guidance-document-for-researchers_basic-research.pdf
BASIC RESEARCH: Guidance for researchers
This guiding document is intended for researchers who conduct basic research projects with persons according to chapter 2 HRO and for further use projects of human biological material with or without associated health-related personal data according to chapter 3 HRO. The document does not address research with human embryonic stem cells nor with stem cells derived from surplus embryos. This kind of research falls under the scope of the Federal Act on Research Involving Embryonic Stem Cells (StRA)1.
The guiding document focusses on the most common omissions made during the planning and writing of project research plans (study protocols) for basic research projects and addresses some of the questions raised by the researchers on the submission of those projects to the ethics committees.
What constitutes exactly «basic ‘medico scientific’ research» and does it fall within the scope of The Federal Act on Research involving Human Beings (HRA, HFG, LRH, LRUm)? A broad general definition of Basic Research defines it as a synonym for fundamental research, which is the study of life processes. It includes for example studies in the fields of molecular biology, genetics, biochemistry, physiology, microbiology, immunology, and studies on the properties of drugs and materials in contact with human biological material, i.e., cells or tissues (in vivo, ex vivo and in vivo animal studies). Basic research also includes the development and improvement of analytical procedures such as analytical determination of enzymes, markers or genes. The development of biometric procedures such as statistical test procedures, modeling and statistical evaluation strategies also belongs here2.
The Federal Act on Research Involving Human Beings (Human Research Act, HRA) applies to research concerning human diseases and concerning the structure and function of the human body (HRA Art. 2 para. 1). It does apply to uncoded or coded but not to anonymized3 biological material and anonymously collected nor to anonymized healthrelated personal data4 (HRA Art. 2 para. 2).
Basic research projects as mentioned above may fall within one of several different study categories subjected to prior ethics committee approval. When planning a basic research project, it is thus worth considering if the project can alternatively be conducted with anonymized human biological material and anonymized or anonymously collected health-
Stem Cell Research Act (StRA); Stammzellenforschungsgesetz (StFG); Loi relative à la recherche sur les cellules souches (LRCS); Legge sulle cellule staminali (LCel). 2 Modified from: Dtsch Arztebl Int. B. Röhrig et al. 2009 Apr; 106(15): 262–268. 3 Anonymized biological material and anonymized health-related data means biological material and
health-related data which cannot (without disproportionate effort) be traced to a specific person. 4 Health-related personal data means information concerning the health or disease of a specific or
identifiable person, including genetic data.
related personal data, instead of using uncoded or coded5 biological material and data. It is emphasized here that the anonymization of biological material and associated health-related personal data might not always be possible, practicable or even desirable. A research project conducted with anonymous biological material and associated anonymous health-related personal data does not fall within the scope of the HRA and thus it does not require an ethics committee approval.
The researchers have to describe the procedure of anonymization in the project research plan and must inform the donors on the proposed anonymization of their biological material and related personal data for research purposes, especially on the consequences of anonymization with regard to results concerning their health, and on their right to dissent (HRO Art. 30).
In case of doubt on whether the research project requires ethics committee approval, the researchers should submit a clarification of responsibility6 through the web-portal BASEC to the ethics committee for clarification, before starting the project. If apllicable, the ethical committee can also give an advisory opinion according to HRA Art. 51 para.2. Regardless of whether a research project requires ethics committee approval or not, the ethical principles must always be respected. For example, when submitting the clarification of responsibility, the researchers should address the question: Has the person consented to the use of his/her biological samples for research? The procedure to submit a clarification of responsibility is given here.
What are the most common omissions made during the submission of a project of basic research to the ethics committee? Quick links: 1. Missing information on the origin and storage of the biological material (e.g., missing biobank regulation, material transfer agreement)
2 Use of «research-products», including human cell-lines
3 Informed Consent
4. Use of biological material (cells) from healthy volunteer for testing, controls, etc.
5 Scientific value / undefined or vague projects objectives and endpoints
6 Missing / incomplete statistical analysis plan
7. Changes to the project research plan during the course of the project (amendments)
8 Ethical issues / Missing information on the handling of incidental findings
9 Incomplete information to the donors on genetic investigation
10. Missing or imprecise information on what happens to the biological material / healthrelated personal data at the end of the project
5 Coded biological material and coded health-related personal data means biological material and data
linked to a specific person via a code. 6 The clarification of responsibility is called in German “Zuständigkeitsabklärung”, in French
“Clarification des compétences”, and in Italian “Esame della competenza”.
