Fertility Preservation in Young Women With Cancer: an International Registration Study From the International Network on Cancer, Infertility and Pregnancy (INCIP)
Conditions: Cancer, Fertility
Sponsor: University Hospital, Gasthuisberg

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S59981 
 
Study Protocol 
Fertility preservation in young women with cancer 
 
 
22-06-2018 
Version 2.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol ID 
S59981 
Short title 
INCIP fertility substudy 
EudraCT number  
n.a. 
Version 
2.2 
Date 
22-06-2018 
Coordinating investigator/project 
leader 
 
Prof. dr. Frédéric Amant 
UZ Leuven, Department of Gynaecological Oncology 
Herestraat 49 
3000 Leuven, Belgium 
Phone: +32 16 34 42 73 
Fax: +32 16 34 46 29 
E-mail: frederic.amant@uzleuven.be 
 
And  
Netherlands Cancer Institute (NKI) – Antoni van 
Leeuwenhoek Hospital 
Plesmanlaan 121 
1066 CX Amsterdam, The Netherlands 
E-mail: f.amant@nki.nl 
 
Dr. Carla Tomassetti 
UZ Leuven, Department of Obstetrics and Gynaecology  
Herestraat 49 
3000 Leuven, Belgium 
Phone: +32 016 34 08 25 
E-mail: carla.tomassetti@uzleuven.be 
 
 

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Multicenter research 
Coordinating centers per country: 
 
The Netherlands 
 
Prof. dr. Frédéric Amant 
Dr. C.A.R. Lok 
Center Gynaecologic Oncology Amsterdam 
Netherlands Cancer Institute (NKI) 
Antoni van Leeuwenhoek Hospital 
 
 
Dr. I.A. Boere 
Department of Medical Oncology  
Erasmus Medical Center, Rotterdam 
 
Dr. P.B. Ottevanger 
Department of Medical Oncology 
University Medical Center St Radboud, Nijmegen 
 
Dr. P.O. Witteveen 
Department of Medical Oncology 
University Medical Center Utrecht 
 
Prof. Dr. V.A.C. Tjan-Heijnen 
Department of Medical Oncology 
Maastricht University Medical Center 
 
Dr. C.P. Schröder 
Department of Medical Oncology 
University Medical Center Groningen 
 
Dr. J. Kroep 
Department of Medical Oncology 
Leiden University Medical Center 
Other 
Members from INCIP will in addition be invited and 
facilitated to participate to this substudy. 
Sponsor  
UZ Leuven 
 
 

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PROTOCOL SIGNATURE SHEET 
Name 
Signature 
Date 
Coordinating 
Investigator/Project 
leader/Principal Investigators: 
Prof. dr. F. Amant 
 
 
Dr. C. Tomassetti 
 
 
 
 
 
 
 
 
 
22-06-2018 
 
 
PROTOCOL SIGNATURE SHEET PARTICIPATING SITE 
Authorization of 
Ethical 
Committee/IRB 
Authorization of 
Competent Authority 
Insurance 
Informed consent 
form 
o Not required 
o Required 
o Not required 
o Required 
o Not required 
o Certificate 
available 
o Not required 
o Required 
 
 
Name Participating Site & 
Investigator 
Declaration 
Signature and Date 
 
_________________________ 
 
_________________________ 
I hereby agree (1) with this protocol version (2) to submit this protocol 
version to the Ethical Committee (EC)/IRB or Competent authority, 
if required (3) to provide access to Prof. Amant upon his request, to 
the supporting documentation relating to EC/CA approval(s), ICF and 
insurance, where required.  
 
