Roadmap for study startup

7/29/2019 Roadmap for study startup

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Section 1: Introduction and overview

1.1 Introduction

Eective management o the clinical trials process can signicantly aect a companys

bottom line.

According to a study by Cutting Edge In ormation, companies stand to lose between $600,000

and $8 million or each day that clinical trials delay a products development and launch.

Furthermore, only 6% o clinical trials are completed on time, and 72% o trials run more than

one month behind schedule (Cutting Edge Inormation 2004). A key challenge is that the clinical

trials process spans so many dierent parties, including study sponsors, contract research

organizations (CROs), site management organizations (SMOs), patient recruiters, investigators,

and patients.

By observing and working with customers across many industries over the last decade, Adobe

has developed solid technologies that can help decrease cycle times and reduce errors by

automating key manual tasks and processes.

I you currently have a process thats manual and heavily paper-based or one that involves a legacy

I inrastructure, the task o automating dierent steps in the clinica l trials process may seem

daunting. Tis roadmap ocuses on one key area o the clinical trials processstudy startupand

shows how Adobe technology can help you gain a signicant competitive advantage in new

product development.

Te study startup phase, which includes investigator enrollment and submission o new

investigator packages, is a time-consuming component o the clinical study process. Te

Signatures and Authentication or Everyone (SAFE) BioPharma Association recently identied

Form 1572, used by clinical investigators participating in trials, as the single most redundant

paper orm received by the FDA. Te newsletter goes on to state that bet ween 220,000 and

240,000 1572 orms are received each year by the U.S. agency and that conversion rom paper

to an electronic orm would save an average o $159 per ormor more than $38 million per

year (Shields-Uehling 2006).

Tis roadmap identies opportunities to develop pilot projects and implement larger strategies

to streamline your companys study startup process while simultaneously delivering

immediate ROI.

Tis roadmap is a guide or deploying Adobe technology to automate certain processes associated

with the initiation o clinical studies. It is not a substitute or agency-issued regulations or

guidances, nor is it a substitute or in-house SOPs that have been created in accordance with any

government regulations or guidances. Rather, this roadmap is intended to be a supplement that

provides step-by-step instructions or implementing Adobe technology to streamline certain

procedures. Many actors outside the scope o this document must be considered to successully

complete the processes associated with the initiation o clinical studies. Please reer to the

appropriate government and industry regulations and guidances concerning the conduct o

clinical studies:

www.da.gov/cder/index.html

www.da.gov/cber/index.html

www.emea.eu.int

www.sae-biopharma.org

www.phrma.org/updated_principles_or_conduct_o_clinical_trials_and_

communication_o_clinical_trial_results


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Tis document explains how Adobe technology can help automate the well-dened, repetitive

processes associated with getting a clinical trial up and running. It provides inormation

concerning the technical implementation o Adobe technology as well as guidance or

modications to the overall processes.

1.2 Overview of the clinical study process

Te Guidance or IndustryE6 Good Clinical Practice: Consolidated Guidance (reerred to in this

guide as the guidance) is an international ethical and quality standard or designing, conducting,

recording and reporting tria ls that involve the participation o human subjects. Te ull guidance

can be ound at www.da.gov/cder/guidance/959nl.pd. Te guidance was developed within the

Expert Working Group (Ecacy) o the International Conerence on Harmonization o echnical

Requirements or Registration o Pharmaceuticals or Human Use (ICH) and has been subject to

consultation by the regulatory parties, in accordance with the ICH process.

As detailed in the guidance, all clinical studies require the development and approval o a protocol,

which is a document that describes the objective(s), design, methodology, statistical consideration

and organization o a tria l, and usually includes the background and rationale or the trial. Te

protocol should describe the scientic basis or the study in a clear, detailed manner.

Te protocol also details t he requirements or identiying the appropriate Institutional Review

Board/Independent Ethics Committee (IRB/IEC) and or identiying and enrolling investigators

to assume responsibility or the proper conduct o the trial. Beore initiating a trial, investigators

are required to provide written approval rom the IRB/IEC or the protocol, written inormed

consent, subject recruitment procedures, and any other written inormation to the subjects.

Investigators are also required to provide the IRB/IEC with their current investigators brochure.

1.3 Investigator responsibilities

Te term investigator is dened on page 5 o the guidance as, A person responsible or the conduct

o the clinical trial at a trial site. I a tria l is conducted by a team o individuals at a trial site, the

investigator is the responsible leader o the team and may be called the principal investigator.