1. Missing information on the origin and storage of the biological material (e.g., missing biobank regulation, material transfer agreement) The origin of the biological material used for the research must be given in detail in the research plan. If the biological material is obtained from different sources, all sources must be listed. The material transfer agreement (MTA)7 must be submitted to the ethics committee through the web-portal BASEC, as a standalone document. The MTA should not be integrated in or annexed to the project research plan.
Additionally, the researchers must indicate if the biological material and, if applicable, the associated health-related personal data will be received and used in uncoded or coded form. It also should be explained how the donors will consent or have consented to the use of their biological material for research (general consent, project specific consent, no consent for all – some of the samples8).
If the biological material is obtained from a biobank, the biobank regulation9 must be submitted to the ethics committee through the web-portal BASEC, as a standalone document. The biobank regulation should not be integrated in or annexed to the project research plan.
For biological material and/or data imported from abroad, proof of legality (e.g., an ethics committee positive decision from country of origin of the biological material, material transfer agreement or similar verification document) is needed.
The sample size (amount of blood or other biological material) used for the research project should always be given (see also below point 5. ‘Missing / incomplete statistical analysis plan’).
2 Use of «research-products»10, including human cell-lines
A basic research project with cell-lines falls within the scope of the HRA if it is a methoddriven search for generalizable knowledge (Art. 3, a, HRA) and if the biologic material used in the research project is coded (Art. 3, h, HRA) or uncoded (i.e., not anonymized, Art. 3, i, HRA).
Generally, research projects that use commercially available cell-lines (e.g., HeLa, HEK-293, Jurkat, etc.) or that use other immortalized cell-lines from the academic research community do not fall within the scope of the HRA. Therefore such research projects do not require ethics committee approval. These cell-lines are often so called «research-products» that have been produced or developed on the basis of human cell material11. The processing
7 The MTA is a legally binding agreement that governs the transfer of biological material and data
between two parties, when the recipient intends to use them for research purpose. It defines the rights and obligations of the provider and recipient with respect to the use of the material and data and other related issues, such as confidentiality or intellectual property rights. A template to write the MTA can be downloaded from the webpage of the Swiss Biobanking Platform (swissbiobanking.ch). 8 If no consent for all – some of the samples/data exist, HRA Art. 34 might apply. 9 The biobank regulation is a document that defines the biobank purpose, activities, organization and
reflects its daily practices. More detailed information on biobanks/biobank regulations can be found on the webpage of the Swiss Biobanking Platform (swissbiobanking.ch). 10 This Chapter 2 does not apply to products in scope of the Medical Devices Ordinance (MepV, SR
812.213) of 1 July 2020 and the Clinical Trials with Medical Devices Ordinance (KlinV-Mep, SR 810.306) of 1 July 2020. 11 This includes research projects with Induced pluripotent stem cells (iPS cells or iPSCs), a type of
pluripotent stem cell that can be generated directly from a somatic cell, and with organoids.
steps have created a «research-product» from the donor's isolated biological material, which is no longer considered a «part of the human body»12.
Human biological material becomes a «research-product» if it was substantially processed.13 Substantially processed means it underwent at least one of the following processing steps: a) the multiplication of cells via cell culture; b) the genetic modification of cells, or c) the differentiation or activation of cells. Thus, by analogy, human biological material is also considered a «research-product» if the substantial processing took place in animals (e.g., xenograft animal models, human cell-line derived xenograft (CDX), or patient derived xenograft (PDX)).
