The DigniCap® Scalp Cooling System consists of a computer controlled system that includes a refrigerated tank containing the liquid coolant that is maintained at -7 ± 2°C. The coolant circulates from the cooling unit to and through the channels of the cap and back to the cooling unit. The scalp temperature is monitored by three separate sensors. Deviations from the treatment temperature are automatically adjusted by the system (scalp temperature can be controlled with an accuracy of ± 2.0°C). The DigniCap® Scalp Cooling System components include the following:
Digni C3 – Is a refrigerator unit with an integral control system operated via a touch screen and is capable of controlling two separate DigniCap® Cooling caps independently of each other. Scalp cooling is performed in conjunction with a silicone inner cap (DigniCap®), an outer neoprene cap (DigniTherm), and the liquid coolant (DigniCool).
DigniCap® – A soft, tight-fitting silicone cap which has two separate cooling circuits, one for the front and one for the back of the head. Each cooling circuit is equipped with a temperature sensor, and the cap is also equipped with a third sensor for safety control. The cap is available in different sizes.
DigniCool - The liquid coolant monopropylene glycol.
DigniTherm - The outer neoprene cap that insulates and keeps the inner cap in place. This neoprene cover cap, called the DigniTherm, comes in different sizes and is colored coded to match the corresponding DigniCap® Cooling cap.
DigniStick- A component used to save data from a treatment or for troubleshooting. It can also be used to update software.
DigniCard - A key card which has to be inserted in order to start a treatment.

AI/ML Overview

The provided document is a 510(k) summary for the DigniCap Scalp Cooling System. It focuses on the substantial equivalence to a predicate device and an expanded indication for use.

Based on the document, here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The FDA 510(k) summary for K170871 does not explicitly define acceptance criteria in terms of specific performance metrics (e.g., success rate thresholds) that the device must meet for this specific submission. Instead, it relies on demonstrating substantial equivalence to a previously cleared device (DEN150010) and provides a literature review of clinical studies from outside the U.S. to support the expanded indication for use.

The clinical studies vary in their definitions of success and methods of assessment. Here's a summary of the reported success rates and the conditions under which they were achieved, derived from "Table 1 Clinical Data with the DigniCap® Scalp Cooling System Outside of U.S.":

Study (Year)	Chemotherapy Regimens (Examples)	Sample Size	Completed Cooling %	Reported Device Performance (% Success with <50% hair loss/no visible hair loss)
Hernández et al., 2016	Weekly TX (12 cycles); Weekly TX (12 cycles) + AC (4-6 cycles); AC (6-8 cycles)	204	72% (98/120)	84% (82/98)
Fehr et al., 2016	PT+carboplatin (6 cycles); D+C (4 cycles) followed by DT (4 cycles); E+C (4 cycles) followed by PT (12 weeks); PT (16 weeks); DT+C (4 cycles); F+E+C (3 cycles) followed by DT (3 cycles); DT+D+C (6 cycles)	55	78% (43/55)	56% (28/50) (up to 25% hair loss)
Drinkut et al., 2016	E/C + PT	34	56% (19/34)	100% (Patient: all <50% hair loss; Nurses: all <25% hair loss)
Schaffrin-Nabe et al., 2016	Neo-adjuvant EC-PT	40 (32 cooled)	100% (32/32)	63% (20/32) (no visible hair loss)
Traub et al., 2016	EC → PT; PT → EC; EC; PT Mono; Nab-PT Mono; PT plus Myocet	12	75% (9/12)	75% (9/12) (<20% hair loss)
Campennì et al., 2016	EC; EC-TX +/- Trastuzumab; TC	109	79% (86/109)	77% (84/109)
Schaffrin-Nabe et al., 2015	Various combinations of E, C, PT, DT, F (FEC), Carboplatin	226	3.1% (7/226)	65% (no or not visible hair loss, CTC 0-1)
Andrews et al., 2014	AC or combination FEC or FEC-D; TC; Other	122	80.5% (98/122)	50% (61/122)
Friedrich and Carstensen, 2014	Various combinations of E, C, DT, F (FEC), Carboplatin, Taxol, Herceptin, Halaven, Avastin, Gemcitabine, Cisplatin	83	77% (64/83 finished)	52.6%
Udrea et al., 2014	Various combinations including E, C, DT, PT, Carboplatin, Irinotecan, Etoposide, TXT, Cisplatine, Capecitabine	108	96% (104/108)	57% (62/108) (No alopecia / crown like alopecia)
Meunier et al., 2013	Various combinations of E, C, Taxotere (FEC, TCH); Taxane +/- anthracyclines; Paclitaxel, Eribuline, Carbo + cisplatin, gemcitabine	133	44.6%	(Neo) adjuvant: 65%; Palliative: 83%
Ekwall et al., 2013	PT + carboplatin	43	91% (43/47)	51%
Abramov et al., 2011	ANR; TX; ANR+TX	20	Not stated	100% (ANR); 50% (TX); 29% (ANR+TX) (no hair loss, Grade 1)
Kato et al., 2011	PT + C; PT + H; E + C; Other combinations (5FU, CPT-11, Gemcitabine, CBDCA)	359	Not stated	96% (<30% hair loss)
Byahov et al., 2006	ANR; Non-ANR	77	Not stated	ANR: 79%; Non-ANR: 94%
Ridderheim et al., 2003	Various combinations of PT, Carboplatin, E, DT, Gemcitabine, 5-FU, D, Cisplatin, Vinorelbine, Bleomycin, Vinblastin, Darcabazin, Etoposide, Topotecan	74	97% (72/74)	Minimal to no hair loss in ANR or TX treated patients. Median VAS 6 in combined.
Henriksen et al., 2003	FEC	26	Not stated	88% success rate (23/26 patients choose not to use a wig)
Lundgren et al., 1999	PT; DT; FEC; CMF	9 (3 ovarian, 6 breast)	100%	100% (Minimal to no hair loss (VAS < 2.5) in all scalp cooled patients.)