Investigator responsibilities include:

Subjectrecruitment

Medicalcareofsubjects

Collect ionofsubjectsinformedconsentforms

CommunicationwiththeIRB/IEC

Protocolcompliance

Investigationalproducts

Randomizationandblindingprocedures

Datareporting

Safetyreporting


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1.4 Clinical trial timelines

Although the end-to-end timeline or clinical trials varies depending on the type o trial, the

number o patients, and the length o the trial, the process steps required to initiate, conduct, and

complete any clinical trial are consistent across all trials (see Figure 1). Tis roadmap ocuses on

the activities associated with conducting study startup procedures, with an emphasis on enrolling

investigators, ling the IND amendments or new investigator packages, and perorming duties

surrounding drug accountability. Because these processes are repetitive and consistent across all

clinical trials, once process eciencies are implemented or these procedures, savings can be

realized across all clinical trials, regardless o the project, type, or length o the trial.

PDF

Figure 1. Clinical study process overview

No

Yes

Yes

PROTOCOL

Create/update clinical

study report

Create/update clinical protocol

CLINICAL PROTOCOL

File protocol with

appropriate agencies

PDF

PDF

Get protocol approval

File clinical study report

with agencies

Collect, analyze, and

summarize data

REPORT

End

Start

Conduct study startup

procedures

Conduct clinical study

Complete study

Conduct study

closeout procedures

PDF

SUBMIT

1

2

3

4

CLINICAL PROTOCOL

No


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Section 2: Study startup procedures

Adobe technology helps automate study startup procedures (which are illustrated in Figure 2).

Tese technologies are exible; they can be implemented incrementally to achieve optimal process

eciency over time. Tis roadmap provides detai led descriptions to help you implement some or

all o those technologies based on your desired level o automation.

Details concerning the implementation o Adobe technology are provided in each step described

in this guide. It is important to note that the only sofware required or investigators is the ree

Adobe Reader and an e-mail account to send and receive orms and documents.

Sponsors and CROs may need additional Adobe inrastructure components, including:

LiveCycle PDF Generator ESEnables investigator packages to be assembled as Adobe PDF

les or submission to the agency

LiveCycle Rights Management ESEnables document-level version and access control o

Adobe PDF les and Microsof Word and Excel documents, so condential in ormation is

restricted to intended recipients

LiveCycle Reader Extensions ESEnables the use o the ree Adobe Reader client

LiveCycle Process Management ESEnables the management o ad hoc processes

with investigators

Adobe Acrobat ProfessionalEnables creation o PDF les as well as commenting anddigital signatures

LiveCycle Digital Signatures ESEnables the validation o digital signatures

LiveCycle ES Connectors for ECMEnables seamless integration between LiveCycle ES

solution components and your ECM system

For more inormation about Adobe LiveCycle ES solution components, visit www.adobe.com/

liesciences/solutions/livecycle . For details on Acrobat Proessional, visit www.adobe.com/acrobat.

Figure 2. Study startup procedures

Start

Identify IRBs/IECs

Enroll investigators

SUBMIT

Recruit additional

investigators

+IRB IEC

No

YesOK

$

Identify investigators

Ship study drug

Collect nancial

disclosure information

Monitor patient

recruitment

Patient

End


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2.1 Identifying and enrolling investigators

Te process o identiying and enrolling investigators is linear in nature and is consistent

across all therapeutic areas. Te process is well dened by the U.S. FDA and is repetitive,

which allows eciencies to be implemented across all t herapeutic areas. Figu re 3 shows an

overview o the process.

2.1.1 Identifying investigators

Investigators whose expertise qualies them or the study are identied. Section 4, Page 13, o

the guidance details investigator qualications as ollows:

4.1.1 Te investigator(s) should be qualied by education, training, and experience to assume

responsibility or the proper conduct o the trial, should meet all the qualications specied by

the applicable regulatory requirement(s), and should provide evidence o such qualications

through up-to-date curriculum vitae and/or other relevant documentation requested by the

sponsor, the IRB/IEC, and/or the regulatory authority(ies).

4.1.2 Te investigator should be thoroughly amiliar with the appropriate use o the

investigational product(s), as described in the protocol, in the current Investigators Brochure,

in the product inormation, and in other inormation sources provided by the sponsor.