_________________ 
 
_________________ 
 

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TABLE OF CONTENTS 
1. 
SUMMARY 
7 
2. 
INTRODUCTION AND RATIONALE 
8 
3. 
STUDY DESIGN 
9 
3.1 
Objectives 
9 
3.2 
Inclusion criteria 
9 
3.3 
Sample size 
9 
3.4 
Study procedures 
10 
4. 
STUDY POPULATION 
10 
4.1 
Population (base) 
10 
4.2 
Inclusion criteria 
11 
4.3 
Exclusion criteria 
12 
5. 
METHODS 
12 
5.1 
Randomisation, blinding and treatment allocation 
12 
5.2 
Study procedures 
12 
5.3 
Withdrawal of individual subjects 
12 
5.4 
Replacement of individual subjects after withdrawal 
12 
5.5 
Follow-up of subjects withdrawn from treatment 
12 
5.6 
Premature termination of the study 
12 
6. 
STATISTICAL ANALYSIS 
12 
7. 
SAFETY REPORTING 
13 
7.1 
Section 10 WMO event 
13 
7.2 
AEs, SAEs and SUSARs 
13 
7.2.1 
Adverse events (AEs) 
13 
7.2.2 
Serious adverse events (SAEs) expected 
14 
7.3 
Data Safety Monitoring Board (DSMB) 
14 
8. 
ETHICAL CONSIDERATIONS 
15 
8.1 
Regulation statement 
15 
8.2 
Recruitment and consent 
15 
8.3 
Objection by incapacitated subjects (if applicable) 
15 
8.4 
Benefits and risks assessment, group relatedness 
15 
8.5 
Compensation for injury 
15 
8.6 
Incentives 
16 
9. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
16 
9.1 
Handling and storage of data and documents 
16 
9.2 
Amendments 
16 
9.3 
Public disclosure and publication policy 
17 
9.4 
Insurance 
17 
10. 
COMPENSATION 
17 
11. 
REFERENCES 
17 
 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CRF 
Case Report Form 
CV 
Curriculum Vitae 
DSMB Data Safety Monitoring Board 
EU 
European Union 
GCP 
Good Clinical Practice 
IC 
Informed Consent 
n.a. 
Not applicable 
(S)AE 
(Serious) Adverse Event  
WMO 
Medical Research Involving Human Subjects Act 
 
 

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1. SUMMARY 
Rationale:  
Cancer is the second leading cause of death during the reproductive years. The long term survival 
improves for most cancers, reaching 80% for pediatric cancer and more than 70% for cancers in adults 
between 20 and 49 years of age. Early detection and improvements in cancer treatment contribute to 
these figures. As a result, quality of life of which preservation of fertility is one aspect, becomes more 
important. Fertility may however be influenced by surgery and by the gonadotoxic effects of chemo 
and/or radiotherapy. Therefore, fertility sparing treatments are offered to young patients in order to 
maintain the wish to conceive after cancer treatment. This however is associated with deviation of 
standard treatment and many different strategies are applied among different centers. In addition, there 
is a lack of studies investigating the oncological safety of these fertility sparing treatment protocols. The 
results of this study will enable us to better inform clinicians and patients on the efficacy of fertility 
sparing cancer treatment. 
 
Objective:  
To record the incidence, treatment and long term follow up of fertility preserving cancer treatment. Both 
the oncological and fertility outcome are recorded. 
 
Study design: International multicentre prospective observational trial 
 
Study population: All female adults with a cancer for whom a fertility preserving cancer treatment is 
applied. The results of the study population are compared to young women undergoing standard cancer 
treatment. 
 
Intervention (if applicable): n.a. 
 
Main study parameters/endpoints:  
Registration of cancer diagnosis, treatment and outcome. Both the oncologic and fertility outcome are 
registered. 
 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness:  
All patients receive fertility sparing cancer treatment on their specific request. Participation in this 
observational registration study is not associated with burdens or risks, since participation will not alter 
the treatment regimens.  