Note: Research with embryonic stem cells derived from surplus embryos are governed by the Federal Act on Research Involving Embryonic Stem Cells (StRA14). Any person wishing to derive embryonic stem cells from surplus embryos with a view to conducting a research project and to conduct a research project involving embryonic stem cells must obtain the approval of the ethics committee and requires a licence from the Federal Office of Public Health (FOPH).
3 Informed Consent
When should the researchers obtain a written informed consent, i.e., a study specific consent or a general consent for the further use of the donor’s biological material, and when is an informed consent not required? Here we distinguish between research projects with human biological materials that fall within the scope of the HRA and projects that are not in scope.
1 Research projects that fall within the scope of the HRA. The researcher must
obtain the written informed consent of the donor before its biological material can be used in the research project. The origin of the biological material and confirmation that the informed consent of the donor was properly obtained must be submitted to the ethics committee with the application. The research project cannot begin previous approval by the ethics committee.
2. Research projects that do not fall within the scope of the HRA. There is no legal obligation for the researcher to obtain the donor’s written informed consent for the use of the donor’s biological material in the project. However, the trust of the participants in research projects and in the biomedical research in general, which is built on transparency and fair communication, is fundamental for the research involving human beings. It is therefore for ethical reasons that swissethics recommends that the researchers undertake the necessary efforts to obtain the written consent of the donors whenever possible.
12 Dispatch on the Federal Human Research Act, of 21 October 2009, Chapter 2.1.2.6 Prohibition of
commercialisation (Art. 9) (in German, in French, in Italian) 13 In analogy to the regulations on definition of transplantation products (which are not considered part
of the human body as well) described in the Transplantation Act of 8 October 2004 (SR 810.21) and Transplantation Ordinances of 16 March 2007 (SR 810.211), which are referenced in in chapter 2.1.2.6 of the Dispatch on the Federal Human Research Act of 21 October 2009. 14 Stem Cell Research Act (StRA); Stammzellenforschungsgesetz (StFG); Loi relative à la recherche
sur les cellules souches (LRCS); Legge sulle cellule staminali (LCel).
4. Use of biological material (cells) from healthy volunteer for testing, controls, etc. If biological material (cells) from healthy volunteers is used for example as negative control in an experiment, as feeder cells, for the establishment of cell-staining, for tests-runs made before an important experiment, etc., in the context of a research project to study human diseases or the structure and function of the human body (again method-driven search for generalizable knowledge) then the research project falls within the scope of the HRA and requires ethics committee approval.
If the biological material (cells) is not used in the context of a research project to study human disease or the structure and function of the human body, then its use does not fall within the scope of the HRA. However, a general consent or a specific written informed consent must be obtained from the volunteers (donors).
In case of doubt, before starting the research project, the researchers should submit a clarification of responsibility through the web-portal BASEC to the ethics committee to clarify whether the research project falls within the scope of the HRA. The procedure is given here.
5 Scientific value / undefined or vague projects objectives and endpoints
In basic research projects, it is sometimes not possible to clearly define the scientific value from the very beginning. However, whenever possible, it is necessary to describe a scientific question and present the methodology of the project, including the statistical analysis plan (see below Chapter 6. ‘Missing / incomplete statistical analysis plan’). Thus, although it may not always be possible to give clear cut endpoints when conducting basic research projects, well-thought-out research objective(s) should nonetheless be provided. The researchers should provide with the initial submission the raw road map, supported with hypotheses, prestudy observations, etc., on how the research objective(s) have been set.
The researchers are invited to discuss beforehand with the ethics committee if changes to the project objective(s) should be submitted to the ethics committee as a substantial amendment to the project research plan or as a standalone new research project (for more details, see below the chapter 7. ‘Changes to the project research plan during the course of the project (amendments)’).
6 Missing / incomplete statistical analysis plan
For some basic research projects, it may not be possible to write a detailed statistical plan, as instructed in the swissethics template for project research plan for HRO Chapter 2 research projects, i.e., with detailed statistical methods, level of significance, power, etc. Nonetheless, if different statistical methods (e.g. descriptive statistic) rather than hypothesis testing are used, those should be described in detail.
