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CHAPTER 10 Clinical Assessment Report

10.1. Abstract
10.2. Introduction
10.3. Data analysis
10.4. Literature research of product
10.5. Clinical data and equivalent devices
10.6. Results
10.7. References (Annex 13)

10.1. ABSTRACT

Sensitization, irritation and cytotoxicity test reports of HYACYST were conducted at

Hacettepe University Faculty of Pharmacy, Department of Pharmacology
Laboratories. According to test results, HYACYST (Syringe/bottle form) does not
cause any intracutaneous (intradermal) irritation (test reports are included in the
relevant sections of technical file). Sterility and endotoxicity test reports have been
prepared by stem Medikal Tbbi Cihaz San. ve Tic. LTD. T. According to test
result, bacteria have not been growth excluding positive control parameter for vial and
syringe. Product was considered as noncytotoxic (test reports are included in the
relevant sections of technical file).

According to TS EN ISO 14971, all data are evaluated in conclusion of the committed
risk analysis. Actions to reduce risk of problems that may occur in conclusion provide
to stroke an acceptable level of risk. Thus, when compared to the benefits to the
patient, the associated risks are acceptable level.

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10.2. INTRODUCTION

Product: HYACYST
1. HYC-4050 50ml Vial contains 50 ml of HYACYST solution (40mg sodium
hyaluronate)

2. HYC-1250 50ml Vial contains 50 ml of HYACYST solution (120mg sodium

hyaluronate)

3. HYC-1250 S 50ml Syringe contains 50 ml of HYACYST solution (120mg sodium

hyaluronate)

Manufacturer: STEM MEDKAL TIBB CHAZ ve SAN. LTD. T

Product Profile and Intended Application

HYACYST is a medical device composed of a solution of highly purified
hyaluronic acid of non-animal origin. It is used as sterile rinsing fluid in case of
changes of the urothelium in the ureter, the urinary bladder and the initial part of
the urethra.

HYACYST does not have any pharmacological effect on the tissue after the
insertion. Its action is based on physical properties.

It is for example known that inflammations of the urothelium cause a loss of

hyaluronic acid in the mucous membrane.

A loss of hyaluronic acid in the bladder mucosa occurs in particular in case of

interstitial cystitis (IC). The urothelium can be regenerated through the substitution
of hyaluronic acid.
This results in a;
regulation of the permeability of the bladder wall

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containment of the inflammatory reaction

support of the wound healing
The constituents of HYACYST are biocompatible.

The development of HYACYST is based on the assessment of the relevant clinical

literature on CYSTITAT and Uropol for the treatment of the different forms of
cystitis.

Reference for Use

The total volume of the solution is installed by means of a syringe and instillation
catheter in the urinary bladder after complete drainage of the urinary bladder. For vial,
first with drown the solution into a syringe and connect the syringe to an appropriate
catheter using the Luer Lock connector. You can directly use pre-filled syringe content
by removing the cap from the syringe and connecting the syringe to an appropriate
catheter using the Luer Lock connector. In order to achieve optimal results, HYACYST
should remain as long as possible in the urinary bladder (min. 30 minutes. max. 2 hours)
In order to alleviate interstitial cystitis, it is recommended in the available clinical
literature to carry out the treatment once a week over four weeks.

HYACYST should be used once thereafter a month as a maintenance therapy until the
symptoms have disappeared. If no success is recognizable after 4 weeks, the possibility
of a different therapy should be considered.

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10.3. DATA ANALYSIS

Lifetimes pain and urge?

There are diseases that are very quickly identified by physicians, a corresponding
treatment approach then results in the patient's recovery.

Interstitial cystitis (IC) is a disease that has a complex character the cause(s) of which is
(are) currently largely unknown and for which different treatment methods with
partially poor success are used.

Hardly any disease requires as much patience from the patient and from the physician as
CI, since in many cases its hidden course means a riddle for many years.

A chronic, non-bacterial inflammation of the bladder wall

Interstitial cystitis is not caused by bacteria. It develops slowly and therefore is only
detected very late using complex diagnostics. Women and men of different age can be
affected by interstitial cystitis.