2. Sample size used for the test set and the data provenance

Test Set (Clinical Data): The document refers to a literature review of 18 clinical evaluations outside of the U.S.
- The total number of unique patients across all studies where a sample size is specified appears to be over 1000. For instance, Hernández et al. had 204 patients, Fehr et al. had 55, Drinkut et al. had 34, Campennì et al. had 109, Schaffrin-Nabe et al. (2015) had 226, Andrews et al. had 122, Friedrich and Carstensen had 83, Udrea et al. had 108, Meunier et al. had 133, Ekwall et al. had 43, Abramov et al. had 20, Kato et al. had 359, Byahov et al. had 77, Ridderheim et al. had 74, Henriksen et al. had 26, and Lundgren et al. had 9.
- Data Provenance: The studies were conducted in various countries outside the U.S., including: Mexico, Germany, Switzerland, Australia, Romania, France, Sweden, Russia, and Japan.
- Retrospective or Prospective: The studies are a mix of retrospective, single-arm prospective non-randomized studies, and one randomized prospective study (Ekwall et al., 2013). The document explicitly mentions "These studies did not have long term follow up, and were single armed non-randomized prospective studies" in a general statement (Page 6), though "Table 1" clarifies the nature of each study more specifically.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

The document does not provide details on the number of experts or their specific qualifications (e.g., number of years of experience) used to establish ground truth. Assessments of hair loss were performed by:

Physicians/Treating Physiicans: Campennì et al., Henriksen et al.
Nursing staff: Drinkut et al.
Patients/Patient self-assessment: Drinkut et al., Campennì et al., Meunier et al., Ekwall et al., Henriksen et al.
Independent observers/Investigators: Lundgren et al., Ekwall et al.
Photos/Photo documentation: Hernández et al., Drinkut et al., Friedrich and Carstensen, Ekwall et al., Kato et al., Ridderheim et al.

4. Adjudication method for the test set

The document does not describe specific adjudication methods (e.g., 2+1, 3+1) for the assessment of hair loss. The methods vary by study and typically involve a single assessment by the listed parties (physicians, nurses, patients, or independent observers), or photograph review.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

No, an MRMC comparative effectiveness study was not done. This document pertains to a medical device (scalp cooling system), not an AI algorithm for diagnosis or interpretation. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable in this context.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

Not applicable. The DigniCap Scalp Cooling System is a physical medical device. It is not an algorithm, and the concept of "standalone performance" for an algorithm without human involvement does not apply. The device's performance is measured by its efficacy in reducing hair loss in human patients undergoing chemotherapy.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The "ground truth" for assessing the device's effectiveness was primarily based on:

Clinical assessment of hair loss: This was done using various scales (Dean scale, WHO scale, US NCI CTCAE scale) and patient self-assessments.
Photo documentation: Used in several studies for objective assessment of hair loss.
Patient outcomes data: Success was often defined by a percentage of hair loss (e.g., <50% hair loss, <25% hair loss, no visible hair loss, not needing a wig).
Hair-mass-index (HMI) using a trichometer: Schaffrin-Nabe et al. (2016).

8. The sample size for the training set

This 510(k) relies on previous testing and a literature review for an expanded indication. It does not describe a "training set" in the context of an AI/machine learning model. The clinical data reviewed are for validating the device's efficacy, not for training an algorithm.

9. How the ground truth for the training set was established

Not applicable, as there is no mention of a training set for an AI/machine learning model. The efficacy data are drawn from existing clinical studies.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

July 3, 2017

Dignitana AB % Mr. Michael Billig Experien Group, LLC 224 Airport Parkway. Suite 250 San Jose, California 95110

Re: K170871

Trade/Device Name: DigniCap Scalp Cooling System Regulation Number: 21 CFR 878.4360 Regulation Name: Scalp Cooling System to Reduce the Likelihood of Chemotherapy Induced Alopecia Regulatory Class: Class II Product Code: PMC Dated: March 21, 2017 Received: March 23, 2017

Dear Mr. Billig:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Actinclude requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR

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Part 807); labeling (21 CFR Part 801); medical device reporting (reporting of medical devicerelated adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely.

Jennifer R. Stevenson -S3

For Binita S. Ashar, M.D., M.B.A., F.A.C.S. Director Division of Surgical Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known)

K170871

Device Name DigniCap® Scalp Cooling System

Indications for Use (Describe)

The DigniCap® Scalp Cooling System is indicated to reduce the likelihood of chemotherapy-induced alopecia in cancer patients with solid tumors.