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2. INTRODUCTION AND RATIONALE 
Never ending research in cancer treatment and optimization of prevention methods have led to 
increased survival rates in people diagnosed with cancer. The long term survival improves for most 
cancers, reaching 80% for pediatric cancers and more than 70% for cancers in adults between 20 and 
49 years of age (1). As the prognosis for malignancies improves, the long-term side effects become 
more important. The focus has switched from a purely oncology point of view towards oncofertility, in 
which fertility, as one of the major factors for a good quality of life, becomes substantially more 
important (2).  
Decreased ovarian reserve, premature ovarian insufficiency and premature menopause due to surgery 
and the gonadotoxic effects of chemotherapy and radiotherapy may however result in fertility 
impairment. As more than 60% of patients with cancer is most concerned about the impact of the 
treatment on their fertility, fertility sparing treatments should be offered to young patients in order to 
maintain the wish to conceive after cancer treatment (5). 
Counselling and referring patients, who wish to safeguard their reproductive potential, to a fertility 
center is of great importance as up to 75% of young cancer survivors want to have children (4). 
Embryo cryopreservation is the most frequently used intervention to preserve fertility, for patients 
undergoing a gonadotoxic treatment. Oocyte cryopreservation is less frequently used, but has a similar 
outcome and could be a good alternative for single women. 
Other more experimental alternatives are cryopreservation of ovarian tissue, temporary translocation 
of the ovaries when pelvic radiotherapy is needed and ovarian function suppression with GnRH-
analogues during chemotherapy (5). 
Regarding cancer of the female genital tract, in which radical surgery is mostly the standard, 
alternatives are being investigated to preserve fertility. There are still a lot of gaps in research 
regarding these fertility sparing surgical treatments and the interventions are often experimental, as 
there is no standardized technique available due to lack of data. This leads to many different strategies 
being applied among different centers. In addition, there is a lack of studies investigating the 
oncological safety and obstetric outcome of these fertility sparing treatment protocols. Another major 
consequence of the absence of a standard technique is the difficulty to inform patients about the best 
treatment. 
It is important to obtain a significant amount of cases in order to make a thorough study especially 
since several types of cancer do not occur regularly. It is in this respect that this study aims to fill the 
gap in current research. 
 
The purpose is to enable us to obtain a significant amount of data to create more standardized fertility 
sparing treatment protocols and to better inform clinicians and patients on the efficacy of fertility 
sparing cancer treatment. 

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3. STUDY DESIGN 
The proposed research concerns a multicenter prospective observational cohort study. European 
collaboration is utilized in order to include sufficient number of patients.  
 
This is a study, for which primary approval was granted by UZ Leuven. UZ Leuven is the initiator of 
the study and the ethical committee of UZ Leuven is the central ethical committee. The UZ Leuven 
protocol is used in all centers, including the international collaborators. 
 
3.1 Objectives  
Primary Objective:  
To record the incidence and oncological outcome when a fertility preserving cancer treatment is 
applied in young women and compare the oncological outcome with a control group. 
Secondary Objective(s):  
To record the incidence and fertility outcome when a fertility preserving cancer treatment is applied 
in young women and compare the obstetrical and neonatal outcome with the general population. 
 
3.2 Inclusion criteria 
Histological proven cancer in young women under the age of 40 for whom a fertility preserving 
cancer treatment is applied. For the control group, patients are eligible when they are in the fertile 
age but over 18 years of age and undergoing standard cancer treatment.  
 
3.3 Sample size  
We aim for at least 500 cases per tumour type + 1 control patient per study patients (resulting in 500 
control patients per tumour type). This is a minimum that allows us to calculate the oncological 
prognosis (secondary objective). 
 
 

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3.4 Study procedures  
In women younger than 40 years old with a cancer diagnosis for whom a fertility preserving treatment 
is applied, the most important oncological data will be registered, as well as information on the 
fertility and oncological outcome. Control patients are women who are younger than 40 years of age 
diagnosed with cancer and who received standard treatment. All types of cancer and all types of 
treatment will be registered. Patients can be included both prospectively and retrospectively. For 
every study patient, we include one control patient. 
 
