Supplementary materials
Supplementary Annex 1. Methodology
Determination of CS response variables using principal component analysis
Using patient-reported data collected during the 4 weeks prior to treatment (screening), the
analysis derived clinically meaningful response thresholds for the most relevant outcomes
related to patient functioning in those living with a neuroendocrine tumor (NET), a concept
referred to here as “carcinoid syndrome (CS) response.” The objectives of the analysis were
to compare the effect of lanreotide versus placebo on the incidence of CS response during
screening to week 12 of the double-blind phase and to explore the association between the
primary ELECT1 endpoint (use of subcutaneous [sc] octreotide rescue medication) and the
CS response measures.
Two types of patient-reported outcomes (PROs) were collected during the screening and
double-blind phases of the ELECT trial. An interactive voice response system (IVRS) was
used to collect symptoms of CS from screening through the 16 weeks of double-blind
treatment. Frequency (ie, daily events) and overall severity (0 = absent, 1 = mild, 2 =
moderate, 3 = severe) of diarrhea and flushing were obtained on a daily basis. Quality-of-life
(QoL) data were collected at baseline and at the end of week 12 using the 30-item European
Organisation for the Research and Treatment of Cancer (EORTC) Core Quality of Life
Questionnaire Version 3.0 (QLQ-C30, or “C30”) and the 21-item disease-specific QoL
questionnaire for gastrointestinal NETs (QLQ-GINET21, or “GINET21”).2 In addition, the
use of sc octreotide rescue medication (which was also collected through the IVRS) was
included as a proxy for a patient-reported variable because octreotide use may mask future
symptoms or, alternatively, may reflect the severity or frequency of existing symptoms.
Rescue medication use can thus be considered a “masked symptom.”
This multidimensional space of correlated variables was reduced to a smaller set of
independent variables, called principal components (PCs), by applying principal component
analysis (PCA) to the baseline (ie, pretreatment) values of 14 subscale scores of the C30
questionnaire and 8 subscale scores of the GINET21 questionnaire, the 4 symptom score
variables, and rescue medication use, a total of 27 variables. The C30 overall health/QoL
subscale was excluded because it is an overall summary measure. The GINET21 Sexual
Function subscale was excluded due to a high degree of missing values.
Inspection of the PC loadings indicated that PC1 primarily consisted of variables derived
from the QoL questionnaires (Supplementary Annex 1, Figure S1A), while the symptom
variables and the QoL subscales related to these symptoms (the C30 Diarrhea [DI] and
Endocrine Symptoms [ENS] subscales) exhibited weak loadings toward PC1. PC2 was
primarily loaded by the frequency and severity of diarrhea variables as well as the C30 DI
subscale (1B). Flushing frequency and severity were the strongest loading variables in PC3,
together with the GINET21 ENS subscale (1C).
C30 summary score
The MCID for the C30-SS score was derived using the standard error of measurement (SEM)
technique. The SEM technique is adequate for this response variable because it is assembled
as a linear combination of different response variables of the questionnaire for which a
reliability coefficient can be determined. The SEM is given by:
SEM=s √1−r
where s is the standard deviation of the C30-SS at baseline, which equals 13.328, and r is a
reliability coefficient, for which typically the Cronbach’s alpha is used (0.8202 in this case),
which leads to:
SEM=13.328√1−0.8202=5.6506
Diarrhea and flushing
Because BD was highly correlated (r=0.71; P<0.0001) with the DI in the C30, DI was used
as an anchor to establish the MCID for BD. Similarly, the ENS was highly correlated
(r=0.71; P<0.0001) with BF and hence used as anchor.
For both BD and BF, the MCID was established by maximizing the proportion of true
positives and true negatives vis-à-vis the respective anchor variables DI and ENS, which
resulted in MCIDs of 0.62 and 0.31 for BD and BF, respectively.
References
1. Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA. Evaluation of
lanreotide depot/autogel efficacy and safety as a carcinoid syndrome treatment
(ELECT): a randomized, double-blind, placebo-controlled trial. Endocr Pract
2016;22(9):1068-1080.
2. Giesinger JM, Kieffer JM, Fayers PM, et al. Replication and validation of higher
order models demonstrated that a summary score for the EORTC QLQ-C30 is robust.
J Clin Epidemiol 2016;69:79-88.
3. U.S. Department of Health and Human Services Food and Drug Administration.
Guidance for Industry. Patient-Reported Outcome Measures: Use in Medical Product
Development to Support Labeling Claims. December 2009.
http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf.
Supplementary Annex 1, Table S1. Correlations between the 3 main PCs and the baseline
symptom domains
Domain PC1 P-value PC2 P-value PC3 P-value
PC1 1.000 0.000 . . . .
PC2 0.000 1.000 1.000 0.000 . .
PC3 0.000 1.000 -0.000 1.000 1.000 0.000
QL -0.639 0.000 0.056 1.000 0.067 1.000
PF -0.658 0.000 0.066 1.000 0.102 1.000
RF -0.681 0.000 0.053 1.000 0.156 1.000
EF -0.700 0.000 0.142 1.000 -0.068 1.000
CF -0.595 0.000 0.250 1.000 -0.047 1.000
SF -0.641 0.000 0.212 1.000 0.068 1.000
FA 0.764 0.000 0.019 1.000 -0.133 1.000
NV 0.513 0.000 0.039 1.000 -0.260 1.000
PA 0.484 0.000 -0.176 1.000 -0.180 1.000
DY 0.480 0.000 -0.111 1.000 0.135 1.000
SL 0.621 0.000 0.054 1.000 0.069 1.000
AP 0.585 0.000 -0.009 1.000 -0.272 1.000
CO 0.078 1.000 -0.425 0.002 -0.041 1.000
DI 0.304 0.753 0.725 0.000 -0.322 0.352
FI 0.508 0.000 -0.160 1.000 0.101 1.000
ENS 0.514 0.000 0.230 1.000 0.656 0.000
GIS 0.642 0.000 0.025 1.000 -0.062 1.000
TRS 0.098 1.000 -0.229 1.000 0.258 1.000
SOF -0.671 0.000 0.180 1.000 0.016 1.000
DRW 0.520 0.000 -0.294 1.000 0.149 1.000
MBP 0.426 0.002 -0.074 1.000 -0.072 1.000
BIM 0.279 1.000 -0.045 1.000 -0.419 0.003
ICF -0.134 1.000 0.008 1.000 0.177 1.000
SEF -0.520 0.003 0.158 1.000 0.220 1.000
QLQ -0.943 0.000 0.047 1.000 0.164 1.000
FreqD 0.254 1.000 0.806 0.000 -0.181 1.000
SevD 0.208 1.000 0.838 0.000 -0.256 1.000
BDa 0.253 1.000 0.854 0.000 -0.211 1.000
FreqF 0.365 0.053 0.358 0.074 0.710 0.000
SevF 0.357 0.076 0.375 0.032 0.619 0.000
BFa 0.381 0.024 0.379 0.027 0.725 0.000
FreqO 0.114 1.000 -0.044 1.000 -0.311 0.566
aDiarrhea and flushing burden were obtained by averaging the average baseline frequency
and severity for each subject.
Abbreviations: AP, C30 appetite loss; BD, burden of diarrhea; BF, burden of flushing; BIM,
GINET21 body image C30, EORTC (European Organization for the Research and Treatment
of Cancer) core quality-of-life questionnaire QLQ-C30; CF, C30 cognitive functioning; EF,
C30 emotional functioning; CO, C30 constipation; DI, C30 diarrhea; DRW, GINET21
disease related worries; DY, C30 dyspnea; ENS, GINET21 endocrine symptoms; FA, C30
fatigue; FI, C30 financial difficulties; FreqD, diarrhea frequency; FreqF, flushing frequency;
FreqO, frequency of octreotide use; GINET21, EORTC quality-of-life questionnaire for
gastrointestinal neuroendocrine tumors (QLQ-GINET21); GIS, GINET21 GI symptoms;
MBP, GINET21 muscle/bone pain symptoms; ICF, GINET21 information/communication
function; NV, C30 nausea vomiting; PA, C30 pain, PC, principal component; PF, C30
physical functioning; QL, C30 global health/QoL; QLQ, C30 summary score; RF, C30 role
functioning; SEF, GINET21 sexual function; SevD, diarrhea severity; SevF, flushing
severity; SF, C30 social functioning; SOF, GINET21 social function; SL, C30 insomnia;
TRS, GINET21 treatment related symptoms.