Type of Use (Select one or both, as applicable)

X Prescription Use (Part 21 CFR 801 Subpart D)

| Over-The-Counter Use (21 CFR 801 Subpart C)

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K170871 510(k) Notification DigniCap® Scalp Cooling System Page 1 of 15

510(k) Summary (K170871)

Applicant

Dignitana AB Traktorgränden 3 Lund, Sweden SE-226 60 Phone: +46 46 16 30 92 Fax: +46 46 16 30 99 Johan Ericsson, CEO johan.ericsson@dignitana.se

Contact Person:

Michael J. Billig, CEO Experien Group LLC Regulatory Consultant to Dignitana AB 224 Airport Parkway, Suite 250 San Jose, CA 95110 Tel: (408) 400-0856 Fax: (408) 400-0865 mjb@experiengroup.com

Date of Summary: June 20, 2017

Device Proprietary Name	DigniCap® Scalp Cooling System
Common/Usual Name	Scalp Cooling System
Classification Names /Numbers and Code	21 CFR	Classification Name	Product Code
	878.4360	Scalp Cooling System	PMC
Regulatory Class	II
Prescription Status	Prescription Device
Device / ClassificationPanel	General & Plastic Surgery
Predicate Device	DigniCap® Scalp Cooling System DEN150010
Description of Device	The DigniCap® Scalp Cooling System consists of a computercontrolled system that includes a refrigerated tank containing theliquid coolant that is maintained at -7 $\pm$ 2°C. The coolantcirculates from the cooling unit to and through the channels of thecap and back to the cooling unit. The scalp temperature ismonitored by three separate sensors. Deviations from thetreatment temperature are automatically adjusted by the system(scalp temperature can be controlled with an accuracy of $\pm$ 2.0°C).The DigniCap® Scalp Cooling System components include thefollowing:

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Description of Device (cont.)	Digni C3 – Is a refrigerator unit with an integral control systemoperated via a touch screen and is capable of controlling twoseparate DigniCap® Cooling caps independently of each other.Scalp cooling is performed in conjunction with a silicone innercap (DigniCap®), an outer neoprene cap (DigniTherm), and theliquid coolant (DigniCool).
	DigniCap® – A soft, tight-fitting silicone cap which has twoseparate cooling circuits, one for the front and one for the back ofthe head. Each cooling circuit is equipped with a temperaturesensor, and the cap is also equipped with a third sensor for safetycontrol. The cap is available in different sizes.
	DigniCool - The liquid coolant monopropylene glycol.
	DigniTherm - The outer neoprene cap that insulates and keepsthe inner cap in place. This neoprene cover cap, called theDigniTherm, comes in different sizes and is colored coded tomatch the corresponding DigniCap® Cooling cap.
	DigniStick- A component used to save data from a treatment orfor troubleshooting. It can also be used to update software.
	DigniCard - A key card which has to be inserted in order to starta treatment.
Indications for Use	The DigniCap® Scalp Cooling System is indicated to reduce thelikelihood of chemotherapy-induced alopecia in cancer patientswith solid tumors.

Limitations

The sale, distribution, and use of DigniCap™ Scalp Cooling System are restricted to prescription use in accordance with 21 CFR 801.109.

Limitations on device use are also achieved through the following statements included in the instructions for use:

Contraindications

The use of Dignicap is contraindicated in pediatric patients.

The use of Dignicap is contraindicated in adult patients with:

cold sensitivity,
cold agglutinin disease, ●
cryoglobulinemia ●
cryofibrinogenemia. ●
Cold urticaria
CNS malignancies (either primary or metastatic),
squamous cell carcinoma of the lung,
small cell carcinoma of the lung,
cancers of the head and neck, ●
skin cancers including melanoma, squamous cell carcinoma, and Merkel cell ● carcinoma.
hematological malignancies treated with curative intent by chemotherapy ●

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K170871 510(k) Notification DigniCap® Scalp Cooling System Page 3 of 15

solid tumor malignancies with a high likelihood of metastases in transit.
patients who are scheduled for bone marrow ablation chemotherapy
patients who are scheduled to undergo skull irradiation ●
patients who have previously received skull irradiation

Warnings

Scalp and/or cutaneous metastases have been reported in patients with non-small cell lung cancer, colon cancer, renal cell carcinoma, ovarian cancer, and bladder cancer. Patients with advanced forms of these cancers may be more likely to experience scalp metastases with the scalp cooling svstem.

Use of Scalp Cooling in the palliative setting in patients with metastatic cancer may also increase the risk for scalp metastases.

Use of scalp cooling with taxanes plus anthracyclines when used in combination has not been shown to be successful in preventing chemotherapeutic drug induced alopecia. Dignicap® Scalp Cooling System should not be used in these patients.

Scalp radiation can cause stenosis of small cutaneous vessels decreasing device effectiveness.

The effectiveness of this device in patients who have received previous chemotherapy has not been evaluated.

The risk of scalp-cooling may outweigh the benefits in patients receiving chemotherapeutic agents with low incidence of inducing alopecia.

Long-term effects of scalp-cooling and risk of scalp metastasis have not been fully studied.

Clinical studies have demonstrated variable success rates in patient reduction of chemotherapy induced alopecia with scalp cooling since the outcome is dependent on multiple factors including chemotherapy regimen, dose, duration of drug infusion, chemotherapy drug metabolism, and concomitant comorbidities. Data have shown that women who experience hair loss in spite of using scalp cooling might have worse quality of life than women who did not have scalp cooling.

Comparison to Predicate Devices

Aside from the change in the Indications for Use, the DigniCap® Scalp Cooling System is identical in technological characteristics, design and performance to the predicate.

