scPharmaceuticals, Inc.Furoscix™ Furosemide), 80 mg/10 mL, Drug-device combination product

NDA 209988 COMPLETE RESPONSE

scPharmaceuticals, Inc.

Attention: Sanjay Sehgal, PhD

Senior Vice President

Regulatory Affairs, QA & Compliance 2400 District Ave, Suite 310 Burlington, MA 01803

Dear Dr. Sehgal:

Please refer to your New Drug Application (NDA) dated and received August 23, 2017, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Furoscix™ Furosemide), 80 mg/10 mL, Drug-device combination product.

We have completed our review of this application and have determined that we cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address these issues.

CDRH/DEVICE

1. As part of the device description, we were unable to locate the following alarms consistent with the FDA Guidance, Infusion Pumps Total Product Life Cycle within your submission for the Furoscix Infusor: ¢ Occlusion detection alarm e Low or empty reservoir alarm e Undocking alarm e Key pressed alarm e Tone test failure alarm

The Agency believes these alarms are critical to the safe operation of the device. Make appropriate changes to the device, provide a justification for why these alarms are not necessary, or provide alternative mitigations.

2. Inthe study, CP-00001 Product Design Clinical Validation, you defined the volume accuracy endpoint as “Delivery 80mg +10% = minimal 9mL dispensed from device.” This is inconsistent with the device specifications which state dose accuracy as volume to be delivered: © Therefore, according to the device specifications the delivery volume should be between! mL. It is unclear how dose

Reference ID: 4275803

NDA 209988

Page 2

Reference ID: 4275803

accuracy was measured in this pivotal study. Since dose accuracy is a critical endpoint this discrepancy needs to be resolved. Please describe how you measured dose accuracy in the study and how the study validates the design specifications for the device.

. According to the results from the CP-00001, Product Design Clinical Validation study

you did not meet the predefined endpoints. Please address how the improvements since the study was completed result in a device that can meet the pre-defined endpoints for this particular study and provide evidence to validate that these changes are likely to address the errors or provide a new clinical validation study. (Please see the Clinical comments for additional information regarding study CP-00001).

You provided several documents outlining the Risk Management process for the Furoscix Infusor in Sequence 0001/3.2R. The risk assessment criteria and risk acceptability as outlined in RA-0002, scPharmaceuticals Risk Management Plan, Appendix I, defines the severity, occurrence and detection ratings in accordance with ISO 14971. Additionally, you have defined the risk threshold for the intended use of the Furoscix Infusor on p.7-8

as: (b) (4)

The resulting risk and hazard analyses do not follow the definitions as defined in RA- 0002.pdf. From a high-level perspective, the Agency disagrees with the severity ratings assigned in the Use Error Analysis (DD-0001.pdf), scPharmaceuticals Risk Management Report (RA-0023.pdf), seCFAS Risk Analysis Report (RA-0010.pdf) and scPharmaceuticals Hazard Analysis (RA-0007.pdf) to the hazards of underdosing, infection and over-diuresis for the following reasons:

a. Hazard — Underdosing: Device failures resulting in underdosing, especially undetected, can lead to decompensation in patients with congestive heart failure which requires medical intervention or hospitalization. Revise your risk analysis document to make all hazards with harm of underdosing, a severity of 4.

b. Hazard — Infection: Harm causing local or systemic infection in patients with congestive heart failure requires medical intervention. Revise your risk analysis document to make all hazards with harm of infection, a severity of 4.

c. Hazard — Over-Diuresis: Over-Diuresis in patients with congestive heart failure can lead to electrolyte imbalances which require hospitalization to stabilize. Revise your risk analysis document to make all hazards with harm of over- diuresis a severity of 4.

You will need to update your risk management documentation to reflect these new severity ratings and then recalculate the Risk Level (Risk Analysis and FMEA) and Risk Priority Numbers (Process FMEA and Design FMEA). Based on the revised risk

NDA 209988 Page 3

analysis you will need to update your design verification/validation documents, Human Factors documentation (See Human Factors section, request for updated use-related risk analysis) and Risk Analysis documents (including the Safety Assurance case) to reflect

the new evaluation of the risk for each hazard. You should use these new evaluations to drive the mitigation measures as appropriate for each hazard.

