CER+Comfort+Family+Group+21 06

Clinical Evaluation Plan/Report
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Responsible Document Type: Clinical Evaluation Document Status:

RA
Dept.: Report (CER)
DHF No.: Project Name: Document No.:
Created by / ATC Approved by / Version:

Date: Date:
21.06.2018
Valid date: Change No.: Edited by:
This document is the property of ConvaTec and is to be treated as confidential by the party to whom it has been
submitted by ConvaTec and is not to be disclosed to any third party without the specific prior written permission of
ConvaTec.
Clinical Evaluation Report
On
Infusion Set
comfortTM, comfortTM short, Silhouette®,
Silhouette® Paradigm, ACCU-CHEK®, Varisoft,
DuoTM infusion tubing
For subcutaneous infusion with 20°-45° degree
3915000[8] Template for Clinical Evaluation Report. Electronic copy – not controlled if printed
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Contents
Executive Summary ..........................................................................................................4
1. Scope of this Clinical Evaluation Report .............................................................................4
2. General details and device history....................................................................................5
3. Characteristics of the device ..........................................................................................5
3.1. Components ......................................................................................................6
3.1.1. Characteristics ...........................................................................................8
3.1.2. Mode of action ...........................................................................................8
3.1.3. Duration of use and body contact .................................................................9
3.2. Intended Use, Indications, Contraindications/Precautions .................................................9
3.3. Claims ........................................................................................................... 11
3.4. Preclinical tests ................................................................................................. 11
3.4.1. Technical tests ......................................................................................... 11
3.4.2. Biocompatibility ....................................................................................... 12
3.4.3. Drug compatibility test .............................................................................. 13
3.4.4. Usability/Human factor testing ................................................................... 14
4. Clinical background, current knowledge, state of the art ........................................................ 14
4.1. Introduction ..................................................................................................... 14
4.2. Usage of infusion set in DM .................................................................................. 14
4.3. Risk versus benefits for using infusion sets ................................................................ 15
5. Device under evaluation ............................................................................................. 15
5.1. Context of the evaluation and choice of clinical data types .............................................. 15
5.2. Demonstration of equivalence ............................................................................... 16
6. Summary of the clinical data and appraisal ....................................................................... 17
6.1. Clinical data generated and held by the manufacturer ................................................... 17
6.1.1. Sales Data .............................................................................................. 17
6.1.2. Complaint databases ................................................................................ 17
6.1.3. Field corrective actions and other PMS data ................................................. 18
6.1.1. Summary of clinical trials conducted by Unomedical ...................................... 19
6.2. Summary Clinical data from literature ....................................................................... 19
6.3. Overall Summary Conclusion of clinical data .............................................................. 20
7. Risk management ..................................................................................................... 24
8. Analysis of the clinical data .......................................................................................... 25
8.1. Requirement on performance (MDD ER3 / AIMDD ER2) ................................................ 25
8.2. Requirement on safety (MDD ER1 / AIMDD ER*)......................................................... 25
8.3. Requirement on acceptable benefit/risk profile (MDD ER1) ............................................. 25
8.4. Requirement on acceptability of side effects (MDD ER6) ................................................ 25
9. Post market surveillance ............................................................................................. 26
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10. Conclusions ........................................................................................................ 26

11. Date of the next clinical evaluation ............................................................................. 27
12. References ......................................................................................................... 28
13. Appendix I: ......................................................................................................... 33
14. Appendix II: ........................................................................................................ 34
15. Appendix III: ........................................................................................................ 45
16. Appendix IV: ....................................................................................................... 46
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Executive Summary
The Clinical Evaluation Report (CER) presents the data to support safety and performance for comfortTM family
infusion sets such as comfortTM, comfortTM short, Silhouette®, Silhouette® Paradigm, ACCU-CHEK/TenderLink,
Varisoft infusion sets. comfortTM family infusion sets with soft cannula insertion at a 20°- 45° degree insertion
angle is designed for a single use subcutaneous drug delivery. The infusion set is designed to be used with an
external infusion pump.
The comfortTM family infusion sets and cannula are sterile, non-pyrogenic class IIb medical device per Annex
IX, Rule 8 of the EC Council Directive 93/42/EEC of 14 June 1993 [2] and amended by Directive 2007/47/EEC
also a class II according to Food and Drug Administration (FDA).
DuoTM infusion tubing only offered for P-cap connector is a sterile class IIa medical device per Annex IX, Rule
8 of the EC Council Directive 93/42/EEC of 14 June 1993 [2] and amended by Directive 2007/47/EEC.
comfortTM, comfortTM short, Silhouette®, Silhouette® Paradigm, ACCU-CHEK/TenderLink, Varisoft infusion sets
are intended to subcutaneous delivery of medication administered by an external pump for the treatment of
Diabetes Mellitus (DM) in adults and children.
The purpose of this CER is to verify the safety and performance of aforementioned infusion sets to ensure that
the available clinical data is documented in accordance with current regulatory requirements as required by
MEDDEV 2.7.1, Revision 4, June 2016 and to make conclusions in regard to compliance with Essential
Requirements 1, 3 and 6 of Directive 93/42/EC as amended. The sufficient clinical evidence included in the
CER has been identified through manufacturer generated data such as bench testing as well as through a
literature review of available clinical data used for relevant clinical indication combined with a review of state of
the art/existing knowledge of similar products.
Verification of safety and performance is supported by the examination of post-market surveillance (PMS) data
as well as by the data identified in the risk analysis that has accumulated.
Based on successful review of all data included in the current CER, it can be concluded that comfortTM, comfortTM
short, Silhouette®, Silhouette® Paradigm, ACCU-CHEK/TenderLink, Varisoft infusion sets, all manufactured by
Unomedical A/S are well documented in relation to safety and performance and suitable for use as intended.
Consequently, there has not been identified any outstanding risks that will justify the enrollment of patients in a
clinical investigation of an investigational medical device and as such, a clinical investigation is not necessary
to demonstrate conformity with the requirements concerning the characteristics and performance referred to in
the MDD 93/42/EEC and amendments.
Few reports on adverse events and no product recalls related to the subject devices were identified, and With
a performance-related complaint ratio of 0.00649631%, this CER concludes that using of comfortTM, comfortTM
short, Silhouette®, Silhouette® Paradigm, ACCU-CHEK/TenderLink, Varisoft is safe, compliant with state of the
art as well as the risk associated with the use of the similar device is acceptable when weighed against the
benefits to the patient.
The overall benefit vs. risk ratio for comfortTM, comfortTM short, Silhouette®, Silhouette® Paradigm, ACCU-
CHEK/TenderLink, Varisoft infusion sets remains favourable.
Based on assessment of all available data in respect of aforementioned infusion sets, it is considered that the
subject devices fully complies with the conformity assessment requirements of ER1, ER3 and ER6 as set out
in the Medical Device Directive 93/42/EEC as amended by 2007/47/EC [2].
1. Scope of this Clinical Evaluation Report
The Clinical Evaluation is performed to evaluate and verify the suitability of the subject device for its intended
use as well as its clinical safety, thus fulfilling the essential requirements (ER) for CE-marking (MDD 93/42/EEC
Annex I, points 1., 3., and 6) and / or the requirements for registration and marketing in countries outside the
EU (e.g. as Canadian MDR).
The Clinical Evaluation is performed according to the guidelines for medical devices provided by the European
Commission, MEDDEV 2.7.1 rev 4 [1] and Clinical evaluation: a guide for manufacturers and notified bodies.
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This CER will assess and critically analyze following:

 A compilation of all manufacturer generated data and ancillary documentation (e.g. product claim sheets,
Instructions for Use (IFU), labels, risk management documentation etc).
 A critical evaluation and an analysis of PMS data from 2011 to the data lock point 2018.
 A comprehensive review of relevant scientific literature, published between January 2007- September
2017.
 All data is assessed and critically analyzed in the context of the risk analysis of comfortTM, comfortTM
short, Silhouette®, Silhouette® Paradigm, ACCU-CHEK/TenderLink, Varisoft infusion sets, and a
conclusion regarding the resulting risk-benefit is drawn.
 The purpose of this clinical evaluation is to identify aspects that need to be addressed during PMS, e.g.
in post market clinical follow-up (PMCF). This include estimation of residual risks and uncertainties or
unanswered questions (such as rare complications, uncertainties regarding long-term performance,
safety under wide-spread use).
Statement of Interest.
Author
I do hereby declare, on my honour that, to the best of my knowledge, the only direct or indirect interests in
ConvaTec Limited or affiliate, I have currently (at the time of completion of the form) or have had (in the last 3
years) are those listed below.
Date: 21.06.2018
Signed:
Evaluators
The evaluators of this CER are employed by ConvaTec Limited. Subject to the disclosure below, neither the
author the evaluator or any members of their respective families have any other direct or indirect financial, or
commercial interest in the ConvaTec products which may benefit them either financially, or in kind such as
hospitality, royalties, grants or any other gain.
ConvaTec Limited is an indirect subsidiary of ConvaTec Group Plc. ConvaTec Group Plc is listed on the London
Stock Exchange and its shares can be purchased and sold by members of the public, including the author, the
evaluator and any members of their respective families.
Date:
Signed: _________________ ___________ ____________ ____________
Author name Evaluator name Evaluator name Evaluator name
2. General details and device history

This clinical evaluation is an assessment of comfortTM, comfortTM short, Silhouette®, Silhouette® Paradigm,
ACCU-CHEK/TenderLink, Varisoft infusion sets with soft cannula infusion at a 20°-45° degree insertion angle.
In this CER, this group of infusion sets will be named “comfortTM infusions set product family”.
Infusion sets with an angled insertion and a soft catheter have been on the market for more than 20 years.
Unomedical introduced the first 20°-45° degree angled soft cannula infusion set comfort infusion set in 1994,
followed by comfort short infusion set in 2003 – In between comfort TM and comfort TM short infusion sets, the
branded infusion sets, TenderLInk and Silhouette where also launched.
The devices under evaluation are used only for Diabetes mellitus (DM) patients.
3. Characteristics of the device
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comfortTM family infusion sets are designed as being functional infusion sets enabling safe and easy 20-45
degree angled insertion and used for continued drug delivery. The aforementioned infusion sets are designed
to be used with an external infusion pump with a maximum usage time of 72 hours.
 All infusion sets connect to a pump’s reservoir and lock into place to avoid leaks. Most pumps use
standard Luer-lock connections, which means they work with any Luer lock–capable infusion set and
that’s most of them. Some pumps, however, use a different type of connector. comfortTM infusion set
(Figure 1) is the original product initially launched by Unomedical. comfortTM infusion set was the first
insulin pump infusion set that combined angled insertion with at-site disconnection; however today is
also distributed under separate brand names. And with only moderate changes, by redesigning the
cannula housing the visible needle is shortened and a shorter needle version of comfortTM has been
launched and is today also branded as Silhouette® and Accu-chek/TenderLink (figure 2). Silhouette®
with Luer Lock and Silhouette® paradigm (figure 3) infusion set with P-cap connector offered for
Medtronic insulin pump. Accu-Chek TenderLink is offered with microdosage insulin pumps and is
manufactured by Roche Diabetes Care.
Varisoft infusion set with T-Cap connector offered for specific Tandem insulin pump (figure 4). ACCU-
Chek/TenderLink, Silhouette® with Luer Lock, Silhouette® paradigm and Varisoft are available in 2
versions based on the Comfort™ and Comfort™ short.
Figure 1. The same set of comfortTM family infusion sets
Figure 2. comfortTM short, Silhouette®/ Accu-chek TenderLink
Figure 3. Silhouette®paradigm infusion set with P-cap Figure 4. Varisoft infusion set with t:lock
3.1. Components
comfortTM infusion set product family consists of a cannula housing, with at pre-attached adhesive tape, a
cannula (25-gauge 13mm or 17mm in length), and an introducer needle (27G stainless steel) and a introducer
needle hub, this making up the adjustable angled insertion part – individualizing the insertion angle and depth.
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The tubing part of the infusion set is secured by a connector and connector needle, which before use is protected
by a separate cannula housing. By removing the separate cannula housing the tubing can be connected to the
infusion set part and access to the external pump is secured. comfortTM infusion set product family is available
in 4 tubing lengths (30, 60, 80 and 110) and two needle lengths (13 and 17 mm).
As the infusion set part (cannula) and the tubing part are delivered in the sterile packaging as two separate
parts. comfortTM, comfortTM short, Accuchek/TenderLink, Silhouette infusion sets are also available in a “cannula
only” version.
Silhouette paradigm is available in “cannula only” and “tubing only/ DuoTM infusion tubing” version. DuoTM
infusion tubing with P-cap connector is also in 30, 60, 80 and 110 lengths.
Figure 5. Illustration of components of aforementioned devices
The table 1 presents the raw material of comfortTM infusion set product family components, which have different
contact with either the patient or the user. Materials in contact with skin/tissue/drug for up to maximum 72 hours
are known materials.
Table 1: Materials of construction and material compliance of comfortTM product family
Component Material
Needle protector Polypropylene
Introducer needle Stainless steel (AISI 304)
Catheter Polytetrafluoroethylene (PTFE)
Adhesive tape Non-woven polyester
Cannula housing Polypropylene
Introducer needle hub Polypropylene
Catheter bushing Polycarbonate, white
Injection port Silicone
Segment Polyoxymethylen (POM)
Connector needle Stainless steel
Connector Meta-Acrylonitrile Butadiene Styrene
Tubing Inner: Polyethylene
Outer: Polyurethane
Glue UV-cured Glue
Standard Luer Lock Meta-Acrylonitrile Butadiene Styrene
comfortTM and comfortTM short infusion set is also delivered to costumer with and external insulin pump with a
proprietary tubing connection.
As a consequence of this tubing part of the Silhouette infusion set is with a proprietary connection at the tubing
end and also a redesigned introducer needle in the infusion set part.
The connector hub at end of the tubing part is a 3 part component made up by a needle (AISI 304, a membrane
(PFTE) and the pump connector – also referred to as a P-cap.
The introducer needle hub has been redesigned with two holes, that fits into a reusable insertion device (called
the Sil serter) for the Silhouette infusion set fits with the introducer needle protector part of the infusion set
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(Picture 6). The redesigned introducer needle of the infusion set part allows the user to choose between manual
insertion or insertion with the aid of a reusable insertion device (n manufactured by Medtronic).
Figure 6: MiniMed Sil-serter