In the field of medicine, professionals more and more take the view that this disease
with its lengthy course may pass from the bladder to the entire urogenital area.

This disease affects the epithelium tissue (urothelium), i.e. the mucous membrane of the
bladder as well as the bladder muscle.

What are the possible symptoms of interstitial cystitis?

Frequent emptying of the bladder of small quantities of urine during the day
(pollakisuria)
In most cases, only dripping is possible since the bladder is empty. Patients have a
strong feeling of pressure accompanied by pain and straining.

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Increased secretion of urine at night (nycuria)

The frequency of urination can be the first symptom in the early stage of the disease.

Reduced bladder capacity

Functional bladder capacity decreases clearly and is lower than 250 ml.

Painful urinary urgency

Pains occur in the entire urogenital tract. The intensity of the pain becomes the actual
problem for the patients.

Therapy options
The clinical picture of interstitial cystitis is difficult to diagnose clinically, a positive
influencing of the disease through the available therapies is even more complicated.
Since the patients have a clearly reduced quality of life and psychological problems, the
therapy approaches are very different and complex.

Interstitial cystitis (IC)

Definition
Interstitial cystitis is a chronic inflammatory disease of the bladder without delectable
bacteria in the urine. It is a disease that has not been cleared up completely up to now
and from which the patients often suffer worse than from a tumor disease. The US
National Health Institute has classified interstitial cystitis also as a high-priority disease.
The quality of life can be affected extremely through strong urge to urinate, frequent
urination during the day as well as at night and increasing pain.

Occurrence
Occurrence of interstitial cystitis stated in the USA is 52-67 cases/100,000 people and in
Europe 18 cases/100,000 people in the population. The difference is explained by the
differently pronounced knowledge of the disease and its diagnostics; furthermore, the
disease seems to increase according to recent statistics. The patients in whom the

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disease occurs usually are of middle age. The disease occurs 7 times more frequently in
women than in men. The reason for that is the female anatomy, since the female urethra
is shorter than the male one. This results in a higher susceptibility for ascending urinary
tract infections. In women with repeated (recurrent) urinary tract infections, the mucosa
of the bladder is damaged to a rather large extent. This constant irritation may result in
the not bacterial, chronic interstitial cystitis.

Symptoms of the disease

The most common symptoms of interstitial cystitis, expressed in percent, are:
Increased urge to urinate (91.9%)
Frequent urination (91.2%)
Intense pain of the pelvis, the lower abdominal region and the perineum (69.9%)
Pelvic pressure (63.3%)
Painful urination associated with the discharge of very small quantities of urine
(60.5%)
Intense pain during (55.2%) and after sexual intercourse (36.7%)
Burning sensation (55.1 %)
Massive difficulty in maintaining sleep due to pains (50.8%)
Blood in the urine (21.6%).

The symptoms of interstitial cystitis can e.g. intensify in case of increased sensitivity to
pain or psychological factors.

Development of the disease

Bacteria, microcrystals, proteins or harmful, dissolved components of the urine (e.g.
urea) directly reach deeper layers of the bladder mucosa through gaps in the protective
layer of the bladder mucosa (glycosaminoglycan (GAG) layer) and there cause further
damage.

The damage to the bladder mucosa and the chronic inflammation lead to repair
processes with scarring. This may result in a decreased elasticity of the wall of the

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bladder and an increasing loss of the capacity of the urinary bladder. A contracted
bladder may develop in the later stage of interstitial cystitis and the surgical removal of
the urinary bladder may be required. Therefore, an early detection and therapy is
important for avoiding the late stage of interstitial cystitis.

Causes
The main cause of interstitial cystitis is the affection of the bladder mucosa. The mucosa
of the bladder is guarded against micro-organisms, carcinogen substances, crystals and
other harmful substances that are found in the urine through a protective layer that,
among other things, includes hyaluronic acid. This protective layer is extremely
hydrophilic and develops a "water film" and thus another physical barrier against the
harmful substances in the urine.
Patients with interstitial cystitis present defects in this protective layer of the bladder
mucosa. In particular, a loss of hyaluronic acid has been found. The protective layer of
the bladder mucosa can be regenerated through the substitution of this hyaluronic acid.