Recruitment of patients:  
Because information on pregnant state is not available in most cancer registries prospective 
recruitment of patients is done as followed networking (e.g. INCIP), newsletters, presentation at 
conferences for obstetricians, oncologists, haematologists, and also a website for professionals 
(www.cancerinpregnancy.org) and for patients (http://www.uzleuven.be/kanker-en-zwangerschap).  
 
We will collect the following data: 
At baseline: 
Oncological data include type of cancer, the date of diagnosis, tumour histology, stage of the disease, 
the type of treatment, cancer recurrence and survival. 
Fertility data include gravidity and parity, menstrual pattern after cancer treatment, conception 
(artificial of natural), obstetrical complications, gestational age at delivery and mode of delivery 
(induction, caesarean section, spontaneous labour).  
Paediatric data that will be collected include birth weight, gender, congenital malformations, 
admission to neonatal care unit and reason of admission.  
Annually until end of study: 
We will request information from the treating physician regarding patient’s health status (pregnant 
yes/no, relapse yes/no, site of relapse, treatment of relapse, date of relapse, date of death if 
applicable). 
 
This study does not involve any direct input or effort from the patient. Only the collection of existing 
information through the medical records is aimed for. 
 
4. STUDY POPULATION 
4.1 Population (base)  
All women under the age of 40 diagnosed with cancer for whom a fertility preserving cancer 
treatment is applied will be eligible for inclusion.  
 

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Fig. 1: Most common cancer in women 15–39 years old. *Incidence rates per 100,000.(6,7) 
 
Fig. 2: 
Model-based cumulative probabilities of first post diagnosis parenthood. For the young adult 
diagnostic age group, the curves represent conditional cumulative probability of parenthood given 
the patient had no children at age 20. The dashed line represents siblings and the solid line 
represents cancer patients.(8) 
4.2 Inclusion criteria 
Histological proven cancer in womenup to 40 years old but in their fertility years with a wish to 
preserve their fertility by undergoing fertility preserving cancer treatment.  

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4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation in 
this study: 
- 
Mentally disabled or significantly altered mental status that would prohibit the 
understanding and giving of informed consent.  
 
5. METHODS 
5.1 Randomisation, blinding and treatment allocation 
n.a. 
 
5.2 Study procedures 
For this study, it will not be necessary to postpone diagnostic procedures or treatment. Participation 
in this study does not influence normal treatment.  
 
5.3 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason and if they wish to do so this will be without 
any consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
 
5.4 Replacement of individual subjects after withdrawal 
n.a. 
 
5.5 Follow-up of subjects withdrawn from treatment 
n.a. 
 
5.6 Premature termination of the study 
No reasons for premature termination of the study are anticipated.  
 
6. STATISTICAL ANALYSIS 
We plan to use descriptive statistics (mean +/- standard deviation), two-sided tests, and Wilcoxon rank 
sum test to compare continuous variables in two groups, for more than two groups, the Kruskal-Wallis 
exact test will be used. For comparing a proportion with an expected value, a binominal exact test will 
be used. Results are considered significant at P<.05. 

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Analysis will be performed with SAS (version 9.2) and Statistical Package for Social Sciences for 
Windows (version 16). Statistical analysis will be performed under supervision of Prof. B. Van Calster 
(Leuven Cancer Institute, Belgium). 
 
7. SAFETY REPORTING 
7.1 Section 10 WMO event 
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects and 
the reviewing accredited ethical committee if anything occurs, on the basis of which it appears that 
the disadvantages of participation may be significantly greater than was foreseen in the research 
proposal. The study will be suspended pending further review by the accredited METC, except in so 
far as suspension would jeopardise the subjects’ health. The investigator will take care that all 
subjects 
are 
kept 
informed.  
 