3.1.1. Characteristics
The table 2 presents technical characteristics of comfortTM infusion set product family infusion sets.
Table 2: Characteristics of devices under evaluation
Subject Definition
comfortTM infusion A sterile, non-pyrogenic, single use continuous subcutaneous infusion sets with soft cannula
set product family insertion at a 20°- 45° insertion angle.
Mechanical connection for delivery of medication from an external pump to an infusion set.
3.1.2. Mode of action

The purpose of an infusion set is to constantly deliver the drug in the subcutaneous tissues under the skin. The
user (patient and the caregiver or HCP) inserts the infusion set in a site as recommended by the healthcare
professional. The user peels off the paper protecting the adhesive pad and carefully inserts the needle beneath
the skin. The introducer needle is pushed (inserted) into the subcutaneous tissue below the skin taking the
cannula with it. The introducer needle is necessary to puncture the skin to insert the infusion set. After insertion,
the introducer needle is removed immediately after. The adhesive tape holds the Soft cannula and the cannula
housing securely in place onto the body.
The user must fill a reservoir with the drug according to the pump manufactures instruction. The tubing will be
filled/primed with the drug. The connection and lock is with the Connector and the fluid path is established with
the needle (through the septum). The pump is ready to infuse the drug through the tubing and the Soft cannula
into the patient’s subcutaneous tissue.
Directions for use (Figure 7) [6-9]:
A) Inserting the infusion set:
 Wash your hands before inserting infusion sets.
 Use an insertion site as recommended by your healthcare professional. The choice of site depends
on treatment and patient specific factors. Check that the insertion site is free of skin irritation such
as redness, scar tissue etc.
 Clean the area for insertion with a disinfectant as directed by your healthcare team. Be sure the
area is dry before inserting the product. If needed, remove hair around the insertion site to ensure
proper attachment of the adhesive tape to the skin.
 Remove the front part of adhesive backing paper and protective needle cover.
 Fold back front edge of self-adhesive.
 Pinch and hold subcutaneous tissue. Insert needle and soft cannula into skin at 20°-45° angle.
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 Introducer Needle Removal: Press front half of self-adhesive firmly onto skin to hold self-adhesive
in place. Press side clips and pull gently needle out of skin.
 Being careful not to bend the cannula too far forward, remove remaining adhesive backing. Press
self-adhesive firmly onto skin.
 Priming: Attach connector to pump. Press side clips of circular protective cap and remove. Prime
tubing according to pump’s instructions until insulin emerges from connector needle. Do not leave
air bubbles in pump cartridge or tubing.
 Connecting With rounded side up, connect tubing to cannula housing. Fill cannula with 0.7 U insulin
bolus.
 NOTE: Do not connect tubing to cannula housing before priming.
Figure 7: User steps preparation and insertion comfortTM family product IFU [6-9]
3.1.3. Duration of use and body contact

The initial guidelines to change an infusion set every 2-3 days (48-72) were published in 1983 and were based
on anecdotal case report. The manufacturer recommends changing infusion sets with soft cannula and infusion
sites every 48-72 hours (2-3 days), or per the patients’ HCP instructions, in order to avoid skin irritation, infusion
sites reaction and other undersides side effects of subcutaneous therapy.
3.2. Intended Use, Indications, Contraindications/Precautions
The subject devices are intended to subcutaneous delivery of insulin administered by an external pump for the
treatment of Diabetes Mellitus (DM) in adults and children.
Diabetes Mellitus (DM)
Diabetes mellitus is a metabolic disorder that results in hyperglycemia (high blood glucose levels) due to the
body. It is characterised by the body being unable to metabolise glucose (a simple sugar). This leads to high
levels of blood glucose which over time may damage the organs of the body.
Contraindications:
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The aforementioned infusion sets are not intended for use with blood, blood products or intravenous infusion
(I.V.).
Precautions:
 The products are only sterile and non-pyrogenic if the insertion device is unopened and undamaged.
Do not use if the insertion device is already open or has been damaged. Ensure sterility by checking if
the sterile paper and tamper-proof seal are undamaged.
 Carefully examine the instructions for use before inserting the product. Failure to follow instructions may
result in pain or injury.
 When using the product for the first time, do so in the presence of a healthcare provider. Since different
individuals have varying amounts of subcutaneous layer, ensure that an appropriate cannula length is
chosen to fit your needs.
 If blood is seen in the product, change to a new product and new site.
 Do not in any way bring disinfectants, perfumes, deodorants or other products containing alcohol or
disinfectants into contact with the connector or the tubing, as these may affect the integrity of the
infusion set.
 The product is a single use device and should be disposed of immediately after use. Do not clean or
re-sterilize.
 The product can be disposed of safely after insertion if the lid has been placed back on. Please consult
your local pharmacy for sharp containers.
 Be sure that the needle guard is removed before insertion.
 Release the tubing with caution as a hard pull of the tubing can result in damage to the infusion
set/introducer needle. Ensure that the infusion set is properly in place when the tubing is fully released.
 Do not position the tubing in the slot prior to loading the infusion set.
 Do not leave air in the infusion set. Make sure to fill the product completely.
 Inaccurate medication delivery, infection and/or site irritation may result from improper insertion or
maintenance of your infusion site.
 Change the infusion set after maximum 72 hours in consultation with your healthcare professional.
Please also refer to the drug company’s instructions for use for recommendations related to usage time
for the specific drug.
 If the soft cannula bends during insertion, discard and apply a new product immediately.
 Replace the infusion set if the adhesive tape becomes loose or is displaced from its original site. Since
the cannula is soft, it will not cause any pain if it slips out, and this may take place without notice. The
soft cannula must always be completely inserted to receive the full amount of medication.
 If your infusion site becomes inflamed, replace infusion set and use new site until the first site has
healed.
 Do not re-insert the introducer needle into the infusion set. This could cause a tearing of the soft cannula
and unpredictable medication flow.
 Never try to fill or free clogged tubing while the infusion set is inserted. This may result in unpredictable
medication flow.
 Consult your healthcare provider on how to compensate for missed medication when disconnected.
 Protect the product from direct sunlight and atmospheric humidity. Store in a dry place at room
temperature.
 Never point a loaded insertion device towards any body part, where insertion is not desired.
 Reuse of the product may cause infection, site irritation, or damage to the cannula/ needle. A damaged
cannula/needle may lead to inaccurate medication delivery.
 Avoid mechanical stress on the infusion site and on the devices under evaluation.
 Pay attention when carrying heavy weights.
 Prepare the infusion site before insertion according to CDC (Centers for Disease Control and Prevention)
guidelines or institutional protocol. •
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 Check blood glucose level 1–2 hours after inserting your infusion set and inspect the infusion site on a
regular basis.
 When infusing insulin, do not changes the infusion set just prior to bedtime, unless blood glucose can
be checked 1-2 hours after insertion.
3.3. Claims
Table 3. Claims for comfortTM family product
Claims Reference
DM therapy [5,8,10,11,12]
Skin-friendly adhesive [22]
3.4. Preclinical tests

3.4.1. Technical tests
The devices have undergone mechanical tests according to EN/ISO standards.
Relevant bench test such as flow test, tensile test and leak test that demonstrate performance of the
aforementioned infusion sets was fulfilled on the predicate devices and Silhouette infusion set (table 4, 5) DHF
[5].
Table 4. Mechanical test for comfortTM and comfortTM short
Test Product design verification tests Internal test criteria
Leak tightness: The product is designed to withstand a This set is tested at 3 bars for 30 sec.
pressure of 4,5 bars in 30 sec. No air The set is immersed in water and no
bubbles must be observed during the air bubbles must be observed.
tst period when the Infusion Set is
immersed in water.
Flow (occlusion): Free flow of air must be observed at The set is tested at 1 bar and free flow
min. 40 ml/min. of air bubble observed.
Breaking strength of connection: Any connections between fluid path The connections Tubing/Luer Lock
components shall withstand a force of and Tubing/Connector must with
no less than 22,5 Newton. stand a pull from 1,5kg weight for 15
sec.
Pull test of soft cannula: The bonding must withstand a force -
larger than 3 Newton.
Pull test of stainless steel needle The strength of the bonding must The bonding must min. withstand a
in tubing connector: withstand a force larger than 7.5 pull from a 0.5kg weight for 15 sec.
Newton.
Pull test of introducer needle: The strength of the bonding must -
withstand a force larger than 15
Newton.
Transportation test: The transportation test is to -
demonstrate that the device remains
safe and effective the device has been
subjected to a transportation test
according to the guidelines in ISTA 2A.
Table 5. Mechanical test for Silhouette®

Test Product design verification tests Internal test criteria
Leak tightness: The product is designed to withstand a This set is tested at 3 bars for 30 sec.
pressure of 4,5 bars in 30 sec. No air The set is immersed in water and no
bubbles must be observed during the air bubble must be observed.
test periode when the Infusion Set is
immersed in water.
Flow (occlusion): The set is tested at 1 bar and free flow The set is tested at 1 bar and free
at min.40 ml/min is observed. flow air bubbles are observed.
Flow test of the p-cap vent - To ensure that the p-cap vent
membrane: membrane holes are not occluded,
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(only relevant for silhouette the p-cap is flow tested at 0,71 -0,75
Paradigm) psi. The Acceptance criteria : Flow
must be grater than or equal to 5
SCCM*
(*Square cubic centimetres pr.minute)
Breaking strength of connection: Any connections between fluid path The connection between Tubing/Luer
components shall withstand a force of Lock is tested must with stand a pull
no less than 22,5 Newton. from a 1,5 kg weight for 15 sec.
Pull test of soft cannula: The bonding must withstand a force -
larger than 3 Newton.
Pull test of stainless steel needle The strength of the bonding must The bonding must min. withstand a
in tubing connector: withstand a force larger than 7,5 pull from 0,5 kg weight for 15 sec.
Newton.
Pull test of introducer needle: The strength of the bonding must . -
withstand a force larger than 15
Newton.
Transportation test: The transportation test is to -
demonstrate that the device remains
safe and effective the device has been
subjected to a transportation test
according to the guidelines in ISTA 2A.
The difference between comfort™ infusion set and the Silhouette infusion set is a replacement of connector
used with the P-cap connector assembly for the Medtronic pumps. The P-cap is an established component and
is included in the various infusion devices i.e. Quick set and MioTM 30.
The projects introducing T-Cap for Tandem Diabetes Care in already existing Unomedical infusion sets
demonstrated performance of the T-Cap connector that replaced the current standard Luer Lock existing in all
Unomedical devices. In the Design Verification, all tests performed are related to the T-Cap, the infusion set is
not subject for this testing. No changes to the existing concept of the products [5].
The predicate devices fulfill the requirements and expectations demanded by the end-user. Based on the tests
performed on predicate devices, it is able to confirm that the devices under evaluation meet the requirements
of the EC Directive 94/62/EEC. No additional tests are needed [14].
3.4.2. Biocompatibility
The devices under evaluation have undergone biocompatibility tests according to EN/ISO standards ISO 10993-
1:2009. Relevant biocompatibility testing that demonstrates safety of comfortTM, comfortTM short, Silhouette®,
Silhouette® Paradigm, ACCU-CHEK/TenderLink, Varisoft infusion sets are based on information gathered in
the available BRA rapport on previously approved predicate infusion set, comfortTM, comfortTM short and
summarized in the statements [15].
The adhesive type is the only competent with skin contact. It is therefore classified as surface devices under
the category of skin with a contact duration of permanent. These results are categorized in three tests which
are Cytotoxicity, Sensitization and Irritation/Intracutaneous (Table 6).
The rest of the components, except for them with no contact defined, are all classified as externally
communicating devices under the category of tissue/bone/dentine/communicating, where tissue includes tissue
fluid and subcutaneous spaces. The contact duration is classified as permanent. This classification results in
testing within several areas, where these areas are Cytotoxicity, Sensitization and Irritation/Intracutaneous.
Acute systematic toxicity, Subchronic toxicity, Genotoxicity, and Implantation (Table 6) [15].
Materials which do not have any contact with skin, drug or tissue do not require biocompatibility testing.
Table 6: Overview of device classification
Device Categories
Biological Effect
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Body contact Contact

duration
Subchronic toxicity
Acute systematic
Intracotaneous
Sensitization
Implansation
Genotoxicity
Cytotoxicity
Irritation/
toxicity
Surface device Skin Permanent X X X - - - -
(>30 days)
Externally Tissue/
communicating bone/dentin/
X X X X X X X
devices communicating
Component and contact type:

The names of each of the components are listed in Table 7, and 8 where materials are shown for the different
components as well as the type of contact.
Table 7: Biological characteristics of comfortTM family product- cannula set with tubing
Component Material
Needle protector Polypropylene None None None
Introducer needle Stainless steel (AISI 304) Yes None Yes
Catheter Polytetrafluoroethylene (PTFE) Yes Yes Yes
Adhesive tape Non-woven polyester Yes None None
Cannula housing Polypropylene Yes None None
Introducer needle Polypropylene None None None
hub
Catheter bushing Polycarbonate, white None Yes None
Injection port Silicone None Yes None
Segment Polyoxymethylen (POM) None None None
Connector Stainless steel None Yes None
needle
Connector Meta-Acrylonitrile Butadiene Styrene None None None
Tubing Inner: Polyethylene None Yes None
Outer: Polyurethane Yes None None
Glue UV-cured Glue Yes None None
Table 8. Biological characteristics of connectors
Component Material Skin Drug Tissue
Standard Luer Lock Meta-Acrylonitrile Butadiene Styrene Yes Yes None
T-cap Methyl methacrylate-acrylonitrile-butadiene-styrene None Yes None
P-Cap Connector Glycol-modified
None Yes None
Polytetrafluoroethylene Terephthalate
P-Cap Membrane Polytetrafluoroethylene None None None
P-Cap Needle Stainless steel None Yes None
P-Cap Glue UV-cured glue None None None
P-Cap Connector Glycol-modified
None Yes None
Polytetrafluoroethylene Terephthalate
All tests passed successfully.
The testing showed that the relevant parts of infusion set are biocompatible [15].
3.4.3. Drug compatibility test
Drug stability tested with the below listed short acting insulin analog:
 Regular human insulin (Humalog®)
 Aspart (NovoLog®)
 Glulisin (Apidra®)
All tests have been passed successfully [5].
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3.4.4. Usability/Human factor testing

In accordance with IEC 62366-1:2015 and the FDA’s guidance on human factors, the purpose of the usability
study is to evaluate whether the user interface (UI) of the device, including the information for safety (e.g. the
Instructions for Use), is safe and effective to use by intended users in intended use environments.
The usability analyze & evaluation, conducted by Unomedical within comfortTM showed that comfortTM infusion
set and information to be supplied with the infusion set is found sufficient and easy to understand for the intended
users, its intended uses in the intended use environments.
Based on the provided data, product information provided by Unomedical, clinical opinion provided by HCP, it
can be concluded that comfort™ product family fulfills the requirements for usability such as an intuitive and
unambiguous use, and the design of the user interface has an acceptable, safe usability. Comfort™ product
family complies with the Essential Requirements and fulfills the clinical needs and end-user expectations with
regard to user-friendliness proficiency, patient safety and technical performance [16].
4. Clinical background, current knowledge, state of the art
4.1. Introduction
In 1926, Prof MacLean, was convinced that “insulin is by far the greatest boon that has ever been discussed on
the suffering diabetic patient, for through its proper use he may, in almost every instance, regain a great measure
of health and strength [42].
Since, the management of DM focuses on improving glycaemic control by means of lifestyle modification and
pharmacological therapy with the aim of reducing risk and progression of microvascular and macrovascular
complications [42]. Studies such as the Diabetes Control and Complications Trial (DCCT) in T1DM and the
United Kingdom Diabetes Prospective Study (UKPDS) in T2DM have shown that intensive glycaemic control
improves patient outcomes especially for complications [42].
Diabetes is a condition in which glucose (sugar) in the blood is too high because the body does not respond to
insulin or not enough insulin is made. Insulin is a hormone made by the pancreas, which allows glucose to enter
the cells where it is used as fuel by the body. Controlling blood sugar levels is important because levels that are
too high or too low can affect the brain and other organs such as cardiovascular and renal systems of the body.
Many people who take insulin find that both use of standards injection (SI) therapy and CSII have inherent
drawback. For this reason, many people with diabetes do not take advantage of what insulin therapy can offer
[4]. Various literature based evidence indicated that use of infusion sets are a well-known and proven technology
and that this technology is safe and effective in treatment of children and adults with T1DM.
4.2. Usage of infusion set in DM
Despite the economic and technological challenges and the complexity of patient training associated with CSII,
it is estimated that more than 500 000 patients worldwide are currently being treated with CSII [36]. When
applying CSII, the insulin is administered via an infusion set, which is composed of a polymer cannula or steel
needle located in the subcutaneous tissue, and which is connected to the insulin container in the pump device
by means of a plastic tube. To avoid skin irritation, infusion site reactions and other adverse effects, it is
recommended that infusion should not occur for longer than 48 to 72 hours at the same tissue location [36].
The infusion sets differ respectively. Some infusion sets have a steel needle, which is inserted under the skin,
and others have a plastic cannula. Plastic cannulas are flexible, to some extent, and may be more comfortable
to wear therefore than steel needles. However, cannulas can sometimes kink causing problems with insulin
delivery [31]. The needle or cannula commonly varies between about 6 to 9 mm in length. Shorter needle or
cannula lengths are more suitable for people with less body fat, larger lengths are more suitable for people with
more body fat [4].
Infusion sets can have the cannula facing directly (90 degrees) towards the skin’s surface or at an angle
(commonly between 10 and 45 degrees) to the skin’s surface. Angled infusion sets can be useful for people
with less body fat [4].
The infusion sets include also an adhesive tape to keep the infusion set stuck to the skin. Some people may
find they are more prone to having the adhesive wear away, typically if the skin gets sweaty or wet, say from
showering, sport or hot weather [www.diabetes.co.uk]. The basic requirement for the adhesive patch is to
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provide an environment favorable to protect and cover of the injection site to avoid infections and staying firmly
in place without causing skin trauma during removal as well as maintaining an optimal moisture balance to
maximize the rate of healing. This in turn must be fulfilled in the context of patient comfort by avoiding frequent
changes as well as mitigating pain [37, 38, 40].
The manufactures provide the infusion set with a number of different adhesives, e.g. an adhesive that provides
a stronger bond with the skin or is for sensitive skin if needed.
The quick disconnection device allows the user to temporarily disconnect the pump and tubing, say for
showering, without needing to take out the entire infusion set. Some infusion sets detach but leave a small
length of tubing still attached [www.diabetes.co.uk].
Infusion sets are usually changed every 2 or 3 days. If infusion sets are left in longer, there’s a higher risk that
infections could occur under the skin or occlusions (blockages in the cannula) could occur [www.diabetes.co.uk].
There is also mentioned on different diabetes forums [www.diabetes.co.uk] as well as in the published literature
that regularly re-use the same infusion site can lead to the subcutaneous tissue (fatty tissue just under the skin)
becoming harder (Lipohypertrophy), which can lead to inconsistent absorption of insulin and could therefore
result in unexpectedly high or low blood sugar levels [www.diabetes.co.uk].
Some insulin pumps need particular infusion sets to be used with the pump whereas other pumps are designed
to work with a wider range of infusion sets.
4.3. Risk versus benefits for using infusion sets
Specific to usage of infusion sets for drug administration within DM therapy the following risks and benefits has
been identified in current literature.
To the risk benefit sections, it is important to mentioned what environmental impact infusion sets have. Since
1980, the potential environmental impact of pharmaceutical device has become (next to safety and efficacy) a
major point of consideration in development of new product. The loss or resources with regular continuous
subcutaneous infusion therapy is considerably lower than the loss or resources induced by patch pumps.
In literature, the most commonly reported AEs were local skin nodules at the injection site related to the
treatment. Some patients develop itching, bruises or pain depending on concentration and infusion time or depth
of injection. Development of nodules can be avoided by changing the injection sites frequently. It is
recommended to change the infusion set and site every 12 hours [5].
The duration of infusion is individualized which can be more comfortable for the patient and has dramatically
improved the patient’s quality of life and expanded life [28]. Many patients prefer to perform their infusion during
the night, but since this therapy takes time for some patients can give decreased comfort. Furthermore, the
subcutaneous route can produce painful skin irritation, but the intravenous route has higher risk of infection or
thrombosis of the indwelling central catheter which make the subcutaneous route more safe. However, the
increased comfort is high comparing to the aforementioned risk of local side effects.
5. Device under evaluation
5.1. Context of the evaluation and choice of clinical data types
A literature search will be conducted for the period from 2007-2017, with the purpose to investigate data on the
performance and safety for devices under evaluation intended for subcutaneous infusion of insulin and based
on an existing and well-established technology.
To conduct the present CER of the safety and performance characteristics of devices under evaluation several
strategies were chosen. The data used in the present report were based on published scientific literature and
clinical data from comfortTM and comfortTM shortTM and similar products.
The literature search for current CER has been conducted using PubMed, Medscape, Prospero, Cochrane and
ClinicalTrials.gov. For search in PubMed following filter activated: humans, English, published from 01.01.2007
to 01.09.2017. For search in Medscape, Prospero, Cochrane and ClinicalTrials.gov no filter achieved.
The keywords that were utilized for the searches included the following:
1. Diabetes AND infusion set
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2. (“infusion set” AND “comfort”) AND safety

3. Infusion set AND insulin AND (contraindication OR “adverse event”)
4. “Infusion set” OR “comfort” AND polyester tape AND skin irritation
5. "comfort” AND "infusion set"
6. "Silhouette" AND "infusion set"
7. "varisoft" AND "infusion set
The information used in the current CER to address safety and performance of subject devices is a collection
of both favorable and unfavorable clinical data from published literature and experience of infusion sets.
Literature search was performed with use of different databases. For full description of the search strategy, see
LSR [Appendix II].
The following clinical data has been evaluated:
• A systematic literature review of PubMed database
• Medscape
• Prospero
• ClinicalTrials.gov
• Cochrane Database of Systematic Reviews
• Regulatory agencies:
o Medicines and Healthcare products Regulatory Agency (MHRA) database
o MHRA medical device alerts and field safety notices (FSN): https://www.gov.uk/drug-device-
alerts ;
o Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) field corrective actions:
http://www.bfarm.de/medical_device/field_corrective_actions ;
o Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience
(MAUDE): https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/search.cfm
o DEAN https://www.tga.gov.au/database-adverse-event-notifications-daen
o SARA https://apps.tga.gov.au/Prod/sara/arn-entry.aspx
o MHDP http://www.hc-sc.gc.ca/index-eng.php
• Safety data from clinical experience with Suction Handles and Sets.
5.2. Demonstration of equivalence
A comparison between comfortTM and comfortTM shortTM, Silhouette®, Silhouette® Paradigm, ACCU-
CHEK/TenderLink, Varisoft infusion sets and other available infusion set devices has been made. The
equivalent device is identified with equivalent clinical, technical and biological means as defined in MEDDEV
guideline 2.7.1 Rev. 4 [1].
Clinical:
Used in same clinical indications and purpose, in the same site in the body, in similar population (including age,
anatomy, physiology), and have similar critical performance according to the expected clinical effect for specified
intended use.
Technical:
Used under similar conditions of use, similar specifications and properties, similar design, similar deployment
methods, sterilization method, materials, critical performance requirements and have similar principles of
operation.
Biological:
Use same materials in contact with the same tissue and body fluids.
Conclusion
Equivalent devices may be used to support the safety, performance, and “state of the art” of the subject device
when they are used under the same conditions and intended use as the subject device. VariSoft with T-Cap
connector, ACCU-CHEK/Tender, Silhouette, with Luer lock connector and Silhouette paradigme ® with p-
Cap are comparable to Unomedical A/S infusion set: comfortTM, comfortTM short, and this comparison has been
found relevant in all three aspects [14].
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The devices are deemed to be “Equivalent” when they have the same characteristics or the noted variations of
characteristics are rationalized to be sufficiently similar with supporting discussion of their clinical impact in
relation to each.
The existing differences are not expected to affect the clinical performance and clinical safety of the devices
under evaluation. The devices are considered equivalent in regard with their clinical considerations as they are
all intended to be used for the similar indications and patient populations, are technically and biologically similar.
6. Summary of the clinical data and appraisal
6.1. Clinical data generated and held by the manufacturer
6.1.1. Sales Data
The resent PMS trends for comfortTM and comfortTM shortTM and Silhouette®, Silhouette® Paradigm, ACCU-
CHEK/TenderLink, Varisoft from 2011-2018 are included and summarized in table 9.
Table 9. The number of sale
Product 2011 2012 2013 2014 2015 2016 2017 2018 Total Unit
YTD sold
Comfort TM 730,250 696,075 641,985 609,785 631,685 569,640 408,760 251,210 4,539,390
Comfort TM 460,110 523,000 485,650 568,995 686,795 623,570 482,830 233,020 4,063,970
short
Silhouette 677,880 766,550 608,370 615,820 447,180 583,750 478,860 318,900 4,497,310
Silhouette 9,127,86 9,548,12 8,144,11 7,704,06 8,416,13 8,363,46 9,485,28 3,648,72 64,437,752
paradigm 6 0 0 6 0 0 0 0
Accu-Chek 292,310 178,330 170,494 191,956 143,308 105,260 59,870 20,740 1,162,268
Tender
Accu-Chek 2,890,38 2,208,27 2,197,27 2,226,70 1,820,29 1,579,08 1,060,33 598,150 14,580,478
TenderLink 4 0 0 0 0 4 0
VariSoft NA NA NA NA NA NA 279,560 79,880 359,440
Over this review period, at total of 93,640,608 products have been sold.
6.1.2. Complaint databases
Unomedical TrackWise database
The most recent PMS data for predicate and similar devices covered during current search period shows few
reportable adverse event incidents (Table 10).
Table 10. Number of complaints for comfortTM family product
Product Total Unit sold Complaints Ratio Report Ratio
received
Comfort 4,539,390 533 0.0014083 242 0.0006703
Comfort short 4,063,970 447 0.0010013 260 0.0005918
Silhouette 4,497,310 161 0.0003729 87 0.0001911
Silhouette 64,437,752 6088 0.000857 3427 0.0004981

paradigm
Accu-Chek 1,162,268 31 0.0007069 22 0.0004936
Tender
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Accu-Chek 14,580,478 100 0.0001111 74 0.0000822