Sources o inormation or identiying investigators include, but are not limited to:

In-houseinvestigatordatabases

www.clinicaltrialnetwork.com

CROsenlistedtoassistintheconductoftheclinicaltrial

Figure 3. Enrolling investigators

Sponsor downloads1572 as an intelligent PDF

form from FDA website

Sponsor enables SAFE

signature for investigator,applies security/policy

PDF

FDA

1572

Sponsor completes

appropriate sections

of 1572

Investigator

completes required

information on 1572

Sponsor routes electronic1572 to investigator

Investigator receives 1572

Investigator applies

SAFE signature and

attaches CVs

Investigator

electronically routespackage to sponsor

Sponsor receives

electronic 1572from investigator

Sponsor conducts

QC according to

in-house SOP

FDA

1572

errors

Sponsor summarizes

errors/questions for

investigator

questions

?

FDA1572

Has investigator

information changed?

?

Update in-house

investigator

database

Update electronic

trial master le with

components and

metadata

MASTER

Update project

tracking information

File new

investigator package

PDF

Is information

correct?

Investigator

Yes

No

Yes

No

1572

EndEnd

Start

1572572

PDF

157257

PDF

15721572

PDF

1572157

PDF

1572572

PDF

1572572

PDF

PDF

PDF

questions

Standards

of

Procedure


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2.1.2 Enrolling investigators

Once the investigators are identied and the site initiation procedures have been completed, the

procedures to enroll investigators or the purpose o conducting the trial are complete. For trials

conducted under the regulations o the FDA (both CDER and CBER), the steps illustrated in

Figure 3 must be ollowed. Tis section rst examines each o these steps and then identies how

Adobe technology ca n help streamline t he process.

1. Te sponsor starts Form 1572, which is available on the FDA website at www.da.gov/opacom/

morechoices/daorms/deault.html. Form 1572 must be completed or each investigator to be

enrolled. Certain elds can be prepopulated with data (such as elds 15, 7, and 8). Te orm

can be sent electronically or printed and physically mailed to each investigator.

2. Te investigators receive the orm. Investigators who receive an electronic orm can use Adobe

Reader to complete it, print it, attach any required documentation such as CVs, sign it, and

return it to the sponsor. Investigators who receive a paper orm in the mail need to ll out the

paper version, sign it, attach the CVs, and mail it back.

3. Once the sponsor receives the paper version, the individual responsible or the study does

the ollowing:

Reviewsthenewinvestigatorpackagetoensurethattheformhasbeencompletedcorrectly,

the inormation is valid, and the appropriate supporting documents have been attached. I

errors or questions are identied that require changes to the 1572, the sponsor must contact

the investigator and ofen must route an updated orm to the investigator or a new signature. Veriesthatanyupdatedinformation(suchastheinvestigatorsaddress)isenteredintothe

in-house database(s) used to create the 1572.

Retainsacopyofthe1572withattachmentsforthetrialmasterle.

RetainsinvestigatorCVsforthetrialmasterleandtheproductapplicationtotheFDA.

Tis roadmap identies high ROI areas based on past customer implementations in the

pharmaceutical industry and other industries. In addition, it provides options to automate the

manual process described in the previous section to reduce the cycle times and cost or enrolling

investigators in a clinical study. Similar problems and challenges have been addressed in other

industries, such as nancial services and telecommunications. Mobile phone applications and

mortgage applications are two examples o processes that Adobe has helped streamline to provide

signicant ROI in terms o costs savings in paper and processing time. Many challenges at thecore o these processes are also present in the study startup process.

Adobe technology oers several opportunities to dramatically streamline the investigator

enrollment process, enabling you to reduce cycle time and resources required to complete

investigator enrollment or clinical studies:

Information collection and tracking. Each study may require many investigators to be recruited,

and each investigator must complete a 1572. It is time-consuming and costly to prepare and route

paper versions o the orm. Once routed, the orms must be tracked to ensure that investigators

return the orms in a timely manner. While e-mailing electronic orms to investigators is an

improvement, utilizing l l-and-print orms still restricts optimal unctionality.

Information management. Whether e-mailing or mailing the orm to the investigator, the

sponsor must still process the paper version o the orm and attachments when they are returnedI there are errors, the sponsor must work with the investigator to correct the inormation, which

may include reprocessing the 1572. Te returned in ormation may also be compared with

database inormation used to create the orm. I the inormation has been modied, the sponsor

must manually update any in-house databases used to create the 1572. Finally, sponsors must

ensure that copies o the returned documents are placed in the appropriate repositories or

maintaining the trial master le as well as ensuring the availability o investigator CVs or

inclusion in a uture application.