7.2 AEs, SAEs and SUSARs 
 
Definitions in Law of May 7, 2004 concerning experiment on the human person 
 
Adverse event (AE): any untoward medical occurrence in a patient or subject of the treated group 
during an experiment, and which does not necessarily have a causal relationship with this treatment 
 
Serious adverse event (SAE): any untoward medical occurrence or effect that results in death, is 
life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in 
persistent or significant disability or incapacity, or is a congenital anomaly or birth defect;  
 
Suspected unexpected serious adverse reaction (SUSAR): is an AR that is serious and 
unexpected (meaning that nature or severity of the AR is not consistent with the Investigational 
Medicinal Product reference safety information, which is the Investigator’s Brochure) and is 
judged by either the investigator or the sponsor as having a reasonable suspected causal 
relationship with the investigational medicinal product. 
7.2.1 
Adverse events (AEs) 
All adverse events caused by study interventions reported spontaneously by the subject or 
observed by the investigator or his staff will be recorded. We do not expect any study related 
adverse events for this study. 

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7.2.2 
Serious adverse events (SAEs) expected 
The investigator shall report all study intervention-related serious adverse events immediately, 
after first knowledge, to the sponsor except for those that the protocol or investigator's 
brochure identifies as not requiring immediate reporting. The immediate report shall be 
followed by detailed, written reports. The immediate and follow-up reports shall identify 
subjects by code numbers. For reported study intervention related deaths of a subject, the 
investigator shall supply the sponsor and the accredited ethics committee with any additional 
information requested. 
The sponsor shall keep detailed records of all study intervention-related adverse events which 
are reported to him by the investigator or investigators. These records shall be submitted to the 
minister if the experiment is being conducted in Belgium, if he so requests. Regarding those 
study intervention-related serious adverse events the Principal Investigator will take all 
reasonable measures, in consultation with Sponsor, to protect subjects at risk following the 
occurrence of such events. 
Participation in this study holds an extremely low risk of AEs and study intervention-related 
SAEs since no invasive interventions are performed. Since this study holds an extremely low 
risk of a study intervention-related SAE and no invasive interventions are performed, this 
present study is relieved of reporting non study related SAEs. 
 
7.3 Data Safety Monitoring Board (DSMB)  
Data safety monitoring board is not needed. As this study is a study with extremely low risks and 
does not falls under the scope of the WMO, no monitoring is needed. 
 
 

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8. ETHICAL CONSIDERATIONS  
8.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki (WORLD 
MEDICAL ASSOCIATION DECLARATION OF HELSINKI) Ethical Principles for Medical 
Research Involving Human Subjects Version Edinburgh, Scotland, October 2000, with Note of 
Clarification on paragraph 29 added by the WMA General Assembly, Washington 2002 end note of 
clarification on paragraph 30 added by the WMA General Assembly, Tokyo 2004 and in accordance 
with the Medical Research Involving Human Subjects Act (WMO) and other guidelines, regulations 
and Acts.  
 
8.2 Recruitment and consent 
Eligible patients will be informed about the study by the supervising physician (e.g. gynaecologist, 
surgeon or medical oncologist) primarily treating the malignancy. The patient will also obtain 
written information about the study. The patient can think about participation and discuss the study 
with her family. They will be given enough time to consider their decision and are free to reconsider 
their decision at any moment during the trial. In case of participation the informed consent should 
be signed prior to registration of patient data. This is applicable for the prospective part of this study. 
An exception is made for the retrospective part of this registration study; retrospective data without 
the need for follow-up may be collected anonymously without a signed consent form for evaluation 
of quality of care since it does not fall under the scope of the WMO.  
 
8.3 Objection by incapacitated subjects (if applicable) 
No incapacitated subjects will be included in the study. 
 
8.4 Benefits and risks assessment, group relatedness 
As this study will not change treatment nor randomize patients, participation in this study will not 
affect patients’ outcomes. As this is an observational study, no additional risks from the study are 
expected.  
  