TenderLink
Varisoft 359,440 175 0.00203881 17 0.0014111
During the period 2011 to 2018, 93,640,608 units of subject devices have been sold worldwide. During this time
span, Unomedical has received total 7535 product related complaints corresponding to a performance-related
complaint ratio 0.00649631%.
The complaints were related to skin irritation/ skin infection/allergy, bent/kinked cannula, leakage and clogged
tubing. No complaints related to other biocompatibility issues were reported.
Since low percentage of complaints related to the performance of subject devices were identified, and with a
performance-related complaint ratio of 0.00649631%, this CER concludes that comfortTM and comfortTM shortTM
and Silhouette®, Silhouette® Paradigm, ACCU-CHEK/TenderLink, Varisoft are safe and compliant with state of
the art and the overall benefit vs. risk ratio for the device remains favourable.
MAUDE, MHRA, BfArM, DAEN, MHDP data
The United States Food and Drug Association (FDA) publish reports on adverse events (AE) involving medical
devices on their website in the Manufacturer and User Facility Device Experience Database (MAUDE).
Moreover, the Medicines and Healthcare Products Regulatory Agency (MHRA) in UK also publish reports on
adverse events involving medical devices. Likewise, the Federal Institute for Drugs and Medical Devices
(Bundesinstitut für Arzneimittel und Medizinprodukte), - (BfArM) that is an independent federal higher authority
within the portfolio of the Federal Ministry of Health has been used. Although MAUDE, MHRA, BfArM, DAEN,
MHDP data is not intended to be used either to evaluate rates of AE or to compare AE occurrence rates across
devices, the data can be used as a procedure of the type of risks that may be associated with the use of a
device type.The data is summarised in LSR.
Review of the MAUDE, BfArM, MHRA, DAEN and MHDP databases on AEs involving the subject devices and
similar devices, revealed that more than 92 reports were identified. More than 35 medical device alerts/warning
was identified concerning comfortTM and comfort TM short included in this evaluation.
Full search in safety databased is described in the LSR [Appendix Il].
6.1.3. Field corrective actions and other PMS data
A search from Medical Devices Alerts/Warning letters were carried out in the period from January 2011 to June
2018. Manufacturer has identified an increase in reports of the tubing becoming detached at the
connect/disconnect location. If tubing detachment occurs, insulin delivery is interrupted and can result in diabetic
ketoacidosis (DKA). DKA is a serious condition that can cause a severe impact to health.
Unomedical issued a Field Safety Notice in November 2014 and advising patients to continue to use the infusion
sets while following the directions below:
• When changing your infusion set, closely follow the instructions for use included in the product box.
Check the tubing at the site connector location to make sure it is not loose.
• Monitor your blood sugar levels frequently using your blood glucose meter. Proactively check your
tubing connections occasionally to ensure tubing is secure. It is especially important to check your
blood sugar and tubing connections at bedtime to confirm insulin delivery is occurring.
• If you experience high blood sugar, check your tubing connections and infusion site closely to ensure
your tubing is secure.
If you discover that the tubing is detached:
• Do not attempt to reattach the tubing. Replace the infusion set immediately.
• Treat any high blood sugar based on guidelines provided by your healthcare professional.
• Call your distributor (see table below) to report the issue and receive instructions on how to return the
affected infusion set to the company.
• Call the Medtronic 24‐Hour Helpline to report this issue.
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Figure 8. Example of Tubing Detachment

All relevant information is included in the IFU.
6.1.1. Summary of clinical trials conducted by Unomedical
No clinical trials conducted by Unomedical.
6.2. Summary Clinical data from literature
The medical database PubMed was mainly used, since it is the largest database on peer-reviewed medical
articles available and found to be adequate for the purpose of this literature search. There has been
complemented by search using other databases such as Medscape, Prospero, Cochrane and Clinicaltrials.gov
and to support relevant articles that are not available on PubMed.
Only studies in English were included and the data had to be relevant and related to specific characteristics of
comfortTM and comfortTM shortTM, Silhouette®, Silhouette® Paradigm, ACCU-CHEK/TenderLink, Varisoft infusion
sets. Furthermore, the literature included use of the device in question and similar devices with respect to clinical,
technical and biological characteristics as defined in MEDDEV 2.7.1 rev 4 [1] were included.
References were excluded if similarity in clinical, technical or biological similarity as described in the MEDDEV
2.7.1 rev 4 [1] could not be established. References were also excluded if they were not related with the use in
humans.
The data obtained from literature and included in the current CER has been appraised and weighted to
determine the suitability to address question comfortTM and comfortTM shortTM, Silhouette®, Silhouette®
Paradigm, ACCU-CHEK/TenderLink, Varisoft infusion and its contribution to demonstrating the safety and
performance of the device under evaluation. All publications have been evaluated consistently by the criteria
described in LSR.
For this review 52 publications were presumed useful to identify sufficient clinical evidence, 5 articles were
appraisal as sufficient to support safety and performance of the aforementioned infusion sets, 19 included in
the state of the art section, and a total of 24 of these are referenced [Appendix II].
Articles of level 1 (clinical data of the subject device and/or equivalent device) and 2 clinical data (clinical data
of the similar device) has been included, and the available published literature is considered adequate to support
the clinical use of comfortTM infusion set product family product due to the long history of use of infusion set for
this application.
The datasets demonstrated the overall safety and performance of the subject devices consists of clinical data
obtained from published literature on Level 1 and Level 2. One article on Level 1 covering comfortTM and 5
articles on level 2 covering the use of the similar devices in terms of materials, design and clinical indication
were identified and critical reviewed and analyzed. Nineteen publications on level 3 that is a collection of data
including clinical data, guidance documents and review articles with limiting grading only to be used in state of
the art section were included.
The datasets considered being the pivotal dataset or most important to demonstrate the overall safety and
performance of the devices under evaluation consists of clinical data from an open-label, case study design,
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double-blind cross-over study and cross over study including use of the subject device and non-equivalent
infusion sets.
An overall evidence level is assigned to the clinical data (see LSR) based on the equivalence criteria to evaluate
its relative contribution to the safety and performance assessment.
6.3. Overall Summary Conclusion of clinical data
Table 11. Summary of performance data
Ref Purpose Study Design Study Objective Summary of Key Results
Patel et al. To compare steel A randomized, 19 (12–45 years old) The outcome of this study showed
versus Teflon open-label, single- patients with type 1 satisfied efficacy of using the
infusion set side, crossover diabetes for at least 1 year, tested infusion sets and concluded
(Dupont TM, design. 2014 who had been using a that infusion sets are a viable
Quick-Set TM or Medtronic insulin pump for alternative to multiple daily
Sure-T TM) in at least 3 months were injections.
people with type enrolled in the study. No difference between steel and
T1DM. Teflon infusion sets was found
when used for up to 7 days.
15% of Teflon sets failed because
of kinking on insertion. The
strongest predictor of prolonged 7-
day infusion set function was the
individual subject, not the type of
infusion set.
Bon et al. Comparison of An open-label, During 39 weeks’ study 288 Increased duration of infusion sets
insulin glulisine three-way patients were randomized. showed decreased occurrence of
(GLU) with crossover, The outcome measure was unexplained hyperglycemia and
insulin aspart controlled unexplained hyperglycemia occlusion.
(ASP) and insulin multicenter study. and/or perceived infusion The results supported that using of
lispro (LIS) 2011 set occlusion. the infusion sets is effective as part
administrated by of the CSII treatment when used as
continuous recommended.
subcutaneous
insulin infusion
(CSII) using
Medtronic and
Roche devices.
DM therapy
Many of DM patients feel they can wear steel infusion sets for longer time than Teflon infusion sets. In order to
prepare a systematic study comparing the length of wear using steel compared with Teflon infusion sets the
authors of the recent study paralleled different infusion sets [43]. The study by Patel et al [43] showed that 15%
of Teflon sets failed on the first day because of kinking that was associated with use of the Teflon infusion sets.
The failures were not recognized by the investigator or subject until there was hyperglycemia and/or high-
pressure alarms hours later and can be assumed that were secondary to kinking and could be related to
performance of the device. The author referred to other recent published research by Højbjerre et al that
demonstrating that a steel infusion set would have an advantage over Teflon [43]. However, when comparing
the effect of the type of infusion set (steel vs. Teflon) and the effect of the individual subject on infusion set wear,
it was the individual (P = 0.002) and not the type of infusion set that was most significant in determining infusion
set survival [43]. The reason for individually variability is still unknown. Nevertheless, the study limitations
included self-management of infusion site induration and erythema by the participant, which could affect
duration of infusion set wear and its performance. However, the study investigated only 90o-angled infusion sets,
which are similar to the subject devices. Still, the study by von Bon [44] indicated that the majority of the patients
change the infusion set at a time interval greater than 2 days whatever the angle of needle. The mean time
noted for routine change was 19.7h and the overall change was 19.3h [44].
The prospective study Mecklenburg et al. [46] recorded the types of and frequencies of cannula defects. The
most common malfunction was due to occlusion of the infusion set. This was in agreement with other findings,
which have shown that insulin delivery failures due to blockage of the indwelling needle/cannula were the most
common cause of acute loss of glycemic control. It was suggested that the occlusion of the cannula might be
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due to insulin precipitation [46].

