##  1\. General

In the PAPA-ARTiS trial, the Clinical Trial Centre (CTC-L) at the University
of Leipzig will be responsible, on behalf of the legal trial sponsor the
University of Leipzig, for implementation of procedures for data collection,
storage, protection, retention and destruction. The CTC-L has implemented a
data safety and security concept according to the requirements of the German
Federal Office for Information Security (  _www.bsi.bund.de_ )  . All PAPA-
ARTiS related procedures will be developed in cooperation with the data
security engineer of the CTC-L and have to be approved by the official data
protection officer of the University of Leipzig prior to implementation.

The chapters 11-13 of the trial protocol lists all detailed aspects of data
collection, handling, storage, verification and protection.

##  2\. Data Collection

Three types of data will be collected in the PAPA-ARTiS trial:

  1. _clinical data_

  

  2. _information from patient questionnaires_ and 

  

  3. _imaging data_

  

  

Investigators in the recruiting trial centers will initially collect all data.
Together with information on the trial, eligible patients will be informed
about data capture, transmission and analysis processes. Once a patient is
eligible, and has given his/her informed consent to trial participation and
data collection, the investigator will assign the patient a unique patient
identification code. Patient identification code lists will be generated in
advance by the CTC-L and forwarded to the recruiting centers. These lists are
part of the investigator site file and remain at the recruiting site.
Furthermore, these lists are the only documents that allow for
reidentification of the patients.

The CTC-L will design CRFs and develop validated eCRFs (electronic case report
forms) for data capture directly at the trial sites. Additionally, CTC-L is
responsible for the eCRF training to staff of all sites and all monitors. The
investigators (or their designated staff) will enter all clinical data into
these eCRFs. Patient data will be recorded in pseudonymized form (i.e. without
reference to the patient’s name) using exclusively the patient’s
identification code. One member of the study team transfers information from
the questionnaires to the eCRF.

The staff at the trial site will document the data related to a patient’s
visit in due time after each visit.

In order to facilitate the documentation as per protocol in case of
malfunction of the electronic system or any of its components, a paper version
of the CRF will also be provided. The data transfer of the data entered into
this paper version to the eCRF will done as soon as the electronic system is
available again.

The investigator or an authorised member of the study team will sign each eCRF
page electronically. This confirms that all data on the eCRF are correct and
havn’t been changed. If a value on the eCRF is changed later on, the
electronic signature will be set back automatically and the corresponding page
has to be signed again. This ensures that changes on the eCRF will be dated
and signed as well. All entries and data changes will be tracked automatically
including date, time and person who entered/changed information (audit trail).
Major correction or major missing data have to be explained.

However, the investigator has final responsibility for the accuracy and
authenticity of all clinical and laboratory data entered in the CRF.

All information required by the protocol, and therefore collected during the
clinical trial, has to be verified by source data (e.g. patient’s records).
The investigator and the trial staff are responsible for adequate source data
documentation.

##  3\. Data Storage

The EDC Tool secuTrial® by InterActiveSystems GmbH will be used for database
programming. SecuTrial® uses an underlying Oracle database. The study database
will be developed and validated according to the Standard Operating Procedures
(SOPs) of the CTCL prior to data capture. All information entered into the
eCRF by the investigator or an authorized member of the local study team will
be systematically checked for completeness, consistency and plausibility by
routines implemented in the database, running every night. Data management
staff of the CTC-L will check error messages generated by these routines. In
addition, the query management tool of secuTrial® will show discrepancies,
errors or omissions to the investigator/data entry staff based on the pre-
programmed checks. The CTCL will supervise and aid in the resolution of
queries, should the site have questions. Corrected data will be re-checked by
automatic routines during the night after entry.

If a query cannot be resolved, the Data Management staff of the CTC-L will ask
the coordinating investigator and/or the biometrician, if they may close the
query (e.g. if it is clear that these data cannot/ were not collected).

Final analysis will be performed when the data of all enrolled patients have
been collected, all queries have been the resolved and the database has been
closed.

##  4\. Data Protection

###  4.1 Access

During the whole course of the study, all data undergo a daily backup. An
access concept for the trial database will be implemented, based on a strict
hierarchy and role model. Thus, data access is limited to authorized persons
only, and unauthorized access to pseudonymized patient data is prevented. Any
change of data (e.g. error correction during query management) is recorded
automatically via an audit trail within the database. At the end of the study,
once the database has been declared complete and accurate, the database will
be locked. Thereafter, any changes to the database are possible only by joint
written agreement between coordinating investigator, biometrician and data
manager.

According to ICH-GCP, the investigator must permit all authorized third
parties access to the trial site and the medical records of the trial subjects
(source data). These include the clinical trial monitors, auditors and other
authorized employees of the co-ordinating investigator, as well as members of
the local or federal authorities. All these persons are sworn to secrecy.

###  4.2 Monitoring

Monitoring is mandatory for all participating study groups. Monitoring
procedures will be country specific and as agreed by the co-ordinating
investigator and the individual regional offices in all involved countries.
General principles for monitoring will be outlined in the monitoring plan of
the trial, which will be written by the CTC-L in cooperation with the
coordinating investigator and distributed to the regional offices.

Central and statistical monitoring procedures combined with on-site monitoring
visits will ensure high protocol compliance and data quality, as well as
ensure patients’ safety and rights.

A risk-based monitoring strategy will be implemented as required by ICH E6
[1]. According to the risk analysis, treatment delivery parameters, adverse
events, follow-up information, data transmission and protection and informed
consent documents comprise risk-bearing trial aspects and will be monitored.

