good clinical practice & monitoring activities for the roche diagnostics dataset

Good Clinical Practice & Monitoring activities for the Roche Diagnostics dataset

of the OPTIMIST trial

12-Dec-2012

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Contents

Julius Clinical

Good Clinical Practice

Informed Consent Procedure

Data collection and Source Data basic requirements

Noncompliance

Drug Safety

Basic requirements investigator

Essential Documenten

Amendments

Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial12-Dec-2012

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Contents

Roche Diagnostics Data Set; Objective and Characteristics

Roche Diagnostics Data Set; Scope of Work

GCP: Monitoring definition

GCP: Monitoring purposes

General Monitoring

Scope of Julius Clincial Monitoring

Definition of Roche Key Data (“Study Documentation”) from

OPTIMIST Study

Data Sets

Contact persons

Good Clinical Practice & Monitoring activities for a Roche Diagnostics data set of the OPTIMIST trial12-Dec-2012 Julius Clinical ESB_EC

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Academic Research Organization (ARO)

Academic Excellence

Operational Performance

Julius Clinical


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Good Clinical Practice

Good Clinical Practice (GCP) is an international ethical and

scientific quality standard for designing, conducting,

recording an reporting trials that involve the participation

of human subjects. This guideline has been incorporated in

the Dutch law.

All principles are based on the 2 pillars of GCP:

Protection of the trial subject: voluntary, with no pressure, oral and written approval, privacy protection

Quality of trial data

Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trialVersie: 06-dec-2012

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Informed Consent Procedure

Informed Consent procedure:

Check use of correct approved version

Inform verbally

Give time to consider participation and to ask any questions

Have Informed Consent Form signed by all parties by themselves

Check whether all the data have been filled in

Give the subject a copy or have the subject sign 2 original ICFs

Document on the patient status of EPD


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Attention points IC procedure

Look out!

The person conducting the IC procedure must be authorized for this by the PI

The subject must always sign first

The most recently approved version must be signed

The subject must fill in her own name and signature date

Study procedures may not start before the ICF is signed

If the procedure develops otherwise, this must be documented on a Note to File


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#1 audit findings!

No signature investigator; use of a stamp

Signature date missing, incomplete or different

Missing Informed Consent Forms

Informed Consent Process not documented

Signed after the first study procedure

Signed by a non-authorized person

Incorrect version used

Patient Information Sheet and Informed Consent Form are a unit and must be filed together

Patient Information Sheet/Informed Consent Form


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Data collection basic requirements

Collected subject data must be unidentifiable: no name,

patient number or date of birth on CRF or on

correspondence

Only data necessary for the specific objective as described

in the protocol may be collected

All CRF data must be present in the Source Data (paper or

electronic) unless otherwise specified in the protocol

If data need to be corrected, the original text must be

crossed out in a way that it remains legible. The correct

data must be entered and provided of signature, date and if

necessary the reason of the correction

The CRA needs limited access to Source Data of the study

subjectsGood Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trialVersie: 06-dec-2012

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Source Data requirements

Traceable

to the observer, by signature and date

Readable

and reported on a permanent medium

Timely

reported at the moment of the observation. Any later additions must be signed and dated

Original

the original observations

Acurate

and compleet reflection of the observation


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Noncompliance

Noncompliance with the protocol, SOPs, GCP and/or

applicable regulatory requirements

Depending on the seriousness, noncompliance constitutes a

deviation or a violation

Protocol deviation:

It does not influence the risks or advantages for the subject

It does not influence the value of het collected data

It was an unintended mistake of the study team

Protocol violation:

It leads to a risk for the subject, or

It has an influence on the scientific value of the data, or

There is proof that the mistake was intended and its consequences were overlooked


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Noncompliance documentation

To document a deviation:

Write a Note to File, unless the deviation can be explained on another document

Indicate on the Note to File what was done to correct the mistake and what was done to prevent this mistake from happening again

To document a violation:

Write down the violation in the Source Data and/or the CRF

Discuss with the sponsor the steps that must be followed

Fill in a Protocol Violation form and indicate which steps are taken to prevent the problem from happening again

Send a copy to the sponsor and file the original in the ISF


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Drug safety (1)

Adverse Event (AE)

Any untoward medical occurrence in a patient or clinical investigation

subject

administered a pharmaceutical product and which does not necessarily

have a

causal relationship with this treatment.