The literature findings support the use of infusion sets in patients with diabetes. The infusion sets seem to
facilitate optimal glycemic control in both children and adults with DM. In addition to the clinical benefits in terms
of glucose control, insulin systems can improve the quality of life for patients with diabetes. The time for
changing infusion sets can be individualized with some patients requiring a change every 2-3 days whereas
others can change a set less frequently and indicated that the infusion sets perform sufficient. Furthermore, it
is considered effective when patients are well trained and educated by the HCP to follow the recommendation
in using the infusion sets and know the importance of changing their infusion set and the infusion site regularly
after 72 hours of use in order to avoid skin reactions, and to ensure a stable and reliable efficacy of the applied
insulin. In order to attain stable glycemic control, insulin absorption, subcutaneous deposit, length of
subcutaneous cannula and infusion set site are similar in importance to the dose of insulin delivered.
These results indicate that the commercially available similar to the devices under evaluation perform sufficient
when used as intended.
Table 12. Summary of safety data
Patel et al To compare steel A randomized, 19 (12–45 years old) The outcome of this study
versus Teflon open-label, single- patients with type 1 showed satisfied efficacy of
infusion set (Dupont side, crossover diabetes for at least 1 using the tested infusion sets and
TM, Quick-Set TM or design. 2014 year, who had been using concluded that infusion sets are
Sure-T TM) in people a Medtronic insulin pump a viable alternative to multiple
with type T1DM. for at least 3 months were daily injections.
enrolled in the study. No difference between steel and
Teflon infusion sets was found
when used for up to 7 days.
15% of Teflon sets failed
because of kinking on insertion.
The strongest predictor of
prolonged 7-day infusion set
function was the individual
subject, not the type of infusion
set.
Bon et al Comparison of An open-label, During 39 weeks’ study Local reactions at the infusion
insulin glulisine three-way 288 patients were site were recorded and divided
(GLU) with insulin crossover, randomized. into four categories: infection;
aspart (ASP) and controlled The outcome measure inflammation or erythema;
insulin lispro (LIS) multicenter study. was unexplained pruritus; and pain.
administrated by 2011 hyperglycemia and/or In the analysis, the time to
continuous perceived infusion set change the infusion set
subcutaneous occlusion. influenced unexplained
insulin infusion hyperglycemia and occlusion.
(CSII) using For every increase of 6h the
Medtronic devices. chances for hyperglycemia and
infusion set occlusion decreased
by 9%.
No significant differences in
percentage of patients were
demonstrated between GLU
versus ASP (P=1.00) and GLU
versus LIS (P=0.70) regarding
experiencing one or more site
infections or site
inflammation/erythema or
pruritus or isolated pain.
No death occurred during the
trial.
No differences in serious
adverse events were reported for
the three insulins: GLU, 10.6%;
ASP, 6.8% (P=0.157 vs. GLU);
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and LIS, P.4.1% (P=0.0038 vs.
GLU).
The author concluded that
increased duration of infusion
sets shows decreased
occurrence of unexplained
hyperglycemia and occlusion.
The results showed that using of
the infusion sets is safe as part of
the CSII treatment.
Conwell et To describe the A cross-sectional 50 children younger than18
al dermatological study. 2008 years that use of CSII for at least
changes associated 6 months were enrolled in the
with continuous study.
subcutaneous The exclusion criterion was the
insulin infusion presence of a pre-existing skin
(CSII) therapy in condition affecting the regions
youth with T1DM used for CSII (e.g., psoriasis,
To assess their eczema, or panniculitis).
association with Most of infusion sets used during
duration of CSII, the study was Quick-set from
age, adiposity, Medtronic, but also Silhouette,
HbA1c, insulin Soft-set and Sure-T were used.
dose, insulin brand, The most common change was
infusion set or site. scars < 3 mm diameter with
surrounding hyperpigmentation,
which were observed in 94% of
subjects. Larger scars were
observed less frequently (12%).
Erythema was observed either
as an isolated finding or in
association with subcutaneous
nodules.
In subjects using infusion sets
with a non-metal catheter, those
inserted at 90° (Medtronic
Quickset, Medtronic
Softset) were associated with
significantly lower total severity
scores than those inserted at a
smaller angle.
In 1 patient, the erythema was
clearly in the distribution of the
edge of additional tape used to
secure the site. Only 4% of
parents and 2.4% of the patients
reported considering CSII
discontinuation because of
dermatological concerns.
Pfützner et To investigate the A prospective 24 patients with type 1 The number of infusion set
al tolerability of 2-day randomized patients during 2x 3- related adverse events was 290
use of infusion sets controlled month observation with 2-day use versus 495 with 4-
in comparison to crossover study. periods were enrolled. day use (P < .05).
4-day use in a real- 2015 Patients were trained on The overall treatment satisfaction
world setting. the use of the infusion set was higher with 2-day use (very
Mio® or inset™ II and high/high satisfaction) 90.4%
randomized to any of the versus 4 day-use 77.3% (P
2 treatment sequences. < .05).
Observation parameters
included treatment and
nature of device-related,
and procedure-related
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adverse events and
patient preference.
Pickup et al To report a survey A clinic based Pump, infusion set, and infusion
of patients with survey. 2014 site Problems remain common
T1DM who had with CSII, even with
been treated by contemporary technology.
CSII for more than 6
months.
DM therapy
One of the complications recognized during use of infusion set found in the literature search was kinking [43,
44, 47, 48]. This complication can result in reduction of the medication administration. Moreover, common
problem with CSII therapy is the development of unexplained hyperglycemia that resolves with changing the
infusion set. What triggers this problem is not clear but unappropriated use of the device can increase glucose
level. However, problems are not related to the type of infusion set but only to the unappropriated use of the
device [43, 44].
Pickup et al. [47] analyzed responses on perceived complications of SCII therapy from 92 patients who have
been treated by CSII for more than 6 months, and the mean duration of infusion set use was 3.2 +/- 0.7 days.
The commonest problem reported was kinking and the Quick TM Set and Inset TM II infusion set was the common
infusion set in use (64.1% of subjects at some time, with 12% of the total number of patients observing frequent
kinking). They found the infusion set kinking and blockage were common - about 10 % of patients experience
this problem. It is possible that some patients misinterpreted blocking as kinking, and vice versa, because early
blockage is often caused by kinking and late blocking by insulin aggregation /precipitation [47].
In general, part of the technical issues with infusion sets is related to the type of needle used. In particular,
perpendicularly inserted soft cannulas entail the risk of kinking, bending, or crimping. This may go unnoticed
either during the insertion process or during use. To minimize the risk of an incorrect insertion, the authors
recommend for Teflon infusion sets use of an insertion devices with integrated inserter [48]. Clinicians report a
significant number of failure rates (up to 10%) with autoinserters [48]. If the attachment of the infusion set on
the skin shifts laterally (e.g., in case of profound sweating), this can result in an infusion set occlusion [48].
During use, ensuring proper application of the adhesive can reduce the risk of soft cannula kinking and crimping.
However, the authors of this review pointed that use of the infusion sets are well-established and safe option
[48].
Other complications recognized as failed correction dose, pruritus, pain at the infusion site and adhesive tape
issues as well as infection and erythema were reported and described by the authors as common incidents [43,
44]. The adhesives associated problems and strip the superficial layer of the skin when the adhesive is removed
can occur during use of infusion set [43]. However, it was not possible to concretize level of injuries as the local
reactions at the infusion site and serious adverse events were not described in the article reviewed.
Dermatological complications, specifically Lipohypertrophy and Lipoatrophy, have been associated with
subcutaneous insulin injections and use of infusion sets. Dermatological complications may be important to
consider because of cosmetic effects but they may also be associated with acute effects, long-term effects on
insulin absorption and glycemic control, or both [41, 45].
The study by Conwell et al [45] described dermatological changes and severity of these changes associated
with CSII therapy in youth with T1DM using infusion sets as Comfort TM, Quick TM Set, Sure-T which all are based
on the Unomedical infusion set technology but branded by Medtronic company. The most common change was
scars < 3 mm diameter with surrounding hyperpigmentation, which were observed in 94% of participants. Larger
scars were observed less frequently (12%) [45]. Furthermore, erythema not associated with nodules and
inflammation was also observed. Possible reason of the erythema associated with catheter, adhesive tape, or
topical agents was not differentiated in the scoring and is unclear. In only 1 patient, the erythema was clearly in
the allocation of the edge of adhesive tape used to secure the site which can be associated with an allergic
reaction. However, this is not concluded. Only 4% of parents and 2.4% of the patients reported considering
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CSII discontinuation because of dermatological concerns [45]. The author emphasizes that dermatological
complications occurred are possibly not associated with use of the infusion sets or the adhesive tape but are
rather complications associated with insulin treatment [45].
The prospective, randomized, controlled cross-over study by Pützner et al [41]. Investigated the tolerability of
2-days use of InsetTM II in comparison to 4 days use in real-world setting. The results showed that use of the
InsetTM II infusion set as recommended by Unomedical A/S manufacture is safe where prolonged use resulted
in clinically relevant increase in treatment related tolerability harms and a decrease in treatment efficacy [41].
For use with insulin pumps the predicate device comfort TM is recommended for use of 2-3 days as stated in the
IFU at the same tissue location to avoid local skin reactions otherwise tolerability problems can occur [5].
Based on above, it can be concluded that using infusion set is safe when used as intended and recommended
by HCP.
7. Risk management
Risk assessments have been formed for the entire product range of soft cannula infusion set inserted in an 90
degree angle in the subcutaneous tissues, to identify the risks associated with the infusion set and how such
risk have been addressed. Following these evaluations, all risks were considered acceptable.
A risk analysis on comfortTM, comfortTM shortTM, Silhouette®, Silhouette® Paradigm, ACCU-CHEK/TenderLink
and Varisoft has been performed in accordance with Unomedical A/S Risk Management procedure describing
process and planning of the risk managing, and the risk management covering devices under evaluation and
manufacturing processes in the Unomedical A/S [17].
This risk analysis is a component of the risk analysis process and is used to identify risks of the device. The risk
analysis includes aspects associated with the medical procedure for which the device is intended, technical
solution adopted, design, process and aspects specific to the use of the particular device. The risk analysis in
conjunction with conclusions drawn from the evaluation of pertinent technical characteristics and literature-
based clinical data for comfortTM, comfortTM shortTM, Silhouette®, Silhouette® Paradigm, ACCU-
CHEK/TenderLink, Varisoft infusion sets have been used to demonstrate compliance with the EN/ISO 14971 –
Application of Risk Management to Medical Devices.
No new potential risks were identified in the CER that have not been identified through the bench testing
performed on the subject devices and associated with the use of the similar device for its intended purpose.
The potential risks identified in the literature includes:
 Insertion issues due to use error
 Lack of adhesion
 Leakage
 Skin irritation
 Lipodystrophy and scar tissue formation
 Infection and inflammation
 Unexplained elevated blood glucose level due to intra patient variation
All identified risks have been found to be well known and at an acceptable level for the use of infusion sets.
The potential risks identified in the risk analysis have been addressed by bench testing and clinical data, and
additional means of risk migration and no additional risk reduction activities are required. The potential clinical
risks associated with use of the infusion sets identified in the literature are all taken into consideration in the
materials for devices under evaluation held by the manufacturer [17].
All identified risks have been found to be well known and at an acceptable level for the use of infusion sets. The
potential risks identified in the risk analysis have been addressed by non-clinical tests, available clinical data,
and additional means of risk migration and no additional risk reduction activities are required.
During the lifetime of devices under evaluation continuous monitoring of varies elements will be carried out.
Elements that will be monitored are following [18]:
 Information from manufacturing, installation and maintenance.
 New or revised standards.
 Failures on competitor devices.
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 Previously unrecognized hazard or hazardous situation.

 Risk that is higher than previously estimated or no longer accepted.
Details can be found in the Risk Management File (RMF) for aforementioned infusion sets.
It can be concluded that the residual risks related to devices under evaluation have been mitigated to an
acceptable level and the overall residual risk is considered safe for its intended use.
8. Analysis of the clinical data
8.1. Requirement on performance (MDD ER3 / AIMDD ER2)
According to Annex IX, Medical Device Directive 93/42/EEC confirmation of conformity with the requirements
concerning the characteristics and performance of class IIb devices can be based on existing clinical data when
this can be duly justified [2].
The clinical data underpinning the performance of the subject devices are data based on the device under
evaluation and the non-equivalent infusion sets manufactured by Unomedical, and report data to confirm the
expected performance characteristics of comfortTM and comfortTM shortTM, Silhouette®, Silhouette® Paradigm,
ACCU-CHEK/TenderLink, Varisoft, in particular with respect to DM treatment.
The data available is considered to support the assessment that devices under evaluation to achieve their
intended performances during normal conditions of use and this is supported by sufficient clinical evidence in
the context of the overall state of the art and the paucity of clinical data available in this particular field. Therefore,
it fulfils the essential requirement on performance (MDD ER3).
8.2. Requirement on safety (MDD ER1 / AIMDD ER*)
Based on the assessment of all the available (manufacturer and scientific literature) data in respect of comfortTM
and comfortTM shortTM, Silhouette®, Silhouette® Paradigm, ACCU-CHEK/TenderLink, Varisoft, it is considered
that the subject devices complies with the conformity assessment requirements of ER1, as set out in the Medical
Devices Directive (93/42/EC) as amended.
Information supporting the devices, specifically the Instructions for Use (IFU) have been assessed within the
context of the available supporting data including bench-top tests as well as the RMR, PMS and complaint data
for the period 2011-2018. The IFU and product literature have been reviewed to make sure that product
information about contraindications, warnings and precautions have been addressed and described. The
proposed IFU and product literature are consistent with the sufficient clinical evidence reviewed in this CER. All
relevant clinical information has been incorporated to make sure that patient hazards and other clinical
information that may impact the use of comfortTM, comfortTM shortTM, Silhouette®, Silhouette® Paradigm, ACCU-
CHEK/TenderLink, and Varisoft are described.
Together, these data are considered sufficient to adequately assess the performance and safety of devices
under evaluation and to conclude that the information materials supplied by the manufacturer remain
appropriate.
8.3. Requirement on acceptable benefit/risk profile (MDD ER1)
The subject devices are medical devices that are based on existing, well-established infusion set technology
and their use during medical procedures have been common for many years. Clinical data described is available
to support usage of comfortTM, comfortTM shortTM, Silhouette®, Silhouette® Paradigm, ACCU-CHEK/TenderLink
and Varisoft infusion sets used for their intended use.
Based on an assessment of benefit provided within the evidence of risks associated with the device from clinical
trial data, it is considered that infusion sets under evaluation has an acceptable benefit-risk profile within the
context of its intended use and is consistent with that for similar infusion sets currently used.
It is concluded that comfortTM and comfortTM shortTM, Silhouette®, Silhouette® Paradigm, ACCU-
CHEK/TenderLink, Varisoft infusion sets complies with the conformity assessment requirements of ER 1 in
respect of an acceptable benefit-risk profile.
8.4. Requirement on acceptability of side effects (MDD ER6)
Any undesirable side effect must constitute an acceptable risk when weighed against the performances intended.
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As set out in the MEDDEV 2.7.1, Revision 4 guidance, a reasonable probability (80%) of observing at least one
event of an undesirable side effect at the 1% level would require a minimum of 161 subjects. Based on sales,
equivalent to 93,640,608 devices there is a significant side-effect information from PMS data. Using these data,
an Adverse Event (AE) frequency, based on PMS information has been calculated to be 4,129 product
exposures with performance-related ratio of 0.003927% . All were mild application site reactions.
The combined PMS and available clinical data support conformity with ER6.
9. Post market surveillance
An important step to monitor risks pertaining to a medical device on the market is to capture customer feedback
and review this feedback on a regular basis. comfortTM and comfortTM shortTM, Silhouette®, Silhouette®
Paradigm, ACCU-CHEK/TenderLink, VariSoft infusion set is based on well-known infusion set technology and
the product family has been on the market for several years with safety records and has been used in clinical
application and is well investigated within clinical safety and performance.
Safety or performance issues have been identified with the subject and equivalent devices in the vigilance
databases such as FDA Databases MAUDE, BfArM, MHRA, DAEN, SARA, MHDP.
The user feedback included relates to all aspects of the handling, wear and disposal of any kind of Unomedical
A/S infusion sets.
Post Market Surveillance Plan
The PMS plan for the device will ensure design reviews to be held as required by regulations and company
Standard Operating Procedures (SOP) whereby adverse event reports, customer complaints and any additional
internal or externally derived clinical evidence (whether investigative, literature-based or otherwise) will be
assessed. The frequency of on-going reviews will be based on risk management principles. The risk assessment
will be updated accordingly. If required the CER will also be updated.
Unomedical has an implemented PMS plan [20] ensuring that Unomedical is kept informed about specific user
feedback in connection with the usage of infusion sets. Feedback from patients, HCPs and distributors are
included in the PMS plan.
The internal procedures for the PMS comfortTM and comfortTM shortTM, Silhouette®, Silhouette® Paradigm,
ACCU-CHEK/TenderLink, VariSoft infusion sets are established through the implemented procedure CS-10777
Post Market Surveillance for Medical Devices. Hereby, Unomedical follows the guidelines stipulated in the MDD
93/42 EEC, Annex IX and amendments, the European Union (EU) NB-MED/2.12/Rec1 guidance document,
“Post-Marketing Surveillance (PMS)” and as appropriate, the MEDDEV 2.12-2 guidance document, “Guidelines
on Post-Market Clinical Follow-Up”.
Post Market Clinical Follow up
PMCF activities on comfortTM and comfortTM shortTM, Silhouette®, Silhouette® Paradigm, ACCU-
CHEK/TenderLink, Varisoft infusion sets are not required, as it is recognized that the infusion set in general has
an acceptable level of risk associated with their use and the clinical evidence presented showed that subject
devices complies with the conformity assessment requirements of ER1, 3 and 6. Consequently, there has not
been identified any outstanding risks that will justify the enrollment of patients in a clinical investigation of an
investigational medical device and as such, a clinical investigation is not necessary to demonstrate conformity
with the requirements concerning the characteristics and performance referred to in the MDD 93/42/EEC and
amendments.
10. Conclusions
This clinical evaluation addresses comfortTM and comfortTM shortTM, Silhouette®, Silhouette® Paradigm, ACCU-
CHEK/TenderLink, Varisoft infusion sets. This report demonstrates ongoing support for the safety and
performance of subject devices verified by bench testing performed and held by the manufacturer prior to this
evaluation as well as clinical data obtained from literature review and PMS data giving sufficient clinical evidence.
The use of infusion sets is still a well-established and considered state of the art for medical procedures. State-
of-the-art in the intended indication DM therapy, as set out in this document, indicates that use of an infusion
set is important and have shown a clinical benefit in terms of performance and safety, comfortTM and comfortTM
shortTM, Silhouette®, Silhouette® Paradigm, ACCU-CHEK/TenderLink, VariSoft are considered to be fully
consistent with state of the art.
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No new or unknown patient risk connected with the use of infusion sets have been reported during this
evaluation.
11. Date of the next clinical evaluation
The clinical evaluation should be updated according to the interval for clinical evaluation review as defined.
The risk class for medical devices according to MDD 93/42/EEC has been chosen as the criterion to determine
the frequency for regular reviews of clinical evaluations. As a class IIb medical device the regular revision for
comfortTM and comfortTM shortTM, Silhouette®, Silhouette® Paradigm, ACCU-CHEK/TenderLink, Varisoft infusion
sets should be performed annually.
However, in order to fully demonstrate conformity with the requirements concerning the performance referred
to in the MDD 93/42/EEC and amendments the next revision will be performed when PMCF data are available.
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12. References
1. MEDDEV guideline 2.7.1, rev 4, 2016. Guidelines on medical devices. Clinical Evaluation: a guide for
manufacturers and notified bodies.
2. Medical Device Directive (93/42/EEC) as amended by MDD 2007/47/EC Consolidated version
3. GHTF: http://www.imdrf.org
4. AADE: www.diabeteseducator.org
5. Design History File (DHF). Unomedical A/S
6. Instruction for Use. comfortTM. Unomedical A/S
7. Instruction for Use. SilhouetteTM. Unomedical A/S
8. Instruction for Use. Accuchek/Tender. Unomedical A/S
9. Instruction for Use. varisoftTM. Unomedical A/S
10. 390928 U-FMEcA for Inset 30. Unomedical A/S
11. CCR-OSTID-2016-0050 Qualification Test Plan for T-Cap InsetTM II
12. 3A06100 D-FMEcA for Inset 30. Unomedical A/S
13. Rationale for exclude tensile test of connector and p-cap for design verification of Mio 30. Change
request no. I-2014-109. Unomedical A/S
14. D016-000779. Rationale - Substantial Equivalence
15. Statement biocompatibility Inset products, version 01.0
16. Usability Study Report for comfortTM furcated infusion set. Unomedical A/S 3706010.
17. Risk Management procedure. Unomedical A/S
18. 3806092. Risk Management Monitoring. Unomedical A/S
19. Post Market Surveillance (PMS data). Unomedical A/S
20. Post Market Surveilance Plan. Unomedical A/S
21. 3802061. Complaint Trending and reporting. Unomedical A/S
22. Biological Safety Testing, October 2011, Data on File, Unomedical A/S (skin friendly adhesive)
23. Curley, Ann. Diabetes 101: Understanding the disease. October 22, 2007
http://ww.cnn.eom/7.007/HEAI.TH/conditions/10/19/diabetes.hasics/index.html
24. The Diabetes Control and Complications Research Group. The effect of intensive treatment of
diabetes on the development and progression of long-term complications of insulin-dependent
diabetes mellitus. N Eng. J Med. 1993; 329:997-1036
25. Levinson Paul D. Eighty years of insulin therapy: 1922-2002. Medicine and Health Rhode Island April
2003 American Diabetes Association. National Diabetes Faet Sheet. 2005
26. Osterberg Ole, Erichsen Lars, Ingwersen Steen H.: Pharmacokinetics and Pharmacodynamic
Properties of insulin as part and Human Insulin. Journal of Pharmacokinetics and Pharmacodynamics
Vol 30 Num 3 2003.
27. Hanas, R. & Ludvigsson, J. Side Effects and Indwelling Times of Subcutaneous Catheters for Insulin
Injections: a new device for injecting insulin with a minimum of pain in the treatment of insulin-
dependent diabetes mellitius. Diabetes Research and Clinical Practice, 1990,10, 73-83.
28. Schade David S. Virginia Valentine: To Pump or Not to Pump. Diabetes Care 25:2100-2102,
29. Agrawal P, Welsh JB, Kannard B, Askari S, Yang Q, Kaufman FR. Usage and effectiveness of the
low glucose suspend feature of the Medtronic Paradigm Veo insulin pump. J Diabetes Sci Technol.
2011 Sep 1;5(5):1137-41
30. Gibney M, Xue Z, Swinney M, Bialonczyk D, Hirsch L. Reduced Silent Occlusions with a Novel
Catheter Infusion Set (BD FlowSmart): Results from Two Open-Label Comparative Studies.
Diabetes Technol Ther. 2016 Mar;18(3):136-43
31. Heinemann L, Fleming GA, Petrie JR, Holl RW, Bergenstal RM, Peters AL. Insulin pump risks and
benefits: a clinical appraisal of pump safety standards, adverse event reporting and research needs.
A joint statement of the European Association for the Study of Diabetes and the American Diabetes
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Association Diabetes Technology Working Group. Diabetologia. 2015 May;58(5):862-70.

