aknof - clinical study, botanical / acne

A B

C

D

Rif volontario: 01

A-B-C-DCute papulo comedonica pustolosa infiammata

presenta una quantità notevole di sebo

Tempo t0

A B

C D

A B

C

D

A-B-C-D A t=60 giorni non si evidenziano stati infiammatori .

Rif volontario: 01 Tempo t60

A B

c D

Rif volontario: 02

A-B-C-DCute papulo comedonica infiammata.

Tempo t0

A B

C DA

B

C

D

A-B-C-D Dopo l’uso del Prodotto si evidenzia un significativo

miglioramento della cute.


A B

c DA

B

C

D

Rif volontario: 02

A-B-C-DCute papulo comedonica infiammata.

Tempo t0

A B

C DA

B

C

D

A-B-C-D Dopo l’uso del Prodotto si evidenzia un significativo



A B

c DA

B

C

D

Rif volontario: 03

A-B-C-DCute comedonica infiammata con presenza di

elevata seborrea.

Tempo t0

A B

C D

A

B DC

A-B-C-D Dopo l’uso del Prodotto la cute presenta un minor numero

di comedoni


A B

c D

A

B DC

A

B

C

D

Rif volontario: 04

A-B-C-D Cute con presenza di papule-pustole infiammate.

Tempo t0

A B

C D

A

B

C

D

Rif volontario: 04

A-B-C-DNon si rilevano nuove papule-pustole.

Tempo t60

A

C D

B

AB

C

D

Rif volontario: 05

A-B-C-D Cute con acne papulocomedonica.

Tempo t0

A B

C D

AB

C

D

Rif volontario: 05

A-B-C-DDopo il trattamento

si nota un netto miglioramento .

Tempo t60

A B

C D

A

B

C

Rif volontario: 06

A-B-CCute con acne papulosa.

Tempo t0

A B

C

A

B

C

Rif volontario: 06

A-B-CDopo l’uso del Prodotto si evidenzia un significativo


Tempo t60

A B

C

A

B

C

Rif volontario: 07

A-B-CCute papulo comedonica pustolosa infiammata

presenta una quantità notevole di sebo

Tempo t0

A B

C

A

B

C

Rif volontario: 07

A-B-CA t=60 giorni si evidenzia ancora un lieve stato

infiammatorio .

Tempo t60

A

C

B

A

B

C

D

Rif volontario: 08

A-B-C-DPapule evidenti.

Tempo t0

A B

C D

A

B

C

D

Rif volontario: 08

A-B-C-DSi nota un significativo miglioramento dopo il

trattamento.

Tempo t60

A B

C D

Ricerca - Sviluppo - Valutazione

Documentazione Dermo-cosmetologica

Via Antonio Panizzi, 10

20146 Milano (Italy)

Tel.(039 2) 4155729 tel/fax (039 2) 4150184

Valutazione dell'efficacia di un prodotto cosmetico

coadiuvante il trattamento dell'acne

mediante test clinico

Clinical evaluation of the efficacy of a cosmetic product

in the treatment of acne

Protocollo n°/ Record no. 0302A08F

AKNOF

Luogo e data di emissione: MILANO – 14 Aprile 2003

Place and date of issue: MILAN – 14th

April 2003

UNIVERSITA’ DEGLI STUDI DI PAVIA

DIPARTIMENTO DI SCIENZE

FISIOLOGICHE-FARMACOLOGICHE

CELLULARI - MOLECOLARI.

Dott. Fulvio MARZATICO

SEZIONE DI FARMACOLOGIA E

BIOTECNOLOGIE FARMACOLOGICHE

Piazza Botta 11 - 27100 PAVIA (Italy)

Tel. (39) 0382 - 506390 - Fax: 506385

e-mail: [email protected]

Protocollo n°/ Record no. 0302A08F AKNOF

Pag. 2 di 18 / page 2 out of 18

PARTE SPERIMENTALE Experimental part

Protocollo n° / Record no. 0302A08F

Titolo / Title

Clinical evaluation of the efficacy of a cosmetic product in the treatment of acne.

Scopo / Aim

The objective of this clinical test is to evaluate if the tested cosmetic product is effective in the treatment of acne.