Summary of Testing

Pre-clinical Testing

No additional testing was conducted for this 510(k) to support substantial equivalence. The device in this submission is identical to the previously cleared device, as the purpose of this application was for the expansion of the treatment population only. Testing of the predicate device included biocompatibility, shelf-life, shipping and packaging, electromagnetic compatibility and electrical safety, software, bench testing, and two clinical studies. All tests met the pre-determined specifications and acceptance criteria and demonstrated the DigniCap® Scalp Cooling System to be safe and effective as labeled.

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K170871 510(k) Notification DigniCap® Scalp Cooling System Page 4 of 15

Clinical Data

The efficacy of scalp cooling with the DigniCap System has been reported in 18 clinical evaluations outside of the U.S. These studies investigated the effects of scalp cooling on the incidence of alopecia in patients with various malignancies using a variety of chemotherapy regimens in both the adjuvant and palliative settings. Efficacy has best been demonstrated in chemotherapy regimens containing docetaxel, paclitaxel, cyclophosphamide, and/or carboplatin. These studies did not have long term follow up, and were single armed non-randomized prospective studies. Long-term effects of scalp-cooling and scalp metastasis have not been fully studied in the adjuvant setting outside of stage I and II breast cancer. It is not clear whether there is increased risk of recurrence, particularly scalp or skull metastases, based on the data available. Some of the studies did not list the names of the solid tumor malignancies or their frequencies.

A literature review was conducted to address the safety and effectiveness of the DigniCap device. A search in PubMed, EMBASE, Clinical Trial register and Manufacturer and User Facility Device Experience Database - (MAUDE) was performed using the following search terms: DigniCap, Digni and scalp, Digni and alopecia, Digni and hypothermia, and Dignitana. Abstracts and peer reviewed articles (Table 1) of clinical trials covering the majority of the relevance and methodology questions in the appraisal plan of the pivotal clinical evaluation report were selected. Due to the literature review method and the design of these studies, safety and effectiveness results presented in these studies may not be accurate.

Based on the above published data there is insufficient evidence to assess long term effect. Use of DigniCap Scalp Cooling System in these patients may increase the risk of scalp metastasis, metastasis elsewhere in the body or impact the natural course of the disease

Conclusion

The DigniCap Cooling System described in this application is unchanged from the device approved in DEN150010. This application is limited to a revision of the indication for use. The clinical data described in the literature documents provided in this application do demonstrate that the DigniCap Cooling System can be used to reduce the likelihood of chemotherapy-induced alopecia in cancer patients with solid tumors.

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Table 1

Clinical Data with the DigniCap® Scalp Cooling System Outside of U.S.

Publication(author, year,institution)	Type of study(RCT, retrospective,single armprospectivenonrandomizedstudies.)	Treatment group	Control group	Sample size	Length ofFollow- up	Follow-up schedule	Completed Cooling%	% Success with<50% hair loss	List of AdverseEvents	Reason fordiscontinuationof cooling
Hernández et al., 2016American BritishCowdray, ABC MedicalCenter, Mexico City	RetrospectiveConsecutive series ofpatients;December 2010 -January 2015.	Weekly TX for 12 cycles(n=4).Weekly TX for 12 cycles andAC every 3 weeks for 4-6cycles (n=66).AC every 3 weeks for 6-8cycles (n=28).	N/A	204 patients withStage I-V breast(n=120), ovary,lung, uterus,esophagus,prostate, chest,urethra, rectum,larynx, bladder,colon, liver cancerand non-Hodgkin´slymphoma.	Not stated	Hair loss - PhotosDean scale	72% (98/120)	84% (82/98)	At follow-up:no side effectsor scalpmetastasispresent.	Hair loss.
Fehr et al., 20161. Clinic of Kempten-Oberallgäu, Germany2. Cantonal HospitalFrauenfeld, Switzerland	Non randomizedprospective	PT 175 mg/m2 andcarboplatin 6 AUC (areaunder the curve) for 6 three-week cycles [n = 12 (22%)]D 60 mg/m2 and C 600mg/m2 for 4 three-weekcycles, followed by DT 100mg/m2 for 4 three-weekcycles [n = 11 (20%)]E 90 mg/m2 and C 600mg/m2 for 4 three-weekcycles, followed by PT 80mg/m2 weekly for 12 weeks[n = 10 (18%)]PT 80 mg/m2 weekly for 16weeks [n = 8 (15%)]DT 75 mg/m2 and C 500mg/m2 for 4 three-weekcycles [n = 6 (11%)]F 500 mg/m2, E 100 mg/m2,and C 500 mg/m2 for 3 three-week cycles, followed by DT100 mg/m2 for 3 three-weekcycles [n = 64 (7%)]DT 75 mg/m2, D 50 mg/m2,and C 500 mg/m2 for 6three-week cycles [n = 4 (7%)	N/A	Women with breast,endometrial, orovarian cancer(n=55)Breast cancer35adjuvant,5 palliative,2 neo- adjuvantOvarian cancer 12(22%)Endometrial cancer1 patient (1.8%)	Not stated	Photographs of thepatient's head from5 different views.WHO scale.Grade 0: no hair lossGrade 1: minimalhair loss (>0% to25%).Corresponds toDean score 0 and 1.	78% (43/55)	56% (28/50)(up to 25% hairloss)	1.8% (1/55)could nottolerate scalpcooling.	Hair loss (n=7),death (n=3),change of treatmentcentre (n=1),and doubts aboutstudy participationresulting in withdrawalof consent within 30minutes of initiation ofthe 1st cycle (n=1).
Publication(author, year,institution)	Type of study(RCT, retrospective,single armprospectivenonrandomizedstudies.	Treatment group	Control group	Sample size	Length ofFollow- up	Follow-up schedule	Completed Cooling%	% Success with<50% hair loss	List of AdverseEvents	Reason fordiscontinuationof cooling
Drinkut et al., 2016MedizinischeHochschule Hannover,Klinik fürFrauenheilkunde undGeburtshilfe, Hannover,Germany	Non randomizedprospectiveJune 2014 - February2016	4 x E/C 90/600 mg/m2 + 12 xPT 80 mg/m2	N/A	Women with breastcancer (n=34)	Not stated	Quantification ofhair loss by patientsand nursing staff.Photos.	56% (19/34)	100%(Patientassessm.: all<50% hair loss,Nursesassessm.: all<25% hair loss)	Not stated(>50% ofpatients did notreport any sideeffects.)	Cold sensation (n=6)Other (n=9)
Schaffrin-Nabe et al.,2016GemeinschaftspraxisBochum, Germany	Non randomizedprospective	Neo-adjuvant EC-PT	Neo-adjuvantEC-PT	Breast cancerpatients (n=40)Scalp cooled (n=32),controls (n=8)	Not stated	Hair-mass- index(trichometer)No visible hair losswas consideredtreatment success.	100% (32/32)	63% (20/32)(no visible hairloss)Complete hairloss in controls.	Not stated.	N/A
Traub et al., 2016Agaplesion MarkusKrankenhaus Frankfurtam Main, Germany	Non randomizedprospectiveOctober 2015 -	4 × EC → 12 × PT (n = 7)4 × PT → 4 × EC (n = 1)4 × EC (n = 1)18 × PT Mono (n = 1)4 × Nab-PT Mono (n = 1)18 × PT plus Myocet (n = 1)	N/A	Women with breastcancer (n=12)	Not stated	Objectiveassessment ofphotographs.	75% (9/12)	75% (9/12)(<20% hair loss)	Cooling-induced sideeffects	Hair loss (n=1),or cooling-inducedside effects (n=2)
Campennì et al., 2016European InstituteOncology, Milan	Non randomizedprospective	ECEC-TX +/- TrastuzumabTC	N/A	Patients with stage I-III breast cancerreceiving adjuvantchemotherapy(n=109).	Not stated	Hair lossPatient self-assessment &assessment bytreating physicianDean scale	79% (86/109)	77% (84/109)	Headaches andcoldness.No seriousadverse events.	Hair loss (n=12),Discomfort during thecooling period (n=4),other reasons (n=7).