Revise your risk documentation to reflect the new severity ratings including any new mitigations that are resulting from the higher risk categorization. Provide evidence to support the new mitigations including any additional testing to support design or labeling changes.

5. When revisiting the risk analysis, the Agency has the following comments that need to be addressed for specific aspects of the submission including the risk management, design verification/validation and human factors sections (See Human Factors section, request for updated use-related risk analysis).

You will need to update you risk documentation to use consistent definitions of limited, moderate, severe and catastrophic health hazards.

b. You have provided multiple severity ratings for individual hazards. Each hazard should have a single severity rating. You will need to revise the risk documentation to be consistent in defining the severity rating for each hazard.

c. Inthe Use Error Analysis (which we refer to as the use-related risk analysis), we note a discrepancy, please refer to Human Factors section, request for updated use-related risk analysis.

6. In your safety assurance case, you have not provided evidence to support the following claims: °

Reference ID: 4275803

NDA 209988 Page 4

(b) (4)

Without evidence to support the claims, the safety assurance case is incomplete and does not support the top level goal of safety. Therefore you will need to provide arguments supported by evidence for all claims in the safety assurance case.

7. In your safety assurance case under the risk mitigations for under-dosing (S#10375) you have not considered any use errors or environmental factors which may contribute to an under-dosing event. Therefore, the safety assurance case is not complete. You will need to update your assurance case and any supporting evidence to consider environmental factors and user errors which might contribute to under dosing.

8. Because of the deficient reports, the evidence does not support that acceptable mitigations have been implemented and verified to support the top-level goal of safety. Therefore, the deficient reports will need to be resolved before the safety assurance case can be deemed complete and acceptable.

9. You provided several reports to support the verification and validation of the performance criteria of your device. However, the Agency identified several deficiencies in the reports. You will need to resolve the following deficiencies associated with the reports:

a. Report-0154 — Lay

i. All test reports should have clearly stated objectives, acceptance criteria, methods, results (including raw data) and a conclusion that states how the results met the

user requirement. Report-0154 does not contain this information and it is not clear

which requirements are being supported by this report. For that reason, the report

is deficient. Provide a test report © that provides all the required elements to support design verification. ii. Report-0154, © was performed with an earlier version

of the software. Provide a justification for why the updates to the software since the testing do not impact the results of the verification testing or repeat the testing with the current version of the software.

b. Report-0167 — © - Report- 0173 — ©. Report-0170 — ae © Report-0172 — a: Report-0186 — a

Reference ID: 4275803

NDA 209988

Page 5

i. Reports -0167, -0170, -0172, -0173 and -0186 are audits of the actual verification tests. While you state the tests were conducted and passed, you do not provide the specific test methods, specifications, or results. Therefore, the Agency cannot determine whether the reports support the user requirements. Provide a test report that contains the objective, acceptance criteria, methods, results (including raw data) and a conclusion that states how each test satisfies the user requirements.

c. Report-0178 — UL Test Report (IEC 60601-1) Medical electrical equipment

i. It is unclear what system-level performance verification was performed to verify the system-level performance requirements at the intended environmental conditions and at reasonable challenged environmental conditions. It is unclear how this report supports the user requirements. Provide a test report that explicitly states the objective, acceptance criteria, methods, results (including raw data) and a conclusion that states how the test satisfies the user requirements.

d. Report-0185 —

i. In Report-0185, © "did not provide the scope/objective or methods. It is not clear which requirements are being supported by this report. Provide a test report that contains the objective, acceptance criteria, methods, results (including raw data) and a conclusion that states how each test satisfies the user requirements.

ii. This testing was performed with an earlier version of the software. Provide a justification for why the updates to the software since the testing do not impact the results of the verification testing or repeat the testing with the current version of the software.

iii. Per the sample size requirements in Report-0185 more than 30 samples are needed to establish a 95/95 confidence interval for the acceptance criteria. Provide a justification for why only 30 samples were used or repeat the testing with a sample size large enough to establish a 95/95 confidence interval as

lescribed in the acceptance criteria.

e. Report-0190 - tay i. Within Report-0190, i , you have not provided evidence that the device can continue to perform essential functions aid) (0)(4) wm

You will need to provide evidence ow

f. Report- 0151 Summative Human Factors Report

s report is insufficient (See Human Factors section). You will need to provide validation of the design requirements. This may require resolution of the leficiencies associated with the Human Factors Summative Report, additional testing, or new methods for validation.