Controllo Qualità / Quality Control

Dr. Claudio ANGELINETTA, laurea in Chimica presso l’Università degli Studi di Milano - specializzato in Scienza e

Tecnologia Cosmetiche presso l’Università degli Studi di Milano -

Direttore tecnico BIO BASIC EUROPE S.r.l.

Via Antonio Panizzi, 10 - 20146 Milano

Tel 02 4155729

Fax 02 4150184

Monitor

Prof. Dott. Fulvio MARZATICO

UNIVERSITA' di PAVIA

Dip. Scienze Fisiologiche - Farmacologiche - Cellulari - Molecolari

Sezione di Farmacologia e Biotecnologie Farmaceutiche.

Piazza Botta, 11 - 27100 PAVIA

Tel. (0382) 506.390

Fax (0382) 506.390

Sperimentatore / Experimenter

Dott. Carlo CARRERA

Medico Chirurgo- Specialista in Dermatologia e Venereologia

consulente C.D.C. - Via A. Panizzi, 10 - 20146 MILANO

Tel 02/4155729

Fax 02/4150184



Soggetti del test / Test subjects

30 subjects with acne, both males and females, with an age between 18 and 28 years of age, have been selected for the

test, following the undermentioned inclusion criteria:

- good state of general health

- no dermatopathies

- no pharmacological treatment in progress

- promise not to change the usual daily routine

- no atopy in the anamnesis

Preparazione dei campioni / Preparation of the samples

Samples of the products have been applied following their usual use: as they are.

Metodo di applicazione dei campioni / Method of application of the samples

Samples of the product have been applied on clean face, following the instructions reported in the form given to the

volunteer. Application was uniform.

Valutazione e calcolo dei risultati / Evaluation and reckoning of the results

The sebum, moisturizing* and TEWL** differences are evaluated by analysing the values taken on the face before and

after the product’s application by using the Sebometer (SKINLAB), the Corneometer * (SKINLAB) and the

Tewameter.

The measurements are taken:

• at [t0] (basal value)

• after the product use:after15 days [t15], 30 [t30] and 60 [t60].

The sebometric, moisturizing and TEWL measurements are taken by the experimenter in the medical institute and then,

are analysed and reported in a graph.

*Skin moisturising has been evaluated by instrumental measurements with a Corneometer.

Corneometry is an indirect model of skin hydration measurements, since it is based on the electric conduction of the

skin in presence of water. Biological tissues and skin conductance vary according to their water content.

**The Tewameter indicates the transepidermal water loss (TEWL), in terms of quantity of evaporated water for the

considered skin unit. The method measures the gradient of steam tension between two electrodes located at different

distances from the skin surface. The method allows evaluating integrity of the corneal layer, functionality of the skin

barrier. The shift of TEWL values from high levels to normal levels, in subjects with altered skin barrier functionality

indicates an increase of hydration, while an increase of TEWL values from normal values to high levels indicates a

damage of the barrier functionality of the skin.

A series of skin pictures are taken by a polarized light telecamera with 20x magnifications.



Finally, to carry out a statistical survey and to be able to evaluate the skin variations in a specific period of time, the

following skin parameters have been analyzed:

Variazione dello stato infiammatorio

delle papule/pustole

Variation of the inflammation of

papules/pustules

Nessuna variazione rispetto all'inizio della

sperimentazione

No variation (in comparison with the

beginning of the experimentation)

Nessuna

Absent

Leggera variazione rispetto all'inizio della

sperimentazione

Slight variation (in comparison with the


Leggera

Slight

Discreta variazione rispetto all'inizio della

sperimentazione

Fairly good variation (in comparison with

the beginning of the experimentation)

Discreta

Fairly good

Variazione significativa rispetto all'inizio

della sperimentazione

Good variation(in comparison with the


Buona

Good



TABELLA RIASSUNTIVA DEI SINGOLI DATI

Summarizing Table of the Values found out

Rif.

Volontario

Ref.