.
Supplementary Annex 1, Figure S1. Variable loadings on (A) PC1, (B) PC2, and (3) PC3.
C30, EORTC (European Organisation for the Research and Treatment of Cancer) core
quality-of-life questionnaire QLQ-C30; GINET21, EORTC quality-of-life questionnaire for
gastrointestinal neuroendocrine tumors (QLQ-GINET21); PC1, principal component 1; PC2,
principal component 2; PC3, principal component
Supplementary Annex 1, Table S1. Correlations between the 3 main PCs and the baseline symptom domains
Domain PC1 P-value PC2 P-value PC3 P-valuePC1 1.000 0.000 . . . .PC2 0.000 1.000 1.000 0.000 . .PC3 0.000 1.000 -0.000 1.000 1.000 0.000QL -0.639 0.000 0.056 1.000 0.067 1.000PF -0.658 0.000 0.066 1.000 0.102 1.000RF -0.681 0.000 0.053 1.000 0.156 1.000EF -0.700 0.000 0.142 1.000 -0.068 1.000CF -0.595 0.000 0.250 1.000 -0.047 1.000SF -0.641 0.000 0.212 1.000 0.068 1.000FA 0.764 0.000 0.019 1.000 -0.133 1.000NV 0.513 0.000 0.039 1.000 -0.260 1.000PA 0.484 0.000 -0.176 1.000 -0.180 1.000DY 0.480 0.000 -0.111 1.000 0.135 1.000SL 0.621 0.000 0.054 1.000 0.069 1.000AP 0.585 0.000 -0.009 1.000 -0.272 1.000CO 0.078 1.000 -0.425 0.002 -0.041 1.000DI 0.304 0.753 0.725 0.000 -0.322 0.352FI 0.508 0.000 -0.160 1.000 0.101 1.000ENS 0.514 0.000 0.230 1.000 0.656 0.000GIS 0.642 0.000 0.025 1.000 -0.062 1.000TRS 0.098 1.000 -0.229 1.000 0.258 1.000SOF -0.671 0.000 0.180 1.000 0.016 1.000DRW 0.520 0.000 -0.294 1.000 0.149 1.000MBP 0.426 0.002 -0.074 1.000 -0.072 1.000BIM 0.279 1.000 -0.045 1.000 -0.419 0.003ICF -0.134 1.000 0.008 1.000 0.177 1.000SEF -0.520 0.003 0.158 1.000 0.220 1.000QLQ -0.943 0.000 0.047 1.000 0.164 1.000FreqD 0.254 1.000 0.806 0.000 -0.181 1.000SevD 0.208 1.000 0.838 0.000 -0.256 1.000BDa 0.253 1.000 0.854 0.000 -0.211 1.000FreqF 0.365 0.053 0.358 0.074 0.710 0.000SevF 0.357 0.076 0.375 0.032 0.619 0.000BFa 0.381 0.024 0.379 0.027 0.725 0.000FreqO 0.114 1.000 -0.044 1.000 -0.311 0.566
aDiarrhea and flushing burden were obtained by averaging the average baseline frequency and severity for each subject.
Abbreviations: AP, C30 appetite loss; BD, burden of diarrhea; BF, burden of flushing; BIM, GINET21 body image C30, EORTC (European Organization for the Research and Treatment of Cancer) core quality-of-life questionnaire QLQ-C30; CF, C30 cognitive functioning; EF, C30 emotional functioning; CO, C30 constipation; DI, C30 diarrhea; DRW, GINET21 disease related worries; DY, C30 dyspnea; ENS, GINET21 endocrine symptoms; FA, C30 fatigue; FI, C30 financial difficulties; FreqD, diarrhea frequency; FreqF, flushing frequency; FreqO, frequency of octreotide use; GINET21, EORTC quality-of-life questionnaire for gastrointestinal neuroendocrine tumors (QLQ-GINET21); GIS, GINET21 GI symptoms; MBP, GINET21 muscle/bone pain symptoms; ICF, GINET21 information/communication function; NV, C30 nausea vomiting; PA, C30 pain, PC, principal component; PF, C30 physical functioning; QL, C30 global health/QoL; QLQ, C30 summary score; RF, C30 role functioning; SEF, GINET21 sexual function; SevD, diarrhea severity; SevF, flushing severity; SF, C30 social functioning; SOF, GINET21 social function; SL, C30 insomnia; TRS, GINET21 treatment related symptoms
Supplementary Annex 2. List of Ethics Committees and/or Institutional Review Boards from the ELECT study
Country / Site
Central Ethics Committee Local Ethics Committee
Brazil1309
Comissão Nacionalde Ética em Pesquisa(CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF - CEP
70058-900, Brazil
Comitê de Ética em Pesquisa em Seres Humanos da Irmandade da Santa Casa de Misericórdia de Porto AlegreRua Professor Annes
Dias, 295,Porto Alegre – RS, CEP90020-090 - Brazil Coordinator: Claudio Teloken
Brazil1304
Comissão Nacionalde Ética em Pesquisa(CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF - CEP70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos da Faculdade de Ciências da Saúde – UNB Campus Universitário Darcy Ribeiro – Faculdade de Ciências da Saúde, Brasília, DF, CEP70910-000 – Brazil
Brazil1302
Comissão Nacionalde Ética em Pesquisa(CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF - CEP70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos do Hospital Vera CruzRua Timbiras 3156 – 9º andar – Sala 902, Barro Preto,Belo Horizonte-MG, CEP 30140-060 - Brazil
Brazil1306
Comissão Nacionalde Ética em Pesquisa(CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF - CEP
70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos do Hospital SOCORRua Tupis, 1540 – BarroPreto,Belo Horizonte, MG –CEP 30190-062 - Brazil
Brazil1301
Comissão Nacionalde Ética em Pesquisa(CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF - CEP
70058-900, Brazil
Comitê de Etica emPesquisa em Seres Humanos do Fundação Antônio Prudente-Rua Prof.Antônio Prudente, 211- Liberdade-São paulo BrazilChairperson: RicardoRenzo Brentani
Brazil1307
Comissão Nacionalde Ética em Pesquisa(CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF - CEP70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos do Hospital Erasto Gaertner/ Liga Paranaense de Combate ao CâncerRua Dr. Ovande doAmaral, 201 – Jardin dasAmericasCuritiba, PR – CEP81620-060 - BrazilBrazil
1308Comissão Nacionalde Ética em Pesquisa(CONEP) Esplanada dos Ministerios, Bloco "G" - EdificioAnexo - Ala B - 4o andar- Sala 436BBrasilia - DF - CEP70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos do Hospital Moinhos de VentoRua Ramiro Barcelos,910,Porto Alegre – RS, CEP90035-001 -Brazil
Brazil1303
Comissão Nacionalde Ética em Pesquisa(CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF - CEP70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos da Faculdade de Medicina de São José do Rio PretoAv. Brigadeiro Faria
Lima, 5416 –São José do Rio Preto, SP - CEP 15090-000 - Brasil –Coordinator: FernandoBatigalia
Brazil 1305
Comissão Nacionalde Ética em Pesquisa(CONEP) Esplanada dos Ministerios, Bloco "G" - EdificioAnexo - Ala B - 4o andar- Sala 436BBrasilia - DF - CEP70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos do Hospital Lifecenter,Avenida do Contorno,4747 - 20.o andar –Funcionários,Belo Horizonte – MG –CEP 30110-090 – Brazil
Czech Rep.0301