8.5 Compensation for injury 
Participation in this study does not imply any study related actions and only carries negligible risks 
for the research subjects. However, the sponsor shall be liable, even without fault, for any damages 
incurred by a study subject and linked directly or indirectly to the participation to the study. 

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Sponsor shall enter into an insurance agreement in order to cover the liability for any damages 
incurred by a study subject from a Belgian participating site. See paragraph 9.4 for further 
information.  
8.6 Incentives 
Eligible participants do not receive any special incentives that may encourage participation in this 
study. 
 
 
9. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
9.1 Handling and storage of data and documents 
The investigator records clinical data, using a paper or electronic case report form (CRF), all data is 
collected in an online database that is available through www.cancerinpregnancy.org, such database 
being the ownership of Sponsor. Participating physicians have a personal account to log in to the 
registration page and access the electronic CRF. They will have permanent access only to their own 
series of patients. The participating physician ensures the confidentiality, accuracy, completeness, 
legibility and timeliness of the data recorded. Data handling and statistical analysis will be done 
anonymously by the investigator, with the subject identification code list only available to the local 
investigator (and research nurse if applicable) working in the local center. The code will be based on 
the birth date and center abbreviation (and not patient initials). The investigator will be the owner of 
the data. Data will be kept for 20 years. 
Sponsor, participating physicians and sites agree and commit to handle and protect the data in 
accordance with the terms and provisions of all applicable data protection rules and legislation 
including the Belgian law of 08 December 1992 on Privacy Protection in relation to the Processing 
of Personal Data and the Belgian law of 22 August 2002 relating to patient’s rights. 
 
9.2 Amendments  
Amendments are changes made to the research after a favourable opinion by the accredited ethical 
committee has been given. All amendments will be notified to the ethical committee that gave a 
favourable opinion.  
 
 
 

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A ‘substantial amendment’ is defined as an amendment to the terms of the ethical committee 
application, or to the protocol or any other supporting documentation, that is likely to affect to a 
significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the ethical committee and to the competent authority. 
Non-substantial amendments will not be notified to the accredited ethical committee and the 
competent authority, but will be recorded and filed by the sponsor.  
 
9.3 Public disclosure and publication policy 
 
This study is registered with ClinicalTrials.gov, number NCT02878434. 
All publications from this study will be done by the principle investigators and other investigators 
according to their contribution to this study. 
 
9.4 Insurance 
Sponsor shall be liable, even without fault, for any damages incurred by a study subject and linked 
directly or indirectly to the participation to the study. 
Sponsor shall enter into an insurance agreement in order to cover the liability for any damages 
incurred by a study subject from a Belgian participating site. 
If an insurance coverage is required by local laws of non-Belgian participating sites, such 
participating sites shall have and maintain in full force and effect during the term of this Agreement 
(and following termination of the study to cover any claims arising from the study) adequate 
insurance coverage for any damages linked directly or indirectly to the subjects’ participation to the 
study at participating sites. Participating sites shall provide a corresponding insurance certificate to 
Sponsor. 
 
 
10. REFERENCES 
 
1) National Cancer Institute. SEER cancer statistics review 1975-2011. 2011, last update 2014 
[cited 19/09/2016]. Available from: http://seer.cancer.gov/archive/csr/1975_2011/ 
2) Duffy C, Allen S. Medical and psychosocial aspects of fertility after cancer. Cancer J 2009, 
15(1): 27-33. 