Serious Adverse Event (SAE)

Any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (at the moment of the event)

Requires inpatient hospitalization or prolongation of existing hospitalization

Is a congenital anomaly/birth defect

Results in persistent or significant disability / incapacity

Exceptions must be established on the protocol!


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Drug safety (2)

Procedure SAE reporting

Consult the procedure in the protocol or study manual

Fill in the SAE form and fax or e-mail a scan of this form within 24 hours of the Sponsor’s knowledge of the event (unless the sponsor is the coordinating investigator)

The Sponsor reports the SAE in ToetsingOnline

Send any additional documents or information via a follow-up form


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Drug safety (3)

(SUSAR)

Suspected Unexpected Serious Adverse Reaction

Suspected – posibly related to the study treatment

Unexpected - the nature or severity of the reaction is not consistent with the applicable product information


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Drug safety (4)

Expedited reporting SUSAR (WMO) to CBG

When the incident takes place under “your”protocol

Within 15 days since the sponsor received the first information about the incident

For fatal or life-threatening incidents, within 7 days

When the incident takes place under another protocol

Semi-annual line listing

If the incident has far-reaching safety consequences, expedited timelines must be considered

SUSARs must also be reported to the IRB/IEC, CA and investigators within these timelines


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Drug safety (5)

Annual safety report (WMO) by the Sponsor

During the whole study

Once a year, together with the Study Progress Report

Summary of every SAE and SUSAR in the study


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Basic requirements investigator

According to the NFU guidelines, the investigators in

University Hospitals must be BROK-certified. Investigators

in other centres must have provable GCP knowledge (add

GCP certification to the CV)

Other study staff must be authorized by the PI before the

start of the study

The PI must take care that every person who works on the

trial has been trained in the protocol, the IMP and the

tasks/obligations

The PI must guarantee that all those involved are qualified

for the tasks that are delegated to them


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Essential documents

Investigator Site File (ISF)

A folder of the investigator containing all documents

relevant for that specific site and all general documents

applicable.

The investigator or delegated party is responsible for

maintaining the ISF.

Archiving of files, CRFs en medical dossiers

Standard: 20 years after the end of the study in University

Hospitals (archiefwet) and 15 years in other Hospitals

(GCP)


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Amendments

Any changes to the study protocol or procedures must be

approved by the METC before implementation

Changes are considered substantial or nonsubstantial (only

administrative changes) amendments to be submitted to the

METC


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Study Objective:

Roche Diagnostics is developing a new automated immunoassay for Anti-Müllerian-Hormon (AMH). Based on data collected from a sub-population of the OPTIMIST study population, Roche desires to study the value of the Elecsys AMH test in predicting the response to controlled ovarian stimulation in IVF/ICSI patients treated with a standard dose of 150 IU of recombinant FSH.

Summary of sub-study characteristics:

Optimist study participants

1.000 women, age 18-44 years, with an indication for IVF or IVF-ICSI receiving a standard stimulation dose of 150 IU/d FSH, only in the first cycle of treatment.

Women will participate in this part for approximately 10 months.

Roche Diagnostics Data Set; Objectives and Characteristics


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Monitoring activities on site: February 2013 – March 2015

Last Patient First Visit: December 2013

On average 5 visits per site (depending on # of patients per

site):

2 monitoring visits in 2013 (8 hours)

2 monitoring visits in 2014 (8 hours)

1 monitoring visit in 2015 (4 hours on site for monitoring of pregnancy outcome).