10. You provided scP-00-02 Adhesion Study as validation for the effectiveness of the

Reference ID: 4275803

adhesive for your device. However, the study design was not designed to validate the adhesive, oe

©® You did not define the requirements and specifications om You did not provide evidence to verify the device meets the specifications or validate the

NDA 209988 Page 6

requirements. The adhesive is part of the essential performance for the device and therefore should be defined, verified and validated. You will need to develop design controls and corresponding evidence for the adhesive.

1

Reference ID: 4275803

NDA 209988 Page 7

Address the following deficiencies: . Provide your justification and/or testing

. Because a software alarm is used to prevent a hazard we deem to have a severity of 3, you need to make the additional revisions to your document! i. For the hazards associated with hn ; arm not triggering due to a software defect or the audio or visual components of this alarm fail to trigger, change the severity to a 4 and reassess if your risk mitigation strategy is appropriate

for these hazards. If not, provide the revised SRS, SDS, risk and verification documentation.

Page 65 discusses your justification for classifying your software as Safety Class {i}per IEC 62304. Since we consider the alarm an alarm that could prevent potential death or serious injury, change your classification to Safety Class C. With this change, describe the additional measures you need to take to comply with Safety Class C and provide the evidence.

specification document.

not provide any traces from the SRS requirements to the SDS requirement.

Provide an SDS specification document and revise your trace document to trace

the SRS requirements to their SDS documents.

b. For any SRS that defines internal checking performed by your software outside of the POST testing, include the frequency at which this testing is performed. This frequency is not defined in your SRS requirements. This should include how often device status messages are relayed to the module that monitors it (i.e. battery level checking, etc.).

c. The following SRS requirements define errors but you did not define how they

are triggered (voltage values, etc.). In the SRS requirement provide how the error masts means a pounce rans if amici

Reference ID: 4275803

NDA 209988

Page 8

14.

Reference ID: 4275803

(b) (4)

© "Note: some of these requirements reference the ELDD (Electronic Design Description) but this document does not appear to have been provided. It is preferred if you provide these values directly in the SRS requirement.

d. It is not clear what software modules are included in some of your POST testing. Describe where in the software architecture, the error code mechanisms in SRSs:

© and ®® look for faults. Indicate if there are any software units these mechanisms do not test and justify why they do not.

e. It is not clear from your requirements how the pump checks to determine if its system time is correct and is not affected by a software defect or data corruption. Since your five-hour delivery profile has two phases, a defect to the system time can affect the length of each phase thus causing potential over- or under-delivery. Provide the SRS and SDS specifications that describe how your pump ensures the integrity of its time data and if there are any errors that triggered if this information is corrupted. If you do not have an error code for this situation, devise and provide the SRS, SDS, risk and verification documentation.

f. There are no requirements for the maximum load (data usage and error messages) the memory can handle or how the system may purge information so this maximum load is not met. Correct this deficiency by 1) explaining how the data generated from 100 use cycles cannot affect the memory of the system or 2) providing the SRS requirements defining maximum load and/or purge, and the verification testing, and stress testing to verify these requirements.