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K170871 510(k) Notification DigniCap® Scalp Cooling System
Page 7 of 15

Publication(author, year,institution)	Type of study(RCT, retrospective,single armprospectivenonrandomizedstudies.)	Treatment group	Control group	Sample size	Length ofFollow- up	Follow-up schedule	Completed Cooling%	% Success with<50% hair loss	List of AdverseEvents	Reason fordiscontinuationof cooling
Schaffrin-Nabe et al.,2015Gemeinschafts praxisfür Hämatologie undOnkologie Bochum,Germany	Non randomizedprospective	E 90 mg/m² + C 3w→PT wE 90 mg/m² + C 2w→ PT wE 90 mg/m2 + C 3w ->DT 100mg/m²F + E 100 mg/m² + CF + E 90 mg/m² + CDT 75 mg/m² CarboplatinAUC6F + E 100 mg/m² + C → DT100 mg/m²E 150 mg/m² + PT 225mg/m² + C 2000 mg/m²DT 75 mg/m² + A50 C 500mg/m² PT 100 mg/m² +Carboplatin AUC2Gemcitabine 1000 mg/m² +Carboplatin AUC2DT 75 mg/m2 + C 600 mg/m2	N/A	In total 226 cancerpatients with solidtumors.Breast cancerreceiving (neo)adjuvant andpalliativechemotherapy(n=136).	Not stated	Hair loss, commontoxicity criteria (CTCGerman version 1.0)scale for alopecia.No or not visible hairloss, CTC 0-1.	3.1% (7/226)	65%(no or notvisible hair loss,CTC 0-1.)	Slight and welltolerablesensation ofcold and mildcranialpressure. Noskin irritationsrecorded.	Cold intolerance andaversion.
Andrews et al., 2014Patricia Ritchie Centre,the Mater HospitalSydney, Australia	Prospective feasibility	AC or combinationFEC or FEC-DTCOther	N/A	Early stage breastcancer (n=122)	Not stated	Completion rateHair loss: Dean score	80.5% (98/122)	50% (61/122)	Not stated	Adverse events notlisted specifically forpatients using theDigniCap.