Volunteer

t0 t15 t30 t60

0 15 30 60

01SM 38,2 39 36,1 38,9

02DML 44,3 52,4 39,5 40,5

03AAM 30,5 33,1 34 36,2

04MA 38,7 39 39,9 40,3

05PG 35,3 39,1 37,9 39,9

06GM 34,5 35,4 36,3 40

07FR 32,9 35 35,5 38,1

08VMT 34,9 39,1 38 45

09SS 32,5 33,6 34 38,3

10PE 40,2 40,8 41 45

11SG 36,7 38 39,1 40,3

12AE 35,9 36,1 38 38,2

13GV 37 38,9 39,7 40

14BS 34,5 35,2 35,6 36,2

15LL 38,6 39 39,5 40,6

16LLAI 39,1 42,8 42,8 43,4

17AA 35,1 35,3 35,6 36,6

18RR 34,2 35,9 36 37

19RD 30,2 32,2 33 35,7

20GG 36 36,6 37 38

21ZI 35,4 36,7 36,7 38

22RG 36,6 37,1 38,1 38

23PN 33 34 34,1 34,6

24BE 37,8 38 37,5 39,5

25DFP 32,1 33,4 34,6 35,5

26CG 29 39,9 40 40

27CA 32,4 33,6 34,7 35,6

28GF 36,6 37 38,8 39

29RCP 35,5 36 37 37,2

30UM 34 36,6 36,6 38Media

Average 35,39 37,29 37,22 38,79

Dev. STD 3,1954008 3,7918182 2,3451197 2,5659217

Test t

Student

2,0670362 2,4863348 4,4634212

NO NO SI/yes

Idratazione cutanea

Values taken with the corneometer after the

prolonged use of the product

sign 99%

(val. est.

+- 2,7)

34,00

36,00

38,00

40,00

Idratazione cutanea

Values taken w ith the corneometer

Media/Average 35,39 37,29 37,22 38,79

t0 t15 t30 t60



Rif.

Volontario

Ref.

Volunteer

t0 t15 t30 t60

0 7 15

01SM 19,0 18,2 18,0 7,3

02DML 11,0 9,3 9,6 7,1

03AAM 24,3 24,2 22,2 18,9

04MA 27,0 19,5 15,8 13,6

05PG 14,1 10,0 9,9 6,9

06GM 18,0 16,3 16,5 15,9

07FR 20,3 17,6 16,6 10,0

08VMT 21,0 19,0 16,2 14,4

09SS 11,6 11,0 10,0 6,0

10PE 18,0 17,6 15,8 12,1

11SG 16,9 16,0 12,4 9,6

12AE 17,9 13,1 12,1 9,0

13GV 11,6 11,2 8,6 8,0

14BS 15,8 13,3 12,3 8,0

15LL 19,0 14,5 14,0 10,0

16LLAI 17,2 15,6 15,3 10,3

17AA 17,8 16,6 16,1 14,0

18RR 19,0 18,9 17,4 14,4

19RD 20,2 18,3 14,0 13,0

20GG 11,3 9,4 9,0 6,1

21ZI 9,0 8,7 8,0 7,0

22RG 16,0 15,8 14,0 13,3

23PN 19,0 18,0 18,5 17,0

24BE 16,5 15,4 15,0 14,3

25DFP 12,2 11,9 9,8 9,0

26CG 14,7 12,3 11,9 10,4

27CA 8,5 7,7 6,6 5,9

28GF 11,0 10,2 9,9 8,0

29RCP 20,0 18,4 17,0 16,6

30UM 19,0 18,0 18,0 16,6

Media

Average 16,6 14,9 13,7 11,1

Dev. STD 4,3774094 4,0049395 3,7759752 3,8133477

-1,539985 -2,682812 -5,077085

NO NO SI/yes

Variazione TEWL

TEWL variation

Test t

student

sign 99%

(val. est.