The FDA guidance document, Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices, issued on May 11, 2005, recommends a SDS document be provided for software with a Major Level of Concern, and the traceability document to trace the SRS to the SDS. https://www.fda.gov/RegulatoryInformation/Guidances/ucm089543.htm

The FDA guidance document, General Principles of Software Validation, issued on January 11, 2002, recommends SRS and SDS requirements are complete. https://www.fda.gov/MedicalDevices/ucm085281.htm

Your document, o)(4)

, you describe two unresolved defects #325 and #368. Provide the following additional information for these defects: a. Is defect #325 and #368 the only unresolved defects you have © Tf not, provide a list of all unresolved defects with adequate description of the problem and impact of the defect. b. Defect #325 a

(b) (4)

Explain © how this defect can - A (by (4) impact delivery :

NDA 209988 Page 9

c. Defect #368, (4)

Your description of the impact is inadequate because you did not provide enough detail on the problem to determine if your occurrence rate is correct. Provide answers to the following questions:

i. (b) (4)

lil.

If this is a software defect, then you need to correct this issue before releasing to the market because you cannot predict software defect occurrence rates regardless of how much testing you perform. IEC 62304 recommends performing software risk analysis based on severity alone because if there is a defect it will always present when you understand the actual user actions that causes the defect. Answer our questions above to determine if it is a software defect © If it is a software defect, correct it and provide the verification to show it was adequately corrected and the correction did not inadvertently affect your device.

The FDA guidance document, Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices, issued on May 11, 2005, recommends unresolved software defects be explain with adequate detail. https://www.fda.gov/RegulatoryInformation/Guidances/ucm089543.htm

15. Your document, Software Unit and Integration Test Plan, Project SCIP, Version 1.0, states © tests must reach statement coverage goals only. The test goal in percent will be defined in each code review. Correct the following omissions:

a. We could not find your statement coverage goals in the documentation you provided. Provide your statement coverage goals.

b. Your Software Unit and Integration Test Plan does not provide any detail how you will perform white-box testing outside of code coverage. Please describes your white-box testing strategy including what programs you use to perform your static analysis.

The FDA guidance document, General Principles of Software Validation, issued on January 11, 2002, recommends unit testing is performed per a protocol with adequate description including the code coverage. https://www.fda.gov/MedicalDevices/ucm085281.htm

16. You have provided cytotoxicity testing on the “scFAS (sub-cutaneous Furosemide

Administration System) Cartridge”, wa

(b) (4)

Reference ID: 4275803

NDA 209988 Page 10

a. Please clarify if the adhesive was the only component included in this testing, or if other components were included. If other components were included, please clarify the components included in this test.

b. Please provide a rationale for why the cytotoxic component(s) will not result in an adverse biological response or expose the patient to toxic compounds. This rationale should include an identification of the cause of the cytotoxicity.

c. Ifthe adhesive has been used in a previously cleared device or approved combination product (with no modifications to manufacturing/processing and similar intended use/duration of contact), please provide the submission number or masterfile (with letter of authorization).

17. You have provided cytotoxicity testing on the ““scFAS (subcutaneous Furosemide Administration System), Skin-Contacting Components”, (device-rpt-0039).

to support the biocompatibility of a component: i. Please provide a justification

Additionally, please include a description of the manufacturing process, including any manufacturing/processing agents in your rationale. Please also include the amount of the compounds to which the patient will be exposed (i.e., the formulation).

extractable/leachable chemicals from the to-be marketed pump and the original version of the pump included in the biocompatibility studies. This information can be used to evaluate if there is an increased toxicological risk for systemic endpoints; however, you have not provided an evaluation of how any new compounds or increased amounts of compounds

Reference ID: 4275803

NDA 209988 Page 11

would impact the following endpoints: cytotoxicity, irritation, sensitization, hemolysis, and pyrogenicity. Provide a discussion on why each new compounds or compounds with increased amounts would not impact the biocompatibility of the device, for each of the following endpoints: cytotoxicity, irritation, sensitization, hemolysis, and pyrogenicity.