Ethics Committee ofthe General University Hospital PragueNa bojisti1128 08 Prague 2Czech Republic Chairperson: Josef Sedevy
NA
Czech Rep.0302
Ethics Committee ofthe General University Hospital PragueNa bojisti1128 08 Prague 2Czech Republic Chairperson: Josef Sedevy
Eticka komise Fakultninemocnice Na BulovceBudinova 2, 180 81Praha 8Czech republic
India1109
NA Institutional EthicsCommittee Basavatarakam Indo American Cancer Hospital & Research InstituteRoad#14, Banjara Hills500034 Hederabad (AP) IndiaChairperson: Dr. S. S. Reddy
India1104
NA Institutional EthicsCommittee, Shatabdi Super Specialty Hospital Suojit city centre Opp.Mahamarg Bus StandMumbai Naka422005 Nasik India Chairperson: Dr.Neelima Chafekar
India1110
NA Ethics Committee,Bhagwan Mahaveer Cancer Hospital & Research CentreJawahar Lal Nehru Marg302017 JaipurIndia
India1101
NA The Ethics CommitteeJaslok Hospital & Research Centre15,Dr. G. Deshmukh Marg, Peddar Road Mumbai 400 026IndiaChairperson: A. A. Cazi
India1106
NA Institute of MedicalSciences, Banaras HinduUniversityDepartment of medicine Lanka-221005 Varanasi IndiaChairperson: Dr. J. K. Agrawal
India1108
NA Institutional EthicsCommittee, IGIMS, PatnaRegional Cancer Centre Indira Gandhi Institute of Medical Sciences Sheikhpura-800014Patna India Chairperson: Dr. S.N.P.Sinha
India1102
NA Ethics Committee-SirGanga Ram HospitalMargRajinder NagarNew Delhi 110060IndiaChairperson: Dr. S.D. Seth
India1111
NA Institutional EthicsCommitteeOffice of Research Cell Chhatrapati Shahuji Maharaj Medical University Uttar Pradesh226003 Lucknow (UP) IndiaChairperson: Dr. U. C. Chaturvedi
India1107
NA Institutional EthicsCommitteeCancer Hospital & Research institute Jan Vikas Nyas4740009 Gwalior (MP) India
India1103
NA Ethics Committee,Santokba Durlabji Memorial Hospital D-201Bhawani Singh MargNear Rambag Circle302015 Jaipur RajasthanIndiaChairperson: Dr. B.R Madan
India1105
NA Human EthicsCommittee,Tata Memorial CentreDr. E Borges Road, Parel400012 Mumbai, India Chairperson: Dr. Madhuri Gore
India1112
NA MAARG IndependentEthics CommitteeSree Nilayam, Plot No.38, P & T Colony, Trimulgherry, Secunderabad,Andhra Pradesh-500015, India.Chairperson: Dr. AnandA. M
India1113
NA Northern IndependentEthics Committee,84, Savitri Nagar, New Delhi, 110017, India,Chairperson: Dr. Prashant Gupta
India1114
NA Ethics Committee,SMS Medical College & Hospital,JLN Marg, Jaipur-302004Rajasthan, India Chairperson: Dr. V. N. Sharma
Latvia0401
Ethics Committeefor Clinical Research at Pauls Stradins Clinical University Hospital DevelopmentSocietyPilsonu 13LV 1002 RigaLatvia
NA
Poland050105020505
Ethics Committee.Medical University of BialystokUl. Jana Kilińskiego115-089 BiałystokPoland
NA
Russia0606
Ethics Committee atFederal Service on Surveillance in Healthcare and Socila DevelopmentPetrevskii Boulevard127051 MoscowRussia
Ethics Committee at Rossiyskiy Oncologicheskiy Nauchnyi Tsentr im. N.N.Blokhina RAMN24 Kashirskoe shosse115478 MoscowRussia
Russia0604
Ethics Committee atFederal Service on Surveillance in Healthcare and Socila DevelopmentPetrevskii Boulevard127051 MoscowRussia
Independent EthicsCommittee of Negosudarstvennoe Uchrezhdenie Zdravookhraneniya "Tsentral'naya Clinicheskaya Bol'nitsa#1 OAO "RossiyskieZheleznyie Dorogi"84 Volokolamskoe shosse125367 MoscowRussia
Russia0603
Ethics Committee atFederal Service on Surveillance in Healthcare and Socila DevelopmentPetrevskii Boulevard127051 MoscowRussia
Ethics Committee of fLeningradskii Oblastnoi Onkologicheskii Dispanser37 Liteyny pr.191104 Saint-PetersburgRussia
Russia0605
Ethics Committee atFederal Service on Surveillance in Healthcare and Socila DevelopmentPetrevskii Boulevard127051 MoscowRussia
NA
Serbia1001
NA Etički Komitet Kliničkogcentra Srbije, KliničkiCentar Srbije ul. Pasterova 2Beograd 11000Serbia
Serbia1003
NA Klinički Centar NišEtički Odbor Blvd. Dr. Zorana Djindjica 4818000 NisSerbia
Serbia1002
NA Etički Komitet Institutaza onkologiju VojvodineInstitutski put 4Sremska Kamenica21204Serbia
South Africa1202
NA Pharma-Ethics123 Amcor RoadLyttletown Manor 0157Republic of South Africa
South Africa1204
NA Pharma-Ethics123 Amcor RoadLyttletown Manor 0157Republic of South Africa
South Africa1203
NA Pharma-Ethics123 Amcor RoadLyttletown Manor 0157Republic of South Africa
South Africa1205
NA Biomedical ResearchEthics Committee Westville campus Govan Mbeki Building Private bag X 540014000 DurbanKwaZulu-natal, SOUTH AFRICAChairperson: Prof. D. Wassenaar
South Africa1201
NA Research EthicsCommitteeRoom E52-24 Groote Schuur hospital old Main BuildingObservatory7925 Cape Town South Africa Chairperson: Prof. M. Blockman
Turkey0801080208030804
Ethics Committeefor Clinical Research Ankara University- Faculty of Medicine, Office of the Dean Morfoloji Binası,06100 Sıhhiye- Ankara/Turkey Chairperson: Prof. Dr. Mehmet MELLİ
NA
Ukraine070107020703070407060708070907100711
Ministry of Healthof Ukraine CentralEthics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: OlgaVasylivna Silantieva
NA
Ukraine070707120713
Ministry of Healthof Ukraine CentralEthics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: OlgaVasylivna Silantieva
NA
USA0216*
NA NA
USA0217*
NA Providence Health andServicesInstitutional ReviewBoard5251 NE Glisen Street Building A, 3rd Floor Portland, OR 97213
USA0218*
NA Louisiana StateUniversity Health Science Center – New Orleans IRB433 Bolivar Street, 2ndFloorNew Orleans, LA 70112
USA0219
NA UCLA Office ofProtection of ResearchSubjects11000 Kinross Ave, Suite102, Box 951694Los Angeles, CA 90095
USA0220
NA University ofPennsylvaniaOffice of RegulatoryAffairs3624 Market StreetSuite 301 SPhiladelphia, PA 19104-6006
USA0223
NA Institutional ReviewBoard and Research Development Committee VAGLAHS, WLA11301 Wilshire Blvd. Building 114 Room 329Los Angeles, CA 90073
USA0224
NA OHSU InstitutionalReview Board3181 S.W. Same JacksonPark Rd.Mailcode: L-106-R1Portland, OR 97239
USA0225
NA Chesapeake ResearchReview Inc.7063 Columbia GatewayDrive, Suite 110Columbia, MD 21046
USA0226
NA Cedars Sinai MedicalCenter8700 Beverly Blvd.Los Angeles, CA 90068
USA0229