Julius Clinical SOPs, Forms and Templates will be used

Julius Clinical will not be involved in study management

tasks like obtaining approval for any amended study

documents

Roche Diagnostics Data Set; Scope of Work


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The act of overseeing the progress of a clinical trial, and of

ensuring that it is conducted, recorded and reported in

accordance with the protocol, Standard Operating Procedures

(SOPs), Good Clinical Practice (GCP), and the applicable

regulatory requirements

GCP: Monitoring definition


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GCP: Monitoring purposes

The purposes of trial monitoring are to verify that:

The rights and well-being of human subjects are protected

The reported trial data are accurate, complete and

verifiable from source documents (source data verification)

The conduct of the trial is in compliance with the currently

approved protocol/amendment(s), with GCP, and with all

the applicable regulatory requirements


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General Monitoring


UMCU monitor will make appointment with site

UMCU monitor will visit the site together with the Julius

Clinical monitor

Site will have a combined meeting with both monitors at

the end of the visit

UMCU monitor will be the major site contact in between

visits

UMCU monitor will sent requests to the site like queries,

action lists

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Scope of Julius Clinical Monitoring


100% check on ICFs (re-consent form dated May 2012)

100% SDV for max. 1000 patients who receive the standard

dosis, the fertility work-up and first IVF/ICSI cycle (only 1.

IVF cycle, no cryo cycle, Roche Key Data set)

Check query process & assist Investigators in solving

unanswered SDV queries (only 1 IVF cycle, no cryo cycle,

Roche Key Data set)

Check if study personnel has attended the OPTIMIST

training meeting

Write report within 3 weeks after every visit and send a

copy to Roche and Study Coordinator

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Definition of Roche Key Data (“Study Documentation”) from OPTIMIST Study


First Data Set: to include all key data as specified in the

next slides until completion of first IVF treatment cycle

except information upon Pregnancy Outcome.

Second Data Set: to include all key data as specified in the

next slides of first IVF treatment cycle including

information about Pregnancy Outcome.

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GENERAL PART: Patient

Case number (unique per patient) □□-□□□□ Month & year of birth (mm-yyyy) or Age at cycle (years) Record created (dd-mm-yyyy) Last modified (dd-mm-yyyy) Modified by (trial center)

Inclusion criteria Indication for IVF/ICSI (Y/N) Female age < 44 (Y/N) Regular cycle of 25-25 days (Y/N) No large uterine or ovarian abnormalities on ultrasound (Y/N) No previous IVF/ICSI cycles (Y/N)

Exclusion criteria Oocyte donation (Y/N) Medical reason against IVF/pregnancy (Y/N) PCOS (Y/N) Endocrine or metabolic abnormalities (Y/N)

Consent Informed consent (Y/N) __________________________________________________________________________

Antral follicle count

Date of AFC ultrasound - - (dd-mm-yy) Cycle day O 1 O 2 O 3 O 4 O ≥5 Number of follicles 2-10 mm left ovary (0-30) Number of follicles 2-10 mm right ovary (0-30) Total AFC (0-60 __________________________________________________________________________

Blood sampling

O n O y, if y then date of blood sampling - - (dd-mm-yy)

Data Sets


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Data Sets


Randomization OPTIMIST

Patient randomised for: 01= 100 EH verwachtte high responder (AFC > 15) 02= 150 EH verwachtte high responder (AFC > 15) 03= 150 EH geen randomisatie (AFC 11-15) 04= 225 EH verwachtte low-normal responder (AFC 8-10) 05= 150 EH verwachtte low-normal responder (AFC 8-10) 06= 450 EH verwachtte low responder (AFC <8) 07= 150 EH verwachtte low responder (AFC <8)

__________________________________________________________________________

FERTILITY WORK-UP:

B1) Referred by 01= GP 02= gynaecologist 03= urologist 04= own initiative 05= other

B2) Race 01 = Caucasian 02 = Indian/ Pakistani/ Bangladesi 03 = Afro-Caribbean (Antilles, Surinam-creole) 04 = Hindu, Caribbean (Surinam – hindu) 04 = African (sub-Sahara) 05 = Middle-Eastern + North African (Turkish and Moroccan) 06 = Asian 07 = Other 08 = Unknown

