Federal Register / Vol. 86, No. 40 / Wednesday, March 3, 2021 / Notices 12471 

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, 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 


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12472 Federal Register / Vol. 86, No. 40 / Wednesday, March 3, 2021 / Notices 

1Available 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. 

2Section 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. 

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 

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 

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 


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Federal Register / Vol. 86, No. 40 / Wednesday, March 3, 2021 / Notices 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 

§ 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 

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. 

ACTION: Notice. 

SUMMARY: 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: 

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 

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 


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