NA Stanford UniversityResearch and Compliance Administrative Panel on Human Subject in Medical Research Administrative Panels Office1215 Welch Road, Modular AStanford, CA 94305-5401
USA0230*
NA Western InstitutionalReview Board (WIRB)3535 Seventh AvenueSWOlympia, WA 98508
USA0231
NA Penn State College ofMedicinePenn State Milton S. Hershey Medical Center Human Subjects Protection Office600 Centerview Drive, PO Box 855Hershey, PA 17033-0855
USA0232*
NA IRBUniversity of MississippiMedical Center2500 North State StreetJackson, MS 39216-4505
USA0234*
NA NA
USA0235*
NA MCW/FH InstitutionalReview Board8701 Watertown PlankRoadMilwaukee, WI 53226
USA0236
NA Western InstitutionalReview Board (WIRB)3535 Seventh AvenueSWOlympia, WA 98508
USA0237
NA University of MichiganMedical School Institutional Review Board (IRBMED)2800 Plymouth RoadBuilding 200, Room2086Ann Arbor, MI 48109-2800
Brazil1309
Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala436B – Brasilia- DF - CEP70058-900, Brazil
Comitê deÉtica em Pesquisa em Seres Humanos da Irmandade da Santa Casa deMisericórdia de Porto AlegreRua Professor Annes Dias,
295,Porto Alegre– RS, CEP90020-090 - Brazil
Brazil1304
ComissãoNacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala436B – Brasilia- DF - CEP70058-900, Brazil Coordinator: Gyselle Saddi Tannous
Comitê deÉtica em Pesquisa em Seres Humanos da Faculdadede Ciências da Saúde – UNBCampusUniversitário Darcy Ribeiro – Faculdadede Ciências da Saúde, Brasília, DF, CEP 70910-000 - Brazil Coordinator: Natan Monsores de Sa
Brazil1302
Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala436B – Brasilia- DF - CEP70058-900, Brazil Coordinator: Gyselle
Comitê deÉtica em Pesquisa em Seres Humanos do Hospital Vera Cruz RuaTimbiras3156 – 9ºandar – Sala902, BarroPreto, Belo Horizonte- MG, CEP30140-060 - Brazil Coordinator: Carlos Ernesto Ferreira StarlingBrazil
1306Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala436B – Brasilia- DF - CEP70058-900, Brazil Coordinator: Gyselle Saddi Tannous
Comitê deÉtica em Pesquisa em Seres Humanos do Hospital SOCORRua Tupis,1540 – BarroPreto, Belo Horizonte, MG – CEP30190-062 - Brazil Coordinator: Luiz Ricardo de Ataide Castro
Brazil1301
Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala436B – Brasilia- DF - CEP70058-900, Brazil Coordinator: Gyselle Saddi Tannous
Comitê deEtica em Pesquisa em Seres Humanos do Fundação Antônio Prudente- Rua Prof. Antônio Prudente,211- Liberdade- São paulo Brazil Chairperson: RicardoRenzoBrentani
Brazil1307
ComissãoNacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala436B – Brasilia- DF - CEP70058-900, Brazil Coordinator: Gyselle Saddi Tannous
Comitê deÉtica em Pesquisa em Seres Humanos do Hospital Erasto Gaertner/ Liga Paranaense de Combate ao Câncer Rua Dr. Ovande do Amaral, 201– Jardin das Americas Curitiba, PR– CEP81620-060 - Brazil
Brazil1308
ComissãoNacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala436B – Brasilia- DF - CEP70058-900, Brazil Coordinator: Gyselle Saddi Tannous
Comitê deÉtica em Pesquisa em Seres Humanos do Hospital Moinhos de VentoRua RamiroBarcelos,910,Porto Alegre– RS, CEP90035-001 - Brazil
Brazil1303
ComissãoNacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala436B – Brasilia- DF - CEP70058-900, Brazil Coordinator: Gyselle Saddi Tannous
Comitê deÉtica em Pesquisa em Seres Humanos da Faculdadede Medicina de São José do Rio PretoAv. Brigadeiro
Faria Lima,5416 –São José do Rio Preto, SP - CEP15090-000 - Brasil –
Brazil1305
ComissãoNacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala436B – Brasilia- DF - CEP70058-900, Brazil Coordinator: Gyselle Saddi Tannous
Comitê deÉtica em Pesquisa em Seres Humanos do Hospital Lifecenter, Avenida do Contorno,4747 - 20.o andar – Funcion- ários,Belo Horizonte – MG – CEP30110-090 - Brazil Secretary:Pa triciaCaixeta DosSantos
CzechRep.0301
EthicsCommittee of the General University Hospital Prague Na bojisti1128 08 Prague2Czech Republic Chairperson: Josef Sedevy
NA
CzechRep.0302
EthicsCommittee of the General University Hospital Prague Na bojisti1128 08 Prague2Czech Republic Chairperson: Josef Sedevy
Eticka komise Fakultni nemocnice Na Bulovce Budinova 2,180 81 Praha8Czech republic
India1109
EthicsCommittee of the General University Hospital Prague Na bojisti1128 08 Prague2Czech Republic Chairperson: Josef Sedevy
InstitutionalEthics Committee Basavatarak am Indo American Cancer Hospital & Research Institute Road#14, Banjara Hills500034Hederabad(AP) India Chairperson: Dr. S. S. Reddy
India1104
NA InstitutionalEthics Committee, Shatabdi Super Specialty Hospital Suojit city centre Opp.Maham arg Bus Stand Mumbai Naka422005Nasik India Chairperson: Dr. Neelima Chafekar
India1110
NA EthicsCommittee, Bhagwan Mahaveer Cancer Hospital & Research Centre Jawahar Lal Nehru Marg302017JaipurIndia
India1101
NA The EthicsCommittee Jaslok Hospital & Research Centre15,Dr. G. Deshmukh Marg,Peddar RoadMumbai 400026India Chairperson: A. A. Cazi
India1106
NA Institute ofMedical Sciences, Banaras Hindu University Department of medicine Lanka-221005Varanasi India Chairperson: Dr. J. K. Agrawal
India1108
NA Institutional Ethics Committee, IGIMS, Patna Regional Cancer Centre Indira Gandhi Institute of Medical SciencesSheikhpura-800014Patna India Chairperson: Dr. S.N.P. Sinha
India1102
NA EthicsCommittee- Sir Ganga Ram Hospital Marg Rajinder NagarNew Delhi110060India Chairperson: Dr. S.D.Seth
India1111
NA InstitutionalEthics Committee Office of Research Cell Chhatrapati Shahuji Maharaj Medical University Uttar Pradesh226003Lucknow(UP) India, Chairperson: Dr. U. C. Chaturvedi
India1107
NA InstitutionalEthics Committee Cancer Hospital & Research instituteJan VikasNyas4740009Gwalior (MP) IndiaChairperson: Dr. S.K. Shrivastava
India1103
NA EthicsCommittee, Santokba Durlabji Memorial HospitalD-201Bhawani Singh Marg Near Rambag Circle302015Jaipur Rajasthan India Chairperson: Dr. B.R Madan
India1105
NA HumanEthics Committee, Tata Memorial CentreDr. E BorgesRoad, Parel400012Mumbai, India Chairperson: Dr. Madhuri Gore
India1112
NA MAARGIndependent Ethics Committee Sree Nilayam, Plot No. 38, P & T Colony, Trimulgherr y, Secunderaba d,AndhraPradesh-500015, India.