Clinical monitors appointed by the CTC-L (for Germany) or ECRIN (for all other
involved countries) will regularly visit the recruiting centres. The frequency
of monitoring visits will depend on the trial site’s recruitment rate as well
as on potential problems detected during previous on-site visits or by central
monitoring. During the visits, the monitor will verify the informed consent
forms. Only after monitors confirmed that a patient has unambiguously given
his or her consent for trial participation as well as for data capture,
transmission and analysis, the data will be used for analyses. Further tasks
of the monitors are: source data verification of the key data in a random
sample of patients, targeted source data verification for patients with
possible deviations, discussion of open queries, check of essential parts of
the investigator site file, check of source data for non-reported AEs or SAE´s
and check for GCP-breaches and/or protocol violations.

Prior to recruitment, each participating centre will receive a site initiation
visit, during which the trial protocol and the eCRFs will be reviewed with
centre staff and any necessary training will be provided.

###  4.3 Pseudonymization

Local investigators will be trained by the CTC-L prior to study start on the
pertinent procedures for pseudonymization. There is no risk for
pseudonymization failure as far as the eCRFs are concerned, because no
identifying data will be entered in the eCRF. However, pseudonymization
failures may arise with the imaging data. It may happen that investigators
upload images labelled with the patient’s name. A SOP will be developed by the
CTC-L together with the imaging reference centres on how to deal with this
situation (e.g. ask the responsible investigator to delete the non-
pseudonymized record and upload a pseudonymized record instead, retrain
investigators at the site concerned, inform the trial sponsor on the problem).

Additionally, human cells/tissue will be collected in a sub-group of patients
for a scientific subproject. Labelling of the samples will be exclusively with
the trial identification number of the trial participant. Samples will be
processed, stored and analyzed only by using the trial identification number.
Any scientific research making use of the data beyond what is spelled out in
the protocol of the clinical trial will be conducted in accordance with the
applicable law on data protection and the patient will be asked explicitly to
provide consent on participation in the scientific projects and pseudonymized
storage and use of his/her samples.

Since in the course of the trial contact between the trial centre and the
patients might be necessary, the patients’ full name, address and telephone
number will be ascertained and stored at the treating trial site after
obtaining written permission to do so. This information will be stored
separately from the trial data.

###  4.4 Withdrawal of Consent

Patients may withdraw their consent to participate at any time without giving
reasons. Nevertheless, the patient should be asked for the reason of the
premature termination after being informed that he/she does not need to do so.
Information as to when and why a patient was registered/randomized and when
he/she withdrew consent must be retained in the documentation.

In the event of withdrawal of consent, the necessity for storing data and/or
samples will be evaluated. While Regulation (EC) No 45/2001 of the European
Parliament and of the Council [2] strengthen personal data protection rights,
encompassing the right to access, rectification and withdrawal of data, it
also specifies the situations when restriction on those rights may be imposed.
The withdrawal of informed consent should not affect the results of activities
already carried out, such as the storage and use of data obtained on the basis
of informed consent before. Data not needed will be deleted as requested, with
full documentation of the reasons for deletion. Similarly, samples will be
discarded as wished.

###  4.5 Data Exchange

There will be an “ownCloud” as file sharing platform in the PAPA-ARTiS-trial.
Hosting and maintenance of the “ownCloud” takes place at the University of
Leipzig, behind the firewall of the institution.

The “ownCloud” file-hosting system will be used for exchange of central trial
documents as well as for imaging data for reference evaluation. Access to the
“ownCloud” follows the same hierarchical role concept as the trial database.
Data will be uploaded without personal information, using exclusively the
trial identification number. Trial centers will only be able to upload data
and see data concerning their own patients, while the reference organization
may exclusively download data essential for their evaluation.

Using an eCRF as well as the “ownCloud” file-hosting system, both located on
servers of the CTC-L and thus behind the firewall of University of Leipzig,
reduces the risk of unauthorized or unlawful access, disclosure,
dissemination, alteration, destruction or accidental loss in comparison to
data transmission over a network. Access to the servers is secured via https
protocol, and requires user-specific login and password.

###  4.6 Transfer of Personal Data

The co-ordinating investigator certifies herewith that the transfer of
pseudonymized personal data will take place according to the documentation and
communication regulations of the GCP-guidelines (E6; 2.11) [1]. Moreover, the
co-ordinating investigator certifies that trial participants who do not permit
the transfer of data will not be admitted to the trial.

##  5\. Archiving

All relevant trial documentation (Trial Master File), the electronically
stored data, the original CRFs and the final report will be stored for 30
years by the co-ordinating investigator’s institution after the trial’s
completion.

At the investigating sites, all completed study related documents (e.g.
investigators’ files, patient identification lists, signed written consent
forms, copies of all CRFs, initiation visit and monitoring visits reports,
staff signature lists) and the patients’ files will be stored for 30 years
after the trial’s completion. With this time span all local rules and legal
requirements regarding archiving at all sites will be addressed.

##  6\. Data Sharing

Data sharing with the scientific community will be carried out according to
the recommendations of the International Committee of Medical Journal Editors.
Previously published data sets may be made available to the scientific
community upon request (e.g. for meta-analysis, disease-related registers)
after agreement by the trial consortium.

##  7\. Adherence to National and EU Legislation

We hereby confirm that all clinical trial information will be recorded,
processed, handled, and stored by CTC-L on behalf of the co-ordinating
investigator in such a way that it can be accurately reported, interpreted and
verified while the confidentiality of records and the personal data of the
subjects remain protected. This is done in accordance with the applicable law
on personal data protection, with Directive 95/46/EEC [3] and regulation (EC)
No 45/2001 of the European parliament and of the council [2]. This also
accounts for the reference centers and the investigators at the trial sites.
The clinical site contracts will also ensure that the clinical sites comply
with national data protection laws.