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

Contents Julius Clinical GoodClinicalPractice Informed Consent Procedure Data collection and Source Data basic requirements Noncompliance Drug Safety Basic requirements investigator EssentialDocumenten Amendments Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial 12-Dec-2012

Contents Roche Diagnostics Data Set; ObjectiveandCharacteristics 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 trial 12-Dec-2012 Julius Clinical ESB_EC

Julius Clinical • Academic Research Organization (ARO) • Academic Excellence • Operational Performance Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial 12-Dec-2012

GoodClinicalPractice • GoodClinicalPractice (GCP) is aninternationalethicalandscientificquality standard fordesigning, conducting, recordinganreporting trials thatinvolve the participation of human subjects. Thisguideline has been incorporated in the Dutch law. • Allprinciples are basedon the 2 pillars of GCP: • Protection of the trial subject: voluntary, with no pressure, oralandwrittenapproval, privacy protection • Quality of trial data Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Informed Consent Procedure • Informed Consent procedure: • Check use of correct approvedversion • Informverbally • Give time toconsiderparticipationandtoaskanyquestions • Have Informed Consent Form signedbyallpartiesbythemselves • Check whetherall the data have been filled in • Give the subject a copy or have the subject sign 2 originalICFs • Document on the patient status of EPD Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Attention points IC procedure • Look out! • The person conducting the IC procedure must beauthorizedforthisby the PI • The subject must alwayssign first • The most recentlyapprovedversion must besigned • The subject must fill in her own name andsignature date • Study procedures maynot start before the ICF is signed • If the procedure developsotherwise, this must bedocumented on a Noteto File Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Patient Information Sheet/InformedConsent Form • #1 audit findings! • No signature investigator; use of a stamp • Signature date missing, incomplete or different • Missing Informed Consent Forms • InformedConsent Processnotdocumented • Signedafter the first study procedure • Signedby a non-authorized person • Incorrect versionused • Patient Information Sheet andInformed Consent Form are a unitand must befiledtogether Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Data collection basic requirements Collected subject data must beunidentifiable: no name, patientnumber or date of birth onCRF or on correspondence Only data necessaryfor the specificobjective as described in the protocol maybecollected AllCRF data must be present in the Source Data (paper or electronic) unlessotherwisespecified in the protocol If data needtobecorrected, the originaltext must becrossed out in a way thatitremainslegible. The correct data must beenteredandprovided of signature, date andifnecessary the reason of the correction The CRA needslimited access to Source Data of the study subjects Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Source Data requirements • Traceable • to the observer, bysignatureand date • Readable • andreported on a permanent medium • Timely • reported at the moment of the observation. Any later additions must besignedanddated • Original • the originalobservations • Acurate • andcompleet reflection of the observation Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Noncompliance • Noncompliancewith the protocol, SOPs, GCP and/or applicableregulatoryrequirements • Depending on the seriousness, noncomplianceconstitutes a deviationor a violation • Protocol deviation: • It does notinfluence the risks or advantagesfor the subject • It does notinfluence the value of het collected data • It was anunintendedmistake of the study team • Protocol violation: • It leads to a risk for the subject, or • It has aninfluence on the scientificvalue of the data, or • There is proofthat the mistake was intendedanditsconsequenceswereoverlooked Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Noncompliancedocumentation • To document a deviation: • Write a NotetoFile, unless the deviationcanbeexplained on another document • Indicate on the NotetoFile what was donetocorrect the mistakeandwhat was donetopreventthismistakefrom happening again • To document a violation: • Write down the violation in the Source Data and/or the CRF • Discusswith the sponsor the steps that must befollowed • Fill in a Protocol Violation form andindicatewhich steps are taken toprevent the problemfrom happening again • Send a copy to the sponsor andfile the original in the ISF Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Drug safety (1) • Adverse Event (AE) Anyuntowardmedicaloccurrence in a patient or clinicalinvestigation subject administered a pharmaceutical product andwhich does notnecessarily have a causalrelationshipwiththis treatment. • SeriousAdverse Event (SAE) Anyuntowardmedicaloccurrencethat at anydose: • Results in death • Is life-threatening (at the moment of the event) • Requiresinpatienthospitalization or prolongation of existinghospitalization • Is a congenitalanomaly/birth defect • Resultsin persistent or significant disability / incapacity Exceptions must beestablished on the protocol! Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