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Te investigator enrollment process, while well-dened and repetitive in nature, presents many

challenges that can add considerable delays in getting a clinical tr ial started. Te manual process

could easily result in weeks o elapsed time or each 1572 orm that you process. Multiplying the

number o investigators recruited each year with the elapsed time spent by an organization or

each investigator, results in a signicant cost. Tese delays in completing the study startup phase

can also lead to delays in submission, approval, and product launchmeaning potential lost

revenues o millions o dollars. Additionally, allocating resources to the manual routing and

tracking o the 1572 orms is costly in terms o both money and valuable resources that could be

allocated to other more critical tasks.

Adobe technology can improve the investigator enrollment process. Tis roadmap describes the

improvements in phases, which enable incremental implementation. As each phase is implemented

ROI increases exponentially.

2.1.2.1 Phase 1: Improving information collection

Phase 1 ocuses on acilitating the three steps or enrolling investigators that are outlined in section

2.1.2. Te current 1571 and 1572 PDF orms on the FDA website are locked by the FDA, so their

unctionality cannot be enhanced by adding unctionality such as data saving, digital signatures,

and dynamic barcodes. Te versions o orms 1571 and 1572 supplied with this roadmap have been

revised using Adobe LiveCycle Designer ES to add advanced PDF unctionality. o use the 1572

provided with this roadmap:

1. Add an e-mail button on the 1572 with the e-mail address set to the individual in your

organization that wil l receive the completed orms. Add additional data validation to the

orm with LiveCycle Designer ES to veriy user input and completeness on the orm, such as

adherence to acceptable values or a particular eld and completion o elds that are mandatory

beore a signature can be applied.

2. Enhance the orm using Adobe LiveCycle Reader Extensions ES or Acrobat Proessional

(version 8 or later) to provide investigators with the ollowing rights:

Attachdocuments(availableonlywithLiveCycleReaderExtensionsES)

Updateformelds

Applyanelectronicsignature

Details on using Acrobat Reader-enablement and Adobe LiveCycle Reader Extensions ES can

be ound at www.adobe.com/products/livecycle .

3. E-mail the orm to the investigator or make it available via a portal i a website portal has

been set up or the clinical study.

Once the PDF orm has been enhanced, the investigator can use the ree Adobe Reader to ll out

the orm, sign it using a digital signature (such as SAFE), attach the appropriate supporting CVs,

and send the orm with attachments back to the sponsor. Tese simple steps eliminate the

exchange o paper documents resulting in a reduction in cycle time, errors, and costs.

For more inormation about SAFE, visit www.sae-biopharma.org or www.adobe.com/

liesciences/sae.html.

2.1.2.2 Phase 2: Enhancing information management

Phase 2 provides the capability to automatically manage the 1572s with attachments, as they arereceived rom investigators. Te steps in this phase are:

1. Complete the three steps rom Phase 1 (see section 2.1.2.1).

2. Within your existing e-mail system, set up an e-mail address or LiveCycle Process

Management ES to accept the completed orms.

3. Set up LiveCycle Process Management ES Server to route the attachment (new investigator

package) to the appropriate individual to conduct a quality control inspection.


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4. Congure LiveCycle Process Management ES to route the attachment to LiveCycle Forms ES

Server on approval o QC inspection.

5. Set up LiveCycle Forms ES Server to accept tasks rom LiveCycle Process Management ES and

extract the data (as an XML data stream) rom the 1572 orm.

6. Congure LiveCycle Process Management ES to route the completed new investigator package

as a PDF le or inclusion in the 1571 package.

2.1.2.3 Phase 3: Enhanced integration with existing ECM or project management software

Organizations that do not currently use a repository or managing orms can benet rom

Adobes process management suite, which includes LiveCycle Process Ma nagement ES and

LiveCycle Content Services ES. Tis suite is a good starting point or electronically managing the

status o the orms being sent out and returned across one or many clinical trials. LiveCycle ES

can be congured or event notication and exception reporting and can provide a dashboard

view o the status. Additiona lly, LiveCycle Content Serv ices ES includes an enterprise content

management repository and enables your team to rapidly implement end-to-end processes that

heavily interact with content and automate the assembly and generation o PDF packages to

share with regulators or process participants. For more inormation, visit www.adobe.com/

products/livecycle.

