Frequently asked questions EC Research

EC Research can be reached by telephone between 10 am and 11 am. For technical issues, strong preference is given to mail communication with reference to the S-number, rather than enquiries by phone. May we remind you to use the e-mail address ecstaf@uzleuven.be only to send replies to comment letters. General questions, submissions of initial dossiers, amendments, annual reports,... should be sent to the general e-mail address ec@uzleuven.be. Please do not send the same message to both e-mail addresses. As a reminder: ecsubmission@uzleuven.be does not exist anymore.

A conflict of interest in research refers to situations in which financial or other personal considerations may compromise, or could lead to the perception of compromising a researcher's professional judgment in conducting or reporting research. Hereby we would like to iterate the definition of "conflict of interest”: Conflict of interest: the situation in which the interests of a person to whom this law applies to, could influence the conclusions of an opinion/advice with the aim of obtaining an advantage, financial or not (such as acquiring a certain influence), directly or indirectly. This may include fees, reimbursements, participation in the profit or hospitality for the interested person him/herself, but also for his/her family or any other person with whom he/she has relationships. The benefits may also go to the organization for which he/she works (for example, a university service) or to which he/she is affiliated (for example, a professional organization), such as scholarships, payment of a staff member, allowances, a chair, etc. https://www.health.belgium.be/sites/default/files/uploads/fields/fpshealth_theme_file/hgr_8891_beheer_belangenconflicten.pdf EC Research invite you to highlight any potential conflicts of interest in the cover letter. It is the PI’s responsibility to declare any potential COI. The PI is therefore requested to indicate any conflict of interest for conducting the study by the investigator himself or herself and all members of his/her study team during the course of the study.

For more information on off-label use (i.e. use of a medicine outside the licensed dose, age/patient group, therapeutic indication and/or form of administration), please refer to the website of the Medical Pharmaceutical Committee (MFC). Off-label use is under the responsibility of the prescribing physician and does not require EC approval.

When a subject participates in a clinical study, he/she should not have any costs except those related to the standard of care treatment of their disease. However, the subject can receive a compensation for time investment, efforts and expenses such as travel costs, meals,… EC would like to see the details of the total amount provided for the subjects. Therefore, the sponsor should clearly specify which expenses will be compensated and the amount of each compensation, e.g. travel costs: a fixed amount per visit, the amount per km or the reimbursement of the exact costs,… EC recommends to make the compensation process as easy as possible for the patient (e.g. a fixed amount). Some working parties are in the process of creating more guidance and harmonization about compensation for trial participants (BAREC, CT-College), and we will inform you of the outcome in due time. Compensation for cost or effort/time investment can be made but the compensation might not be excessive.

The use of a lottery proposed as compensation for study participants is, in accordance with the Lotteries Act of December 31, 1851, lotteries, prohibited in Belgium unless organised according to the applicable law and if a license has been obtained. A lottery is characterized by the determining role of chance. The chances of winning a prize do not depend on the (physical or intellectual) abilities of the participants, but solely on the lottery ticket, and this is not allowed in Belgium. This means that the random drawing of winners from a pool of participants is, in principle, prohibited, since the element of coincidence is fully and solely present here. In order to avoid the application of the criminal law, one can make the chance of winning dependent on the participant's skill (thus taking into account the intellectual or physical capacity of the participant and not purely determining the result by chance), for example, by asking match questions or shifting questions. Therefore, please do not refer to it as a "lottery" in that case. An important nuance here is that one may not frame that skill or question in such a way that everyone would know the answer. One may not bypass the requirements of the lottery laws by asking a (too simple) question that everyone knows the answer to.