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Publication(author, year,institution)	Type of study(RCT, retrospective,single armprospectivenonrandomizedstudies.)	Treatment group	Control group	Sample size	Length ofFollow- up	Follow-up schedule	Completed Cooling%	% Success with<50% hair loss	List of AdverseEvents	Reason fordiscontinuationof cooling
Friedrich andCarstensen, 2014Mammazentrum,Jerusalem Hospital,Hamburg, Germany	Non randomizedprospectiveJune 2011-December2012	Multiple combinations(Neo-) adjuvantchemotherapyE 90 mg/m² + C 600 mg/m²(q3w4) → DT 100/175mg/m² (q3w4)F 500 mg/m2 + E 100 mg/m²+ C 500 mg/m² (q3w6)F 500 mg/m2 + E 100 mg/m²+ C 500 mg/m² (q3w6) →DT 100 mg/m2 (q3w3)E 90 mg/m² + C 600 mg/m²(q3w4)CarboplaPt/DT (q3w*6)Palliative chemotherapyTaxol 135/Herceptin 8mg/kgHalaven 1.23Taxol 90 Avastin 10mg/kgCarboplatinGemcitabine/Cisplatin	N/A	Breast cancer(n=83)Adjuvant (n=58)Palliative (n=6)Drop outs (n=19)	Not stated	Hair loss: PhotodocumentationNumerical VAS (1-10)	77%(64/83 finishedchemotherapy andscalp cooling.)	52.6%	Feeling of coldHeadachesHeaviness ofheadScalp painFrequencydifferedbetweenpatients with(neo-) adjuvantand palliativeCT	Out of 19 patients;hair loss (n=5),Cancer relatedemergency cases ordisease progression(n=3),Feeling ofcold/headaches (n=2),Unspecifiedintolerance (n=9).
Publication(author, year,institution)	Type of study(RCT, retrospective,single armprospectivenonrandomizedstudies.)	Treatment group	Control group	Sample size	Length ofFollow- up	Follow-up schedule	Completed Cooling%	% Success with<50% hair loss	List of AdverseEvents	Reason fordiscontinuationof cooling
Udrea et al., 2014Medisprof Oncology dayhospital, Cluj, Romania	Non randomizedprospectiveMarch 2012 -November 2013	E 100mg/m2 + C 600 mg/m2(n=53)DT 100 mg/m² (n=10)PT 175 mg/m² + carboplatinAUC5-6 (n=21)Irinotecan 80 mg/m2 (n=4),Etoposide 100 mg/m² day 1-3 + Carboplatin AUC5 (n=3)TXT 75 mg/m² (n=2)DT 75 mg/m² + Cisplatine 75mg/m² + Capecitabine 1000mg/m² (n=2)Other combinations (n=13)	N/A	108 cancer patients(Treatment ongoingfor 8 patients).	Not stated	Hair loss: US NCI(CTCAE) v4.0.No alopecia / crownlike alopecia	96% (104/108)	57% (62/108)(No alopecia /crown likealopecia)	Not stated	Discomfort (n=4)
Meunier et al., 20131) Service dechimiothérapie, CliniqueCharcot, Lyon, France2) Centre Alexis Vautrin,Nancy, France3) JerusalemKrankenhausMammazentrumHamburg, Germany	Non randomizedprospectivemulticenter	(Neo-) adjuvantchemotherapy4 E90 C600 + 4 Taxotere(n=26)3 FEC100 + 3 Taxotere (n=10)6 FEC 100 (n=15)4 T75C600 +/- Trastuzumab(n=7)Taxane +/-anthracyclines(n=11)Palliative chemotherapyPaclitaxel, Eribuline, Carbo +cisplatin, gemcitabine (n=6)	N/A(Comparison 3versus 8degrees C)	Cancer patients(total n=133).Breast cancer(n=75)(Neo) adjuvant(n=69)Palliative (n=6).	Not stated	Hair loss: Patientself- assessmentVAS 0-100, with 100being total hairpreservation.(success: keeping60-100% of hair)	44.6%	(neo) adjuvant:65%Palliative: 83%	Headaches(22%)Cold sensationor pain to thescalp (4%)	Intolerance (9%)Headaches (9%)Unknown (9%)Hair loss (22%)Stoppedchemo/diseaseprogression (9%)
Publication(author, year,institution)	Type of study(RCT, retrospective,single armprospectivenonrandomizedstudies.)	Treatment group	Control group	Sample size	Length ofFollow- up	Follow-up schedule	Completed Cooling%	% Success with<50% hair loss	List of AdverseEvents	Reason fordiscontinuationof cooling
Ekwall et al., 2013Örebro UniversityHospital,Örebro, Sweden	Randomizedprospective	PT (175 mg/m2) +carboplatin (AUC 5-6)	N/A	Gynecologicalcancer (total n=43);Ovarian cancer(n=22)Endometrial cancer(n=17)Cervical cancer(n=2)Tubal cancer (n=1)Peritoneal cancer(n=1)	Not stated	Hair loss: Photodocumentation asassessed by twoInvestigatorsVAS (0-10) asassessed by thepatients	91% (43/47)	51%	Scalp coolingwas generallyvery welltolerated.HeadachesVAS ≤ 1ColdnessVAS ≤ 3.4	Anaphylactic reactions,peripheral neuropathyand regimenmodification.
