#  Data Summary

The Data Management Plan (DMP) for OSTEOproSPINE project is developed to
facilitate data flow and utilization of the data between the parties,
including third parties/public where appropriate, and ensure proper data
preservation for future use. DMP is developed in line with Guidelines on FAIR
Data Management in Horizon 2020. The purpose of the DMP is to cover the
complete research data life cycle and to describe the types of data that will
be generated/collected during the project, the standards that will be used,
how data will be preserved and what parts will be shared for verification or
use. The team is aware of the sensitivity of clinical data related to personal
data protection, as well as exploitation and licensing needs, so it will keep
certain data closed and stick with "as open as possible, as closed as
necessary".

The purpose of clinical data management is to define the data quality
standards for Protocol GR-OG-279239-03 ensuring the interventional trial
database stores appropriately complete, accurate, and logically consistent
data, sufficient to achieve protocol objectives and accurately represent the
status of subjects. Clinical, non-clinical and industrial data will be
collected throughout the project. The focus of this document will be on
clinical data stored properly by 2KMM. Within WP3 a Clinical DMP will be
generated. The clinical data are collected in the eCRF. 2KMM will provide Data
Management Services for the Sponsor on the GoResearch  TM  EDC Platform. The
TMF collected by CF comprises all documents collected during the trial. The
ISF comprises all documents collected before, during and after the trial. They
will be collected by MUW, KU and MUG (clinical sites). Non-clinical data
represent the data collected from _in vivo_ and _in vitro_ laboratory
experiments, mostly created by UZSM (the coordinator) and UZFVM. CMC data will
be generated by GEN.

Expected size of eCRF clinical data will be up to 10MB in case exporting
collected data to text format, for example .csv, and around 100MB as a
database backup file.

The collected data will be primarily used for the purpose of further
development of the IMP, regulatory reporting and new submissions, IP
protection, licencing and technology transfer but also for results
dissemination and communication to interested stakeholders, including
scientific community, patients and wide public.

#  FAIR data

The FAIR Data Principles (Findable, Accessible, Interoperable, Reusable) have
received worldwide recognition as a useful framework for thinking about
sharing data in a way that will enable maximum use and reuse. The adherence to
the principles: (1) supports knowledge discovery, innovation and knowledge
integration, (2) promotes sharing and reuse of data across disciplines, (3)
supports new discoveries through the harvest and analysis of multiple
datasets. OSTEOproSPINE will follow these principles the best possible.

##  Making data findable, including provisions for metadata

OSTEOproSPINE will collect data from human subjects involved in the Phase II
clinical trial. The clinical health information will include data from medical
and medication history; physical exam; safety lab tests; anti-rhBMP6 antibody
monitoring; quality of life, back pain and leg pain questionnaires
information, X-ray, and adverse event monitoring.

Data collection will be performed using eCRF prepared on the GoResearch™
platform. GoResearch™ is an internet EDC platform for clinical research. It is
compliant with regulatory requirements of FDA’s 21 CFR Part 11 and specific
areas of GCP regarding electronic data.

Over the course of the data collection phase, regular data management
activities will be performed to ensure that data quality standards for the
trial are met and the database stores appropriately complete, accurate, and
logically consistent data, sufficient to achieve protocol objectives and
accurately represents the status of subjects. These activities will include
System Level Data modifications, query processing and management and data
cleaning, including data reviews and self-evident corrections of obvious data
processing errors. Upon completion of data collection, the final data cleaning
will be performed, database locked, and clean study data exported for the
statistical analysis.

Anonymized external data from laboratory will be provided in xls file.

CF will be responsible for:

  * Setup of TMF and ISFs at each site o Auditing of collection of clinical data by CF 

  

  * Execution of clinical trial and gathering of clinical data according to GEN and CF’s SOPs for clinical trials 

  

The clinical sites MUW, KU and MUG will collect the data that will be entered
into the eCRF according to the Study schedule described in the Study protocol.

PV support will be provided by a consortium member CF, who will appoint a PV
manager for the trial. All adverse events in all treatment groups, regardless
of suspected causal relationship to study treatment or seriousness, will be
recorded on the adverse event page(s) of the eCRF and reported in the final
Clinical trial report.