Researchers intending to conduct a study on bodies and/or body material have to submit an application. Different procedures exist for the use of a) bodies of deceased persons who have donated their bodies via their will, b) without will and for the use of body material of living donors. a) Procedure for the use of a body/body material donated via a will If you intend to conduct a study on post-mortem bodies/body material originating from deceased patients who indicated before their death via their will that they agree to certain body materials being used for research at KU Leuven, ethical advice must be obtained via EC Care. You must submit a request via EC Care, after consultation with the responsible persons of Anatomy. This post-mortem material is never disease-specific. When submitting the application, you should make it explicit that: i) it concerns bodies that have been donated to KU Leuven via a will for the benefit of science; ii) the principle of 'bodies must be complete for the funeral’, as required in the guidelines of Anatomy, is met. If it concerns a smaller quantity of tissue that cannot be attributed to an individual body, this must also be made explicit in the protocol. b) Procedure for the use of body material of living donors / deceased donors without a will Other studies involving the use of human body material, whether derived from living donors or deceased donors who have not donated their bodies to science via will, must be submitted to EC Research for approval (cf. Law of 19 December 2008 and Law of 7 May 2004 on experiments), after validation by the Clinical Trial Center (CTC). The same procedure applies to studies involving the 'secondary' use of residual human body material or studies that prospectively collect body material from living donors for research purposes.

The EC approval given for a specific project, is valid for one year. In case no participants have been included during the first year after EC approval, the study will need to be re-evaluated by the EC. Inclusion of participants is evaluated through the annual progress report. Please be informed that if the EC is not notified of the above, the study will be administratively closed.

In accordance with Article 36 of the Law of May 7, 2017, the researcher must be a medical doctor within the meaning of the Law on the Practice of the Health Professions, coordinated May 10, 2015. The investigator may also have the capacity of a dental practitioner, within the meaning of the same law, as regards clinical trials related to dentistry.

ECs must evaluate the suitability of investigators in a clinical trial. As pointed out above, ECs will have to evaluate whether the investigator, who is not affiliated with the site, is suitable to perform the clinical trial. A comprehensive and well prepared CV, highlighting your expertise and competences, is crucial to evaluate this suitability.

A distinction should be made between clinical trials (CTR) and experiments (7 May 2004).

For EudraCT studies (i.e. interventional clinical trials with investigational drugs) conducted under CTR, the principal investigator should conduct the interview. Here, delegation is only possible to a member of the research team who is a physician/dental practitioner or a nurse. This means that a Clinical Trial Assistant (CTA) who has studied biomedical sciences may not legally conduct an interview for the purpose of obtaining informed consent in the context of a clinical trial. There are also some rules regarding who should sign the ICF, below is an overview of some possible situations.

If a nurse conducts the ICF, two signatures are required, those of the nurse herself and of the PI.

If the PI delegates conducting the interview to a nurse and delegates signing the ICF to a co-investigator who is a doctor/dentist, two signatures are required, from the nurse and from the co-investigator.

If the PI only delegates conducting the interview to a co-investigator who is a doctor/dentist, only the co-investigator's signature is required.

If the PI delegates conducting the interview and signing the ICF to a co-investigator (who is a doctor/dentist), only the co-investigator's signature is required.

Experiments are subject to Article 6 of the Law of May 7, 2004 which states that the patient must be informed in a clear and understandable way. It does not specify what the qualifications should be of the person providing the information. If the consenting process is clearly described (confirming a medical doctor is readily available to answer any medically related questions, should such a question be raised by the subject during the consent process) and it is obvious that the person to whom the consent process is delegated, is properly trained (and the task is delegated in the delegation log), EC can allow the delegation for conducting the informed consent interview to members of the study team who may not be health care practitioners according to the law of May 10, 2015, (e.g. a CTA who has studied biomedical sciences). In accordance with article 4.8.8 ICH-GCP, the ICF should be signed by the person who conducted the informed consent interview. The ICF must always be signed by the principal investigator or supervising sub-investigator.