For organizations that currently have a database or investigators, an electronic trial master le,

and/or an electronic project tracking system, LiveCycle ES Connectors or ECM can be congured

to integrate with any or all o these systems to automatically update the attributes, data, andcomponents. Not only can the investigator automatically ll out and sign the orm with the ree

Adobe Reader, but LiveCycle ES can automatically manage the new investigator packages being

returned. You can congure LiveCycle Process Management ES to automatically:

Updatein-houseinvestigatordatabases

Routetheappropriatedocumentstothetrialmasterletheworkowcanbeconguredto

update the tria l master le with t he attachments (such as CVs) and data rom the new

investigator package

Updateanyin-houseprojecttrackingdatabase

For specications concerning these integrations, see www.adobe.com/devnet/livecycle/workfow/

articles/lc_workfow_qpac_overview.pd.

2.1.2.4 Other challenges

Adobes digital signature technology and partnerships with key security vendors ensure that

Adobe products support high-assurance and standards-based methods or applying digital

signaturesincluding SAFE-compliant digital signatures. However, not all processes require or

support digital signatures. In these situations, Adobe LiveCycle Forms ES can be used to place a

2D barcode on an Adobe PDF orm during orm design. Tese high-capacity barcodes capture

data as inormation is entered into the Adobe orm. When complete, the orm can be printed,

signed with a wet signature, and returned to the sponsor. When the paper orm is received, the

sponsor can scan the barcode and extract the inormation as an XML data stream or processing

For more details about Adobe LiveCycle Forms ES, visit www.adobe.com/products/livecycle .

Once the investigator package is complete, it can be led with the Investigational New Drug

(IND) application.

2.2 Filing new investigator submissions

Te documentation supporting studies conducted under a U.S. IND application must be led with

the FDA in accordance with existing regulations. New investigator enrollments must be approved

by the agency prior to the initiation o the study at the investigators site. Te ollowing section

details the process or ling the new investigator package with the FDA and describes how Adobe

technology can automate the process steps. Figure 4 shows an overview o this process.


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Figure 4. Filing a new investigator package

Start

Download 1571 as an

intelligent PDF formfrom FDA website

PDFFDA

1571

Complete 1571 in

accordance with FDA

regulations

Retrieve/assign IND/BBIND

serial number (e-CTD

sequence number)

XXX-XXXX

1571

Create cover letter

1571

Assemble coverletter, 1571, 1572,

and attachments

in accordance withFDA guidance

1572

1571

Apply SAFE signature

Submit package to FDAvia approved transport

PDF

Post electronic in-housecopy of submission for

access by authorized

project team members

RECORDS

Update submission

management

tracking system

EndEnd

Start

2.2.1 Submitting and updating the IND application

Submitting and updating a paper-based IND application is labor intensive and error prone. An

IND application consists o multiple submissions detailing the progress o the project. Te

FDA-dened hierarchy or describing the series o submissions across an IND application is

detailed here:

InitialINDapplication:IDassignedbyagencyplusinitialsequenceorserialnumber,suchas

IND 12345, Serial 0000

Firstupdate:IDassignedbyagency,plussequenceorserialnumberincrementedbyone,such

as IND 12345, Serial 0001

Secondupdate:IDassignedbyagency,plussequenceorserialnumberincrementedbytwo,

such as IND 12345, Serial 0002

Te 1571 is required or submitting or updating an IND application. Multiple new investigator

packages can be included with a single submission or update. Te steps or submitting the IND

application are:

1. Te serial or sequence number is assigned to the submission.

2. All components (cover letter, i applicable, 1571, and 1572s with attachments) are assembled

in accordance with existing agency regulations.

3. Te orm and package are signed and sent to the FDA.

4. Te package, including a ll revisions and updates, is posted internally or in-house consumption.

Adobe technology can help streamline the assembly and submission o IND amendments and

acilitate internal review, approval, and tracking o submissions across your organization. Te

next section shows how Adobe technology can optimize this process.


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2.2.1.1 Assembling, posting, and tracking the IND package

Te enhanced 1571, supplied with this roadmap, can be prepopulated with the correct project

and sponsor inormation. Te entire package can then be assembled in one o two ways:

OnthedesktopwithAdobeAcrobat

OnaserverusingLiveCycleProcessManagementESandLiveCyclePDFGeneratorES

For organizations that process a large number o new investigator packages, using a server is

preerable. Because LiveCycle Process Management ES and PDF Generator ES are server-based

applications, they can be integrated with other enterprise applications or automated processes to

operate with little or no manual intervention.

Once the package is assembled, 1571 orms can be signed with a SAFE digital signature in Acrobat

or Adobe Reader and submitted to the FDA via the e-submission gateway. Te ability to submit

the package electronically oers signicant savings by eliminating many paper-based processes.

