide 
a mechanism for applicants to obtain formal review of one or more 
decisions reflected in a complete response letter (see FDA's guidance 
for industry and review staff ``Formal Dispute Resolution: Sponsor 
Appeals Above the Division Level'' (May 2019)).\1\
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    \1\ Available at https://www.fda.gov/media/126910/download. FDA 
updates guidances periodically. To make sure you have the most 
recent version of a guidance, check the FDA Drugs guidance web page 
at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs.
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    Sanofi submitted a formal dispute resolution request (FDRR) on 
September 3, 2019, concerning the complete response letter issued by 
ODE II. Peter Stein, Director of CDER's OND, denied the FDRR by 
correspondence dated November 29, 2019, based on his determination that 
the drug's immediate, sustained, and substantial increase in DKA risk 
outweighed the modest benefit on glycemic control and any potential 
additional benefits (e.g., reductions in body weight and blood 
pressure). Sanofi submitted another FDRR on December 19, 2019, for 
review of the OND denial. On January 30, 2020, FDA was notified that 
NDA 210934 had been transferred from Sanofi to Lexicon. Robert Temple, 
Deputy Director for Clinical Science, CDER, denied the second FDRR on 
behalf of CDER by correspondence dated March 11, 2020, based on his 
determination that the drug's DKA risk outweighed its benefits, 
reaffirming the reasoning in OND's denial of the prior FDRR.
    On November 10, 2020, Lexicon submitted a request for an 
opportunity for a hearing under Sec.  314.110(b)(3) on whether there 
are grounds under section 505(d) of the FD&C Act for denying approval 
of NDA 210934.

II. Notice of Opportunity for a Hearing

    For the reasons stated above and as explained in further detail in 
the complete response letter and the November 29, 2019, and March 11, 
2020, FDRR denials, notice is given to Lexicon and all other interested 
persons that the Center Director proposes to issue an order refusing to 
approve NDA 210934 on the grounds that the application fails to meet 
the criteria for approval under section 505(d)(2) of the FD&C Act 
because data submitted in the application do not show that the product 
would be safe under the proposed conditions of use.\2\
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    \2\ Section 505(d)(2) of the FD&C Act provides that FDA shall 
refuse to approve an NDA if ``the results of . . . tests show that 
such drug is unsafe for use under [the] conditions [prescribed, 
recommended, or suggested in the proposed labeling] or do not show 
that such drug is safe for use under such conditions[.]'' For the 
reasons explained in this notice, CDER has concluded that the data 
and information submitted in the NDA do not show that the drug is 
safe for use under the proposed conditions of use.
---------------------------------------------------------------------------

    Lexicon may request a hearing before the Commissioner of Food and 
Drugs

[[Page 12473]]

(the Commissioner) on the Center Director's proposal to refuse to 
approve NDA 210934. If Lexicon decides to seek a hearing, it must file: 
(1) A written notice of participation and request for a hearing (see 
the DATES section) and (2) the studies, data, information, and analyses 
relied upon to justify a hearing (see the DATES section), as specified 
in Sec.  314.200 (21 CFR 314.200).
    As stated in Sec.  314.200(g), a request for a hearing may not rest 
upon allegations or denials, but must present specific facts showing 
that there is a genuine and substantial issue of fact that requires a 
hearing to resolve. We note in this regard that because CDER proposes 
to refuse to approve NDA 210934 based on the multiple deficiencies 
summarized above, any hearing request from Lexicon must address all of 
those deficiencies. Failure to request a hearing within the time 
provided and in the manner required by Sec.  314.200 constitutes a 
waiver of the opportunity to request a hearing. If a hearing request is 
not properly submitted, FDA will issue a notice refusing to approve NDA 
210934.
    The Commissioner will grant a hearing if there exists a genuine and 
substantial issue of fact or if the Commissioner concludes that a 
hearing would otherwise be in the public interest (Sec.  
314.200(g)(6)). If a hearing is granted, it will be conducted according 
to the procedures provided in 21 CFR parts 10 through 16 (21 CFR 
314.201).
    Paper submissions under this notice of opportunity for a hearing 
should be filed in one copy. Except for data and information prohibited 
from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C. 1905, 
submissions may be seen in the Dockets Management Staff Office between 
9 a.m. and 4 p.m., Monday through Friday, and on the internet at 
https://www.regulations.gov. This notice is issued under section 
505(c)(1)(B) of the FD&C Act and Sec. Sec.  314.110(b)(3) and 314.200.

    Dated: February 25, 2021.
Patrizia Cavazzoni,
Acting Director, Center for Drug Evaluation and Research.
[FR Doc. 2021-04342 Filed 3-2-21; 8:45 am]
BILLING CODE 4164-01-P
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