Abramov et al., 2011N.N. Blokhin RussianCenter Research,Chemo- therapy andcombined treatmentMoscow. Russianfederation	Non randomizedprospective	ANR (n=5)TX (n=8)ANR+TX (n=7)	N/A	Breast cancer(n=20)	Not stated	Hair loss: CTCAEv3.0 Grade 1:(thinning or patchy)	Not stated.	100%ANR: 100% nohair lossTX: 50% no hairloss, 50% grade1ANR+TX: 29%no hair loss,71% Grade 1	Not stated	N/A
Kato et al., 2011Kato Breast Clinic, Shiga,Japan	Non randomizedprospectiveAugust 2007- October2010	PT 60 mg/m2 weekly + C 400mg/m2 (n=252)PT+ H (n=29)E 40 mg/m2 biweekly+ C 400mg/m2 (n=54)Other combinations (n=24)(Combination by 5FU, CPT-11, Gemcitabine andCBDCA.)	N/A	Breast cancer(n=359)	Not stated	Modified WHO scale(Grade 1-5)Success defined as<30% hair loss.Photos	Not stated	96%	No abnormalscalp sensationor headachesduring or aftertreatment.No scalpmetastasis.	N/A
Byahov et al., 2006Semashko CentralClinical Hospital,Moscow, Russia	Non randomizedprospective	ANR (n=43)Non-ANR (n=34)	N/A	Breast cancer,ovarian cancer,colorectal cancer(total n=77)	Not stated	Hair loss CTCAE v 3.0	Not stated	ANR: 79%Non-ANR: 94%	Well toleratedby all patients.	N/A
Publication(author, year,institution)	Type of study(RCT,retrospective,single armprospectivenonrandomizedstudies.)	Treatment group	Controlgroup	Sample size	Length ofFollow- up	Follow-upschedule	CompletedCooling %	% Successwith<50% hairloss	List ofAdverseEvents	Reason fordiscontinuationof cooling
Ridderheim et al.,2003Lund UniversityHospital, Sweden	Non randomizedprospective pilot	PT 175 mg/m²,Carboplatin AUC 5PT 175 mg/m², E 75mg/m2, Carboplatin AUCടDT 100 mg/m²PT 175 mg/m²Gemcitabine 1,000mg/m² day 1+8, E 75mg/m² day 1E 60 mg/m², C 600mg/m², 5-FU 600 mg/m²D 50 mg/m², Cisplatin 50mg/m²E 50 mg/m², CarboplatinAUC 5Vinorelbine 30 mg/m²D 25 mg/m²Bleomycin 10,000 E/m²Vinblastin 6 mg/m²Darcabazin 375 mg/m²Bleomycin 30,000 day 1,5, 16Etoposide 100 mg/m²day 1-5Cisplatin 20 mg/m² day1—5Topotecan 1.0 mg/m²day 1-5Etoposide 50 mg/day 6-12Topotecan 1.0 mg/m²		In total 74 cancerpatientsOvarian cancer(n=60)Hodgkin´sLymphoma (n=8)Breast cancer(n=3)Endometrialcancer (n=2)Sarcoma (n=1)	15 months(range 3-44).	Hair loss:PhotodocumentationNumerical VAS(0-10)	97% (72/74)	Minimal tono hair loss inANR or TXtreatedpatients.Median hairloss was VAS6 (range 1.5-8) in patientstreated whencombiningANR and TX.	Discomfortwas modest(medianvalue 1.5;range 0.5-8).No presenceof scalpmetastases	Discomfort
Publication(author, year,institution)	Type of study(RCT,retrospective,single armprospectivenonrandomizedstudies.)	Treatment group	Controlgroup	Sample size	Length ofFollow- up	Follow-upschedule	CompletedCooling %	% Successwith<50% hairloss	List ofAdverseEvents	Reason fordiscontinuationof cooling
Henriksen et al.,2003Herlev Hospital,University ofCopenhagenDenmark	Non randomizedprospective interim	Seven cycles of FEC(Adjuvant). Dose notstated.	N/A	Breast cancer(n=26)	Not stated	Hair loss:Patients self-assessmentClinical photosNumerical VAS,wig useSide effects:Numerical VASPost-treatmentquestionnaire	Not stated	88% successrate,23/26patientschoose not touse a wig.	Side effectsand extratimeaccepted bythe patients.	N/A
Lundgren et al., 1999Umeå UniversityHospital & LundUniversity Hospital,Sweden	Non randomizedprospective pilot	PT 135-175 mg/m2 (n=3)DT 100 mg/ m2 (n=3)FEC (n=2)CMF (n=1)	PT	Ovarian cancer(n=3)Breast cancer(n=6)Ovarian cancercontrol (n=2)	Not stated	Hair loss:Numerical VAS (1-10) assessed byindependentobservers.Discomfortassessed by thepatients.	100%	Scalp cooledpatients:100%Controls: 0%(Minimal tono hair loss(VAS < 2.5) inall scalpcooledpatients.)	Discomfortlevel initiallylow (meanVAS 3) anddecreasedafter 10 min(mean VAS1.5).No presenceof scalpmetastases	N/A