In addition, the electronic package can then be posted to in-house repositories (as detailed later

in this section).

In addition to automating the submission o the new investigator package to the FDA, Adobe

technology can automate repetitive tasks such as posting the submission or in-house consumption

and updating an in-house submission management tracking system.

Adobe LiveCycle Process Management ES can be integrated with in-house repositories posting

submission updates and updating submission status to automatically update both the components

and the associated metadata. In addition to automating the assembly and submission o IND

amendments, Adobe LiveCycle ES can automatically manage and track submission components.

You can congure LiveCycle Process Management ES to automatically:

Routetheappropriatedocumentstothedocumentmanagementsystem(DMS)thatstores

the submission components and to update the DMS with the components and metadata o

the IND amendment

Updateanyin-housesubmissiontrackingdatabase

For specications concerning these integrations, see www.adobe.com/devnet/livecycle/workfow/

articles/lc_workfow_qpac_overview.pd.

2.3 Shipping and managing clinical supplies

All records and documentation detai ling the shipping, receipt, storage, handling, and disposition

o investigational products are identied in the guidance as essential documents and must be

maintained both by the investigator at the trial site and by the sponsor at its acilities. Te

procedures or managing clinical supplies and producing the supporting essential documents

can be developed and implemented by each individual sponsor to meet the needs o the company

Each sponsor must document the procedures or managing all clinical supplies, and details o

the procedures must be ound in the individual protocols as well as the sponsors SOPs. Although

the initial shipment o clinical supplies is part o the study startup procedures, the drug

accountability requirement is a process that runs t hroughout the tria l. (Te discussion on drug

accountability contained in this roadmap assumes a monitored trial, which is illustrated in

Figure 5.)


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2.3.1 Shipping clinical supplies to study site in accordance with internal SOPs

Te clinical monitor is responsible or ensuring the ollowing drug accountability conditions

are met:

Storagetimesandconditionsareacceptable,andsuppliesaresucientthroughoutthetrial.

Teinvestigationalproductissuppliedonlytosubjectswhoareeligibletoreceiveitandatthe

protocol specied dose.

Subjectsreceivethenecessaryinstructiononhowtoproperlyuse,handle,store,andreturnthe

investigational product.

Tereceipt,use,andreturnoftheinvestigationalproductatthetrialsitesarecontrolledand

documented adequately.

Tedispositionofunusedinvestigationalproductatthetrialsitescomplieswithapplicable

regulatory requirements and is in accordance with the sponsors authorized procedures.

Beore any clinical supplies are sent to an investigators site, the monitor must complete a site

investigation to ensure that the acilities are adequately prepared to accept, store, use, and

distribute all supplies they will receive to support the study. Clinical supplies are then shipped to

the site based on the number o subjects and the details o the protocol. Te initial shipment is

sent to the site in accordance with the dened procedures. Te steps or sending the supplies are:

1. Te monitor initiates a request or supplies to be sent to the site. Tis request can be an interna

orm that enables the monitor to ll in al l the appropriate inormation concerning the shipment,

or a web-based application that al lows the monitor to ll out the request. Te request may

include, but is not limited to, the ollowing:

Teprotocolnumberandtitle

Teinvestigatorsname,address,andsitewherethesuppliesaretobeshipped

Detailsconcerningthesupplies,suchasnumber,strength,andpackaging

Tedatethesupplieswillbeneeded

Figure 5. Drug accountability process

No

Yes

No

Ship clinical supplies tostudy site in accordance

with internal SOPs

Monitor updates internalrecords to track shipment(s)

Monitor acknowledges receipt

of shipment at study site

Monitor updates siterecords to reect receipt

of shipment

Investigator(s) distributes

clinical supplies inaccordance with protocol

and GCP guidelines

Need more supplies?

Often done with IVRS

Request additional

supplies from sponsor

Monitor inventories remainingclinical supplies per SOPs

Any unused clinical supplies?

Monitor returns unused

supplies per SOPs

Monitor disposes unused

supplies per SOPs

Monitor updates andreconciles records to

account for dispositionof all clinical supplies

End

Start

Sponsor processes returned

unused supplies per SOPs

RECEIVED

DISTRIBUTED

SUPPLIES

SUPPLY REQUEST

SUPPLIES USED

UNUSED

RETURNED

DESTROYED

SUPPLIES

RECEIVED

SUPPLIES USED

UNUSED

Ship

UNUS

ED

CLINICA

L

SUPP

LIES

SOPs state supplies must

be returned?