Other causes of interstitial cystitis may be e.g. autoimmune reactions that are aimed at
the body's own cells in the bladder of previous chronic bacterial infections.

Diagnosis

Symptoms
Typical symptoms are frequent urination, increased urge to urinate as well as, in some
cases, uncontrolled urination (urinary incontinence) and blood in the urine. Intense pain
develops in particular when the bladder is full, typically the pain relieve after urination.
Other signs are pelvic pain, pain of the lower abdominal region and the peritoneum,
pelvic pressure as well as painful urination associated with the fact that urine can only
be discharged drop by drop. Often intense pain also occurs during and after sexual
intercourse.

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Medical history
It is important for the diagnosis of interstitial cystitis that your physician rules out other
bladder diseases having similar symptoms. First of all the physician clarifies whether
the patient has pains from a previous surgery (in particular in the lower abdomen),
whether the inflammation of the bladder was caused by irradiation therapy or
chemotherapy and whether repeated (med. term: recurrent) infections have been present.
Then gynecological, neurological, psychiatric and rheumatologic diseases are ruled out.
Furthermore, there should be no complaints of the vertebral column and allergies should
be ruled out.

Examinations in the clinic

A urine culture and an examination of the cellular components in the urine (urinary
cytology) are carried out in the laboratory.

For ruling out sexually transmissible diseases, a vaginal smear should be performed in
women. Sensitivity to pain is determined by means of palpation of the vagina.

In men, a bacterial culture of the ejaculate is started for ruling out an inflammation of
the prostate gland caused by bacteria. For ruling out a prostate carcinoma, the value of
the prostate specific tumor marker (PSA = prostate-specific antigen) is determined.

By means of an ultrasound examination, the residual urine is determined and the

growing of the prostate into the bladder is ruled out.

Cystoscopy
Cystoscopy is performed under anesthesia. Typical signs of interstitial cystitis are
increased growing of blood vessels into the mucosa of the bladder, accumulations of
fluid in the mucous membrane, bursting of the mucous membrane (glomerulus),
punctiform hemorrhage after distension of the bladder under pressure through
Instillation of water (hydrodistention) as well as signs of bladder ulcers in approx. 10 -
20% of the patients (Hunner's ulcers).

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Determination of bladder capacity

In case of interstitial cystitis, the patients feel a strong urge to urinate already in case of
small quantities of urine; their bladder capacity is reduced. Therefore, the determination
of the maximum filling volume and then a comparative measurement of bladder
capacity (cystometry) are carried out for the diagnosis of interstitial cystitis.

Therapy of interstitial cystitis

At present, there is neither a curative agent for IC nor a treatment method that is
effective for all patients. Most of the patients, however, find relief through one or more
of the following treatment methods.

10.4. LITERATURE RESEARCH OF PRODUCT

1. LITERATURE RESEARCH METHOD
Research time: 10 days
Research by: zlem DADELEN
Date range: 19952014
Data sources;
Science-Direct
Google Academic
Criteria & Basis Data Selection: Meddev 2.7.1 (Rev.3 December 2009) [Annex B, C, D, E]
2. RESULTS OF LITERATURE RESEARCH
a) Research Results with Keywords
NUMBER OF
DATA SOURCES KEYWORDS DATE RANGE
RESULTS

Science-Direct Hyaluronic Acid 19952014 32115

Science-Direct Cystitis 19952014 25091

Science-Direct Interstitial cystitis 19952014 8439

Google Academic Hyaluronic Acid 19952014 66600

Interstitial cystitis
Google Academic 19952014 19800

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b) Literature Search Process and Search Results

1. The reliability and properties of the sources: Unconfirmed source and non-open
literature were screened and studies showing the effectiveness of our products have been
selected.

2. Relationship with the literature searched keywords: The literature and data researched
which selected the same title with our products.

The products and the data were selected that the same features and functionality scanned our
product literature in working.

3. Relationship with clinical assessment: The literature and data were selected which
compatible clinical evaluation results and the intended use of the device.

4. Relationship with device advanced features and functions: Literature and data were
selected the same features with our product.