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Chemotherapy and Abbreviations

ANR: anthracyclines

H: Herceptin

TCH: docetaxel + carboplatin + trastuzumab

AC: doxorubin + cyclophosphamide

M: methotrexate TC: docetaxel + cyclophosphamide

C: cyclophosphamide

D: doxorubicin

DT: docetaxel

E: epirubicin

F: 5-fluorouracil

Mi: mitoxanthrone

PT: paclitaxel

TX: taxanes

Vc: vincristine

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Bibliography:

1. Lundgren-Eriksson,L,etal."Totalpreventionoftacoi-induced alopecia by a new model of cold cap(dignitana)."The European Journal of Cancer. Vol. 35, Supp. 4. September 1999.
1. Henriksen.T.etal."Advanced.computerizedcoldcapforpreventing chemotherapy induced alopecia."The European Journal of Cancer. Vol. 1, No. 5. September 2003. S369.
1. Ridderheim,M,etal."Scalphypothermiatopreventcherapy-induced alopecia is effective and safe: A pilot study oif a new difitized scalp-cooling system used in 74 patients. Support Care Cancer. Vol. 11. 2003. 371-377.
1. Byahov.MandOShevlev."Alopeciapreventioninchemotherapypatients.Methodof controlledscalpcooling."Meditsinskaya Cartoteka.2006.
1. Kato.M.etal."EvaluationofDigniCap System for the Prevention of Chemotherapy-induced Hair LossinBreastCancerPatient."St. Gallen Oncology Conference. 2011.
1. Abramov,MandSemenova,I."CoolingoftheScalptoPreventAnticancerChemotherapy- induced Alopecia."Poster.
1. Ekwall, E, et al."Determinationofthemosteffectivecoolingtemperaturefortheprevention of chemotherapy-inducedalopecia." Molecular and Clinical Oncology. Vol. 1. 2013. 1071.
1. Meunier,A,etal."Evaluationdelatoléranceetdel'efficacitéd'uncasqueàrefrigeration continue (DIGNICAP)danslapréventiondel'alopéciechimio-induite."(Translationfrom French). Presented at the Society For Science-Based Medicine , 2013.
1. Udrea.A. "Scalpcoolingsystemingchemotherapy-induced alopecia: a pilot study on 108 patients -a Romanian oncology -dayhospitalexperience."Medisprof Oncology. Psycho-Oncology 23 (Suppl. 3):169-254 (2014), P1-0062.
1. Friedrichs,KandMCarstensen. "Successfulreductionofalopeciainducedbyanthracycline and taxane containing adjuvant chemotherapy in breast cancer -clinical evaluation of sensorcontrolledscalpcooling."SPrignerPlus. Vol. 3, No. 500 2014. 1-7.
1. Andrews.K.etal. "CrowningGlory:Isthatthewholestory?Implementingscalpcoolingin an Australian setting." Poster presentation at Cancer Nurses Society of Australia, 17th winter congress, 2014.
1. Schaffrin-Nabe,D.etal. "Theinfluenceofvariousparametersonthesuccessofsensor- controlled scalp cooling in preventing chemotherapy-inducedalopecia."Oncology Research and Treatment. Vol. 38. 2015. 489-495.
1. Drinkut,K.etal."coolHAIR-scalp cooling to prevent chemotherapy-inducedalopecia." (Translation from German). Geburtshilfe Frauenheilkunde 2016:76-P171.
1. Schaffrin-Nabe,D,etal."Hair-mass-Index (HMI) as indicator for the efficacy oif scalp cooling(SC)andtheassociatedqualityoflife." Journal of Clinical Oncology. 34. 2016. (suppl: abstr e21692)
1. Traub,L,etal."EfficacyandsideeffectsoftheDigniCap®systemtopreventcytostaticinduced alopecia."(TranslationfromGerman).Geburtshilfe Frauenheilkunde 2016:76-P068
1. Campenni,GM,etal."Preventingchemotherapy-induced alopecia by scalp cooling: preliminary data from a study on the efficacy and safety of dignicap® system in breast cancer patients."Ann Oncol. Vol. 27. Supp. 4. 2016. iv63-iv64.
1. Fehr,MK,etal. "Sensor-controlled scalp cooling to prevent chemotherapy-induced alopecia in

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femalecancerpatients."Current Oncology. Vol. 23, No. 6. December 2016. e576-e582.

1. Hernández R.E. et al., Experience at the ABC Medical Center of Mexico City, 2010-2015, using the scalp cooling system DigniCap® for the prevention of chemotherapy-induced alopecia. Poster 850794 at the San Antonio Breast Cancer Symposium, 2016.
1. Van den Hurk CJ, Mols F, Vingerhoets AJ, BreedWP(2010) Impact of alopecia and scalp c cooling on the well-being of breast cancerpatients. Psych oncol 19(7):701-709.

Regulation Number and Section

§ 878.4360 Scalp cooling system to reduce the likelihood of chemotherapy-induced alopecia.

(a)
Identification. A scalp cooling system to reduce the likelihood of chemotherapy-induced alopecia is a prescription device intended to reduce the frequency and severity of alopecia during chemotherapy in which alopecia-inducing chemotherapeutic agents are used.(b)
Classification —Class II (special controls). The special controls for this device are:(1) Non-clinical performance testing must demonstrate that the device meets all design specifications and performance requirements, and that the device performs as intended under anticipated conditions of use. This information must include testing to demonstrate accuracy of the temperature control mechanism.
(2) Performance testing must demonstrate the electromagnetic compatibility and electrical safety of the device.
(3) Software verification, validation, and hazard analysis must be performed.
(4) The patient contacting components of the device must be demonstrated to be biocompatible. Material names must be provided.
(5) Labeling must include the following:
(i) A statement describing the potential risk of developing scalp metastasis.
(ii) Information on the patient population and chemotherapeutic agents/regimen for which the device has been demonstrated to be effective.
(iii) A summary of the non-clinical and/or clinical testing pertinent to use of the device.
(iv) A summary of the device technical parameters, including temperature cooling range and duration of cooling.
(v) A summary of the device- and procedure-related adverse events pertinent to use of the device.
(vi) Information on how the device operates and the typical course of treatment.
(6) Patient labeling must be provided and must include:
(i) Relevant contraindications, warnings, precautions, and adverse effects/complications.
(ii) Information on how the device operates and the typical course of treatment.
(iii) Information on the patient population for which there is clinical evidence of effectiveness.
(iv) The potential risks and benefits associated with use of the device.
(v) Postoperative care instructions.
(vi) A statement describing the potential risk of developing scalp metastasis.