No, for the time being IC forms are only available for adult study participants. In theory, minors do not give their consent, but they must be able to give written assent to the participation in a study ("assent", recommended from the age of 12). Of course, the parents must always give their consent for their minor child to participate in a study and a separate ICF must also be provided for them. We generally recommend keeping the structure of the main ICF in the assent form for minors so that all important information about the study is included (purpose of the study, description, course, voluntary participation, costs). The sections "samples", "confidentiality" and "insurance" can be mentioned briefly, but for more information you can refer to the ICF for parents. For the rest, it is best to use short sentences, no words that are too difficult, possibly a few illustrative pictures... In this way, the form will be more understandable for minors, both in terms of content and language. For the EC, the ICF for 0-7 year-olds is unnecessary, as these children are generally considered to have not yet reached the age of distinction. Moreover, most of these children cannot read (sufficiently).

We would like to stress the importance of a scientifically valid protocol, including clear research questions and objectives, description of primary and secondary endpoints/outcome. A endpoint/outcome variable is a characteristic of the patient that will be measured during the study. Typically, the objectives of a study are statement regarding the main outcome. For instance, the main endpoint/outcome of study may be patient survival at 1 year, defined as 1 if the patient was alive 1 year after finishing the treatment and zero otherwise. The main objective of the study can then be formulated as, for instance: To demonstrate that the proportion of patients that have survived at 1 year is larger in the experimental group than in the control group. A description in the protocol about the number of participants (sample size) that will be included and why this number was chosen, is very important. The sample size calculation is typically based on a statistical procedure (test, confidence interval, model, etc). Basically, one calculates the sample size necessary to assess the main objective of the study through the use of a statistical test or model. There should be a clear correspondence between the sample size of the study, the main objective and the analysis of the data. The model/tests used to calculate the sample size will define the main analysis that will be carried out with the data of the study. When describing the sample size calculation one should clearly state the outcome used, the statistical test or model employed, the level of significance, the power, as well as the effect size and the estimates for all necessary parameters. One should also state how the estimates of the parameters used in the sample size calculation were obtained. The statistical analysis plan should obviously contain the test/model used for the sample size calculation. It should also contain a description of any other analysis that will be carried out. It is important to clearly state which analysis will be confirmatory (analysis carry out to assess the objectives of the study main and/or secondary) and which ones will be merely descriptive. It is strongly advisable to do so for each study objective separately, rather than merely including a generic list of statistical tools. The analysis plan should include information on how missing data will be handled. Exploratory studies may not require a rigorous statistical formalism but their findings will have to be interpreted with extreme caution. Essentially, these studies generate hypotheses that will need to be tested in further confirmatory studies. The exploratory nature of a study should be clearly stated in the protocol and any subsequent publication. Please also clearly state the method of participant sampling. EC would like to direct you to the following website of the “Leuven Biostatistics and statistical Bioinformatics Centre (L-BioStat)”: https://gbiomed.kuleuven.be/english/research/50000687/50000696. To all researchers of the Group Biomedical Sciences, L-BioStat offers consultation to provide statistical advice on various methodological and statistical aspects of the research project. Free advice is provided through scheduled one hour consulting appointments. Further, it also offers in-depth collaborative consulting, including analysis of data, writing of a statistical report and incorporation of the results in (an) article(s) You can also discuss/collaborate with colleagues from several departments in KU Leuven with extensive biostatistical expertise, both in Biomedical Sciences as in the other groups.

For each specific research project with VIB, an MTA/DTA must be completed and signed. In collaboration with CTC, LRD and VIB templates have been created, which will soon be available on our website. In addition, a specific wording in the ICFs has also been agreed. This is available on our website: https://www.uzleuven.be/nl/ethische-commissie-onderzoek/templates-en-interne-richtlijnen-bij-starten-van-dossier-bij-ec-onderzoek/informed-consent-formulier-icf-opstellen