+-2,7)

8

10

12

14

16

18

Variazione TEWL

TEWL variation

Media/Average 16,6 14,9 13,7 11,1

t0 t15 t30 t60



Rif. Vol

Vol.Ref. t0 t15 t30 t600 30

01SM 26 24 22 16

02DML 22 18 18 15

03AAM 28 27 26 26

04MA 22 20 16 13

05PG 12 12 11 6

06GM 27 25 24 23

07FR 16 14 12 10

08VMT 24 20 22 11

09SS 20 18 17 14

10PE 9 9 8 6

11SG 28 28 26 24

12AE 16 7 6 4

13GV 15 13 12 9

14BS 16 15 14 12

15LL 13 11 11 9

16LLAI 28 27 24 20

17AA 14 12 11 8

18RR 10 9 6 8

19RD 28 27 28 24

20GG 16 14 14 11

21ZI 14 12 11 11

22RG 15 13 12 9

23PN 28 27 25 24

24BE 10 9 8 7

25DFP 16 15 10 10

26CG 29 28 26 25

27CA 25 23 22 21

28GF 26 25 24 23

29RCP 12 11 10 7

30UM 10 9 7 5

Media

Average 19,17 17,40 16,10 13,70

Dev. STD 6,823304 7,025078 7,111671 7,027777

-0,97146 -1,67564 -3,00542

no no SI/yes

sign 99%

(val. est.

±2,7)

Test t

Student

Presenza di sebo

Presence of sebum

Pelle secca /Dry skin 1-10

Pelle normale/ Normal skin 11-25Pelle grassa/ Oily skin 26-100

Valori sebometrici /Sebum values

8

10

12

14

16

18

20

Presenza di sebo

Presence of sebum

Media/Average 19,17 17,40 16,10 13,70

t0 t15 t30 t60



Rif.

Volontariot0 t15 t30 t60

01SM // Nessuna/Absent Nessuna/Absent Nessuna/Absent

02DML // Nessuna/Absent Nessuna/Absent Leggera/Slight

03AAM // Nessuna/Absent Leggera/Slight Leggera/Slight

04MA // Leggera/Slight Leggera/Slight Leggera/Slight

05PG // Leggera/Slight Discreta/Fairly good Discreta/Fairly good

06GM // Nessuna/Absent Leggera/Slight Leggera/Slight

07FR // Nessuna/Absent Nessuna/Absent Leggera/Slight

08VMT // Leggera/Slight Discreta/Fairly good Discreta/Fairly good

09SS // Leggera/Slight Leggera/Slight Leggera/Slight

10PE // Nessuna/Absent Nessuna/Absent Nessuna/Absent

11SG // Leggera/Slight Leggera/Slight Leggera/Slight

12AE // Leggera/Slight Leggera/Slight Discreta/Fairly good

13GV // Leggera/Slight Leggera/Slight Leggera/Slight

14BS // Nessuna/Absent Leggera/Slight Leggera/Slight

15LL // Nessuna/Absent Nessuna/Absent Nessuna/Absent

16LLAI // Nessuna/Absent Nessuna/Absent Leggera/Slight

17AA // Leggera/Slight Leggera/Slight Discreta/Fairly good

18RR // Nessuna/Absent Leggera/Slight Leggera/Slight

19RD // Nessuna/Absent Leggera/Slight Leggera/Slight

20GG // Leggera/Slight Nessuna/Absent Nessuna/Absent

21ZI // Leggera/Slight Leggera/Slight Discreta/Fairly good

22RG // Leggera/Slight Leggera/Slight Leggera/Slight

23PN // Nessuna/Absent Leggera/Slight Leggera/Slight

24BE // Leggera/Slight Leggera/Slight Leggera/Slight

25DFP // Nessuna/Absent Nessuna/Absent Nessuna/Absent

26CG // Nessuna/Absent Leggera/Slight Leggera/Slight

27CA // Nessuna/Absent Leggera/Slight Leggera/Slight

28GF // Leggera/Slight Nessuna/Absent Nessuna/Absent

29RCP // Nessuna/Absent Nessuna/Absent Nessuna/Absent

30UM // Leggera/Slight Leggera/Slight Leggera/Slight

ANALISI STATISTICA

Per la valutazione statistica di dati non parametrici (scores) non indipendenti si è utilizzato il

Test di Friedman (Cosmetic news, 130, January/February (30-32)). Ad ogni giudizio dello

sperimentatore (Variazione: Nessuna, Leggera, Discreta, Buona) viene assegnato un

punteggio da 1 a 4.(t0=1). Per ogni intervallo di tempo si sommano i punteggi attribuiti ad ogni

singolo volontario e si calcolano le relative medie. A questo punto si valutano le differenze tra

le diverse medie. Le variazioni tra le medie risultano essere significative se superano il valore

soglia definito (Intervallo di confidenza 95%).