B3) Country of birth

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Data Sets


B21-47) Obstetrical history

B21) Gravidity (0-15 times) B22) Parity (0-15 times)

* Conception: 1 = Spontaneous 2 = Ovulation-induction 3 = Intrauterine insemination 4 = Donorinsemination 5 = IVF/ICSI

B43) Maternity (0-15 times) B44) Spontaneous miscarriage (0-15 times) B45) Surgical abortion (e.g. vacuum curettage) (0-15 times) B46) Extra-uterine pregnancy (0-15 times)

B47) Duration of subfertility □□□ months

B48-49) Intoxications

B48) Smoking O n O y □□ cigarettes per day

B49) Alcohol O n O y □□ units per week

B50) Height woman: □□□ cm

B51) Weight woman: □□□ kg

B52) Trans-vaginal ultrasound O normal O abnormal, if abnormal please specify □□

01= uterine polyp 02= uterine myoma 03= simple ovarian cyst(s) 04= endometriod cyst(s) 05= PCO (>11 follicles in minimally one ovary) 06= other

B53) Laboratory results FSH □□ IU/L (0-no maximum) cycle day □ (0-4)

(MM-YY) Conception* B23) □□-□□ B24) □ B28) □□-□□ B29) □ B33) □□-□□ B34) □ B38) □□-□□ B39) □

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B54) Hysterosalpingogram performed O n O y

If yes, please specify results:

O Hysterosalpingogram (HSG) normal O Hysterosalpingogram (HSG) occluded left O Hysterosalpingogram (HSG) occluded right O Hysterosalpingogram (HSG) occluded both sides O Hysterosalpingogram (HSG) hydrosalpinx left O Hysterosalpingogram (HSG) hydrosalpinx right O Hysterosalpingogram (HSG) hydrosalpinx both sides

B55) Diagnostic laparoscopy performed O n O y

If yes, please specify results:

O Diagnostic laparoscopy with tubal test normal O Diagnostic laparoscopy with tubal test occluded left O Diagnostic laparoscopy with tubal test occluded right O Diagnostic laparoscopy with tubal test occluded both sides O Diagnostic laparoscopy with tubal test hydrosalpinx left O Diagnostic laparoscopy with tubal test hydrosalpinx right O Diagnostic laparoscopy with tubal test hydrosalpinx both sides

B66) Result fertility work-up

Subfertility based on: □□

01= idiopathic subfertility 02= tubal factor 03= endometriosis 04= andrologic factor 05= anovulation WHO I 06= anovulation WHO II: non-PCO 07= anovulation WHO II: PCO 08= cervix factor

FERTILITY TREATMENT:

E) FIRST IVF/ICSI-CYCLE

E1) Treatment type □ 1= IVF ; 2= ICSI E2) IVF number of this cycle □.□.□ First day of present menstrual cycle □□-□□-□□ (dd-mm-yy)

Data Sets


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Data Sets


E3-6) Downregulation

E3) □ oral contraceptive or progestative □ no oral contraceptive or progestative

E4) □ Decapeptyl □ Synarel □ Suprefact □ Cetrotide □ Orgalutran

□ other, please specify ____________________

E5) Start downregulation □□-□□-□□ (dd-mm-yy)

E6) Date last downregulation administration □□-□□-□□ (dd-mm-yy)

E8-17) Stimulation

E8) □ Gonal-F □ Puregon □ Menopur □ Other, please specify__________

E9) FSH/HMG starting dose □□□ Units E10) Start □□-□□-□□ (dd-mm-yy)

E11) Date last FSH/HMG administration □□-□□-□□ (dd-mm-yy)

E12) FSH/HMG adjustment during cycle? O n O y if yes, please specify

E13) Date □□-□□-□□ (dd-mm-yy)

E14) New FSH/HMG dose □□□ Units

E17) Number of follicles

between 12 and 16 mm on last ultrasound before follicle puncture □□

> 16 mm on last ultrasound before follicle puncture □□ E18) HCG administered?