On the website of the Clinical Trial Center there is a link to a protocol template for a retrospective study when UZ Leuven is the sponsor. From 1st January 2022 it will be mandatory to use this template for submission of such studies to EC Research (or OBC). For the definition of a retrospective study, we refer to the Law of 7 May 2004: a retrospective study is a study based on data from the past already available in existing patient files, medical files or administrative files and to the extent no new data will in any way be collected for the purpose of such study (cf. article 3, §2 of the Law of 7 May 2004). We would like to highlight: In the case of retrospective studies, please always indicate the end date of the data collected; this date must of course be in the past. The head/staff of the clinical department or the responsible care program must be informed and concur with this study; this is the PI’s responsibility. When using data in retrospective research, collegiality and respect for the work and input of colleagues contribute to good collaboration. We therefore invite you to involve in such retrospective research the colleagues who have given intellectual input in your research (as co-researcher, co-author). Contacting the treating physicians will also help to avoid the same patients being published more than once in case studies (case reports and case series). Concerning statistics in retrospective studies: Please always mention the planned sample size in the protocol A retrospective study with a small sample size could often be seen as an exploratory study. Exploratory studies may not require a rigorous statistical formalism but their findings will have to be interpreted with extreme caution. Essentially, these studies generate hypotheses that will need to be tested in further confirmatory studies. The exploratory nature of a study should be clearly stated in the protocol and any subsequent publication. On the intranet page of the CTC (https://wiki.uz.kuleuven.ac.be/display/ctc/Documenten) you will find a link to a new protocol template for a retrospective study when UZ Leuven is the sponsor. If data will be shared with third parties, a data transfer agreement (DTA) must be in place containing GDPR language.

A case report is a detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin) Since many journals require EC/IRB advice for case reports, we recommend submitting them to EC Research directly via ec@uzleuven.be. A template ICF can be found on https://www.uzleuven.be/nl/ethische-commissie-onderzoek/templates-en-interne-richtlijnen-bij-starten-van-dossier-bij-ec-onderzoek/informed-consent-formulier-icf-opstellen. In addition to the ICF (without the patient's name), please also provide a brief explanation (cover letter) of the case description. The ICF can only be signed by the patient after EC submission and approval. Make sure that you do not provide the name of a patient to EC. Also when you intend to write a case report in the context of a master's thesis, we recommend to submit it directly to EC and, after approval, to enter the assigned S-number in SCONE.

We would like to ask the principal investigators to pay extra attention to the cover letter that must be submitted to EC with each new study/substantial amendment. Please make the cover letter specific for UZ Leuven by for example clearly stating which optional tests of the study will be conducted in UZ Leuven (e.g. will UZ Leuven participate in the pediatric study, in the PK-study…?). Please also mention which sites will participate in Belgium. The principal investigator can mandate person(s) of UZ/KU Leuven to sign and submit to the Ethics Committee Research in his/her name. This mandate is valid for one year as from the date of last signature on the delegation mandate cover letter (see website EC). (In case of a substantial amendment): Please state clearly the reason for the substantial amendment in the cover letter.

An information and consent form (ICF) should always be written in a language that is understandable for the participant. If information for patients is submitted in a language other than English or other than the three Belgian national languages, EC Research requests a certificate from a certified translator. If an ICF in the patient's language is not available, we request that an interpreter (independent of the commercial sponsor) is present during the entire process of supply of information to the participant. The following paragraph should be included in the ICF for the participant (available in the template ICF): Witness / Interpreter I have been present during the entire process of supply of information to the participant and I confirm that the information about the objectives and procedures of the study was adequately provided, that the participant (or the participant's legal representative), in all likelihood, has understood the study and that consent to participate in the study has been given voluntarily. Name, first name and function of the witness: Date and signature of witness/interpreter

An informative CV is very important to evaluate the suitability of the investigator. In January 2022, the European regulation will apply to all interventional clinical trials with medicines (CTR 536/2014). When the CTR applies, a study cannot be evaluated by the EC of a participating site. When UZ Leuven is a participating site in a study , the study will be evaluated by an independent EC (which may not know your expertise) and not by EC Research. A comprehensive and well prepared CV gets even more important then. A few highlights for a good and clear CV: Diplomas have to be listed and the most important trial experience should be documented. GCP training should be documented (in the CV or by a GCP certificate), mentioning the name of the certifying organisation and the date; it should not be older than three years A CV template developed by the EU Commission is available on our website.