Variazione dello stato infiammatorio delle papule/pustole

Variation of the inflammation of papulae/pustules

0

STATISTICAL ANALISYS

The Friedman Test allows the statical analisys of non parametric data. (Cosmetic news, 130,

January/February (30-32). A score between 1-4 is given to the experimenter evaluations

(Variation: Absent, Slight,Fairly good, Good).(t0=1). For each period average values are

calculated. The test is significant if the average differences are bigger than the threshold value

(Interval Confidence 95%)



0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

|t15-t0| |t30-t0| [t60-t0]

Serie1 Serie2

Test di

Friedman |t15-t0| |t30-t0| [t60-t0]

sign. 95%

per val > 0,47 0,73 0,93

0,879333 NO NO SI/yes

1

2

3

Variazione dello stato infiammatorio

delle papule/pustole

Variation of the inflammation of

papulae/pustules

Media / Average 1 1,47 1,73 1,93

t0 t15 t30 t60

Criteri di valutazione:

Evaluation criteria:

Nessuna (absent) = 1; Leggera (slight) = 2;

Discreta (fairly good) = 3; Buona (good) = 4.



CONCLUSIONI

Conclusions

Come si può osservare il prodotto denominato

As one can notice the product called

AKNOF

é in grado di modificare in maniera significativa, nel periodo di

trattamento, i parametri clinici valutati nei volontari sottoposti a test.

can significantly change in the period of treatment

the clinical parameters evaluated on the volunteers who underwent the clinical test.

In base ai risultati:

According to the results:

IL PRODOTTO COADIUVA LA RIDUZIONE DEGLI INESTETISMI CUTANEI DERIVANTI DALL’ACNE

This product is effective in reducing cutaneous imperfections due to acne

Sperimentatore / Experimenter Monitor

Dott. Carlo CARRERA Prof. Fulvio MARZATICO

Controllo Qualità / Quality Control

Dr. Claudio Angelinetta



Allegato A: arruolamento / Enclosure A : recruitment

Data (gg.mm.aa) / Date (d/m/y) :

Volontario n° / Volunteer no.:

MODULO DI CONSENSO INFORMATO / Consent Form

Iniziali del volontario / Volunteer’s initials

Titolo / Title

Valutazione dell'efficacia di un prodotto cosmetico coadiuvante il trattamento dell'acne mediante test clinico.



I campioni sono stati testati applicandoli in modo uniforme sul viso, secondo le indicazioni riportate nella scheda

descrittiva consegnata al volontario.

Samples of the products have been applied on the face, following the instructions reported in the form given to the



Confermo che il volontario ha letto la scheda informativa allegata a questo protocollo. Al volontario è stata data

l'opportunità di porre domande ed a queste domande è stata data risposta esauriente, è stato spiegato lo scopo, le

modalità e le caratteristiche dello studio clinico, gli effetti favorevoli ed i possibili effetti collaterali. Il volontario ha

accettato spontaneamente di partecipare allo studio. I confirm that the volunteer has read the enclosed informative form. The volunteer has had the opportunity to ask

questions to which was given an exhaustive answer. The volunteer was explained the aim, the method and the features

of the clinical survey, benefits and possible discomforts. The volunteer has agreed to take part in the test.

Data / Date :

Nome del medico / Physician’s name

(in stampatello) / (in block letters)

Firma del medico / Physician’s signature

_________________________________________

_________________________________________



Allegato B: arruolamento / Enclosure B : recruitment


Volontario n° / Volunteer no. :

VERIFICA DEI CRITERI DI INCLUSIONE ED ESCLUSIONE

Check of the inclusion and exclusion criteria


L'età è di almeno 18 anni e non ancora 70 anni Age: between 18 and 70 years

SI

YES

NO

Buono stato di salute generale Good state of general health

SI

YES

NO

Assenza di patologie cutanee Absence of dermatopathies

SI

YES

NO

Assenza di trattamenti farmacologici in atto Absence of pharmacological treatment in progress

SI

YES

NO

Impegno a non variare dalla normale routine la loro quotidiana attività Promise not to change the usual daily routine