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3) Partridge AH, Gelber S, Peppercorn J, et al. Web-based survey of fertility issues in young 
women with breast cancer. J Clin Oncol. 2004;22(20):4174–83. 
4) Bastings L., Baysal O., Beerendonk C., et al. Referral for fertility preservation counselling in 
female cancer patients. Hum. Reprod. 2014, 29:2228–2237. 
5) Deshpande NA, Braun IM, Meyer FL.. Impact of fertility preservation counseling and 
treatment on psychological outcomes among women with cancer: a systematic 
review. Cancer 2015, 121(22):3938–47. 
6) Ana Milena Angarita, Cynae A. Johnson, Amanda Nickles Fader, and Mindy S. Christianson. 
Fertility Preservation: A Key Survivorship Issue for Young Women with Cancer. Front Oncol. 
2016; 6: 102.  
7) Surveillance, Epidemiology, and End Results (SEER) Program. Cancer Statistics Review 
1975–2012. (2015). Available from: http://seer.cancer.gov/csr/1975_2012/browse_csr.php 
8) Madanat LM1, Malila N, Dyba T, Hakulinen T, Sankila R, Boice JD Jr, Lähteenmäki PM. 
Probability of parenthood after early onset cancer: a population-based study. Int 
J Cancer. 2008 Dec 15;123(12):2891-8. doi: 10.1002/ijc.23842. 
 
 

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11. APPENDIX A 
DATA PROCESSING ANNEX (“DPA”) TO THE PROTOCOL 
Definitions: 
“Protocol” means the document entitled “Fertility Preservation” containing the details 
of the academic study as developed by the Sponsor as approved by the relevant ethics 
committee. 
“Sponsor” means Universitaire Ziekenhuizen Leuven. 
Participating site acts as a data processor as defined under article 4, 8) of the Regulation 
(EU) 2016/679 (“Data Processor”) for the Sponsor who acts as data controller as 
defined under article 4, 7) of the Regulation (EU) 2016/679 (“Data Controller”). 
“Applicable Law”  means any applicable data protection or privacy laws, including:  
(i) 
the Regulation (EU) 2016/679 also referred as the General Data Protection 
Regulation ("GDPR");  
(ii) 
other applicable laws that are similar or equivalent to or that are intended to or 
implement the laws that are identified in (a) of this definition;  
"Personal Data" means any information relating to an identified or identifiable natural 
person (‘Data Subject’), including without limitation pseudonymized information, as 
defined in Applicable Law and described in the Protocol. 
Rights and obligations: 
1) The Data Processor is instructed to process the Personal Data for the term of the Protocol 
and only for the purposes of providing the data processing tasks set out in the Protocol. 
2) The Data Processor must ensure that persons authorized to process the Personal Data 
have committed themselves to confidentiality or are under an appropriate statutory 
obligation of confidentiality. 
3) The Data Processor shall implement appropriate technical and organizational measures 
to prevent that the Personal Data processed is: 
(i) 
accidentally or unlawfully destroyed, lost or altered, 
(ii) 
disclosed or made available without authorization, or 
(iii) 
otherwise processed in violation of Applicable Law.  
4) The appropriate technical and organizational security measures must be determined 
with due regard for: 
(i) 
the current state of the art, 
(ii) 
the cost of their implementation, and 
(iii) 
the nature, scope, context and purposes of processing as well as the risk of 
varying likelihood and severity for the rights and freedoms of natural persons. 
5) The Data Processor shall upon request provide the Data Controller with sufficient 
information to enable the Data Controller to ensure that the Data Processor's obligations 
under this DPA are complied with, including ensuring that the appropriate technical and 
organizational security measures have been implemented. 
6) The Data Controller is entitled to appoint at its own cost an independent expert, 
reasonably acceptable to Data Processor, who shall have access to the Data Processor's 
data processing facilities and receive the necessary information for the sole purpose of 
auditing whether the Data Processor has implemented and maintained said technical and 
organizational security measures. The expert shall upon the Data Processor's request 