The samples for immediate assessments will be collected, handled, processed
and analysed according to the good practices, hospital SOPs and sponsor SOPs.

The data generated related to IMP management include the IMP storage,
packaging, and labelling, QP release and transport to the clinical sites
generated by the subcontractor. All the data generated and documentation
issued by the subcontractor is made available to GEN and to all consortium
members that need to use and store the data according to GMP and GCP
procedures and institutional SOPs. Following delivery of the IMP to the
clinical site the hospital pharmacy and study personnel will generate
necessary documentation related to IMP storage, accountability, dispensing,
discarding, reconciliation and return of the unused IMP.

Non-clinical data entail:

  * Data from the pre-clinical studies: _in vitro_ and _in vivo_ testing 

  

  * CMC data related to IMP manufacturing 

  

  * Data on authorisations and training certificates 

  

The partners generating pre-clinical data are GEN, UZSM and UZFVM and they
operate according to GMP and GLP principles in their facilities and comply
with the institutional SOP’s related to data management.

The raw data are stored in databases on the associated computers or are
transferred to the experimenter’s computer or lab notebook as the primary
storage record. The secondary storage record is the shared drive with folders
available to the researchers on the institutional servers. The folders are
located on shared network drives and are of appropriate size and security.

Additionally, research data are generated from the preclinical _in vitro_
assays and animal models studies that are most meticulously planned,
implemented and data recorded and saved. Two consortium partners will be
involved in the animal experimentation: UZSM and UZFVM.

Laboratory notebooks are used to document all the experiments performed and
are used in paper form. The lab notebooks are kept in secure places and are
archived for at least 20 years.

Data from the study reports in the form of study summaries are used to update
and generate regulatory documentation.

Novel data on rhBMP6 manufacture, quality control and quality assurance will
also be generated enabling increased industrial and technological advancements
of biotech companies involved in the project. The data will be generated by
GEN and UZSM and the approved subcontractors according to GMP procedures. The
data is generated, transferred, stored, used, shared, and archived according
to institutional SOPs and the OSTEOproSPINE Consortium Agreement and policies.
GEN will ensure that all new clinical batches undergo release by an EU
qualified person in accordance with the requirements of Article 13.3 Directive
2001/20/EC (or the new EU CT regulation) and that new batches of DS and rhBMP6
DP are tested and data obtained in accordance with the commitments made to the
regulatory agencies.

For the purpose of complying with ethics principles and ensuring the
conformity with the ethics requirements, the data on authorisations and
training certificates are continuously collected.

They consist of:

  * authorisation certificates related to facilities with adequate physical conditions and equipment and carefully controlled and monitored conditions for animal husbandry as well as 

  

  * appropriate training certificates and/or personal licences for the staff involved in the animal experimentation are obtained by relevant authorities and stored in paper form in the facility archive and as electronic records on shared drive folders. 

  

  * other documentation related to management, distribution of responsibilities, training and continuing education of specialist staff involved and health monitoring as well as regular yearly inspections of the national competent authorities 

  

These data are kept in paper form in secure locations by the manager for the
Animal and Breeding Facility and as electronic records on personal computers
and on shared drive folders and are available to any interested party upon
request.

In order to gain regulatory and ethics approval in the country where the Phase
II clinical study OSTEOproSPINE will be conducted all of the required
regulatory documentation is prepared, shared among the partners and stored
according to GCP principles. The data from the preclinical and clinical
studies are summarized in the documents that represent the core of the CTA
which will be maintained through preparation and submission of substantial
amendments when required.

During the clinical study and in line with the newly generated data, it is
likely that additional changes to the protocol or to other elements of CTA
will need to be introduced. UZSM will evaluate all changes and decide (with
other consortium partners) if they constitute significant changes that need to
be submitted to the relevant regulatory agencies or ethics committees. If they
are, then amendment submissions to relevant authorities will be prepared.

The new EU clinical trial regulation will come into force in 2019/2020.
Consortium members will ensure all regulatory submissions are in accordance
with this once it is applicable.