SI

YES

NO

Anamnesi negativa per atopia No atopy in the anamnesis

SI

YES

NO

E' stato ottenuto il consenso informato secondo le procedure indicate in protocollo In compliance with the procedures mentioned in the survey the volunteer, after having been

informed, has given his or her consent

SI

YES

NO

ATTENZIONE: Un solo segno nella colonna di destra è motivo sufficiente per NON arruolare il volontario nello studio

ATTENTION: Just one mark only indicating “no” is enough to exclude the volunteer from the survey



Allegato C: arruolamento / Enclosure C : recruitment


Volontario n° / Volunteer no. :

SCHEDA INFORMATIVA / Informative form


Titolo / Title

Valutazione dell'efficacia di un prodotto cosmetico coadiuvante il trattamento dell'acne mediante test clinico.



I campioni sono stati testati applicandoli in modo uniforme sul viso, secondo le indicazioni riportate nella scheda

descrittiva consegnata al volontario.

Samples of the products have been applied on the face, following the instructions reported in the form given to the



Premessa / Introduction:

Tutti i prodotti cosmetici sottoposti a test sono formulati utilizzando nessuna sostanza di cui è proibito l'uso in prodotti

cosmetici e di igiene corporale (legislazione CEE), che gli agenti conservanti introdotti nella formula del prodotto,

figurano nella lista positiva pubblicata dalla CEE e sono utilizzati ad una concentrazione conforme all'uso previsto da

questa legge ed inoltre tutte le sostanze di cui c'è un limite di concentrazione, vengono segnalati i limiti e le avvertenze

riportati nei vari allegati nella Normativa CEE 76/768. All tested cosmetic products do not contain any substance which is forbidden by the EEC legislation as far as the use of

cosmetic and personal hygiene products is concerned, the preservatives in the product formula are in the list of

accepted components published by the EEC and are used in a concentration provided for by the law and moreover

limits and instructions, published in the Enclosures of the 76/768 EEC regulation, are mentioned for those substances

for which there is a concentration limit.

Scopo / Aim

Tale test consente di valutare se il prodotto cosmetico sottoposto a test abbia efficacia nel coadiuvare il trattamento

dell’acne.

The objective of this clinical test is to evaluate if the tested cosmetic product is effective in the treatment of acne.



SCHEDA INFORMATIVA (cont.) (cont.) (cont.) (cont.) / Informative Form (Continuation)

Confidenzialità dei dati clinici / The clinical data are strictly confidential

E' possibile che durante o al termine dello studio, funzionari della Società che ha promosso lo studio o funzionari delle

Autorità Sanitarie debbano esaminare la sua cartella clinica.

Questi risultati potranno anche essere pubblicati. In ogni caso Lei non sarà mai indicato per nome se non assolutamente

necessario e che anche in questo caso solo a persone soggette, come noi, al segreto professionale. Tutte le informazioni

che saranno raccolte in questo studio resteranno comunque del tutto confidenziali e Lei non potrà essere identificato da

queste informazioni. During or at the end of the test the promoters of the survey or some Health officers may have to examine your case file.

The results could also be published. In any case your name will never be mentioned, unless if absolutely necessary and

also in this case only to people - who like us - are subject to professional secrecy. All information gathered in the

survey will remain strictly confidential and you will not be identified from it.

Cosa succederà se lei dovesse decidere di non partecipare allo studio? / What happens, if you decide not to take

part in the test ?

La Sua decisione di prendere parte a questo studio deve essere assolutamente volontaria, non deve sentirsi in nessun

modo obbligato a partecipare. Se Lei decidesse di non partecipare allo studio non andrà incontro a nessun inconveniente

né perderà alcuno dei benefici che le sono oggi garantiti. Se Lei dovesse interrompere il trattamento in qualunque

momento durante lo studio, oltre a non andare incontro a nessun inconveniente né perdere alcuno dei benefici che le

sono oggi garantiti. Tuttavia, in caso di interruzione dello studio, è molto importante che ne informi rapidamente il suo

medico e che cerchi comunque di tornare per una visita di controllo.