O n, reason O too little follicles O too many follicles, if so what was estradiol on day of cancellation

□□□□□□ pmol/l or □□□□ ng/L

O other, please specify______ O y, specifically O 10.000 Units Pregnyl O 5.000 Units Pregnyl O Ovitrelle

Date of HCG administration: □□-□□-□□ (dd-mm-yy)

E19) Follicle puncture performed?

O n, reason: O personal O premature/spontaneous ovulation O other, please specifiy_________

O y, Date of follicle puncture: □□-□□-□□ (dd-mm-yy)

E20) Number of oocytes harvested □□

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Data Sets


E21-27) Fertilization E21) Fresh or cryo semen? O fresh O cryo

E24) IVF, number of oocytes inseminated □□

E25) ICSI, number of oocytes injected □□

E26) Total number of fertilized oocytes after 24 hours (2PN) □□

E27) Number of embryo’s for transfer □□ E28-34) Embryotransfer

E28) Embryotransfer O y O n if no, specify reason:__________

E29) If yes, number of days after follicle puncture (puncture day=day 0)

O 2 O 3 O 4

E30) Date embryo transfer □□-□□-□□ (dd-mm-yy)

E31) Number of embryo’s transferred O 1 O 2 O 3

E34) Luteal support □ Utrogestan □ Pregnyl

E35-42) Adverse event (AE) after IVF/ICSI

E35) Adverse event (AE) after IVF/ICSI O n O y

E36) Diagnosis (more answers possible)

Mild ovarian hyperstimulation syndrome (OHSS) O n O y Moderate ovarian hyperstimulation syndrome (OHSS) O n O y Severe ovarian hyperstimulation syndrome (OHSS) O n O y Infection after follicle puncture O n O y Bleeding after follicle puncture O n O y Ovarian torsion O n O y Other, __________________________ O n O y

E37) Resulted AE in Serious Adverse Event (SAE)? O n O y

E41) Relation to study procedure

□ Unrelated □ Unlikely □ Possible □ Probably

E42) AE therapy required? □ No □ Yes, specify___________________

E43) Cryopreservation O n O y

E44) If yes, number of frozen embryo’s □□

OUTCOME OF 1. IVF-CYCLE: Pregnant? O n O y Dropout? O n O y

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PREGNANCY OUTCOME

L) PREGNANCY NUMBER 1

L1) O none O yes

L2) Pregnant after O spontaneously O IVF O ICSI O Cryo

L3) If pregnant after treatment from cyclenumber □.□.□

L4) Date of pregnancy test □□-□□-□□ (dd-mm-yy)

L5) Due date: □□-□□-□□ (dd-mm-yy)

L7) Number of fetal sacs □

L8) Number of intrauterine fetus with heartbeat □

L21) Type of multiple: O none O Diamniotic, dichorionic O Diamniotic, monochorionic O Monoamniotic, monochorionic O Visualization not possible

L22) Pregnancy type O Biochemical O Clinical O Abortion O Extrauterine O Ongoing (defined as vital pregnancy > 12 weeks gestation)

M) Pregnancy questionnaire:

Child 1

M1) Gestational age …………….. weeks

Date of delivery □□-□□-□□ (dd-mm-yy)

M2) Weight …………….. gram

M3) Healthy ο n, please specify……………….. ο y

M4) Other ο n ο y, please specify…………………..

Repetition of same questionnaire for

Child 2 and Child 3

Data Sets


35Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trialVersie: 06-dec-2012

Contact persons

Principal Investigator:

Prof. Dr. F.J. Broekmans, UMCU

Study-coordinator:

Dr. H.L. Torrance, UMCU

PhD student:

Charine van Tilborg, UMCU, [email protected]

UMCU monitor:

Marian Kosterman

Julius Clinical:

Engelien Septer-Bijleveld, Project Manager

Karin Groot, Senior Clinical Research Associate

[email protected]; 0306569125; 063805 9972

Eva Corral, Clinical Reseach Associate

[email protected]; 0306569161; 0621162930

Karin Groot and Eva Corral will be the contact persons for the sites.

good clinical practice & monitoring activities for the roche diagnostics dataset

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