Evaluation will take place in the literature are described below. Rejected literature will be
identified with the reason for rejection.

Table 1. Table of Compliance of the Identified Literature

REASON
N DATA DATE OF SELECT&
KEYWORDS NAME OF LITERATURE FOR
O SOURCE PUBLISH REJECT
REJECTION

Interstitial Where to Start for Clinical Trials in

1 Science-Direct cystitis 2004 IC? A Report on a Recently SELECTED ----
Concluded Trial
Hyaluronic Intravesical Instillation of Sodium
Acid Hyaluronate for the Treatment of
2 Science-Direct 2004 SELECTED ----
Intractable Non-Bacterial Cystitis a
Multi-Centre Study
Interstitial Treatment of Interstitial Cystitis
3 Science-Direct cystitis 2005 with Cystistat: A Hyaluronic Acid SELECTED ----
Product
Hyaluronic Intravesical Hyaluronic Acid in the
4 Science-Direct Acid 1997 Treatment of Refractory Interstitial SELECTED ----
Cystitis
Use of Hyaluronic Acid (Cystistat)
Google Hyaluronic for the Treatment of Late Radiation
5 2014 SELECTED ----
Academic Acid Induced Cystitis in Patients after
Prostate Irradiation

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Hyaluronic Sequential hydrodistension and

intravesical instillation of
Google Acid,
2008
hyaluronic acid under general SELECTED -----
6
Academic Interstitial anaesthesia for treatment of
refractory interstitial cystitis: a pilot
cystitis study

Evaluation of Hyaluronan from

Google Hyaluronic Different Sources: Streptococcus
7 2004 zooepidemicus, Rooster Comb, SELECTED -----
Academic Acid Bovine Vitreous, and Human
Umbilical Cord
Interstitial Cystistat for the Treatment of
8 Science-Direct 2001 Interstitial Cystitis: A 3-Year SELECTED -----
cystitis Follow-Up Study

Google Hyaluronic Method for treating the urinary

9 1999 bladder and associated structures SELECTED -----
Academic Acid using hyaluronic acid
Do Cystometric Findings Predict
Google Hyaluronic
2005
the Results of Intravesical SELECTED -----
10
Academic Acid Hyaluronic Acid in Women with
Interstitial Cystitis?

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10 literatures have been identified for clinical evaluation. Compliance Assessment Criteria are as follows in Table 2 and Table 3.

Table 2. Compliance Assessment Criteria

COMPLIANCE CRITERIA DESCRIPTION SCORING POINT RESULT
SYSTEM

Same Device 3

Equivalent 2
Equivalent Device Has resulting data been researched for related medical device? 2
Device

Other Device 1

Same usage
3
Contacting of Appropriate Have devices been encountered that the produced medical device of research with Slightly 2
Device the same purpose? different 3
Different 1

Appropriate
3
Partially 2
Does the patient group mentioned in the literature, similar with your patient group
Appropriate Patient Group
which benefits from your product? 1 3
Different
patient group

High degree
Acceptable Data / Data Does the report or data include enough information for rational and objective 3
Compilation evaluation? Partial 2 2
difference

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1
Insufficient
Data

EVALUATION OF TEST RESULTS

Completely 3
positive

Test Report Results Does test report results positive from our product? Partially 2
3
positive

Negative 1

Yes 3
Contacting of Appropriate Does the tests and results that were made for your product, mentioned in the 2
Partially 2
Device literature for the found product?
No 1

RISK EVALUATION
Yes 2
Have our product been identified all the risks for users in risk assessment, patient
and with the medium used? 2
No 1

Are identified risks reduced to acceptable levels in accordance with the Yes 2
Risk Evaluation Results 2
regulations?
No 1

Do the identified risks used to obtain objective evidence to be presented to Yes 2

minimize in the methods? 2
No 1

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Yes 3

Contacting of Appropriate
Does device mentioned available risks in the literature? Partially 2
Device 3

No 1

Table 4. Contribution of Data Related to Conformity Assessment

COMPLIANCE CRITERIA DESCRIPTION SCORING SYSTEM
POINT RESULT

Yes
Data Source Type Is work content suitable? 2
2
No 1
Does it show that performance of the Medical Devices by our produce Yes
2
Output Criteria the reported outcome measures? 2
No 1

