2nd European Clinical Data Disclosure Summit

HighlightsSeptember 9-10, 2010

Berlin, Germany

Topics to be discussed…..The European process

◦EudraCT and beyondThe “Multiple Registries” problem

◦Native language◦Emerging registries

Updates and changes to ClinicalTrials.govTechnologyHL7Competitive intelligence

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The protocol is approved

Sorry, but the title exceeds the

maximum number of characters

allowed by the NIH

Is it MeSH or MeDRA Terms ?

I’m working on the

translation for my

local registry

Advantages of a National Registry

Information publicly available in the national language

Users have access to the country’s data as a wholeEasy data retrieval without consultation of several

(international) registriesNational registries provide transparency for the

country’s population, inspiring confidencePromote clinical research

Advantages of a National Registry Overview and evaluation of clinical research in the

specific country Specification of data entry and access to all data

enables data analysis as needed Enable benchmarking compared to other countries Identify neglected areas of clinical research Serve as a basis for funding policy decisions Serve as a WHO primary registry, enabling academic

sponsors to comply with the ICMJE requirements (International Committee of medical Journal Editors)

Requirements of a bilingual RegistryData in national language

◦to inform the national publicData in English

◦for enabling international data exchange◦to collaborate in meta-registries◦To enable international analyses

how to alleviate bilingual data entries?

Cooperation - StructureDecision of the German Ethics Committees Association:

collection of all 20 WHO parameters (minimal data set)Ethics committees launch web portal, which

◦serves as one single contact point when submitting application forms and registering clinical trials for all types of clinical studies

◦allows and supports online completion of forms◦helps to avoid extra work◦provides structured electronic data and/or pdf

Web-PortalShould be the place to go when submitting and

registering trials (drug trials (AMG), medical device trials (MPG), other trials (non AMG/MPG))

Supports the submitter◦filling in the EC-application ◦registering with the DRKS

Should prevent redundant workShould provide structured electronic data

Form Depending on Type of Trial

------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------

• ------• ------• ------• ------• ------• ------• ------• ------• ------

Module 1/EudraCT

Module 2 and additionalWHO-Parameters

XML-file

Completeonline

Trials on medicinal products Non-drug trials

Completeonline

Modified module 2 and additionalWHO-Parameters

DRKS Interface ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------

Modul 1/EudraCT

XML-file

Ethics committees web portal DRKSform

• ------

• ------

• ------

• ------

• ------• ------

• ------• ------• ------• ------

Completeonline

Module 2 and additionalWHO-parameters

The Future for German applicants?

Web-PortalEthicsCommittees

PEI

BfArM

DRKS

EudraCT

International and National CooperationCooperate closely with the International Clinical

Trials Register Platform (ICTRP; WHO) and adhere strictly to international standardisation (use ICTRP data format)

Obtained status as a WHO Primary RegistryFulfilled ICMJE requirements → ICMJE-compliant

registration in GermanyCooperate efficiently with existing registers;

establish processes to share data with partner registries

Member of EudraCT Joint Operations Group at European Medicines Agency

Data ExchangePrerequisiteConsistent data collection

Identical parameter Identical content Identical select list/catalog

◦Data format XML Other structured formats

In Detail

European Medicines Agency◦Phase (Trial Type)

WHO◦Phase

• N/A• 0 (exploratory trials)• 1• 1-2• 2 • 2-3• 3• 4

E.7.1 Human pharmacology (Phase I) E.7.1.1 First administration to humans E.7.1.2 Bioequivalence study E.7.1.3 Other:E.7.1.3.1 If other, please specify

E.7.2 Therapeutic exploratory (Phase II)E.7.3 Therapeutic confirmatory (Phase III)E.7.4 Therapeutic use (Phase IV)

In Detail

EMA◦Phase (Trial Type)

WHO◦Phase

• N/A• 0 (exploratory trials)• 1• 1-2• 2 • 2-3• 3• 4

E.7.1 Human pharmacology (Phase I) E.7.1.1 First administration to humans E.7.1.2 Bioequivalence study E.7.1.3 Other:E.7.1.3.1 If other, please specify

E.7.2 Therapeutic exploratory (Phase II)E.7.3 Therapeutic confirmatory (Phase III)E.7.4 Therapeutic use (Phase IV)

Coding / Standardized Data Entry Data is standardized and coded using existing international

coding systems wherever possible to◦avoid typing errors◦allow automated quality assurance procedures◦allow data exchange◦allow data analysis

Data entry only in one language needed◦Exception: 11 (free text) parameters need double entry

in English and German (e.g. title, brief summary in lay language, interventions, outcomes, inclusion and exclusion criteria)

Automation in updating the dynamic data on clinicaltrials.gov

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Study status update and sites registrationMultiple Monthly Updates of the overall

studies status with study start/endMultiple Monthly Updates of all the sites

participating to the studies (for recruiting studies only)