##  Making data openly accessible

All data planned to be collected within OSTEOproSPINE clinical trial will be
focused on the research and will be collected, processed and stored in the
manner which protects the privacy of the health information. It will be in
strict compliance with Directive 95/46/EC of the European Parliament and of
the Council of 24 October 1995 on the protection of individuals with regard to
the processing of personal data and on the free movement of such data, and its
Article 29 – Working Party on the Protection of Individuals (8/2010 opinion).
On 25/05/2018 the EU GDPR (Regulation (EU) 2016/679), revising Directive
95/46/EC on Data Protection and Privacy, came into force and the consortium
took this into account and will ensure continuous compliance.

Patients’ records obtained in this project, as well as related health records,
will remain strictly confidential at all times. However, these will need to be
made available to others working on

GEN’s behalf, the IDSMB members and Medicines Regulatory Authorities. Informed
Consent Procedure will be implemented according to the EU Regulation No
536/2014 on GCP.

Each Informed Consent will be reviewed and approved by the Institutional
review boards at the study sites, National/Central Ethics Committee and
Regulatory Authority of the countries participating in proposed clinical
trial. By signing the ICF, subjects agree to this access for the current trial
and any further research that may be done. However, OSTEOproSPINE will take
steps to protect all personal information and will not include subject’s names
on any sponsor forms, reports, publications or in any future disclosures. All
information collected in this trial will be treated as confidential and
subject’s identification will not be revealed to outsiders, unless required by
law. Every effort is made to ensure continued privacy of study participants
and the data they have contributed to the study. All subjects will be
identified in study documents by study specific subject identification number.
Each research centre will have the key code list for identification of the
study subject if needed; principal investigator and the study nurse having
access to this list. The samples collected during the study will be coded and
stored in each research centre until analysed centrally. The data created in
the study will not be included in the subject’s medical records.

##  Making data interoperable

To meet GCP requirements, collected clinical data will be managed in line with
the Clinical DMP, which will be developed in WP3, and will represent an
integral part of the overall DMP. A dedicated data management task in WP3 will
develop the necessary structure for clinical data capture and warehousing.
2KMM is an expert in the field and is responsible for this task. Data
classifications will be harmonized across the clinical sites involved in order
to enable them for further integration. Within the consortium, all partners
will follow their own ethical protocols and informed consent, and patient’s
identity will remain in the secured databases at each study centre.

Data management-related activities in WP7 will first focus on the data
harmonization, curation and data integration tasks. The consortium data
originating from various partners collected with different SOP’s and standards
will need to be harmonized. For each data type, the respective delivery sites
will decide on one SOP and harmonization model. All partners will take part in
this effort and harmonize metadata and data formats. UZSM together with Eurice
will be responsible for the DMP. Due to exploitation plans of the
OSTEOproSPINE results, it is crucial to protect the results and all data
created in the project and keep them confidential, in order to retain the
interest of pharma industry that are very sensitive to confidentiality issues,
ownership exclusivity and freedom-to-operate. Consortium members will follow
the principle “as open as possible, as closed as necessary”.

All the data that are generated, will be handled, verified, shared and stored
according to GMP, GCP and GLP procedures and will be available to the partners
authorised to use such data.

##  Increase data re-use (through clarifying licences)

Data relevant for commercial use will be exploited through patenting, know-how
and potentially licensing. In terms of further use for research purposes, the
data will be used to further plan and design later phases of clinical
development and explore the therapeutic utilisation in the context of other
human pathological conditions and ultimately apply the generated knowledge in
the clinical practice for the benefit of patients and healthcare systems.
Furthermore, it is ensured that the results of all OSTEOproSPINE scientific
publications can independently be validated.

#  Allocation of resources

All partners are requested to collect and manage the data in accordance with
the DMP and other common professional practices, especially the task leaders.
The WP leaders will be responsible for the implementation of the DMP and will
monitor data management activities. The list of WPs is presented in Table 1
and Data management is included in all of them.