Did studies to evaluate identify duration and complications the effect Yes
Research 2
of treatment long enough?
No 1 1

Yes 2
Statistical Success Was data provided of statistical analysis? If it does, is it appropriate?
No 1 1

Yes
Clinical Success Is a clinical success significance of a result of treatment? 2
2
No 1
EVALUATION OF TEST RESULTS
Acceptable Data / Data Positive 3 3

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Compilation Are test results positive for mentioned device in the literature? Partially positive 2
Negative 1
(Warning: If Department of
Contacting of Appropriate Completely Validates 3
Device Result (at Table D1) is Are test results carried out for mentioned device in the literature and Partially Validates 2
own product test results confirm each other? 3
positive, fill in this section)
Not validate 1

RISK EVALUATION
Acceptable Data / Data Compilation Completely Validates 3
Are risk assessment carried out for mentioned device in the literature and own
(Warning: If Department of product risk assessment confirm each other? Partially Validates
Contacting of Appropriate Device 2 3
Result (at Table D1) is positive, fill
in this section) Not validate 1

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1. Interstitial Cystitis (IC) is a chronic bladder disease, affecting more women than men (ratio 10:1)
A recent population based study in the United States found that the prevalence of diagnosed IC
was approximately 60/100000 cases. Deficiency of the glycosaminoglycan (GAG) layer is
believed to be a cause or a result of the disease, allowing urine to penetrate and irritate the bladder.
Hyaluronic acid is an important proportion of the protective glycosaminoglycan layer of the
bladder.
The intravesical administration of Cystistat acts as a temporary replacement for the defective
GAG layer, providing symptomatic relief.
Approved in more than countries (including Canada and most of the European Union) as a medical
device indicated for the temporary replacement of the GAG layer of the bladder [1].

2. To evaluate the efficacy of intravesical instillations of sodium hyaluronate in the relief of cystistic
symptoms of recurrent non-bacterial cystitis. 20 patients (aged between 22 - 68) of refractory non-
bacterial cystitis received instillations of Sodium hyaluronate (50 ml solution of 40 mg HA)
intravesically for a total of 12 weeks (weekly for 4 initial weeks and followed by two monthly
instillations). Follow-up visit ended at week 16, when patients filled the symptom assessment
scores according to subjective evaluation.
One patient had mucosa exfoliation before HA instillation. At week 4, the symptoms were not
relieved and the patient discontinued the treatment. Therefore, a total of 19 patients' data was
evaluated. Study results are classified as
1) Total response: symptoms disappear or relieve up to 90% by symptom scores;
2) Partial response: symptom relief between 50-89%,
3) Nonresponder: symptom relief under 49%. At week 16, total positive response rate (total
response + partial response) is 52.6%.
Five patients (25%) reported urethral irritation feelings during the instillation. It is considered to be
mainly caused by the procedure of introduction of the urethral catheter, which disappeared after 1-
2 days. One patient complained of severe bladder pain after instillation. The symptom disappeared
after 3-4 hours. It may be associated with a relatively high speed of instillation, which can cause a
sudden volume change of the bladder. Another 3 patients (15%) had mild dizziness after
instillation. It may be due to the change of position after the treatment (patients were asked to lie
supine for at least 30 min after instillation). During the period of treatment and follow up, there

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was no record of abnormal change in heart rate, blood pressure, blood / urine test or renal-hepatic
function. No severe adverse event was reported, except urinary irritation symptoms caused by
instillation procedure and transient dizziness due to position change.
This study showed satisfactory results of the intravesical instillation of hyaluronic acid for the
treatment of intractable non-bacterial cystitis. Main symptom scores all decreased significantly
(p<0.001), and the improvement became obvious with more instillations. However the overall and
total response rate was not very high (52.6% and 15.8%). This is due to the strict definition of
positive response and only 6 instillations were performed. Moreover, most patients recruited have a
long history and complicated treatment record. 17 patients received and failed on various
treatments before the study. It is worth noting, that the inclusion criteria was not strict and allowed
patients in the study that were suffering from not only interstitial cystitis, but also other non-
bacterial cystitis and even CPPS, which negatively affected the overall efficacy of the treatment.
Therefore, large scale randomized double blind studies with longer follow-up periods is required to
determine the efficacy of sodium hyaluronate for the management of recurrent non-bacterial
cystitis [2].