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Anyadditionalspecicinformationthatmayberequiredfortheshipment,suchas

temperature extremes, bio-hazard, or ragile materials warnings

Temonitorssignature,ifrequiredbythesponsorsSOPs

Note: Regardless o the mechanism or submitting the request, the request orm must be produced

as part o the essential documents in support o the study. ypically, the request would be led in

the appropriate section o the trial master le.

2. Te request is sent to the sponsors location that is responsible or ul lling t he

requesttypically a manuacturing acility responsible or manuacturing, packaging,

and shipping clinical materials.

3. Once the request is received by the manuacturing acility, it is lled out and sent in accordance

with the specics o the request. Details o the shipment, including the expected date o arr iva

at the target site, are produced as an essential document and stored in the tria l master le.

4. Te monitor is notied that the shipment has been sent. Te method or notiying the monitor

is dened in the internal SOPs and/or protocol.

2.3.2 Updating internal records to track shipment

Te monitor is responsible or ensuring that the internal essential documents are produced

and stored in the appropriate location. In addition, once notied, the monitor tracks the status

o the shipment.

2.3.3 Acknowledging receipt of shipment at study site

It is the monitors responsibility to go to the study site once the shipment has arrived. Te duties

the monitor must perorm include but are not limited to:

Openingandinspectingtheshipment,comparingthecontentsoftheshipmentwiththedetails

o the request

Producingdocumentationthatthecontentsoftheshipmentagreewiththedetailsofthe

request or document what is dierent rom the request

EnsuringthatthedocumentationrequiredbytheSOPsand/orprotocolareplacedinthe

appropriate repositories at the investigators site and the sponsors acility

Unpackingandstoringthecontentsoftheshipmentintheappropriatelocationatthesite

2.3.4 Distributing supplies in accordance with the protocolAs the study proceeds, the investigator uses the clinical supplies in accordance with the study

procedures. As the supplies are depleted, additional supplies are requested rom the sponsor. Te

monitor closely tracks the number o subjects being enrolled and randomized, the clinical supplies

being distributed to the subjects, and the additional supplies being requested. As the study

proceeds, the monitor is responsible or the ollowing activities:

Updatingalldocumentationconcerningthereceiptanddistributionofclinicalsupplies,

including how many subjects are enrolled in the study and what supplies were distributed to

each subject

Ongoingsupervisionoftherequests,shipments,andreceiptofadditionalsupplies

Ensuringthatallessentialdocumentsrequiredbytheprotocoland/orSOPsareproducedand

properly placed in the appropriate repositories at the investigators site and sponsors acilities


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2.3.5 Inventorying remaining supplies

Once the site has declared that the last patient has been seen or the last time and that there will

be no urther patients seen in connection with the study, the monitor inventories any remaining

clinical supplies. Te close-out process or drug accountability consists o:

1. Conducting an inventory to determine i any clinical supplies are still at the investigators site

2. Disposing o the supplies in accordance with the details o the protocol and/or SOPs i

supplies remain

3. Packing up supplies, clearly identiying the contents, and sending them back to the sponsor or

disposal i clinical supplies must be returned to t he sponsor

4. Disposing o any unused supplies o at the site, the monitor is responsible or disposal in

accordance with the details o the SOPs and/or protocol i the SOPs state that any unused

supplies should be disposed o at the site

2.3.6 Reconciling records to account for all clinical supplies

At the termination o the study, the monitor is responsible or:

Ensuringthatthedrugaccountabilitydocumentationaccountsforallclinicalsuppliesthat

were shipped to the sitedocumentation must exist detailing which clinical supplies were

given to study subjects and which were returned to the sponsor or disposed o in accordance

with the SOPs and/or protocol

Ensuringthattheessentialdocumentsareproducedandplacedintheappropriaterepositoryat the investigators site and the sponsors acility

2.4 Streamlining the process of shipping and managing clinical supplies

As detailed earlier, the records and documentation produced in connection with shipping, receipt

acknowledgement, storage, handling, and disposition o investigational products are identied in

the guidance as essential documents and, as such, must be maintained both by the investigator at

the trial site and by the sponsor at its acilities. Many companies have automated systems in place

or electronic data capture in connection with the conduct o the study as well as systems or

submitting requests or clinical supplies. Adobe technology provides tools to seamlessly automate

and integrate multiple systems and processesreducing the complexity o interacing with many

dierent systems. Some examples o how Adobe technology can be applied are outlined in the

ollowing sections.