32. Heinemann L, Krinelke L. Insulin infusion set: the Achilles heel of continuous subcutaneous insulin
infusion. J Diabetes Sci Technol. 2012 Jul 1;6(4):954-64.
33. McVey E, Keith S, Herr JK, Sutter D, Pettis RJ. Evaluation of Intradermal and Subcutaneous Infusion
Set Performance Under 24-Hour Basal and Bolus Conditions. J Diabetes Sci Technol. 2015 Aug
27;9(6):1282-91.
34. Pfützner A, Musholt PB, Malmgren-Hansen B, Nilsson NH, Forst T. Analysis of the environmental
impact of insulin infusion sets based on loss of resources with waste. J Diabetes Sci Technol. 2011
Jul 1;5(4):843-7
35. Zahid N, Taylor KM, Gill H, Maguire F, Shulman R. Adsorption of insulin onto infusion sets used in
adult intensive care unit and neonatal cares settings. Diabetes Res Clin Pract. 2008 Jun;80(3):e11-
3.
36. Scheiner G, Sobel RJ, Smith DE, et al. Insulin pump therapy: guidelines for successful outcomes.
Diabetes Educ. 2009;35(suppl 2):29S-41S.
37. Dumville JC, Gray TA, Walter CJ, Sharp CA, and Page T, (2014) Dressings for the prevention of surgical
site infection. Cochrane Database Syst Rev. 9: p. CD003091.
38. Daecke C, Schaller S, Schaller J, and Goos M, (1993) Contact urticaria from acrylic acid in Fixomull
tape. Contact Dermatitis. 29(4): p. 216-7.
39. Geukens S and Goossens A, (2001) Occupational contact allergy to (meth)acrylates. Contact
Dermatitis. 44(3): p. 153-9.
40. Stephen-Haynes J, (2014) The outcomes of barrier protection in periwound skin and stoma care. Br J
Nurs. 23(5): p. S26, S28-30.
41. Pfützner A, Sachsenheimer D, Grenningloh M, Heschel M, Walther-Johannesen L, Gharabli R,
Klonoff D. Using Insulin Infusion Sets in CSII for Longer Than the Recommended Usage Time Leads
to a High Risk for Adverse Events: Results from a Prospective Randomized Crossover Study. J
Diabetes Sci Technol. 2015 Sep 3;9(6):1292-8.
42. Chatterjee S, Davies MJ. Current management of diabetes mellitus and future directions in care.
Postgrad Med J 2015; 91:612–621
43. Patel PJ, Benasi K, Ferrari G, Evans MG, Shanmugham S, Wilson DM, Buckingham BA.
Randomized Trial of Infusion Set Function: Steel Versus Teflon. Diabetes Technol Ther. 2014
Jan;16(1):15-9
44. van Bon AC, Bode BW, Sert-Langeron C, DeVries JH, Charpentier G. Insulin glulisine compared to
insulin aspart and to insulin lispro administered by continuous subcutaneous insulin infusion in
patients with type 1 diabetes: a randomized controlled trial. Diabetes Technol Ther. 2011
Jun;13(6):607-14
45. Conwell LS, Pope E, Artiles AM, Mohanta A, Daneman A, Daneman D. Dermatological complications
of continuous subcutaneous insulin infusion in children and adolescents. J Pediatr. 2008
May;152(5):622-8
46. Mecklenburg RS, Benson EA, Benson JW Jr, Blumenstein BA, Fredlund PN, Guinn TS, Metz RJ,
Nielsen RL. Long-term metabolic control with insulin pump therapy. Report of experience with 127
patients. N Engl J Med. 1985 Aug 22;313(8):465-8.
47. Pickup JC, Yemane N, Brackenridge A, Pender S. Nonmetabolic complications of continuous
subcutaneous insulin infusion: a patient survey.
48. Heinemann L, Krinelke L. Insulin infusion set: the Achilles heel of continuous subcutaneous insulin
infusion. J Diabetes Sci Technol. 2012 Jul 1;6(4):954-64
49. Appendix l: Literature search report
50. Appendixe ll: CV for responsible person writing the report
51. CV’s for Evaluators
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Useful manufacture websites

https://www.diabetes.co.uk/
https://www.tandemdiabetes.com/products/infusion-sets/tlock-connector
https://www.diabetesdaily.com/blog/tandem-launches-tlock-connector-for-pump-cartridges-and-infusion-
sets-479830/
https://www.medtronicdiabetes.com/download-library
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Abbreviations
Item Description
AE Adverse Event
BfArM Das Bundesinstitut für Arzneimittel und Medizinprodukte
BRA Biological Risk Assessment
Clinical Data Clinical data are sourced from:
- Clinical investigation(s) of the MD concerned; or
- Clinical investigation(s) or other studies reported in the scientific
literature, of a similar MD for which equivalence to the MD in
question can be demonstrated; or
- Published and/or unpublished reports on other clinical experience of
either the MD in question or a similar MD for which equivalence to
the MD in question can be demonstrated.
Clinical Evaluation A methodologically sound ongoing procedure to collect, appraise and analyze clinical data
pertaining to a MD and to evaluate whether there is sufficient clinical evidence to confirm
compliance with relevant ER for safety and performance when using the MD according to the
manufactures instructions for use.
Clinical Evidence The clinical data and the CER pertaining to a MD
CEP Clinical Evaluation Plan
CER Clinical Evaluation Report
CSII Continuous Subcutaneous Insulin Infusion
DHF Design History File
DM Diabetes Mellitus
EO Ethylene Oxide
ER Essential Requirements
FDA U.S. Food and Drug Administration
GCP Good Clinical Practice
HCP Healthcare Professional
IFU Instruction for Use
i.v. Intravenous
LSR Literature Search Report
MAUDE Manufacturer and User Facility Device Experience
MD Medical Device
MDD Medical Device Directive
MDR Medical Device Regulation
MHRA Medicines and Healthcare Products Regulatory Agency
P-cap P-cap Connector
PMCF Post Market Clinical Follow up
PMS Post Market Surveillance
RMF Risk Management File
SI Standard Injection
SOP Standard Operating Procedure
T1DM Type 1 Diabetes Mellitus
T-Cap T-cap Connector
T1DM Type 1 Diabetes Mellitus
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Version History
Change Control
Rev. Date Author Name Change Description
Anna Tomanek Set up a new document in accordance with MEDDEV2.7.1
1.0 21.06.2018
Christensen revision 4
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13. Appendix I:
Equivalence matrix from R&D
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14. Appendix II:
Literature Search Report

(LSR)
1. Background and scope

This literature search report (LSR) is performed based on a template set out in MEDDEV 2.7.1, Revision 4 of
June 2016, to support Essential Requirements 1, 3 and 6 of Directive 93/42/EC (updated by 2007/47/EC) along
with device claims made in the respective Design History File (DHF) [1]. Furthermore, the objective of this
literature review is updating the current knowledge regarding infusion sets.
2. Identification of data
The databases presented in table 1 were searched for scientific information. The medical database PubMed
was mainly used, since it is the largest database on peer-reviewed medical articles available and found to be
adequate for the purpose of this literature search. There has been complemented by search using other
scientific and clinical journals and articles and systematic reviews for health care databases such as Medscape,
Prospero, Cochrane and ClinicalTrials.gov to support other relevant articles that are not available on PubMed.
Table 1. Databases used to search for scientific information.
Type of Database Web address Countr
Databas s Name y
e
Medical NCBI http://www.ncbi.nlm.nih.gov/pubmed N/A
database Medscape http://www.medscape.com/
(Scientific Prospero https://www.crd.york.ac.uk/prospero/
and Cochrane http://www.cochranelibrary.com
clinical Clinical https://clinicaltrials.gov/
journals Trials
and Database
articles)
Incident MAUDE www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/search.cfm US
Reports database
BfArM https:// www.bfarm.de GR
FDA www.fda.gov US
MHRA http://www.mhra.gov.uk/Publications/Safetywarnings/MedicalDeviceAlerts/index.ht UK
database m
DAEN https://www.tga.gov.au/database-adverse-event-notifications-daen AU
SARA https://apps.tga.gov.au/Prod/sara/arn-entry.aspx AU
MHDP http://www.hc-sc.gc.ca/index-eng.php CA
(Health
Canada)
PubMed/MedLine, published by the US National Library of Medicine (NLM)
This database is considered to be the principal online bibliographic citation database of NLM's MEDLARS®
system and is used internationally to provide access to more than 5000 titles. The majority of the publications
covered in MedLIine are scholarly journals; a small number of newspapers, magazines, and newsletters
considered useful to identify relevant publications.
Cochrane
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The Cochrane Library is a collection of six databases that contain different types of high-quality, independent
evidence to inform healthcare decision-making, and a seventh database that provides information about
Cochrane groups: Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of
Controlled Trials (CENTRAL), Cochrane Methodology Register (CMR), Database of Abstracts of Reviews of
Effects (DARE), Health Technology Assessment Database (HTA), NHS Economic Evaluation Database (EED),
and About The Cochrane Collaboration. Together these databases offer more than 1 million records. The
Cochrane Collaboration is a global independent network of 37,000 researchers, professionals, patients, carers,
and people interested in health, represented from more than 130 countries. This network produces credible,
accessible health information that is free from commercial sponsorship and other conflicts of interest and
publishes it in The Cochrane Library.
ClinicalTrial.gov
ClinicalTrial.gov is a registry that provides access to information on publicly and privately supported clinical
studies on a wide range of diseases and conditions. Studies listed in the database are conducted in the United
States and in 195 countries around the world. The site was created in 1997 and made available to the public in
February 2000.
Prospero
PROSPERO includes protocol details for systematic reviews relevant to health and social care, welfare, public
health, education, crime, justice, and international development, where there is a health related outcome.
Systematic review protocols on PROSPERO can include any type of any study design.
Medscape
Medscape is the online global destination for physicians and healthcare professionals worldwide, offering the
latest medical news and expert perspectives and providing access to medical-, essential point-of-care drug and
disease information and relevant professional education and CME.
3. Extent of search
The databases were searched using keywords for both the publication titles and the full body of the
corresponding abstracts. All relevant studies published since 2007/01/01 were considered for inclusion.
The following search terms (see table 2) were used for the literature search to capture sufficient references to
achieve objective of LSR and to document attempts to identify all published literature.
Each of the data sets was appraised and assessed collectively to demonstrate compliance with Essential
Requirements 1, 3 and 6. This analysis includes:
 When an evaluation is based on limited data this should be described and justified.
 The adequacy of preclinical (bench-top testing) and clinical testing to verify safety and risks to
patients or users will be described.
 The adequacy of clinical data to support benefits to patients and that the device performs as
intended (performance claims) will be reviewed.
 Reporting of any gaps in evidence, uncertainties or unanswered questions will be reviewed.
 The adequacy of the product information will be reviewed.
 Consistency and alignment between the CER, the product information and Risk Management
Report (RMR) will be discussed.
To maximize search sensitivity and results, no initial limitations were placed with respect to language or
publication type.
With respect to the published data, the first step was to assess the titles, abstracts and keywords of the studies
to identify relevant matches. In a second step, full text of potentially relevant references was assessed. The
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studies selected as relevant in step two will be assessed by reading the entire text (See table 4). Each
publication from the search results, at either the first or second round of review, will be either included or
excluded. The overall search strategy for identifying relevant publications on the devices under evaluation is
presented in table 2 and 2a.
Table 2. Keywords used to limit literature searches.