Status & sites

update(monthly)

CTMS

Previous posting

Gap Analysis +

consistency checking

About 5000 active Investigators

10% to update every month

XML outputs

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Main advantages of the applicationOld Method New Method

Manual registration of the countries enrolled from the data available in the CTMS

Automatic data collection of the countries & sites from the CTMS

Difficulties to identify the study status to be updated

The system detects and calculates the study status to be updated

Sites registration was not possible (too many data)

- Registration at site level now possible- A single upload of XML to update several studies with sites and their status at the same time

Applicable Clinical Trials…generally include interventional

studies (with one or more arms) of drugs, biological products, or devices that are subject to FDA regulation, ◦meaning that the trial has one or more sites

in the U.S, involves a drug, biologic, or device that is manufactured in the US (or its territories), or is conducted under an investigational new drug application (IND) or investigational device exemption (IDE)

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Delayed Submission of ResultsFDAAA allows for Delayed Submission of Results via:• Certification; or• Request for Extension

CertificationA responsible party may submit a certification for delayed submission of results information for an applicable clinical trial that is: • Completed before the drug or device is initially approved,

licensed, or cleared by the FDA ("seeking initial approval"), or

• Studying a new use of an FDA-approved drug or device (i.e., a use not included in the labeling) for which the manufacturer of a drug or device is the sponsor of the trial and has filed or will file within a year an application to the FDA for approval or clearance of that use ("seeking approval for a new use")

Sept 10, 2010Confidential - 180 Global Consulting, LLC 21

Delayed Submission of Results

Request for ExtensionAllows the Director of NIH to provide an extension of the deadline for submission of results information for an applicable clinical trial if the responsible party submits a written request that demonstrates good cause for the extension and provides an estimate of the date on which the results information will be submitted.

When: not later than one (1) year after the earlier of the estimated or actual completion date (PCD) of the trial

Sept 10, 2010Confidential - 180 Global Consulting, LLC 22

Results data elements◦ Results Point of Contact◦ Certain Agreements ◦ Participants Flow◦ Baseline Characteristics◦ Outcome Measures

Statistical Analysis◦ Limitation and Caveat ◦ Adverse Events

Serious Adverse Events◦ – Table of anticipated & unanticipated serious adverse events◦ – Grouped by organ system◦ – Number and frequency of event in each clinical trial arm

Non-Serious Adverse Events◦ Exceed a frequency of 5 percent within any trial arm

Sept 10, 2010Confidential - 180 Global Consulting, LLC 23

Results Disclosure ProcessEl

igib

ilityFDA

RegulatedApplicable Clinical TrialPCD on or after 9-27-07

Prep

arat

ion Create

PRS accountAssign rolesCommunicate to clinical teamTraining

Data

Ent

ryResults xml generationManual data entry

Revi

ew/A

ppro

veReview data for consistency Approve data for disclosure

Rele

ase

or su

bmitRelease

data to clinicaltrials.gov M

onito

r for

QAExpect

QA commentsModify results with team and re-release

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1-3 cycles

Entering Results in PRSOption 1 – Manual data entry directly in the PRS

system◦Test – https://prstest.nlm.nih.gov◦Live – https://register.clinicaltrials.gov

Option 2 – xml upload using the PRS upload function

You must first…◦Request PRS login account as administrator◦Protocol must have NCT # for results entry (except in

PRS Test system)

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Helpful Hints

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Spell out term when first used, acronym in parentheses Use precise language

Do not use “proportion” unless providing a ratio Do not use “rate" unless providing a quantity in relation to

another unit (e.g., participants per unit time) If simply reporting the number of participants, use “number”

for Measure Type In general, spell out symbols such as –

“Percentage” for “%” , “Number” for “#” For measures obtained using a scale -

Name of scale is provided in “Measure Title.” Range and direction of scores (0 = worst; 10 = best) are

indicated in “Measure Description.” “Unit of Measure” is “units on a scale” if no other unit

ClinicalTrials.gov Results Posted*(2009 vs 2010)

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* Data provided by Clinicaltrials.gov As of September 2010 – over 95,000 trials registered on Clincaltrials.gov

What’s new in the Clinicaltrials.gov PRS? New Results Outcome Measure Fields (Sept. 1)

◦ Optional "Type of Units Analyzed" and "Number of Units Analyzed" (per arm/group) for an outcome measure. Use these new fields when the basis for outcome measure analysis is not participants.

Minor Results Display Changes (Sept. 1)◦ In the Results Participant Flow section, the total for all Arm/Groups

(i.e. sum per row) is automatically computed and displayed for each Milestone and "Reason Not Completed".