19. The test reports identified the test article name as 1) scFAS (sub-cutaneous Furosemide Administration System) Cartridge; 2) scFAS (sub-cutaneous Furosemide Administration

System) Cartridge and Vial Adapter; or 3) sc2 Wear Cartridge Fluid Path with © Pump. (b) (4)

© ‘Please update the Table 15- summary of Biocompatibility and Toxicology Studies Conducted (located in SN 0001, 3.2.R.1.P.3 — Device Summary) to include a list of the

. . by (4 components included in each test. | (by (4)

20. You have included two test reports for a number of endpoints both of which appear to be

conducted on the fluid path of the device. (b) (4)

a. For each of the endpoints, please clarify which test was conducted on the fluid path on the final, finished, to-be marketed device.

b. Please confirm that all fluid path components were included (including the needle) and clarify if any skin-contacting components were included.

c. Please clarify the difference between the test articles in the two reports.

Additionally, there are endpoints that are supported by only one test report |, om” © Please clarify that these tests were performed on the fluid path on the final, finished, to-be marketed device.

21. You have not included an evaluation of the particulates that are present within the device fluid-contacting components of the device. Particulates within the device fluid path will be transferred to the drug; therefore, the Agency recommends that the particulate size and amount are in line with the USP <788> . Per the guidance, “Jnfusion Pumps Total Product Life Cycle’, for device related particulate evaluation, you should follow current USP <788> Particulate Matter in Injections Please perform an evaluation of the particulates of the fluid path according to USP <788> particulate matter in injections (Method 1).

22. You have provided a list of the components and materials used in the cartridge (Table 3; (located in SN 0001, 3.2.R.1.P.3 — Device Summary). However, the Agency recommends

Reference ID: 4275803

NDA 209988 Page 12

that you include the following information for each of the patient contacting components (indirect and direct contacting): Material class (e.g., “polypropylene,” “high density polypropylene - HDPE”); General material characteristic (e.g., “thermostable plastic”, “cross linking agent”); Material supplier; and Trade name or common name. You have not included the Material class; General material characteristic; and Material supplier within the list of materials/components. Please provide the above information on the patient contacting materials. This list of materials should include any colorants or additives, used in the

construction of the proposed device.

DRUG PRODUCT QUALITY

23. The container closure integrity validation results using the microbial ingress method and the dye ingress method provided in section 3.2.P.2.5 micro-attributes and 3.2.R device-rpt-0147, respectively, are acknowledged. It is noted that acceptable results from only one method are needed to validate the integrity of the proposed container closure systems. Please address the following:

a. Provide the result of microbial ingress test (6) (4)

(b) (4)

b. Provide the following information for the dye ingress test: 1) description of any positive and negative controls and the actual results of the controls; 2) description of the result readout method; 3) limit of detection. Please note that the dye ingress test

should be shown to be capable of detecting ingression of a small amount of liquid (4)

24. You commit to establish the specification for (Gy bioburden; however, this specification is necessary for review of your application. Provide the specification for |"

bioburden, noting that our recommended | bioburden limit is NMT |}

cfu/mL. Refer to (b)(4) (4)

guidance on © bioburden. CLINICAL

25. The Furoscix Infusor Product Design Clinical Validation Study (PDCV), Study CP-00001 did not meet its primary endpoint, “Absence of Major Product Failure.” Success for this endpoint was based on a success rate for “freedom from major system related failures leading to under-infusion.” The trial was to be deemed successful if the lower limit of the 95% confidence interval of the success rate was >95%. Even when the 7 patients who did not complete the 5-hour infusion period are excluded, the success rate was 63 of 67, or 94%.

Of the 4 device failures among the 67 completers, 3 were dispensing failures related to inadequate preparation of the device coupled with a device design flaw. In each of these

cases, © the device failed to

Reference ID: 4275803

NDA 209988 Page 13

alert © The other dispensing failure resulted from |

© No alarm indicated this failure, either. You , , , 0)(4) ould re-engineer your device to include an alarm :

2

26. In CP-00001, the devices were prepared, attached to the patient and then removed at the end of the 5-hour treatment period by trained study staff. We think it is likely that if patients or lay caregivers had been given responsibility for these tasks in CP-00001, the failure rate in the study might have been higher than it was. Thus, the results from study CP-00001 may overstate the reliability of the studied device. However, we believe that if this product is approved, it will not be uncommon for patients or lay caregivers to set up, attach, and remove the device. Accordingly, if you conduct another study to validate the performance of a re- engineered version of your device, you should require only suitably trained patients or lay care-givers to set up, attach, and remove the device. If the training is performed using a video presentation, the video should be a component of the proposed labeling. The study should include persons with a range of educational backgrounds.