India1113
NA NorthernIndependent Ethics Committee,84, SavitriNagar,New Delhi,110017, India, Chairperson: Dr. Prashant Gupta
India1114
NA EthicsCommittee, SMS Medical College & Hospital, JLN Marg, Jaipur-302004Rajasthan, India Chairperson: Dr. V. N. Sharma
Latvia0401
EthicsCommittee for Clinical Research at Pauls Stradins Clinical University Hospital Development SocietyPilsonu 13LV 1002 RigaLatvia
NA
Poland050105020505
EthicsCommittee. Medical University of BialystokUl. JanaKilińskiego 115-089BiałystokPoland
NA
Russia0606
Ethics Committee at Federal Service on Surveillance in Healthcare and Socila Development Petrevskii Boulevard127051 MoscowRussia
EthicsCommittee at RossiyskiyOncologiche skiy Nauchnyi Tsentr im. N.N.Blokhin a RAMN24Kashirskoe shosse115478MoscowRussia
Russia0604
EthicsCommittee at Federal Service on Surveillance in Healthcare and Socila Development Petrevskii Boulevard127051 MoscowRussia
IndependentEthics Committee of Negosudarst vennoeUchrezhdeni e Zdravookhraneniya"Tsentral'na ya Clinicheskay a Bol'nitsa#1 OAO "Rossiyskie Zheleznyie Dorogi"84Volokolams koe shosse125367MoscowRussia
0601EthicsCommittee at Federal Service on Surveillance in Healthcare and Socila Development Petrevskii Boulevard127051 MoscowRussia
NA
Russia0603 Ethics Committee at Federal Service on
Surveillance in Healthcare and Socila Develop-ment Petrevskii Boulevard127051 MoscowRussia
EthicsCommittee of Leningradski i Oblastnoi Onkologiche skiiDispanser37 Liteyny pr.191104Saint- Petersburg Russia
Serbia1001
NA EtičkiKomitet Kliničkog centra Srbije, Klinički Centar Srbijeul. Pasterova2Beograd11000Serbia
Serbia1003
NA
Klinički Centar Niš Etički Odbor Blvd. Dr. Zorana Djindjica 4818000 NisSerbia
Serbia1002
NA EtičkiKomitet Instituta za onkologiju Vojvodine Institutski put 4SremskaKamenica21204Serbia Chairperson: Dr. Gordana Bogdanovic
SouthAfrica1202
NA Pharma-Ethics123 Amcor Road Lyttletown Manor 0157Republic of South Africa Chairperson: Dr. C.S.J. Duvenage
SouthAfrica1205
NA BiomedicalResearch Ethics Committee Westville campus Govan Mbeki Building Private bag X 540014000 Durban KwaZulu- natal, SOUTH AFRICA Chairperson:Prof. D.Wassenaar
SouthAfrica1201
NA ResearchEthics Committee Room E52-24 Groote Schuur hospital old Main Building Observatory7925 CapeTownSouth Africa Chairperson: Prof. M. Blockman
SouthAfrica1204
NA Pharma-Ethics123 Amcor Road Lyttletown Manor 0157Republic of South Africa Chairperson: Dr. C.S.J. Duvenage
SouthAfrica1203
NA Pharma-Ethics123 Amcor Road Lyttletown Manor 0157Republic of South Africa Chairperson:Dr. C.S.J. Duvenage
Ukraine0708
Ministry ofHealth of Ukraine Central Ethics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: Olga Vasylivna Silantieva
NA
Ukraine0710
Ministry ofHealth of Ukraine Central Ethics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: Olga Vasylivna Silantieva
NA
Ukraine0702
Ministry ofHealth of Ukraine Central Ethics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: Olga Vasylivna Silantieva
NA
Ukraine0703
Ministry ofHealth of Ukraine Central Ethics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: Olga Vasylivna Silantieva
NA
Ukraine0711
Ministry ofHealth of Ukraine Central Ethics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: Olga Vasylivna Silantieva
NA
Ukraine0709
Ministry ofHealth of Ukraine Central Ethics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: Olga Vasylivna Silantieva
NA
Ukraine0706
Ministry ofHealth of Ukraine Central Ethics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: Olga Vasylivna Silantieva
NA
Ukraine0701
Ministry ofHealth of Ukraine Central Ethics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: Olga Vasylivna Silantieva
NA
Ukraine0704
Ministry ofHealth of Ukraine Central Ethics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: Olga Vasylivna Silantieva
NA
Ukraine0712
Ministry ofHealth of Ukraine Central Ethics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: Olga Vasylivna Silantieva
NA
Ukraine0713
Ministry ofHealth of Ukraine Central Ethics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: Olga Vasylivna Silantieva
NA
Ukraine0707
Ministry ofHealth of Ukraine Central Ethics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: Olga Vasylivna Silantieva
NA
USA0216
NA NA
USA0217*
NA ProvidenceHealth and Services Institutional Review Board5251 NE Glisen Street Building A,3rd FloorPortland, OR97213
USA0219
NA UCLAOffice of Protection of Research Subjects11000Kinross Ave, Suite 102, Box 951694Los Angeles, CA 90095
USA0220
NA Universityof PennsylvaniaOffice of Regulatory Affairs3624 MarketStreetSuite 301 S Philadelphia, PA 19104-6006
USA0223
NA InstitutionalReview Board and Research Developmen t Committee VAGLAHS, WLA11301Wilshire Blvd. Building 114Room 329Los Angeles, CA 90073
USA0224
NA OHSUInstitutional Review Board3181 S.W.SameJackson Park Rd. Mailcode: L-106-R1Portland, OR
97239
USA0225
NA ChesapeakeResearchReview Inc.7063Columbia Gateway Drive, Suite110Columbia, MD 21046
USA0226
NA Cedars SinaiMedicalCenter8700BeverlyBlvd.Los Angeles, CA 90068
USA0229
NA StanfordUniversity Research and ComplianceAdministrati ve Panel on Human Subject in Medical Research Administrati ve Panels Office1215 Welch Road, Modular A Stanford, CA 94305-5401
USA0231
NA Penn StateCollege of Medicine Penn State Milton S. Hershey Medical Center Human Subjects Protection Office600Centerview Drive, PO Box 855Hershey, PA17033-0855
USA0232*
NA IRBUniversity of Mississippi Medical Center2500 NorthState StreetJackson, MS39216-4505
USA0234*
NA NA
USA0235*
NA MCW/FHInstitutional Review Board8701Watertown Plank Road Milwaukee, WI 53226
USA0236
NA WesternInstitutional Review Board (WIRB)3535Seventh Avenue SW Olympia, WA 98508
USA0237
NA Universityof Michigan Medical School Institutional Review Board (IRBMED)2800Plymouth Road Building200, Room2086Ann Arbor, MI 48109-2800
Brazil1309 Comissão Nacional de Ética em Pesquisa
(CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF -CEP 70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos da Irmandade da Santa Casa de Misericórdia de Porto AlegreRua Professor Annes
Dias, 295,Porto Alegre – RS, CEP90020-090 - Brazil Coordinator: Claudio Teloken
Brazil1304
Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF -
CEP 70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos da Faculdade de Ciências da Saúde – UNB Campus Universitário Darcy Ribeiro – Faculdade deCiências da Saúde,Brasília, DF, CEP70910-000 – Brazil
Brazil1302
Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF -
CEP 70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos do Hospital Vera CruzRua Timbiras 3156 – 9ºandar – Sala 902, Barro Preto, Belo Horizonte- MG, CEP 30140-060 - Brazil
Brazil1306
Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF -
CEP 70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos do Hospital SOCORRua Tupis, 1540 –Barro Preto,Belo Horizonte, MG –CEP 30190-062 - Brazil
Brazil1301
Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF -
CEP 70058-900, Brazil
Comitê de Etica emPesquisa em Seres Humanos do Fundação Antônio Prudente-Rua Prof.Antônio Prudente, 211- Liberdade-São paulo BrazilChairperson: RicardoRenzo Brentani
Brazil1307
Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF -
CEP 70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos do Hospital Erasto Gaertner/ Liga Paranaense de Combate ao Câncer Rua Dr. Ovande do Amaral, 201 – Jardin das Americas Curitiba, PR – CEP81620-060 - Brazil
Brazil1308
Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF -
CEP 70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos do Hospital Moinhos de Vento Rua RamiroBarcelos, 910, Porto Alegre – RS, CEP 90035-001 - Brazil
Brazil1303
Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF -
CEP 70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos da Faculdade de Medicina de São José do Rio PretoAv. Brigadeiro Faria
Lima, 5416 – São José do Rio Preto, SP – CEP15090-000 -Brasil – Coordinator: Fernando Batigalia
Brazil1305
Comissão Nacionalde Ética em Pesquisa(CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala 436B Brasilia -DF - CEP 70058-900, Brazil
Comitê de Ética emPesquisa em Seres Humanos do Hospital Lifecenter,Avenida doContorno, 4747 -20.o andar –Funcionários,Belo Horizonte – MG– CEP 30110-090 –Brazil
Czech Rep.0301
Ethics Committee of the General University Hospital PragueNa bojisti1128 08 Prague 2Czech Republic Chairperson: Josef Sedevy
NA
Czech Rep.0302
Ethics Committee of the General University Hospital PragueNa bojisti1128 08 Prague 2
Czech Republic Chairperson: Josef Sedevy
Eticka komise Fakultni nemocnice Na Bulovce Budinova 2, 180 81Praha 8Czech republic
India1109
NA Institutional EthicsCommittee Basavatarakam Indo American Cancer Hospital & Research InstituteRoad#14, BanjaraHills500034 Hederabad(AP) IndiaChairperson: Dr. S. S. Reddy
India1104
NA Institutional EthicsCommittee, Shatabdi Super Specialty HospitalSuojit city centre Opp.Mahamarg Bus StandMumbai Naka422005 Nasik India Chairperson: Dr.Neelima Chafekar
India1101
NA The EthicsCommittee Jaslok Hospital & Research Centre15,Dr. G. Deshmukh Marg, Peddar Road Mumbai 400 026IndiaChairperson: A. A. Cazi
India1106
NA Institute of MedicalSciences, Banaras Hindu University Department of medicineLanka-221005VaranasiIndiaChairperson: Dr. J. K. Agrawal
India1108
NA Institutional EthicsCommittee, IGIMS, PatnaRegional CancerCentreIndira Gandhi Institute of Medical SciencesSheikhpura-800014Patna India Chairperson: Dr. S.N.P.Sinha
India1111
NA Institutional EthicsCommitteeOffice of ResearchCellChhatrapati Shahuji Maharaj Medical University Uttar Pradesh226003 Lucknow(UP) IndiaChairperson: Dr. U. C. Chaturvedi
India1107
NA Institutional EthicsCommitteeCancer Hospital & Research institute Jan Vikas Nyas4740009 Gwalior(MP) India
India1103
NA Ethics Committee,Santokba Durlabji Memorial Hospital D-201Bhawani Singh MargNear Rambag Circle302015 Jaipur Rajasthan IndiaChairperson: Dr. B.R Madan
India1105
NA Human EthicsCommittee, Tata Memorial CentreDr. E Borges Road, Parel400012 Mumbai, India Chairperson: Dr. Madhuri Gore
India1112
NA MAARGIndependent EthicsCommitteeSree Nilayam, Plot No. 38, P & T Colony, Trimulgherry, Secunderabad, Andhra Pradesh-500015, India. Chairperson: Dr. Anand A. M
India1113
NA Northern IndependentEthics Committee,84, Savitri Nagar, New Delhi, 110017, India,Chairperson: Dr. Prashant Gupta
India1114
NA Ethics Committee,SMS Medical College & Hospital, JLN Marg, Jaipur-302004Rajasthan, India Chairperson: Dr. V. N. Sharma
Latvia0401
Ethics Committee forClinical Research at Pauls Stradins Clinical University HospitalDevelopment SocietyPilsonu 13LV 1002 RigaLatvia
NA
Poland050105020505
Ethics Committee.Medical University of BialystokUl. Jana Kilińskiego115-089 BiałystokPoland
NA
Russia0606 Ethics Committee at Federal Service on
Surveillance in Healthcare and Socila Development Petrevskii Boulevard127051 Moscow
Russia
Ethics Committee at Federal Service on
Ethics Committee atRossiyskiy Oncologicheskiy Nauchnyi Tsentr im. N.N.Blokhina RAMN24 Kashirskoe shosse115478 MoscowRussia
Russia0604
Ethics Committee at Federal Service on Surveillance in Healthcare and Socila Development Petrevskii Boulevard127051 Moscow
Russia
Independent EthicsCommittee of Negosudarstvennoe Uchrezhdenie Zdravookhraneniya "Tsentral'naya Clinicheskaya Bol'nitsa #1 OAO "Rossiyskie Zheleznyie Dorogi"84 Volokolamskoe shosse125367 MoscowRussia
Russia0601
Ethics Committee at Federal Service on Surveillance in Healthcare and Socila Development Petrevskii Boulevard127051 Moscow
Russia
NA
Russia0603
Ethics Committee atFederal Service on Surveillance in Healthcare and Socila Development Petrevskii Boulevard127051 MoscowRussia
Ethics Committee off Leningradskii Oblastnoi Onkologicheskii Dispanser37 Liteyny pr.191104 Saint- Petersburg Russia
Russia0605
Ethics Committee atFederal Service on Surveillance in Healthcare and Socila Development Petrevskii Boulevard127051 MoscowRussia
NA
Serbia1001
NA Etički KomitetKliničkog centra Srbije, Klinički Centar Srbijeul. Pasterova 2Beograd 11000Serbia
Serbia1003
NA Klinički Centar NišEtički Odbor Blvd. Dr. Zorana Djindjica 4818000 NisSerbia
Serbia1002
NA Etički KomitetInstituta zaonkologiju VojvodineInstitutski put 4Sremska Kamenica21204Serbia
South Africa1202
NA Pharma-Ethics123 Amcor RoadLyttletown Manor0157Republic of SouthAfrica
South Africa1204
NA Pharma-Ethics123 Amcor RoadLyttletown Manor0157Republic of SouthAfrica
South Africa1203
NA Pharma-Ethics123 Amcor RoadLyttletown Manor0157Republic of SouthAfrica
South Africa1205
NA Biomedical ResearchEthics Committee Westville campus Govan Mbeki BuildingPrivate bag X 540014000 Durban KwaZulu-natal, SOUTH AFRICA Chairperson: Prof. D. Wassenaar
South Africa1201
NA Research EthicsCommitteeRoom E52-24 Groote Schuur hospital old Main Building Observatory7925 Cape Town South Africa Chairperson: Prof. M. Blockman
Turkey0801080208030804
Ethics Committee forClinical Research Ankara University- Faculty of Medicine, Office of the Dean Morfoloji Binası,06100 Sıhhiye-Ankara/Turkey Chairperson: Prof. Dr. Mehmet MELLİ
NA
Ukraine0701
NA Ethics Commissionof Municipal Multyprofile Clinical Hospital #431 Blizhnaya str.,49102Dnepropetrovsk –UkraineHead – ShynkarenkoM.D.
Ukraine0702
NA NA
Ukraine 0703
NA
Ethics Commissionof Municipal ClinicalHospital #2,197 Moskovsky pr.61037 Kharkiv –UkraineHead – GvozdykYu.O.
Ukraine 0704 NA NA
Ukraine 0706
NA
Ethics Commissionof National Cancer Institute Lomonosova str.33/4303022 Kyiv –UkraineHead – GubarevaG.O.
Ukraine 0707 NA NA
Ukraine 0708 NA Ethics Commissionof Kyiv CityOncological Hospital,69 Verkhovynna Str.03115 Kyiv –UkraineHead – KalachovO.V.