◦ A new expanded adverse events display is available on the "Results Overview" screen

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What’s on the Horizon?Expanded Results by Rulemaking

FDAAA requires NIH to issue regulations by 27 September 2010 expanding the Registry and Results Data Bank

Issues to be addressed in the rulemaking …1) Inclusion of results for “unapproved products”2) Technical and non-technical summaries 3) Copy of “full” protocol when results are submitted4) Increasing the timeline for submitting results from 12 to 18 months after the earlier of the estimated completion date of the trial or the actual date of completion

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Trial Data Disclosure: IT Perspective

The Value of Consistency

Infrastructure – Data SourcesClinical Trial Management Information

◦ Clinical Trial Management System (CTMS)◦ Clinical Trial Database◦ Trial Spreadsheets

Trial disclosure data collection formsProtocol/Clinical Study ReportClinical Data Management System (CDMS) such as

SASPharmacovigilance System

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Infrastructure – Data Destination Registries

◦ Clincaltrials.gov◦ EudraCT (CTA)◦ India◦ Italy◦ Australia/New Zealand◦ Etc.

Company Trial WebsitePublicationsForm 3674Clinical Trial Insurance Application FormsPatient Recruitment Call Centers

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1. What are your main data sources

2. In what other systems/processes do you use disclosure data

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Departments Responsible for Posting

April 8, 2023Trial Data Disclosure: IT Perspective 34

Department Primarily Responsible for RegistrationClinical OperationsRegulatory AffairsClinical Sciences / Clinical R&DMedical WritingMedical AffairsClinical Communications and StandardsDepartment Primarily Responsible for ResultsRegulatory AffairsClinical OperationsBiostatisticsMedical and Scientific AffairsPublicationClinical R&DMedical WritingClinical Communications and Standards

Trial Disclosure - Stakeholders

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Challenges of Manual Entry

•Often over 250 data points to manually enter into public database

•Clinical teams have often moved on to other studies and now have to regroup to enter data

•Timely•Risk in quality of manually entered data

•Risk of inconsistency with Clinical Study Reports (CSRs) and publications

•Quality control is very lengthy in order to ensure accuracy

Challenges of manual data

entry to a public

database

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Lesson LearnedNeed to automate data capture to

improve:Accuracy

Efficiency

Consistency

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Comparison With Clinical Study Report Preparation

At one time, medical writers would enter statistical data into CSRs

Statisticians and programmers suggested process to automate importation of statistical results to CSR to avoid manual entry by Medical Writers◦ Conversion of Statistical Analysis System

(SAS) data into rich text format (RTF) tables◦ Copy and paste into CSRs◦ QC validation

Desire to have analogous process for Clinical Registry process

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Getting Started

Determine xml capability of the public database

Determine whether xml

upload must be total or may be partial for the

public database

Determine a workflow to

incorporate the input of text in addition to the

statistical data, if necessary

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Determine Required Data

Data NeededParticipant flow

Baseline and demographic

characteristics

Primary outcome measures

Secondary outcome measures

Serious adverse events

Other adverse events

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Build Into Statistical Workflows

Determine milestones in study timeline

• Dataset creation

Develop templates and layouts of SAS datasets for the various scenarios that will be encountered

• Number of study arms• Stratification, if applicable• Type of study (eg, crossover, parallel)• Incorporate data requirements and terminology that

must be used for the public database

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Develop Final Clinical Trial Analysis Datasets in SAS Format

Define SAS datasets based on the requirements of the public database

Develop set of SAS macros to:◦ Create the datasets from clinical trial SAS

database◦ Create an xml file from the datasets according to

the schema of the public databaseDevelop and use QC tool to validate the xml

file according to the public database schema and contents of the xml file

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“Basic Results” Disclosure to a Public Database

Current Strategies to Facilitate the Process

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•Standardized templates for communication•Central Help Desk support Communication With our Customers

•On-boarding of new contacts or new operating companies•Community of practice meetings are held to share best

practices •Central shared access for training materials using Microsoft

SharepointCustomer

Focus

Automation in the Future

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• User-friendly dashboard • Automated workflows • Automated technical quality checks• E-signature • Automation of text to supplement data

A fully automated process facilitating

transfer of data to the various public

databases in consistent manner

• Efficiency and accountability• Reporting capabilities• Tracking• Transparency• Data accuracy• Consistency• Optimized compliance

Benefits

Clinical Registry Processes – Future Considerations for Automation

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Linking statistical, clinical ,and regulatory

databases to Clinical Registry

Linking product dictionary database•Automated feed of molecule data•Provide NCT# automatically

Linking to the publication system•PubMed information is automated

•Central checkpoint for consistent publication

Integration of existing systems that benefits the entire organization

Still have any questions? For additional information on ExL Pharma’s Clinical Data

Disclosure Summits, please visit www.exlpharma.com