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 • Sendanyadditionaldocuments or information via a follow-up form Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Drug safety (3) • (SUSAR) SuspectedUnexpectedSerious Adverse Reaction • Suspected– posiblyrelatedto the study treatment • Unexpected- the nature or severity of the reaction is not consistent with the applicable product information Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Drug safety(4) Expedited reporting SUSAR (WMO) to CBG • When the incident takes placeunder “your”protocol • Within 15 dayssince the sponsor received the first information about the incident • For fatal or life-threateningincidents, within 7 days • When the incident takes placeunderanother protocol • Semi-annualline listing • If the incident has far-reachingsafetyconsequences, expeditedtimelinesmust beconsidered SUSARs must alsobereportedto the IRB/IEC, CA and investigators within these timelines Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Drug safety (5) • Annualsafety report (WMO) by the Sponsor During the wholestudy • Once a year, togetherwith the StudyProgress Report • Summary of everySAE and SUSAR in the study Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Basic requirements investigator According to the NFU guidelines, the investigators in University Hospitals must be BROK-certified. Investigators in othercentres must have provable GCP knowledge (add GCP certificationto the CV) Otherstudystaff must beauthorizedby the PI before the start of the study The PI must take care thatevery person whoworks on the trial has been trained in the protocol, the IMP and the tasks/obligations The PI must guaranteethatallthoseinvolved are qualifiedfor the tasksthat are delegatedtothem Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Essentialdocuments Investigator Site File (ISF) A folder of the investigator containingalldocuments relevant forthatspecific siteandallgeneraldocumentsapplicable. The investigator or delegated party is responsibleformaintaining the ISF. Archiving of files, CRFsen medicaldossiers Standard: 20 yearsafter the end of the study in University Hospitals (archiefwet) and15 yearsin otherHospitals (GCP) Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Amendments Any changes to the study protocol or procedures must beapprovedby the METC beforeimplementation Changes are consideredsubstantial or nonsubstantial (onlyadministrative changes) amendmentstobesubmittedto the METC Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

Roche Diagnostics Data Set; ObjectivesandCharacteristics • 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. Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial 12-Dec-2012

Roche Diagnostics Data Set; Scope of Work • 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 Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial 12-Dec-2012 22

GCP: Monitoring definition The act of overseeing the progress of a clinical trial, and of ensuringthatit is conducted, recordedandreported in accordancewith the protocol, Standard Operating Procedures (SOPs), GoodClinicalPractice (GCP), and the applicableregulatoryrequirements Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

GCP: Monitoring purposes The purposes of trial monitoring are to verify that: The rightsand well-being of human subjects are protected The reported trial data are accurate, complete andverifiablefrom source documents(source data verification) The conduct of the trial is in compliance with the currentlyapproved protocol/amendment(s), with GCP, andwithall the applicableregulatoryrequirements Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012

General Monitoring • UMCU monitor will make appointment with site • UMCU monitor willvisit the site togetherwith the Julius Clinical monitor • Site will have a combined meeting withboth monitors at the end of the visit • UMCU monitor willbe the major site contact in betweenvisits • UMCU monitor will sent requeststo the site likequeries, action lists Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial 12-Dec-2012

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 Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial 12-Dec-2012

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. Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial 12-Dec-2012

Data Sets Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial 12-Dec-2012

Contact persons Good Clinical Practice & Monitoring activities for a Roche Diagnostics sub-study of the OPTIMIST trial Versie: 06-dec-2012 • Principal Investigator: • Prof. Dr. F.J. Broekmans, UMCU • Study-coordinator: Dr. H.L. Torrance, UMCU PhD student: Charinevan Tilborg, UMCU, ctilborg@umcutrecht.nl UMCU monitor: Marian Kosterman • Julius Clinical: • Engelien Septer-Bijleveld, Project Manager • Karin Groot, Senior ClinicalResearch Associate karin.groot@juliusclinical.com; 0306569125; 063805 9972 • Eva Corral, ClinicalReseachAssociate eva.corral@juliusclinical.com; 0306569161; 0621162930 • Karin Groot and Eva Corralwillbe the contact persons for the sites.

Good Clinical Practice & Monitoring activities for the Roche Diagnostics dataset