Anche noi ci riserviamo comunque di poter sospendere il trattamento qualora notassimo che non sia più giustificato

come il migliore a cui Lei ha diritto. Your decision to take part in the test must be absolutely voluntary, you must not feel forced to. If you decide not to take

part, you will neither run into any inconvenience nor lose any benefit which you enjoy at present. If you decide to

interrupt the treatment, you can do it any time and you will neither run into any inconvenience nor lose any benefit you

enjoy now. However, if you decide to interrupt it, you should inform your physician promptly and you should better

come back for a check up. We ourselves reserve the right to interrupt the test if we feel it isn’t any longer good for you.

Lei ha il diritto di rivolgere tutte le domande e tutte le richieste di chiarimento che ritiene opportune, sia ora che in

qualunque momento in seguito, rivolgendosi direttamente a: You can ask questions or you can ask for an explanation any time before, during and after the treatment applying

directly to:

Dott. / Physician __________________________ Telefono / Phone _______________

che la seguirà per tutta la durata dello studio who will attend you throughout the treatment.



Enclosure E: Helsinki Declaration

DECLARATION OF HELSINKI

Ethical Principles for Medical Research Involving Human Subjects

Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by the 29th WMA General

Assembly, Tokyo, Japan, October 1975, 35th WMA General Assembly, Venice, Italy, October 1983, 41st WMA General

Assembly, Hong Kong, September 1989, 48th WMA General Assembly, Somerset West, Republic of South Africa,

October 1996, 52nd WMA General Assembly, Edinburgh, Scotland, October 2000.

A. Introduction

1. The World Medical Association has developed the Declaration of Helsinki as a statement of ethical principles

to provide guidance to physicians and other participants in medical research involving human subjects.

Medical research involving human subjects includes research on identifiable human material or identifiable

data.

2. It is the duty of the physician to promote and safeguard the health of the people. The physician's knowledge

and conscience are dedicated to the fulfilment of this duty.

3. The Declaration of Geneva of the World Medical Association binds the physician with the words, "The health

of my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A

physician shall act only in the patient's interest when providing medical care which might have the effect of

weakening the physical and mental condition of the patient."

4. Medical progress is based on research which ultimately must rest in part on experimentation involving human

subjects.

5. In medical research on human subjects, considerations related to the well-being of the human subject should

take precedence over the interests of science and society.

6. The primary purpose of medical research involving human subjects is to improve prophylactic, diagnostic and

therapeutic procedures and the understanding of the aetiology and pathogenesis of disease. Even the best

proven prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research

for their effectiveness, efficiency, accessibility and quality.

7. In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic procedures

involve risks and burdens.

8. Medical research is subject to ethical standards that promote respect for all human beings and protect their

health and rights. Some research populations are vulnerable and need special protection. The particular needs

of the economically and medically disadvantaged must be recognized. Special attention is also required for

those who cannot give or refuse consent for themselves, for those who may be subject to giving consent under

duress, for those who will not benefit personally from the research and for those for whom the research is

combined with care.



9. Research Investigators should be aware of the ethical, legal and regulatory requirements for research on

human subjects in their own countries as well as applicable international requirements. No national ethical,

legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human

subjects set forth in this Declaration.

B. Basic Principles For All Medical Research

10. It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human

subject.

11. Medical research involving human subjects must conform to generally accepted scientific principles, be based

on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate

laboratory and, where appropriate, animal experimentation.

12. Appropriate caution must be exercised in the conduct of research which may affect the environment, and the

welfare of animals used for research must be respected.

13. The design and performance of each experimental procedure involving human subjects should be clearly

formulated in an experimental protocol. This protocol should be submitted for consideration, comment,

guidance, and where appropriate, approval to a specially appointed ethical review committee, which must be

independent of the investigator, the sponsor or any other kind of undue influence. This independent committee

should be in conformity with the laws and regulations of the country in which the research experiment is

performed. The committee has the right to monitor ongoing trials. The researcher has the obligation to provide

monitoring information to the committee, especially any serious adverse events. The researcher should also

submit to the committee, for review, information regarding funding, sponsors, institutional affiliations, other

potential conflicts of interest and incentives for subjects.

14. The research protocol should always contain a statement of the ethical considerations involved and should

indicate that there is compliance with the principles enunciated in this Declaration.