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sign a non-disclosure agreement provided by the Data Processor, and treat all 
information obtained or received from the Data Processor confidentially, and may only 
pass on, after conferral with Data Processor, the findings as described under 8) (ii) below 
to the Data Controller. 
7) The Data Processor must give authorities who by Union or Member State law have a 
right to enter the Data Controller's or the Data Controller's processors’ facilities, or 
representatives of the authorities, access to the Data Processor's physical facilities 
against proper proof of identity and mandate, during normal business hours and upon 
reasonable prior written notice. 
8) The Data Processor must without undue delay in writing notify the Data Controller 
about: 
(i) 
any request for disclosure of Personal Data processed under the Protocol by 
authorities, unless expressly prohibited under Union or Member State law, 
(ii) 
any  finding of (a) breach of security that results in accidental or unlawful 
destruction, loss, alteration, unauthorized disclosure of, or access to, Personal 
Data transmitted, stored or otherwise processed by the Data Processor under the 
Protocol, or (b) other failure to comply with the Data Processor's obligations, or 
(iii) 
any request for access to the Personal Data (with the exception of medical 
records for which the Data Processor is considered data controller) received 
directly from the data subjects or from third parties. 
9) Such a notification from the Data Processor to the Data Controller with regard to a 
breach of security as meant in 8) (ii)(a) above will contain at least the following 
information: 
(i) 
The nature of the Personal Data breach, stating the categories and (by 
approximation) the number of Data Subjects concerned, and stating the 
categories and (by approximation) the number of the personal data registers 
affected (datasets); 
(ii) 
The likely consequences of the Personal Data breach; 
(iii) 
A proposal for measures to be taken to address the Personal Data breach, 
including (where appropriate) measures to mitigate any possible adverse effects 
of such breach. 
10) The Data Processor shall document (and shall keep such documentation available for 
the Data Controller) any Personal Data breaches, including the facts related to the 
Personal Data breach, its effects and the corrective measures taken. After consulting 
with the Data Controller, the Data Processor shall take any measures needed to limit the 
(possible) adverse effects of Personal Data breaches (unless such consultation cannot 
be awaited due to the nature of the Personal Data breach). 
11) The Data Processor must promptly reasonably assist the Data Controller (with the 
handling of (a) responses to any breach of security as described in 8) (ii) above and (b) 
any requests from Data Subjects under Chapter III of the GDPR (upon its entry into 
force), including requests for access, rectification, blocking or deletion. The Data 
Processor must also reasonably assist the Data Controller by implementing appropriate 
technical and organizational measures for the fulfilment of the Data Controller's 
obligation to respond to such requests. The Data Processor must reasonably assist the 
Data Controller with meeting the other obligations that may be incumbent on the Data 
Controller according to Union or Member State law where the assistance of the Data 

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Processor is implied, and where the assistance of the Data Processor is necessary for the 
Data Controller to comply with its obligations. This includes, but is not limited to, at 
the request to provide the Data Controller with all necessary information about an 
incident under 8) (ii), and all necessary information for an impact assessment in 
accordance with Article 35 and Article 36 of the GDPR.  
Subprocessor: 
12) The Data Processor may only engage a subprocessor, with prior specific or general 
written consent from the Data Controller. The Data Processor undertakes to inform the 
Data Controller of any intended changes concerning the addition or replacement of a 
subprocessor by providing a reasonable prior written notice to the Data Controller. The 
Data Controller may reasonably and in a duly substantiated manner object to the use of 
a subprocessor. The Data Processor must inform the Data Controller in writing of the 
discontinued use of a subprocessor. 
13) Prior to the engagement of a subprocessor, the Data Processor shall conclude a written 
agreement with the subprocessor, in which at least the same data protection obligations 
as set out in this DPA shall be imposed on the subprocessor, including obligations to 
implement appropriate technical and organizational measures and to ensure that the 
transfer of Personal Data is done in such a manner that the processing will meet the 
requirements of the Applicable Law. 
14) The Data Controller has the right to receive a copy of the relevant provisions of Data 
Processor's agreement  with the subprocessor related to data protection obligations. The 
Data Processor shall remain fully liable to the Data Controller for the performance of 
the subprocessor obligations under this DPA. The fact that the Data Controller has given 
consent to the Data Processor's use of a subprocessor is without prejudice for the Data 
Processor's duty to comply with this DPA.