HUMAN FACTORS

27. The human factors (HF) data do not support a conclusion that your proposed product can be used safely and effectively by the intended users for its intended uses and use environments. You have not adequately addressed all the use errors from your validation studies that could lead to patient harm due to delay in treatment, partial treatment, or treatment omission. We acknowledge that you did not consider these use errors to be critical to the safe and effective use of the proposed product because the product is not intended for use in emergency situations. You state that |

© would not cause serious harm to the patient Coy

(b) (4)

©" However, we disagree because delayed, partial, or omitted treatment may require medical intervention and potential hospitalization.

28. We acknowledge that you made modifications to the product design and instructional materials to address some of the errors after studies 123 and 133. While the iterative changes are aligned with the principles of HF engineering, it does not appear that final user interface was validated in the intended user populations. Furthermore, despite the mitigations, participants still experienced errors and difficulty using the product, suggesting the mitigations were not effective.

To address this deficiency, the Agency requests that you conduct adequate root cause analyses for all use errors that could lead to harm (including compromised or delayed care), implement adequate risk mitigation measures, update your use-related risk analysis, and test the effectiveness of your mitigations in a new HF validation study with at least 15 representative users in each distinct user group. We recommend that you submit your updated use-related risk analysis and human factors validation study protocol for review prior to commencing the study.

Reference ID: 4275803

NDA 209988 Page 14

29. We recommend you consider the following as you update your use-related risk analysis and design your HF protocol methodology:

a) Use errors that can cause potential serious harm (including compromised medical treatment, contamination, and infection) should be evaluated as critical tasks!.

b) Hazards that can cause potential damage to the device (i.e., disengaging the device by force) may not be detected and may result in delay of treatment or treatment omission with subsequent treatments. Implement additional mitigation strategies to communicate hazardous situations to the users, and ensure your use-related risk analysis and HF protocol evaluate such hazards and associated mitigations accordingly.

c) Ensure the training methodology employed in your future HF testing (including trainers, training materials, and training decay periods) reflect the training that intended users would receive in real-world, and include justification for the training methodology.

d) We expect your HF study report to document subjective feedback collected from study participants for all use errors, difficulties, and close calls (including participant’s feedback on potential root cause of the use errors, difficulties, and close calls).

e) We expect your HF study to test the final intend-to-market user interface or provide

justification for not testing alterations. Alterations to the device in your HF studies 054)

may have limited testing of the full functionality of the device and effectiveness of the user interface in the simulated studies Oo and

confounds the interpretation of the study results. Furthermore, because you made changes to the instructional materials after HF studies 123 and 133, you may not have adequately validated your final user interface (final instructional material) in the intended user populations.

f) We expect your HF study to evaluate user ability to understand all warnings, alerts, and troubleshooting the device. We consider user’s understanding of critical warnings, alerts, and ability to troubleshoot the device to be critical tasks and should be evaluated in HF validation testing.

30. Our review of the proposed product’s labels, labeling and video identified areas that should be modified. We recommend you implement the following prior to conducting another HF validation study:

a) General Comments (Labels and Labeling, and Video) —

+ Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development and can be found online at: https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM484345.pdf

7 Pages have been Withheld in Full as B4(CCI/TS) Immediately Following this Page

Reference ID: 4275803

NDA 209988 Page 22

The drug product may not be legally marketed until you have been notified in writing that this application is approved.

If you have any questions, please call Brian Proctor, Regulatory Project Manager, at (240) 402- 3596.

Sincerely,

{See appended electronic signature page}

Norman Stockbridge, M.D., Ph.D. Director

Division of Cardiovascular and Renal Products Office of Drug Evaluation I

Center for Drug Evaluation and Research

Reference ID: 4275803

This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

NORMAN L STOCKBRIDGE 06/11/2018

Reference ID: 4275803