15. Medical research involving human subjects should be conducted only by scientifically qualified persons and

under the supervision of a clinically competent medical person. The responsibility for the human subject must

always rest with a medically qualified person and never rest on the subject of the research, even though the

subject has given consent.

16. Every medical research project involving human subjects should be preceded by careful assessment of

predictable risks and burdens in comparison with foreseeable benefits to the subject or to others. This does not

preclude the participation of healthy volunteers in medical research. The design of all studies should be

publicly available.

17. Physicians should abstain from engaging in research projects involving human subjects unless they are

confident that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians

should cease any investigation if the risks are found to outweigh the potential benefits or if there is conclusive

proof of positive and beneficial results.

18. Medical research involving human subjects should only be conducted if the importance of the objective

outweighs the inherent risks and burdens to the subject. This is especially important when the human subjects

are healthy volunteers.



19. Medical research is only justified if there is a reasonable likelihood that the populations in which the research

is carried out stand to benefit from the results of the research.

20. The subjects must be volunteers and informed participants in the research project.

21. The right of research subjects to safeguard their integrity must always be respected. Every precaution should

be taken to respect the privacy of the subject, the confidentiality of the patient's information and to minimize

the impact of the study on the subject's physical and mental integrity and on the personality of the subject.

22. In any research on human beings, each potential subject must be adequately informed of the aims, methods,

sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated

benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the

right to abstain from participation in the study or to withdraw consent to participate at any time without

reprisal. After ensuring that the subject has understood the information, the physician should then obtain the

subject's freely-given informed consent, preferably in writing. If the consent cannot be obtained in writing, the

non-written consent must be formally documented and witnessed.

23. When obtaining informed consent for the research project the physician should be particularly cautious if the

subject is in a dependent relationship with the physician or may consent under duress. In that case the

informed consent should be obtained by a well-informed physician who is not engaged in the investigation and

who is completely independent of this relationship.

24. For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a

legally incompetent minor, the investigator must obtain informed consent from the legally authorized

representative in accordance with applicable law. These groups should not be included in research unless the

research is necessary to promote the health of the population represented and this research cannot instead be

performed on legally competent persons.

25. When a subject deemed legally incompetent, such as a minor child, is able to give assent to decisions about

participation in research, the investigator must obtain that assent in addition to the consent of the legally

authorized representative.

26. Research on individuals from whom it is not possible to obtain consent, including proxy or advance consent,

should be done only if the physical/mental condition that prevents obtaining informed consent is a necessary

characteristic of the research population. The specific reasons for involving research subjects with a condition

that renders them unable to give informed consent should be stated in the experimental protocol for

consideration and approval of the review committee. The protocol should state that consent to remain in the

research should be obtained as soon as possible from the individual or a legally authorized surrogate.

27. Both authors and publishers have ethical obligations. In publication of the results of research, the

investigators are obliged to preserve the accuracy of the results. Negative as well as positive results should be

published or otherwise publicly available. Sources of funding, institutional affiliations and any possible

conflicts of interest should be declared in the publication. Reports of experimentation not in accordance with

the principles laid down in this Declaration should not be accepted for publication.



C. Additional principles for medical research combined with medical care

28. The physician may combine medical research with medical care, only to the extent that the research is justified

by its potential prophylactic, diagnostic or therapeutic value. When medical research is combined with

medical care, additional standards apply to protect the patients who are research subjects.

29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best

current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no

treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.

30. At the conclusion of the study, every patient entered into the study should be assured of access to the best

proven prophylactic, diagnostic and therapeutic methods identified by the study.

31. The physician should fully inform the patient which aspects of the care are related to the research. The refusal

of a patient to participate in a study must never interfere with the patient-physician relationship.

32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist or

have been ineffective, the physician, with informed consent from the patient, must be free to use unproven or

new prophylactic, diagnostic and therapeutic measures, if in the physician's judgement it offers hope of saving

life, re-establishing health or alleviating suffering. Where possible, these measures should be made the object

of research, designed to evaluate their safety and efficacy. In all cases, new information should be recorded

and, where appropriate, published. The other relevant guidelines of this Declaration should be followed.

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