2.4.1 Managing and tracking requests for clinical supplies

LiveCycle Process Management ES can be congured to:

Monitorrequestsforsupplies

Ensureroutingofrequeststotheappropriateindividualforapproval

Routetotheappropriateindividualorsystemtolltherequest

Notifytheclinicalmonitorthattherequestisbeingprocessed

Notifytheclinicalmonitorthattheshipmenthasbeensent

LiveCycle Process Management ES, a long with LiveCycle ES Connectors or ECM, LiveCycle

Forms ES, LiveCycle PDF Generator ES, and LiveCycle Content Services ES can be congured to:

Interfacewiththeappropriatesystemstocreatetherequireddocumentation

Interfacewiththeappropriaterepositoriestoensurethattherequireddocumentationand

metadata are put into the repositories

For more inormation about LiveCycle Process Management ES, visit www.adobe.com/products/

livecycle. For detailed specications concerning this implementation, reer to www.adobe.com/

devnet/livecycle/workfow/articles/lc_workfow_qpac_overview.pd.


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2.4.2 Virtual site monitoring

Once the workow has been dened, all t he processes described in this guide can be automated

by LiveCycle Business Activity Monitoring (BAM) ES to provide a dashboard view o the request

rom initiation to completion. In addition, implementations can be customized to use other

Adobe tools, such as Adobe Flex Builder and Acrobat Connect, to provide a rich, interactive

platorm or process management.

Adobe Flex Builder is an application development tool that can be used to create cross-platorm

rich internet applications that enable you to:

Viewdatafromtheclinicaldatacollectionsystem,suchasnumberofpatientsrandomized Viewdatafromtheclinicalsuppliessystem,suchasnumberofclinicalsuppliesavailableatthe

study site

Navigatethedatauptoandincludingtheactivitiesrequiredtoprocessarequestforadditional

clinical supplies

A Flex application can be implemented across all therapeutic areas or monitoring drug

accountability and can be expanded to include additional activities, including:

Monitoringtherepositoryofessentialdocuments

Monitoringtheongoingsubjectrecruitment

Monitoringthesubjectvisits

Monitoringquestionsandissuesfromthesite

Another Adobe tool that can be used to streamline site monitoring is Acrobat Connect Proessiona

which is a rich web application or acilitating communication between geographically dispersed

parties. Te investigators site and the clinical monitor can use Acrobat Connect to share

documents and data in real time. Tis enables the monitor to address critical questions as they

occur, instead o having the investigators site compile questions and issues that are then addressed

during a scheduled site visit. Such real-time communication over the web can reduce the time it

takes to complete the study.

For more details about Adobe Flex and Flex Builder, visit www.adobe.com/products/fex/

productino/aq. For more details about Acrobat Connect Proessional, visit www.adobe.com/

products/acrobatconnect. For more inormation about Adobe LiveCycle Business Activity

Monitoring ES, visit www.adobe.com/products/livecycle/bam.html.


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Section 3: References

3.1 Sources cited

Cutting Edge Inormation. Accelerating Clinical rials: Budgets, Patient Recruitment, and

Productivity. 2004.

Shields-Uehling, Molly. Message rom the President. SAFE BioPharma Association

newsletter. November 17, 2006.

3.2 Additional references

Guidance or IndustryE6 Good Clinical Practice: Consolidated Guidance. April 1996.

www.da.gov/cder/guidance/959nl.pd

Adobe LiveCycle ES

www.adobe.com/liesciences/solutions/livecycle

Acrobat 8 Proessional

www.adobe.com/products/acrobatpro

Adobe LiveCycle Reader Extensions

www.adobe.com/products/server/readerextensions

Adobe LiveCycle Forms ES FAQ

www.adobe.com/products/server/barcodedpaperorms

Adobe LiveCycle Process Management ESwww.adobe.com/products/server/workfowserver

Enhanced Forms 1571 and 1572

www.adobe.com/liesciences

Adobe Systems Incorporated345 Park AvenueSan Jose, CA 95110-2704USAwww.adobe.com

Adobe, the Adobe logo, Acrobat, Acrobat Connect, Flex, Flex Builder, LiveCycle, and Reader are either registered trademarks or trademarks of AdobeSystems Incorporated in the United States and/or other countries. All other trademarks are the property of their respective owners.

2008 Adobe Systems Incorporated. All rights reserved. Printed in the USA.

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Roadmap for study startup