Table 1. List of WPs  
  
<table>  
<tr>  
<th>

**WP Number**

</th>  
<th>

**WP Title**

</th>  
<th>

**Lead beneficiary**

</th> </tr>  
<tr>  
<td>

WP1

</td>  
<td>

Phase II clinical trial

</td>  
<td>

3-MUW

</td> </tr>  
<tr>  
<td>

WP2

</td>  
<td>

Regulatory support

</td>  
<td>

1-UZSM

</td> </tr>  
<tr>  
<td>

WP3

</td>  
<td>

Data Management and Biostatistic

</td>  
<td>

11-2KMM

</td> </tr>  
<tr>  
<td>

WP4

</td>  
<td>

Investigational medicinal product supply for the clinical trial

</td>  
<td>

2-GEN

</td> </tr>  
<tr>  
<td>

WP5

</td>  
<td>

Studies to boost OSTEOproSPINE differentiation and market potential

</td>  
<td>

1-UZSM

</td> </tr>  
<tr>  
<td>

WP6

</td>  
<td>

Innovation management:

Communication, Dissemination and Exploitation

</td>  
<td>

13-Eurice

</td> </tr>  
<tr>  
<td>

WP7

</td>  
<td>

Project management

</td>  
<td>

1-UZSM

</td> </tr>  
<tr>  
<td>

WP8

</td>  
<td>

Ethics requirements

</td>  
<td>

1-UZSM

</td> </tr> </table>

The task leader of WP3 (Clinical Data Management and Biostatistic) is 2KMM and
will be responsible for the following tasks:

  * Database and users administration; 

  

  * Electronic data transfers; 

  

  * Data reviews; 

  

  * Query management; - Database lock. 

  

The task leader of WP7 (Project management) is UZSM with support of Eurice.

W7 will provide a clear organizational framework and all necessary support
mechanisms to enable smooth project workflow needed for efficient and timely
data management.

Aim of WP7:

  * Provide optimal guidance and support to all partners through a quick set-up of effective management & communication structures 

  

  * Transparency for consortium partners and the EC through proper project documentation 

  

  * Maximize effectiveness of project activities: ensure the timely and qualitative achievement of project results through scientific and administrative coordination. 

  

  * Ensure efficiency: use resources wisely, avoid duplication of efforts, reduce waste of time and energy to a minimum. 

  

A dedicated data management task in WP3 will develop the necessary structure
for data warehousing. All partners will take part in this effort and harmonize
metadata and data formats. Data classifications will be harmonized in all
clinical cohorts to able to compare studies across the sites involved. Within
the consortium, all clinical partners will follow their own ethical protocols
and ensure informed consent signatures, and patient identity will remain in
the secured databases at each cohort centre. The consortium is very much aware
of privacy and GDPR issues and will ensure that subjects cannot be directly or
indirectly identified. Therefore, no identifiable data will be transferred
from the cohorts to the consortium and central databases, but will be replaced
by project-specific codes for data integration. This information is physically
separated from the database and - if stored in electronic form - physically
separated from the network (and internet). Access to this information is only
for authorized persons and will be password protected. Data relevant for
commercial use will be exploited through patenting, know-how and potentially
licensing. In terms of further use for research purposes, the data will be
used to further plan and design later phases of clinical development and
explore the therapeutics in the context of other indications and ultimately
apply the generated knowledge in the clinical practice for the benefit of
patients and healthcare systems. Furthermore, it will be ensured that the
results of all OSTEOproSPINE scientific publications can independently be
validated.

#  Data security

Study related data from MUW will be stored till close-out visit at site, after
that it will be stored according to MUW SOPs.

Study related data from MUG will be stored in lockable cabinets and the
documents are kept for 15 years after the end of the study or as indicated in
the study protocol.

The documents as well as the images in KU are stored in digital form. Study
related data from KU will be stored according to KU SOP.

The current requirements about archiving study documentation are as follows:
the study documentation (ISF) is stored at the research center, usually 15
years after the close-out visit, with the intention of making the
documentation available for possible inspections after the completion of the
trial. In doing so, the internal regulations of health institutions where the
research is taking place are taken into account, and the most stringentrule is
followed.

The sponsor keeps TMF (complete study documentation, for all research centers)
for 15 years.

2KMM is compliant with ISO 27001:2014 Information Security Management System
(certificate since 2010) and ISO 9001:2015 Quality Management System
(certificate since 2009).The building in which the head office of the 2KMM and
the data processing area are located, is protected by a security company and
an electronic alarm system.

Rooms where data processing devices are located and where the data are
processed are secured against outsiders access. Paper documentation in the
form of files, indexes, records, etc. which are database media is stored in
locked office cabinets to which only authorized persons have access.

The server rooms are equipped with a fire safety system to prevent any fire
expansion as well as fire extinguishing system.