3. To determine whether intravesical hyaluronic acid is effective in reducing the urinary frequency
and pain associated with interstitial cystitis/painful bladder syndrome.
Interstitial cystitis (IC) is a chronic disease characterized by bladder pain and urinary frequency.
Because the disease can be difficult to diagnose, prevalence estimates vary widely, ranging from
10 cases per 100 000 population in Finland in 1975 to 510 cases per 100 000 in the US. Although
the etiology of the condition is unknown, a wide variety of causative factors have been suggested,
including occult infection, toxic substances in the urine and a primary defect in the
glycosaminoglycan (GAG) layer of the bladder mucosa. The mucous coat of the bladder
urothelium protects the bladder wall from injury due to ions, microorganisms and toxic molecules.
Hyaluronic acid safely reduced the pain and, to a lesser degree, the urinary frequency associated
with IC [3].

4. There was no significant toxicity attributable to the presence of HA in the bladder.

The HA employed in this study is a highly purified natural compound of high molecular weight,
pyrogen free and lacking antigenicity. The mechanism(s) of action of HA in the treatment of IC is

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not clear. The hypothesis that its fundamental role is the reconstitution of a morphologically
defective GAG layer may prove to be too simplistic. Among the most relevant of these properties
are adherence inhibitions of immune complexes to polymorph nuclear cell [4].

5. To evaluate the efficacy, feasibility as well as the safety of the hyaluronic acid (CYSTISTAT), as
an intravesical treatment for the radiation induced cystitis.
During the radiation treatment the patients were monitored every week with clinical examination.
After the completion of the treatment, the patients were evaluated by a radiation oncologist every
three months for a 24 months period of time. Data at diagnosis (baseline) of radiation cystitis and at
3-months post cystistat injection have been analyzed in this report. A cystoscopy was performed
before cystistat and three months thereafter, by two different urologists. The radiation induced
bladder toxicity was analyzed by using the RTOG/EORTC late toxicity criteria for the bladder.
Symptoms occurring in the follow-up period before and after the cystistat injection were classified
as late.
None of the patients presented any severe event during or after the cystistat instillation. Only two
patients complained for a discomfort during the catheterization. The urinary tract infection (UTI)
rate was minimal, since none of our patients had any symptoms of sepsis from the repeated
catheterizations.
Their study showed that instillation with Cystistat is a feasible and safe modality to treat patients
with radiation induced cystitis. The encouraging treatment results have confirmed the clinical value
of hyaluronic acid in those patients and can be recommended as a treatment option, while a
prospective randomized study stands in need for the confirmation of our results [5].

6. The mechanisms of action of hyaluronic acid in the treatment of IC are not clear. The theory that
its fundamental role is the reconstitution of a morphologically defective GAG layer may be too
simplistic. Hyaluronic acid exhibits a variety of biological activities that may contribute to its
action in interstitial cystitis. Among the most relevant of which are adherence inhibition of immune
complexes to polymorph nuclear cells, marked inhibition of leukocyte migration and aggregation
depending on viscosity, regulation of fibroblast and endothelial cell proliferation, enhancement of
connective tissue healing, creation of a barrier over membranes, thus regulating movement of
solutes, and scavenging of reactive oxygen species present in abundance in synovial fluid of

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patients with rheumatoid arthritis. A recent study by Lokeshwar et al showed that urinary HA
levels were related to the severity of the IC and may be useful for monitoring the disease.
We propose that general anesthetic hydro distensions with intravesical instillation hyaluronic acid
could be an alternative treatment modality for this difficult patient group. It offers an alternative,
especially if these patients have failed one or both treatments alone [6].