Training in ICH GCP guidelines is mandatory for every PI, but also for each member of his/her study team. It is the responsibility of the PI to make sure that all members of the study team are properly trained and in addition, the PI should supervise that the study team is conducting the study according to ICH GCP. The CV of the PI should explicitly mention the date when the most recent ICH GCP certificate has been granted (max. 3 years) and the organization, or alternatively, a copy of the ICH GCP certificate should be included in the submission of the study file. In a collaborative effort, the CTC’s of all 7 Belgian academic hospitals have developed a GCP-e-learning. The training will be offered through the UZ leercentrum & KU Leuven Toledo. The training has been fully validated by TransCelerate and as such, successful completion of the knowledge assessment will result in an internationally recognized training certificate which remains valid for 3 years (or until the next GCP revision). EC Research currently also accepts certificates obtained after attending another online training course approved by Transcelerate, for example at https://globalhealthtrainingcentre.tghn.org/ich-good-clinical-practice/.

If the sponsor wishes to make substantial modifications to the protocol after the start of the study, the reasons for and details of these modifications must be submitted to EC Research in an amendment. Modifications are considered substantial if they are expected to have a significant effect on: the safety or physical and psychological integrity of the participants in the clinical trial the scientific value of the trial. It is up to the sponsor to assess whether a change is "substantial". It is not obligatory to submit non-substantial amendments, although it is advisable to notify EC Research. These modifications should be documented anyway and be included in the submission at a later stage, e.g. with the subsequent submission of a substantial modification. EC Research will send you a notification letter upon receipt of the non-substantial modification, but will no longer send an Acknowledgment of Receipt (AoR).

A translation of a document that has already been approved, is regarded as a non-substantial amendment. The sponsor is responsible for the conformity of the foreign-language documents with the Dutch-language documents. If it concerns a translation into a foreign language (other than Dutch, French, German and English), a letter from a certified translator must be present at the time of submission. This non-substantial amendment is only submitted for notification and not for approval.Thus the correct translation into all other languages remains the responsibility of the sponsor and can be provided at the occasion of the next substantial modification

New documents (that were not part of the initial submission dossier) must be submitted as modifications after approval of the initial dossier. After the initial dossier approval, new or modified documents can only be implemented after new approval by the EC.

For studies that fall under the Law of 7 May 2004, we ask you to submit an annual progress report. We would like to add that this report must be submitted within 30 days of the anniversary date on which the favorable opinion was given, and annually until the study is declared ended. Also, if no patients have been included in the study in the year following EC approval, EC expects to receive a progress report including this information. The submission of an annual progress report to EC according to ICH GCP is mandatory after ethical approval. A progress report is considered an extension of the EC approval, and in the absence of the progress report, the study may be legally closed. A template, in Dutch and English, is available on our website.

Results of clinical trials are used by clinicians, patients, and policy makers to make informed choices about the benefits and safety of interventions. Sharing the methods and results of all trials has therefore long been recognized as an ethical and scientific imperative. As of 21 July 2014, it is mandatory for sponsors to post clinical trial results in the European Clinical trials Database (EUCTR). Following the European Commission guideline 2012/c302/03, sponsors must ensure that all trials registered on EUCTR (EMA) since 2004 disclose their results within 12 months of trial completion. In the BMJ publication dd 16 July 2018 the compliance with requirement to report results on the EU Clinical Trials Register is discussed. This publication stipulates that compliance with the European Commission guideline has been poor. Half of all due trials have not yet reported results. Sponsors doing fewer trials, and non-commercial sponsors such as universities, have particularly low reporting rates. We therefore invite you to: Inform EC of the end of the trial within 90 days (including annex III for EudraCT trials) cfr. Article 21 of the Belgian law of 7 May 2004 on experiments on the human person. If the clinical trial ends prematurely, that date should be considered the end of the trial; Submit a Clinical Study Report (CSR) to EC containing the results within one year after the study was completed. In case of a EudraCT trial, the results must be published in the EUCTR. That report in the EUCTR can be used as the CSR for EC.