Extent of search - Keywords
PubMed
1. ("diabetes mellitus"[MeSH Terms] OR ("diabetes"[All Fields] AND "mellitus"[All Fields]) OR "diabetes mellitus"
"diabetes"[All Fields] OR "diabetes insipidus"[MeSH Terms] OR ("diabetes"[All Fields] AND "insipidus"[A
"diabetes insipidus"[All Fields]) AND (infusion[All Fields] AND set[All Fields]) AND (("2007/01
"2017/09/01"[PDAT]) AND "humans"[MeSH Terms]) AND English[lang])
2. ("infusion set"[All Fields] AND "comfort"[All Fields]) AND ("safety"[MeSH Terms] OR "safety"[All Fields]) AND
(("2007/01/01"[PDAT] : "2017/09/01"[PDAT]) AND "humans"[MeSH Terms] AND English[lang])
3. (Infusion[All Fields] AND set[All Fields]) AND ("insulin"[MeSH Terms] OR "insulin"[All Fields]) AND
(contraindication[All Fields] OR "adverse event"[All Fields]) AND (("2007/01/01"[PDAT] : "2017/09/01"[PDAT])
AND "humans"[MeSH Terms]) AND English[lang])
4. "Infusion set"[All Fields] OR "comfort"[All Fields] AND (("polyesters"[MeSH Terms] OR "polyesters"[All Fields]
OR "polyester"[All Fields]) AND tape[All Fields]) AND (("skin"[MeSH Terms] OR "skin"[All Fields]) AND
irritation[All Fields]) AND (("2007/01/01"[PDAT] : "2017/09/01"[PDAT]) AND "humans"[MeSH Terms] AND
English[lang])
5. "comfort"[All Fields] AND "infusion set"[All Fields] AND (("2007/01/01"[PDAT] : "2017/09/01"[PDAT]) AND
"humans"[MeSH Terms] AND English[lang])
6. "silhouette"[All Fields] AND "infusion set"[All Fields] AND (("2007/01/01"[PDAT] : "2017/09/01"[PDAT]) AND
"humans"[MeSH Terms] AND English[lang])
7. "varisoft"[All Fields] AND "infusion set"[All Fields] AND (("2007/01/01"[PDAT] : "2017/09/01"[PDAT]) AND
Humans[Mesh] AND English[lang])
Medscape
1. (“infusion set” OR “inset II”) AND safety
2. “comfort” AND “infusion set”
3. “silhouette” AND “infusion set”
4. “varisoft” AND “infusion set”
5. “accuchek” AND “infusion set”
Prospero
1. “comfort”
2. “silhouette”
3. “varisoft”
4. accuchek AND “infusion set”
Cochrane
1. (“infusion set” OR “comfort”) AND safety
2. “comfort”
3. “silhouette”
4. “varisoft”
ClinicalTrials
1. “comfort”
2. “silhouette”
3. “varisoft”
Table 2a.
Vigilance
Maude Brand name:
Comfort, comfort short, Silhouette, Silhouette paradigm, ACCUCHEK, varisoft
MHRA Brand name:

FDA Brand name:
Page 36 of 46
Internal
Bfarm Brand name:

DAEN Brand name:
SARA Brand name:
MHDP Brand name:
4. Inclusion Criteria
Only studies in English were included and the data had to be relevant and related to specific characteristics of
comfortTM, comfortTM short, Silhouette®, Silhouette® Paradigm, ACCU-CHEK/Tender, varisoft. Furthermore, the
literature included use of the device in question and similar devices with respect to clinical, technical or biological
characteristics as defined in MEDDEV 2.7.1 rev 4 were included [1]. The definitions used, were as follows:
Data which met one or more of the following criteria were selected for review:
 Inclusion criterion 1: Relevant population and relevant treatment / device
 Inclusion criterion 2: Relevant treatment, not target population, but can be extrapolated
For the current CER a search period covers from 01.01.2007 to 01.09.2017.
5. Exclusion Criteria
Criteria for exclusion:
 Exclusion code NR: Any identified references (based on title or abstract) that do not relate to either the
proposed indications or to the specified devices
 Exclusion code MM: Identified references that contain a mere mention to the subject device, but do not
provide any pertinent data to assess performance or safety
 Exclusion code GR: Identified references that contain generic information only (e.g. review articles),
and do not contribute further to “state of the art”
 Exclusion code P: Identified references, which are protocols for studies and do not provide evidence to
assess performance or safety
 Exclusion D: Duplicates
6. Search results
The literature search results are presented in table 3 that provides details of the database searches and the
numbers of results returned, specifically reported are:
 The date the search was conducted and/or the date cut-off filters were applied
 The database search and number that indicates the database searched and the numerical identifier
attached to the search
 The search term used with any applied filters
 The number of references identified by the search
 The total and selected number of references
Table 3. Results from literature search
Page 37 of 46
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7. Literature Appraisal
Databases Sear Search word. Total Criteria for Useful
ch identified exclusion Articles
no. references with
procedure
Pubmed 1. Diabetes AND infusion set 23 NR, MM, P 15

2. (“infusion set” AND “comfort”) AND 13 D 0
safety
3. Infusion set AND insulin AND 5 D, NR 2

(contraindication OR “adverse
event”)
4. “Infusion set” OR “comfort” AND 7 - 2

polyester tape AND skin irritation
5. "comfort” AND "infusion set" 1 - 1

6. "silhouette" AND "infusion set" 0 - 0
7. "varisoft" AND "infusion set" 0 - 0
Medscape
(“infusion set” OR “comfort ”) AND 12 NR, D, MM 3
1. safety AND diabetes
"varisoft" AND "infusion set" 0 - -
2.
"Accuchek" AND "infusion set" 0 - -
3.
Silhouette AND "infusion set" 0 - 0
Prospero
1. “comfortTM” 0 - 0
2. “varisoft:30” 0 - 0
3. “Accuchek” 0 - 0
4. Silhouette AND “infusion set” 0 - 0
Cochrane
1. “comfortTM” 11 D, NR 1
2. “varisoft:30” 0 - 0
ClinicalTrials.gov
2. “varisoft:30” 0 MM,NR 0
7.1 Criteria for Appraisal
The identified clinical data will be appraised according to the criteria for suitability and contribution suggested
by Global Harmonization Task Force’s (GHTF, now IMDRF) Study Group 5 on Clinical Safety/Performance,
SG5/N2R8:2007 appendix D devices [2]. The criteria are presented in the tables below.
Table 4. Sample Appraisal Criteria for Suitability and data contribution criteria
Table 4a. Sample Appraisal Criteria for Suitability
Suitability Criteria Description Grading system
Appropriate device Were the data generated from the device in D1 Actual device
question? D2 Comparable device
D3 Other device
Appropriate Was the device used for the same intended A1 Same use
device application use (e.g., methods of deployment, A2 Minor deviation
application, etc.)? A3 Major deviation
Page 38 of 46
Internal
Appropriate Were the data generated from a patient P1 Applicable

patient group group that is representative of the intended P2 Limited
treatment population (e.g., age, sex, etc.) P3 Different population
and clinical condition (i.e., disease, P4 (NA: Reserved for bench-top or
including state and severity)? pre-clinical studies)
Acceptable report/data Do the reports or collations of data contain R1 High quality
collation sufficient information to be able to R2 Minor deficiencies
undertake a rational and objective R3 Insufficient information
assessment?
Table 4b. Data contribution criteria
(Grading system used for data contribution criteria was 1 for yes and 2 for no)
Data contribution Description Grading system
criteria
Data source type Was the design of the study appropriate? 1 Yes
(T) 2 No
Outcome measures Does the outcome measures reported reflect the intended 1 Yes
(0) performance of the device? 2 No
Follow-up (F) Is the duration of follow-up long enough to assess whether 1 Yes
duration of treatment effects and identify complications? 2 No
Statistical Has a statistical analysis of the data been provided and is 1 Yes
significance (S) it appropriate? 2 No
Clinical significance Was the magnitude of the treatment effects observed 1 Yes
(C) clinically significant? 2 No
The sufficient clinical data included in the CER have been appraised and weighted to determine the suitability
to address question(s) about the infusion sets, cannula and tubing and the contribution to demonstrate the
safety and performance of comfortTM family product infusion set. All clinical data have been appraised
consistently using the criteria described in table 4.
Evidence level is defined as following:
 Level 1 contains of clinical data on the device under evaluation and/or equivalent device
 Level 2 includes clinical data on a similar device
 Level 3 is a collection of data including clinical data, guidance documents and review articles on similar
device with limiting grading only to be used in state of the art section.
As a general guide, the more level 1 grades, the greater the weight of evidence provided by that particular
dataset in comparison to other datasets, however, it is not intended that the relative weightings from each
category be added into a total score. For more information about medical device harmonization see
www.imdrf.org website since the GHTF website is no longer operational [2].
7.2 Appraisal results
An overall evidence level is assigned to the clinical data (Table 5) based on the equivalence criteria to evaluate
its relative contribution to the safety and performance assessment. Level is defined as following:
Table 5: Appraisal results
Performance Appraisal criteria Appraisal criteria for Overall evidence
(P) and/or for suitability data contribution level
safety (S), state
of the art
Reference P S D A G R T O F S C
Actual device
Conwell LS. et al 2008 - S 1 1 1 1 1 1 2 1 1 Level 1
Similar device
Patel PJ. et al, 2014 P S 2 1 1 1 1 1 2 1 1 Level 2
Bon AC. et al, 2011 P S 2 1 1 1 1 1 2 2 1 Level 2
Pickup JC. et al, 2014 - S 2 1 1 1 1 1 2 2 1 Level 2
Page 39 of 46
Internal
Pfutzner A. et al, 2015 - S 2 1 1 2 1 1 1 1 1 Level 2

Other similar device with limited grading
Curley, Ann. 2007 State of the art 2 1 1 2 1 2 2 1 1 Level 3
Engl N. Med J. 1994 State of the art 3 1 1 2 1 2 2 1 Level 3
Levinson Paul D. 2005 State of the art 3 1 1 2 2 1 2 2 2 Level 3
Osterberg Ole. Et al, 2003 State of the art 3 1 1 2 1 2 1 1 1 Level 3
Hanas R. et al, 1990 State of the art 3 1 1 2 1 1 2 1 1 Level 3
Schade David S. 2002 State of the art 2 1 1 2 2 1 2 2 2 Level 3
Agrawal P. et al, 2011 State of the art 3 1 1 2 2 1 2 2 1 Level 3
Gibney M. et al, 2016 State of the art 2 1 1 2 2 1 2 2 1 Level 3
Heinemann L. et al, 2015 State of the art 3 1 1 2 1 2 1 1 1 Level 3
Heinemann L. et al, 2015 State of the art 2 1 1 2 1 1 1 1 2 Level 3
McVey E. et al, 2015 State of the art 3 1 1 2 1 1 1 1 2 Level 3
Pfutzner A. et al, 2011 State of the art 3 1 1 2 2 1 1 1 1 Level 3
Zahid N. et al,2008 State of the art 3 1 1 2 2 1 2 2 1 Level 3
Scheiner G. et al, 2009 State of the art 3 1 1 2 2 1 1 2 2 Level 3
Dumville JC. et al, 2014 State of the art 3 1 1 2 1 1 1 1 1 Level 3
Daecke C. et al, 1993 State of the art 2 1 1 2 1 2 1 1 1 Level 3
Geukens S. et al, 2001 State of the art 3 1 1 2 1 1 2 2 1 Level 3
Stephen-Haynes J. et al, 2014 State of the art 3 1 1 2 1 1 2 2 1 Level 3
Chatterjee S. et al, 2015 State of the art 2 1 1 2 1 2 2 1 1 Level 3
7.3 Appraisal conclusion