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10.5. CLINICAL DATA AND EQUIVALENT DEVICES

ORAL DRUGS
ELMIRON (pentosan polysulfate sodium): Elmiron was approved by FDA in 1996. It is the only
oral drug approved specifically for the treatment of IC. It is assumed that the mode of action
consists of the repair of a thin or damaged bladder wall.

ANTIDEPRESSANT AGENTS: Tricyclic antidepressants such as Elavil (amitriptyline) have

proven to be effective for relieving the pain and the frequency of urination in IC. These drugs are
used for their pain-relieving properties in IC and not as an agent for the treatment of depressions.

OTHER ORAL DRUGS: They include anti-inflammatory agents, antispasmodics, bladder

analgesic drugs such as Urimax, antihistamines and muscle relaxants.

BLADDER INSTILLATIONS

BLADDER DISTENSION: The bladder is filled with water to distension under anesthesia. This is
a part of the diagnosis procedure for IC and can also be a therapeutic measure.

DMSD (dimethyl sulphoxide): This drug is filled directly into the bladder. It is supposed to have an
anti-inflammatory effect and thus reduce the pains. DMSD can be mixed with steroids, heparin
and/or local anesthetics to a bladder cocktail.

BCG (Bacillus Calmatte-Guerin): This experimental treatment is in the stage of clinical

examination and has not been approved yet by FDA for the treatment of IC. It is assumed that

BCG strengthens the immune system.

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CYSTISTAT (hyaluronic acid):

This medical device already has a long period of application (since 1999). It is approved as
medical devices class IIa in Canada and In Europe (see listing of Medical Devices Licenses 2002-
09-16).
The active substance HA creates a protection of the bladder epithelium against Irritating substances
(bacteria, microcrystals). II has turned out and proven to be a substitute and protection of the
glycosaminoglycan (GAG) layer in the urinary bladder and the efferent urinary passages. Up to
now, 1.5 m treatments have been carried out successfully.
UROPOL
The active substance creates a protection of the bladder epithelium against irritating substances
(bacteria, microcrystals), It has turned out and proven to be a substitute and protection of the
glycosaminoglycan (GAG) layer in the urinary bladder and the efferent urinary passages.

Other bladder instillations: Clorpactin WCS-90 (oxychlorosene sodium) might be very painful
and requires general anesthesia. However, it has already been used in diluted form in practice.
Silver nitrate is used rarely and is considered to be an antiquated therapy.
Other treatment methods
Nutrition: Avoiding certain foodstuffs (acid-containing, spicy) may reduce the severity of the IC
symptoms. IC is aggravated, among other things, by smoking, coffee or tea and alcoholic drinks.

Self-help: Self-help techniques can improve the quality of life and reduce the incidence and
severity of attacks. They include, among other things, changes in the lifestyle, reduction of stress,
visualization, biofeedback, bladder training and physical exercise.

Surgery: A bladder surgery can be taken into consideration for a small number of patients who
have severe symptoms and do not respond to other treatment methods for IC. In some cases,
however, the IC symptoms even do not improve after the surgery. Several types of surgeries have
been used for the treatment of IC, including cystectomy and urinary bypass. Laser surgery should
only be used in case of the Hunner's ulcer form of IC.

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10.6. RESULTS
The presentation of the clinical picture of interstitial cystitis and the possibility of exerting a
positive influence on the treatment using a solution of hyaluronate acid to the idea to manufacture
such a medical device.
The medical device available up to now, Hyacyst, shows very good results in clinical literature.
Therefore, aimed at manufacturing the same product while clearly modifying the pricing policy.
Give the social responsibility in the area of medical devices. This was intended to lead to a trade
price that makes such an effective treatment that improves their quality of life possible for the
people affected.
Hyaluronic acid, unmodified or cross-linked, has been used in medical clinic for many years. There
are a large number of products on this bases that are approved as medical devices.
This main component hyaluronic acid does not contain any potentially immunogenic structures.
Sensitization, irritation and cytotoxicity test reports of HYACYST were conducted at Hacettepe
University Faculty of Pharmacy, Department of Pharmacology Laboratories. According to test
results, HYACYST (Syringe/bottle form) does not cause any intracutaneous (intradermal) irritation
(test reports are included in the relevant sections of technical file). Sterility and endotoxicity test
reports have been prepared by stem Medikal Tbbi Cihaz San. ve Tic. LTD. T. According to test
result, bacteria have not been growth excluding positive control parameter for vial and syringe.
Product was considered as noncytotoxic (test reports are included in the relevant sections of
technical file).
According to TS EN ISO 14971, all data are evaluated in conclusion of the committed risk
analysis. Actions to reduce risk of problems that may occur in conclusion provide to stroke an
acceptable level of risk. Thus, when compared to the benefits to the patient, the associated risks are
acceptable level.
Any significant change of the design of the product is also under control of Notified Bodies and
Competent Authorities in accordance with 93/42/EEC. Significant change has been to inform to
STEM MEDKAL TIBB CHAZ VE SAN. LTD. T. In this case the risk analysis is re-
performed.