Ukraine 0709 NA Ethics Commissionof Chernivtsi Regional Oncology Center242Chervonoarmiyska str.58013 Chernivtsi –UkraineHead – Pakholko L.I.
Ukraine 0710 NA NA
Ukraine 0711 NA Ethics Commissionof KU Odessa Regional Clinical Hospital26, Ac. Zabolotnogo65117 Odessa –UkraineHead – BayazitovM.R.
Ukraine 0712 NA Ethics Commissionof Uzhgorods’ka Tsentral’na Mis’ka Klinichna Likarnya Vul. Hriboedova 2088000 UzhgorodUkraineHead – ChernychkoV.I.
Ukraine 0713 NA NA
Supplementary Annex 3. Minimal clinically important differences (MCID) derivation
for the carcinoid syndrome (CS) response measures
Background: common methods for MCID determination
Patient-reported outcomes (PROs) are frequently incorporated in clinical trials comparing
treatments for chronic diseases. PROs include measures of quality of life, symptoms,
functioning, and other outcomes and provide the patient’s perspective on the effects of
disease and treatment.1
One of the challenges with using PROs is determining if statistically significant differences
also represent a clinically important difference. Therefore, translating observed changes in a
PRO score into clinically meaningful terms is important in the interpretation of study results.
Information on the interpretation of changes (or differences) in PRO scores is based on the
minimal clinically important difference (MCID). The MCID was first defined as the smallest
difference in score in the domain of interest, which patients perceive as beneficial, and which
would mandate a change in the patient’s management.2
To establish an a priori responder definition (ie, the individual patient PRO score change over
a predetermined time period that should be interpreted as a treatment benefit), two general
approaches are used:
1. Anchor-based approaches compare the change in a PRO score to some other measure
of change, considered an objective external criterion or anchor.3 Two requirements for
the anchor apply: it must be interpretable and be at least moderately correlated with
the target PRO instrument.4 Clinically accepted endpoints, patient-rated global
improvement, change in other PRO measures, or some combination of clinical and
patient-based outcomes can be used for defining a meaningful change in a PRO
measure.1,5 It should, however, be noted that few studies have relied on an objective
external criterion. Due to the lack of such satisfying objective assessment, PRO scores
may be compared to another anchor or subjective assessment (eg, a global assessment
rating) in which the patient rates his/her health status as, for example, “better,”
“unchanged,” or “worse.”3 An anchor should have a nontrivial association with
change in the PRO measure, and a minimum correlation threshold of 0.30 is
recommended to define an acceptable association between an anchor and a PRO
change score.5
2. Distribution-based approaches compare the change in PRO score to some measure of
variability, such as the standard error of measurement (SEM), the standard deviation
(SD), the effect size, or the minimum detectable change.3,6 In essence, these methods
convey a notion that a meaningful change can be estimated based on the distribution
of observed scores in a relevant sample.1
Each of these broad approaches can be further subdivided, and currently there is no
consensus on the best strategy to determine a clinically meaningful difference.
As an alternative to anchor-based or distribution-based methods, the entire distribution of
responses for treatment and control group can be presented through cumulative distribution of
response curves. Cumulative distribution displays show a continuous plot of the percent
change from baseline on the X-axis and the percent of patients experiencing that change on
the Y-axis. With this approach, a variety of responder definitions can be identified along the
cumulative distribution of response curve,6 and the impact of alternative responder criteria on
treatment effect can be estimated.
MCID determination in current analysis
In this analysis, the symptom-based response variables, diarrhea burden (BD) and flushing
burden (BF), each represent a composite endpoint defined as the average of frequency and
severity of symptoms. Distribution-based methods to establish a threshold MCID value for a
bi-dimensional response variable are currently lacking. Hence, an anchor-based approach was
explored to determine a meaningful change for this composite endpoint.
In carcinoid syndrome (CS) there is no established objective external criterion to distinguish
responders from non-responders on PRO patient-centered endpoints, nor did the ELECT trial
collect data on a patient- or clinical-rated global assessment of health status. To identify
alternative anchor candidates, we first explored the associations between the targeted concept
of the PRO instrument (BD and BF) and the concept measured by the anchors (the QLQ
subscale scores of diarrhea [DI] and endocrine symptoms [ENS], respectively).6 This was
accomplished by investigating the correlation structure between BD and BF symptom scores
and QLQ subscale scores. Supplemental Table 1 shows the associations between symptom-
based scores and anchor candidates (only those variables with correlations >0.3 are shown).
Baseline BD was highly correlated with DI, as was baseline BF with ENS.
Supplementary Annex 3, Table S1 Correlationsa between baseline symptom-based scores and baseline QLQ subscale scores of the EORTC QLQ questionnaires.
Domain QLQ QL FreqD SevD BD1 DI FreqF SevF BF1 ENS FreqOQLQ 1.000
P 0.000QL 0.604 1.000P 0.000 0.000
FreqD -0.193 -0.197 1.000P 1.000 1.000 0.000
SevD -0.164 -0.140 0.778 1.000P 1.000 1.000 0.000 0.000
BD -0.194 -0.190 0.984 0.878 1.000P 1.000 1.000 0.000 0.000 0.000DI -0.309 -0.129 0.651 0.753 0.710 1.000P 0.051 1.000 0.000 0.000 0.000 0.000
FreqF -0.182 -0.134 0.270 0.129 0.243 0.037 1.000P 1.000 1.000 0.193 1.000 0.494 1.000 0.000
SevF -0.208 -0.146 0.170 0.232 0.196 0.148 0.729 1.000P 1.000 1.000 1.000 0.688 1.000 1.000 0.000 0.000
BF -0.197 -0.143 0.261 0.157 0.244 0.063 0.989 0.822 1.000P 1.000 1.000 0.262 1.000 0.471 1.000 0.000 0.000 0.000
ENS -0.337 -0.249 0.132 0.073 0.122 0.102 0.677 0.666 0.707 1.000P 0.017 0.440 1.000 1.000 1.000 1.000 0.000 0.000 0.000 0.000
FreqO -0.110 -0.119 0.043 0.058 0.049 0.019 -0.148 0.073 -0.108 -0.018 1.000P 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 0.000
aOnly correlations greater than 0.3 are shown.Burden of Diarrhea, (BD), is defined as the average of the diarrhea severity (SevD) and frequency (FreqD), i.e., BD=(SevD+FreqD)/2 while burden of flushing (BF), is defined as the average of the flushing severity (SevF) and frequency (FreqF), i.e., BF=(SevF+FreqF)/2).
Abbreviations: EORTC, European Organization for the Research and Treatment of Cancer; DI, diarrhea subscale of the EORTC core quality of life questionnaire QLQ-C30; ENS, Endocrine subscale of the EORTC quality of life questionnaire for gastrointestinal neuroendocrine tumors (QLQ-GINET21); FreqD, mean diarrhea frequency; SevD, mean diarrhea severity; BD, mean diarrhea burden; FreqF, mean flushing frequency; SevF, mean flushing severity; BF, mean flushing burden; r, Pearson’s correlation coefficient; N, number of case pairs in the correlation analysis.
The associations between changes of the different response variables from baseline to week
12 were further explored. Supplemental Table 2 shows that changes in BD and BF were
highly correlated with changes in DI and ENS, respectively. Therefore, DI and ENS were
retained as anchors to determine the MCID threshold for the BD and BF, respectively.
Supplementary Annex 3, Table S2 Correlationsa between change from baseline to week 12 of symptom-based scores and the changes from baseline to week 12 in the diarrhea and endocrine symptoms subscale scores of the EORTC QLQ questionnaires.