For this review 52 publications were presumed useful to identify sufficient clinical evidence, 5 articles were
appraisal as sufficient to support safety and performance of the aforementioned infusion sets, 19 included in
the state of the art section, and a total of 24 of these are referenced.
The datasets considered being the pivotal dataset or important to demonstrate the overall safety and
performance of devices under evaluation consists of clinical data obtained from published literature on Level 1
(the device under evaluation) and 2 (similar device). The literature included with relative contribution to the
performance and safety assessment are assigned from the following studies: an open-label, case study design,
double-blind cross-over study and cross over study including use of the subject device and non-equivalent
infusion sets.
8. Adverse incident reporting
Table 6: Result from search in regulatory body databases on the comfortTM, comfortTM short, Silhouette®, Silhouette®
Paradigm, ACCU-CHEK/Tender, varisoft. Search period 01-01-2011 to 01-06-2018 for the vigilance database.
Adverse Events/Recall Search
MAUDE adverse event database (US) – Search period 01.01.2011 –01.06.2018 Total
comfort unomedical(advanced search, brand name) 5
Death 1
Page 40 of 46
Internal
Injury 3
Malfunction 1
Other 0
Comfort short unomedical (advanced search, brand name) 1
Death 1
Injury 0
Malfunction 0
Other 0
Silhouette paradigm unomedical (advanced search, brand name) 26
Death 14
Injury 10
Malfunction 2
Other 0
AC/ Tender, unomedical (advanced search, brand name, manufacturer) 5
Death 3
Injury 1
Malfunction 1
Other 0
Silhouette Minimed (advanced search, brand name) 1
Death 0
Injury 1
Malfunction 0
Other 0
Varisoft Tandem (advanced search, brand name) 0
FDA Recall database (US) - Search period 01.01.2011 – 01.06.2018
Death 0
Injury 0
Malfunction 2
Other 0
Death 0
Injury 0
Malfunction 1
Other 0
Silhouette paradigm (advanced search, brand name) 2
Death 0
Injury 0
Malfunction 1
Other 1
ACCUCHEK Roche (advanced search, brand name, manufacturer) 0(3 not
relevan
t)
Death 0
Injury 0
Malfunction 0
Other 0
Death 0
Injury 0
Malfunction 0
Other 2
Bfarm (Germany) - Search period 01.01.2011 - 01.06.2018
comfort unomedical(advanced search, brand name) 0(26
not
relevan
t)
Comfort short unomedical (advanced search, brand name) 0(4 not
relevan
t)
Page 41 of 46
Internal
Silhouette paradigm (advanced search, brand name) 0(not

relevan
t)
ACCUCHEK Roche (advanced search, brand name, manufacturer) 0
Silhouette Minimed (advanced search, brand name) 0(2not
relevan
t)
varisoft 0
MHRA Alerts and Recalls database (United Kingdom) – Search period 01.01.2011 – 01.06.2018
Comfort short unomedical (advanced search, brand name) 0(8 not
relevan
t)
Silhouette paradigm (advanced search, brand name) 0(4 not
relevan
t)
ACCUCHEK Roche (advanced search, brand name, manufacturer) 0
Silhouette Minimed (advanced search, brand name) 0(2non
relevan
t)
varisoft 0
DAEN Database of Adverse Event Notifications (Australia) - Search period 01.07.2012 – 03.02.2018 (database
goes from 01.07.2012 to 07.06.2017)
Death 0
Injury 0
Malfunction 0
Other 2
Death 0
Injury 3
Malfunction 0
Other 1
relevan
t)
Death 0
Injury 1
Malfunction 0
Other 0
SARA Recall Actions (Australia) - Search period 01.07.2012 – 02.06.2018(database only goes back to
01.07.2012)
comfort unomedical(advanced search, brand name) 0(2 not
relevan
t)
relevan
t)
MHDP (Health Canada) - Search period 01.01.2011 –01.06.2018:
comfort unomedical(advanced search, brand name) More
than
10(03/1
1/2014)
Page 42 of 46
Internal
Manufacturer has identified an increase in reports of the tubing becoming detached at the connect/disconnect location. If
tubing detachment occurs, insulin delivery is interrupted and the pump will not alarm to notify patients. The interruption of
insulin delivery can cause hyperglycemia, which if left untreated, can result in diabetic ketoacidosis (DKA). DKA is a
serious condition that can cause a severe impact to health, including death. Symptoms of DKA may include nausea,
vomiting, shortness of breath and excess thirst/urination. Manufacturer is advising patients to seek medical attention
immediately if they are experiencing any of these symptoms.
Comfort short unomedical (advanced search, brand name) More
than
10(03/1
1/2014)
Manufacturer has identified an increase in reports of the tubing becoming detached at the connect/disconnect location.
If tubing detachment occurs, insulin delivery is interrupted and the pump will not alarm to notify patients. The interruption
of insulin delivery can cause hyperglycemia, which if left untreated, can result in diabetic ketoacidosis (DKA). DKA is a
Silhouette paradigm (advanced search, brand name) More
than
10(11.0
9.2017)
All
lots(03/
11/201
4)
Medtronic has become aware of recent reports of potential over-delivery of insulin shortly after an infusion set change.
The reported incidence rate requiring medical assistance related to this issue is less than 1 in every 2 million infusion
sets. Over-delivery of insulin can cause hypoglycemia and in extreme cases, death. Medtronic has received reports of
hypoglycemia requiring medical intervention potentially related to this issue.
Manufacturer investigation has shown this can be caused by fluid blocking the infusion set membrane during the
priming/fill-tubing process. A membrane blocked by fluid may occur if insulin, alcohol, or water is spilled on top of the
insulin reservoir, which then could prevent the infusion set from working properly. Infusion sets currently being shipped
by Medtronic contain a new and enhanced membrane material that signifcantly reduces this risk.
ACCUCHEK Roche (advanced search, brand name, manufacturer) More
than
10(03/1
1/2014)
Manufacturer has identified an increase in reports of the tubing becoming detached at the connect/disconnect location. If
tubing detachment occurs, insulin delivery is interrupted and the pump will not alarm to notify patients. The interruption of
insulin delivery can cause hyperglycemia, which if left untreated, can result in diabetic ketoacidosis (DKA). DKA is a
Silhouette Minimed (advanced search, brand name) All
lots(03/
11/201
4)
Manufacturer has identified an increase in reports of the tubing becoming detached at the connect/disconnect location.
If tubing detachment occurs, insulin delivery is interrupted and the pump will not alarm to notify patients. The interruption
of insulin delivery can cause hyperglycemia, which if left untreated, can result in diabetic ketoacidosis (DKA). DKA is a
A total more than 92 complaints from the regulatory bodies have been reported for the infusion set devices and
this data set represents 19 injuries, 19 deaths, 10 malfunctions and 4 other reasons during the search period.
Complaints reported included comfortTM and comfort TM short. Based on the investigation and test results the
failure reported in the regulatory bodies cannot be confirmed as failures caused the infusion sets.
9. References
Page 43 of 46
Internal
1. MEDDEV guideline 2.7.1, rev 4, 2016. Guidelines on medical devices. Clinical Evaluation: a guide for
manufacturers and notified bodies.
2. Global Harmonization Task Force. www.imdrf.org
Page 44 of 46
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15. Appendix III:
CV for responsible person writing the report

A brief summary is provided that describes the expertise and suitability of the author of this report.
Anna Tomanek Christensen,

Registered Nurse (RN), Master of education Ma (Ed), Graduate Diploma in Business Administration (HD).
Anna Tomanek Christensen (ATC) has a bachelor’s degree in Nursing (2000) and a Master’s in Education from
Aarhus University in Denmark (2009). Besides, she has supplied her education with a diploma in Business
Administration In 2015.
She has years of practice as a nurse from different departments at the Danish University Hospital –
Rigshospitalet. She has sufficient knowledge of metabolic diseases such as Diabetes Mellitus and infusion
therapy. She has worked with physicians for metabolic diseases procedures requiring infusion therapy and use
of infusion set in Pediatric (RH 4053 and 5062 departments), Gastroenterology (RH 3123 and 3124
departments), Diabetes (Department of Dermatology and Wound Healing Centre at Bispebjerg) and with
Interdisciplinary Team for Palliative Care at Home Care Setting. Consecutively, she has clinical experience with
diagnosis and management of conditions required infusion by infusion sets as well as treatment standards in
the aforementioned clinical areas.
Through her Master-level education and research projects for Coloplast and the European Wound Management
Association (EWMA), Hollister and Jacobsen Pharma and MedTech Advice, she obtained knowledge with
research methodology such as clinical investigation design, scientific projects with use of medical devices as
well as a librarianship qualification (e.g. experience with relevant databases as Pubmed, Medline and Embase)
and many years of medical writing. Since, she has extended her knowledge with relevant courses within the
medical and regulatory fields, e.g. a librarianship qualification course from Aarhus University on EndNote
reference management and several clinical evaluation courses conducted by the Medico Industry.
Anna Tomanek Christensen established the medical writing consultancy AML Christensen in 2014 to help
medical device companies comply with European Regulation, and the company consisting of 5 employees
supports clients by offering medical writing services. Within the company, she cooperates with various sub-
contractors in Clinical Operations (ClinOps), Regulatory Affairs (RegAff), Scientific Affairs (SciAff) and Quality
Assurance (QA). Since a new guidelines MEDDEV 2.7/1 ver. 4 was released to the European marked in 2016
Anna Tomanek Christen has performed more than 40 CERs (class IIa, IIb and III) of which many are already
approved by the NBs. All documents produced by the AML Christensen company undergo an internal quality
review to ensure sufficient compliance within all relevant bodies.
Through her Master-level education, training and many years of professional experience with relevant clinical
areas, Anna is suitably qualified to prepare clinical evaluations for medical device companies, including
Unomedical A/S.
Page 45 of 46
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16. Appendix IV:
CV`s for Evaluators
Page 46 of 46
Internal

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Clinical Evaluation Plan/Report

Responsible Document Type: Clinical Evaluation Document Status:

DHF No.: Project Name: Document No.:

Created by / ATC Approved by / Version:

Valid date: Change No.: Edited by:

Clinical Evaluation Report

For subcutaneous infusion with 20°-45° degree

10. Conclusions ........................................................................................................ 26

This CER will assess and critically analyze following:

2. General details and device history

Figure 1. The same set of comfortTM family infusion sets

Figure 2. comfortTM short, Silhouette®/ Accu-chek TenderLink

Figure 6: MiniMed Sil-serter

3.1.2. Mode of action

3.1.3. Duration of use and body contact

3.4. Preclinical tests

Table 5. Mechanical test for Silhouette®

Body contact Contact

Component and contact type:

3.4.4. Usability/Human factor testing

2. (“infusion set” AND “comfort”) AND safety

VariSoft NA NA NA NA NA NA 279,560 79,880 359,440

Comfort 4,539,390 533 0.0014083 242 0.0006703

Comfort short 4,063,970 447 0.0010013 260 0.0005918

Silhouette 4,497,310 161 0.0003729 87 0.0001911

Silhouette 64,437,752 6088 0.000857 3427 0.0004981

Accu-Chek 14,580,478 100 0.0001111 74 0.0000822

Figure 8. Example of Tubing Detachment

due to insulin precipitation [46].

Ref Purpose Study Design Study Objective Summary of Key Results

Ref Purpose Study Design Study Objective Summary of Key Results

 Previously unrecognized hazard or hazardous situation.

Association Diabetes Technology Working Group. Diabetologia. 2015 May;58(5):862-70.

Useful manufacture websites

Equivalence matrix from R&D

14. Appendix II:

Literature Search Report

1. Background and scope

Table 2. Keywords used to limit literature searches.

MHRA Brand name:

Bfarm Brand name:

Table 3. Results from literature search

Pubmed 1. Diabetes AND infusion set 23 NR, MM, P 15

3. Infusion set AND insulin AND 5 D, NR 2

4. “Infusion set” OR “comfort” AND 7 - 2

5. "comfort” AND "infusion set" 1 - 1

Appropriate Were the data generated from a patient P1 Applicable

Pfutzner A. et al, 2015 - S 2 1 1 2 1 1 1 1 1 Level 2

Hanas R. et al, 1990 State of the art 3 1 1 2 1 1 2 1 1 Level 3

Schade David S. 2002 State of the art 2 1 1 2 2 1 2 2 2 Level 3

Agrawal P. et al, 2011 State of the art 3 1 1 2 2 1 2 2 1 Level 3

Gibney M. et al, 2016 State of the art 2 1 1 2 2 1 2 2 1 Level 3

Heinemann L. et al, 2015 State of the art 3 1 1 2 1 2 1 1 1 Level 3

Heinemann L. et al, 2015 State of the art 2 1 1 2 1 1 1 1 2 Level 3

McVey E. et al, 2015 State of the art 3 1 1 2 1 1 1 1 2 Level 3

Pfutzner A. et al, 2011 State of the art 3 1 1 2 2 1 1 1 1 Level 3

Zahid N. et al,2008 State of the art 3 1 1 2 2 1 2 2 1 Level 3

Scheiner G. et al, 2009 State of the art 3 1 1 2 2 1 1 2 2 Level 3

Dumville JC. et al, 2014 State of the art 3 1 1 2 1 1 1 1 1 Level 3

Daecke C. et al, 1993 State of the art 2 1 1 2 1 2 1 1 1 Level 3

Geukens S. et al, 2001 State of the art 3 1 1 2 1 1 2 2 1 Level 3

Stephen-Haynes J. et al, 2014 State of the art 3 1 1 2 1 1 2 2 1 Level 3

Chatterjee S. et al, 2015 State of the art 2 1 1 2 1 2 2 1 1 Level 3