Acc. to Vigilance Procedure, when any incidents or near incidents informed to STEM MEDKAL
TIBB CHAZ VE SAN.LTD.T. this risk analysis will be repeated.

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10.7. REFERENCES (Annex 13)

[1] Whitmore, K., Riviere, M., Where to Start for Clinical Trials in IC? A Report on a Recently
Concluded Trial, Bioniche Life Sciences, Multinational Interstitial Cystitis Association (MICA)
Congress 1 Annual Meeting, Rome ltaly, September 2l-22,2004.

[2] Gang, X., Qing, D., Fan, Z. Y., Hao, S. Y., Liang, X. C., Ran, H. Y., Wei, X., Jie, X. S., Jie, F.,
Intravesical Instillation of Sodium Hyaluronate for the Treatment of Intractable Non-Bacterial
Cystitis a Multi-Centre Study, Eastern China Urology Congress, Shanghai China, July 2-4,2004.

[3] Kallestrup, E. B., Jorgensen, S. S., Nordling, J., Hald, T., Treatment of Interstitial Cystitis with
Cystistat: A Hyaluronic Acid Product, Journal of Urology and Nephrology, 2005; 39: 143-147

[4] Morales, A., Emerson, L., Nickel, J. C., Intravesical Hyaluronic Acid in the Treatment of
Refractory Interstitial Cystitis, Urology 49 (Suppl 5A): 111-113, 1997.

[5] Vasssilis, K., Eftychia, M., Andreas, F., Ivelina, B., Charalampos, A., Dimitrios, C., Michael,
C., Argyris, S., Nikolaos, K., Use of Hyaluronic Acid (Cystistat) for the Treatment of Late
Radiation Induced Cystitis in Patients after Prostate Irradiation, Bioequivalence &
Bioavailability, Vasssilis et al., J Bioequiv Availab 2014, 6:1, Greece

[6] Ahmad, I., Krishna, N. S., Meddings, R. N., Sequential hydrodistension and intravesical
instillation of hyaluronic acid under general anaesthesia for treatment of refractory interstitial
cystitis: a pilot study, International Urogynecology Journal (2008) 19:543546, UK

[7] Shiedlin, A., Biegelow, R., William, C., Arbabi, S., Yang, L., Maier R. V., Wainwright, N.,
Childs, A., Miller, R. J., Evaluation of Hyaluronan from Different Sources: Streptococcus
zooepidemicus, Rooster Comb, Bovine Vitreous, and Human Umbilical Cord, Biomacromolecules
2004, 5, 2122-2127, Washington

[8] Nordling, J., Jorgensen, S., Kallestrup, E., Cystistat for the Treatment of Interstitial Cystitis: A
3-Year Follow-Up Study, Urology 57 (Supplement 6A), June 2001, Denmark

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[9] Morales, A., Alkemade S. J., Method for treating the urinary bladder and associated
structures using hyaluronic acid, US Patent, March 30, 1999

[10] Daha, L. K., Claus, R. R., Lazar, D., Hohlbrugger, G., Pflger, H., Do Cystometric Findings
Predict the Results of Intravesical Hyaluronic Acid in Women with Interstitial Cystitis?, European
Urology, 47 (2005) 393-397, Austria

Prepared by Approved By

Quality Assurance Responsible Management Manager

zlem DADELEN Durdane KALENDER

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