Domain dQLQb dQL dFreqD dSevD dBD dDI dFreqF dSevF dBF dENS dFreqOdQLQ 1.000 . . . . . . . . . .P 0.000 . . . . . . . . . .
dQL 0.222 1.000 . . . . . . . . .P 1.000 0.000 . . . . . . . . .
dFreqD -0.138 -0.211 1.000 . . . . . . . .P 1.000 1.000 0.000 . . . . . . . .
dSevD -0.208 -0.225 0.800 1.000 . . . . . . .P 1.000 1.000 0.000 0.000 . . . . . . .
dBD -0.166 -0.224 0.981 0.902 1.000 . . . . . .P 1.000 1.000 0.000 0.000 0.000 . . . . . .dDI -0.442 -0.210 0.519 0.636 0.578 1.000 . . . . .P 0.002 1.000 0.000 0.000 0.000 0.000 . . . . .
dFreqF -0.087 -0.027 0.222 0.175 0.217 0.074 1.000 . . . .P 1.000 1.000 1.000 1.000 1.000 1.000 0.000 . . . .
dSevF -0.238 -0.189 0.297 0.344 0.326 0.290 0.555 1.000 . . .P 1.000 1.000 0.261 0.053 0.101 0.458 0.000 0.000 . . .
dBF -0.137 -0.076 0.265 0.240 0.269 0.142 0.972 0.736 1.000 . .P 1.000 1.000 0.658 1.000 0.587 1.000 0.000 0.000 0.000 . .
dENS -0.300 -0.162 0.385 0.316 0.379 0.258 0.358 0.463 0.421 1.000 .P 0.418 1.000 0.022 0.226 0.027 1.000 0.057 0.001 0.005 0.000 .
dFreqO -0.154 0.138 0.256 0.263 0.270 0.069 0.057 0.115 0.079 0.078 1.000P 1.000 1.000 0.855 0.700 0.579 1.000 1.000 1.000 1.000 1.000 0.000
aOnly correlations greater than 0.3 are shown.bThe “d” prefix denotes that the variable represents a change from baseline to week 12.
Abbreviations: EORTC, European Organization for the Research and Treatment of Cancer; DI, diarrhea subscale of the EORTC core quality of life questionnaire QLQ-C30; ENS, Endocrine subscale of the EORTC quality of life questionnaire for gastrointestinal neuroendocrine tumors (QLQ-GINET21); FreqD, diarrhea frequency; SevD, diarrhea severity; BD, diarrhea burden; FreqF, flushing frequency; SevF, flushing severity; BF, flushing burden; r, Pearson’s correlation coefficient; N, number of cases in the analysis.
Next, the relevant change in the anchor variables was determined. It is widely accepted that a
change of half a standard deviation in a response variable represents a meaningful change.7
The standard deviations for DI and ENS were 31.0 and 23.6, respectively.
The single-question DI subscale “Have you had diarrhea” varies between zero (“Not at all”)
to 100 (“Very much”), where a one-step change corresponds to a value of 33.3, which is
larger than a full standard deviation and, hence, appropriate as a meaningful change. The 3-
item ENS subscale varies from 0 (“No endocrine symptoms”) to 100 (“Very much”) in steps
of 11.1, which is very close to half a standard deviation. Consequently, patients were
classified as experiencing an improvement (responder) if they experienced a change in DI or
ENS of at least one step from screening to week 12.
Finally, receiver operating characteristics (ROC) curves were used to establish a threshold
MCID level. This is a frequently used approach that aims to select an MCID that allows for
the most accurate discrimination between responders and non-responders (ie, a score that
maximizes the correct classification of patients).1,3,4,8
In this context, the PRO instrument at issue (BD or BF) is considered the diagnostic test, and
the anchor (DI or ENS) functions as the gold standard. The anchor distinguishes subjects who
are importantly improved from those who are not changed or have gotten worse. The
instrument’s sensitivity is the proportion of importantly improved subjects according to the
anchor, who are correctly identified by the PRO instrument as importantly improved. Its
specificity is the proportion of “not changed/worse” subjects according to the anchor, who are
correctly identified as “not changed/worse” by the PRO instrument. The conventional ROC
cut-off point is the value for which the sum of proportions of false-positive and false-negative
classifications ([1-sensitivity] + [1-specificity]) is smallest.
It should be noted that a desirable MCID sensitivity or specificity level has yet to be
determined.3 If they are justified, alternative cut-off points are acceptable.8 In our analysis,
the optimal cut-off point was selected to minimize the number of misclassifications. The use
of the conventional sensitivity/specificity‒based ROC cut-off led to a BF MCID value of
0.05, which we felt to be lacking face validity. Analysis of the underlying data showed this
was due to a large number of patients who had no change in BF, as shown by the horizontal
line in the middle of the X axis on the ROC curve. Hence, the MCID threshold that
maximized the number of accurate classifications for BD was established at 0.62 with a
sensitivity of 62.5% and specificity of 88.0%. The area under the ROC curve was acceptable
at 80.6%.3 Similarly for BF, compared to the ENS anchor, sensitivity was 68.8% and
specificity was 87.8%, with an area under the ROC curve of 79.7%.
Supplementary Annex 3, Figure S1. ROC curves for changes in BD (Figure 1A) and BF
(Figure 1B) vs their respective anchors.
BD, diarrhea burden; BF, flushing burden; ROC, receiver operating characteristics.
As mentioned, anchor-based methods use a clinically accepted criterion or an appropriate
patient-based rating of change in health status for defining a meaningful change in a PRO
measure.5 The ELECT trial did not collect a clinician- or patient-reported assessment of
change at the end of the trial that could be used as an anchor to establish a clinically
meaningful change (responder) on the QoL-C30 summary score (SS). The two-item QL
(Global health status) domain of the QLQ-C30 could be considered as a potential anchor. The
correlation between baseline values of the QLQ-C30 SS was found to be acceptable (0.60);
however, the correlation between change from baseline to week 12 in the QL and SS was
inadequate (0.22). This finding was in line with previous reports that found that the two-item
Global QL scale of the QLQ-C30 was not sensitive enough to detect group differences.9 In
the absence of a suitable anchor for the QLQ-C30, a distribution-based approach was
followed, using the standard error of measurement (SEM) as outlined above.6
REFERENCES
1. Revicki DA, Cella D, Hays RD, Sloan JA, Lenderking WR, Aaronson NK.
Responsiveness and minimal important differences for patient reported outcomes.
Health Qual Life Outcomes. 2006;4:70.
2. Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the
minimal clinically important difference. Control Clin Trials. 1989;10(4):407-415.
3. Copay AG, Subach BR, Glassman SD, Polly DW, Jr., Schuler TC. Understanding the
minimum clinically important difference: a review of concepts and methods. The
spine journal : official journal of the North American Spine Society. 2007;7(5):541-
546.
4. Guyatt GH, Osoba D, Wu AW, Wyrwich KW, Norman GR. Methods to explain the
clinical significance of health status measures. Mayo Clin Proc. 2002;77(4):371-383.
5. Revicki D, Hays RD, Cella D, Sloan J. Recommended methods for determining
responsiveness and minimally important differences for patient-reported outcomes. J
Clin Epidemiol. 2008;61(2):102-109.
6. Food and Drug Administration (FDA). Guidance for industry - Patient-reported
outcome measures: use in medical product development to support labeling claims
2009. http://www.fda.gov/downloads/Drugs/.../Guidances/UCM193282.pdf. Accessed
July 14, 2016.
7. Norman GR, Sloan JA, Wyrwich KW. The truly remarkable universality of half a
standard deviation: confirmation through another look. Expert Rev Pharmacoecon
Outcomes Res. 2004;4(5):581-585.
8. de Vet HC, Ostelo RW, Terwee CB, et al. Minimally important change determined by
a visual method integrating an anchor-based and a distribution-based approach. Qual
Life Res. 2007;16(1):131-142.
9. Giesinger JM, Kieffer JM, Fayers PM, et al. Replication and validation of higher
order models demonstrated that a summary score for the EORTC QLQ-C30 is robust.
J Clin Epidemiol. 2016;69:79-88.
Top Related