In general, the following rules apply with respect to reporting a fatal event during a study that falls under the Experimental Research Act of 7/5/2004: The investigator provides the sponsor and the recognised central ethics committee with all the initial and any additional information. In the case of a death of a patient at UZ Leuven, the investigator must always inform EC Research, even if the committee for the study concerned acts as a local committee. The above applies to all prospective studies. The Law does not make a distinction between a death occurring in a non-interventional study and an interventional study. However, EC Research wishes to deal pragmatically with the reporting of fatal events in observational registry studies in which there is no link with a drug and/or device. In these registry studies, fatal events do not have to be reported to the EC. For registry studies with a link to a medicinal product and/or device (i.e. safety and efficacy registries), the general rules as set out above do apply. The EC expects by mail that the S-number of the study is given, the cause of death and the suspicion whether the death is related to the study or not. Please do not provide us with the name of the deceased.

Please contact the UZ Leuven Data Protection Officer (DPO) griet.verhenneman@uzleuven.be In order to ensure continuity, EC requests the generic contact details of the DPO of UZ Leuven be used in the context of clinical research and that they be listed in the ICF as follows: "DPO - UZ Leuven, Herestraat 49, 3000 Leuven, e-mail gdpr.research@uzleuven.be".

Please note that anonymous/anonymized data is interpreted restrictively under GDPR: it means that the data subject is not or no longer identifiable (by any person or by any means). Note that personal data that have been pseudonymised – e.g. key-coded – falls within the scope of the GDPR. Data that have been anonymised are considered to be out of scope of GDPR: “pseudonymisation” means the processing of personal data in such a manner that the personal data can no longer be attributed to a specific data subject without the use of additional information, provided that such additional information is kept separately and is subject to technical and organisational measures to ensure that the personal data are not attributed to an identified or identifiable natural person. The goal of pseudonymisation is to ensure that individuals can only be identified through the use of additional information. Although many definitions exist and many techniques can be applied to achieve pseudonymisation, it essentially requires two steps. 1. Whilst the direct link between the data subject and the dataset must not be broken, it must be coded. Such a code should be study-specific. The use of a single key which is unique per patient across research projects and studies should be avoided, since it decreases the level of protection. 2. Specific elements in the data set which could allow the indirect identification of the data subject must be replaced, generalised or deleted. In order to determine which elements of the dataset should be considered indirect identifiers you need to consider the 18 elements listed in US HIPAA as personally identifiable information. The principles of data protection do not apply to “anonymous information”, namely information which does not relate to an identified or identifiable natural person or to personal data rendered anonymous in such a manner that the data subject is not or no longer identifiable (by any person or by any means). Where that data subject cannot be identified, the information will not constitute personal data and the duties and obligations of the GDPR will not apply. When assessing anonymity, you should however take into account that GDPR applies to directly identifiable data (the data subject can be identified because of a name or another specific identifier) and to indirectly identifiable data (the data subject can be identified because in their combination the collected data allow to single out an individual). To assess identifiability first of all it has to be taken into account that data cannot be anonymous to you, while they are not anonymous to the holder of the original source data because the possibility to re-establish the link through the original source remains. When no key is being held anymore (by no-one) it moreover needs to be assessed whether or not the richness of the information allows to single out individual profiles which could (with the help of an additional database, for example KWS) allow re-identification. For this assessment the access rights of the researcher to the additional information are irrelevant. The mere possibility to combine databases (lawfully or illicitly) is sufficient to qualify the information as identifiable and hence as personal data. Also in case of aggregated data, where information about many individuals is combined into broad classes, groups or categories, a similar assessment needs to be made, especially in case of small patient populations or rare diseases. Only where each of these possibilities to re-identify the individual, can be excluded, GDPR accepts that information is anonymous or anonymized.