All critical systems are regularly tested according to schedule based on
standard procedures. The computer systems and IT services are continuously
monitored. Critical systems run as fail-over clusters, and all of them are
replicated into backup data centre. Databases backups are made in different
schedules.

Offline media are kept in a safe in 2KMM's protected area room. Media used for
long-term data archiving and their ISO disk image stored on network drivers
are checked regularly. Capacity of backup systems and other carriers depends
on their volume. If it is necessary to increase the capacity of backup
systems, further disk expansion enclosures or disk arrays are added.

The study database will be retained at 2KMM for 15 years after database lock.

For data security CF follows its own SOP procedures.

The pre-clinical and ethics data will be kept, stored, protected and retained
according to the institutional policies. The IT departments of the UZSM, UZVFM
ensures the access, storage, maintenance, protection, and retention of the
folders and the data stored. The data on the computers is protected by the
encryption of the discs. Regular maintenance of servers and internal IT
systems is performed. The data on the internal servers will be retained as
long as required and currently there is no time limit imposed on the data
retention. The data will be stored for 10 years after the end of the project,
and after this period it will be revised whether there will be a need for
further storage.

Data are shared only internally. The clinical data are all in one database.
Data transfer along with study management documentation will be transferred to
GEN in an electronic archive (zip file). Transfer media will be agreed with
the GEN and should guarantee secure handover.

#  Ethical aspects

The rapid scientific and technological advances in the field of bone
regeneration research are contributing to the well-being and the economic
wealth of European citizens. They have, however, evoked some ethics concerns,
which include involvement of human subjects and study related physical
interventions, human cells and tissues, collection and/or processing of
personal data as well as involvement of experimental animals. Such concerns,
together with the relevant national and EU legislation or directives and the
Ethics rules of the Horizon 2020 Framework Programme Regulation, have been
considered by the OSTEOproSPINE consortium and OSTEOproSPINE will operate in
full compliance with the existing national legislation and EC directives and
rules on ethical issues that are relevant to the project.

Based on the Ethics Issues Checklist, OSTEOproSPINE has identified 4 issues
requiring ethics clarification:

  * Involvement of human participants 

  

  * Involvement of physical interventions on the study participants 

  

  * Involvement of personal (health) data collection and/or processing 

  

  * Involvement of experimental animals 

  

WP8 (Ethics requirements) sets out the 'ethics requirements' that the project
must comply with and UZSM as lead beneficiary will coordinate, implement and
report all ethical aspects relevant for project activities.

The consortium is very much aware of privacy issues and will ensure that
subjects cannot be directly or indirectly identified. Therefore, no
identifiable data will be transferred from clinical sites to the consortium
and central databases, but will be replaced by project-specific codes for data
integration. The personally identifiable information will be exclusively kept
at the clinical site, physically separated from the database and - if stored
in electronic form - physically separated from the network (and internet).
Access to this information will be limited to authorized persons only, and
will be password protected, if stored in electronic form.

Data relevant for commercial use will be exploited through patenting, know-how
and potentially licensing. In terms of further use for research purposes the
data will be used to further plan and design higher phases of clinical
development and explore the biomedical uses in the context of other human
pathological conditions and ultimately apply the generated knowledge in the
clinical practice for the benefit of patients and healthcare systems.

#  Other issues

CF will follow its own DM policy in the form of SOP Information Protection
Responsibility.

Every clinical site in OSTEOproSPINE project has SOP´s and DM policies. There
is a new Data protection law and topics related to its implementation will be
continually discussed among consortium members. The new European regulation
(GDPR) is in force since 25  th  of May and this relates also to all
OSTEOproSPINE partners.

2KMM will follow its own DM policy in the form of SOP (listed in Clinical
DMP).

Academic institutions have various policies and SOPs that also include data
management. All are in compliance with GDPR.

Incidental finding is a finding concerning an individual research participant
that has a potential health or reproductive importance and is discovered in
the course of conducting research but is beyond the aims of the study. The
clinical team (composed primarily of experienced orthopaedic surgeons and
radiologists, as well as research nurses) will be primarily in charge of the
data collection and interpretation of clinical findings. Other researchers
will have a limited access to the data with no ability of participant
identification and communication.