It is advised to consider the statistical aspects of the project (type of statistical analysis, sample size, etc.) very early in the stage of project planning/ research plan writing. A justification of the sample size (expected total number of samples/quantities used, expected samples/quantity used per single donor, etc.) should be given.
If the research does not foresee any statistical analysis at all, this must be justified in the study research plan.
7 Changes to the project research plan during the course of the project
(amendments) A guidance document for researcher on “notification of substantial amendments and other changes to the ethics committee” is published on the swissethics webpage (template/checklists/notifications). The document also includes a comprehensive list of changes and their classification in substantial and non-substantial amendments. For example: Addition of research sites, change of the project leader, or changes to the patients’ group without simultaneously changing the project’s objectives, are substantial changes and must be submitted to the ethics committee and approval obtained before the changes are implemented. Changes to the research centre’s SOPs, working instructions, etc. are not substantial changes and can be implemented immediately.
It should be noted here, that changes to the patients group combined with a change of the project’s objectives must be submitted as a new research project. In some cases, the submission of a change as new standalone study protocol, might even be advantageous for the conduct of the project itself15.
The researchers are invited to discuss beforehand with the ethics committee on how to submit changes that are not listed on the guidance document, if it is not immediately clear to what extend the changes listed on the guidance document also concern the projects of basic research, or if the submission of a new research project would be advantageous instead.
Depending on the classification, the ethics committee might also decide that the substantial change to the project research plan is submitted as a new standalone study protocol.
8 Ethical issues / Missing information on the handling of incidental findings
Ethical considerations, as for example communication of incidental findings should be addressed. The handling of incidental findings should not only be described in the patient information/informed consent form, but also in the project research plan. To properly address this point in the project research plan, the researchers are advised to consult the document «guideline for handling incidental findings in medical search»16 and the document «Ethical Framework for Responsible Data Processing in Personalized Health Research»17, for guidance. Only validated clinically actionable findings should be communicated to research participants through competent healthcare professionals, as agreed at the consent. The process is complex and needs ethical expertise.
9 Incomplete information to the donors on genetic investigation
If genetic analysis is done in clinical routine, the Federal Act on Human Genetic Testing (HGTA18) applies, while genetic investigations (germline and non-germline) fall within the scope of the HRA (Art. 3, para. c).
15 For example, fewer regulatory requirements if the study population is changed from minors to
adults, while other changes to the study protocol might significantly simplify the statistical analyses, etc. swissethics, the document is available in German, French, Italian. ELSI Advisory Group, published by SPHN in English. Bundesgesetz über genetische Untersuchungen beim Menschen (GUMG); Loi fédérale sur l’analyse génétique humaine (LAGH); Legge federale sugli esami genetici sull’essere umano (LEGU).
In case of genetic investigation, the donors must be informed that their genetic information (DNA sequences, etc.) may be deposited in national or international databases (e.g. SIB, NIH SNPdb), if this is the case. Some databases explicitly require confirmation and proof that the donors have given their written informed consent for the genetic investigations and for the storage of the genetic information (DNA sequences, sequence variants, genes, etc.). It is recommended that genetic data is stored separately from phenotypic clinical data. If cloud computing of storage is used for storage, this should be mentioned in the research study plan and the informed consent form
Before providing the data, the researchers should check that the databases are compliant to the European General Data Protection Regulation (GDPR) or to the Swiss Federal Act on Data Protection (FADP19). It is recommended to also refer to the data governance/access boards of the involved hospitals.
10. Missing or unprecise information on what happens to the biological material / health-related personal data at the end of the project An expected end date of the project must always be submitted to the ethics committee with the initial submission. The researchers should describe in the project research plan what happens to the biological materials and health-related data at project end: e.g. "After analysis, the biological material will be destroyed at the research center, as per internal SOPs, and the coded data stored for y years at the hospital (address x)."
If the biological material is not immediately destroyed after use, the place and period of storage must be indicated in the project research plan: e.g. "After information to the participants/donors, as per HRO Art. 30, the biological samples and the associated healthrelated personal data are anonymized after evaluation, i.e., the coding-key is destroyed, and stored at the research center (address x) for y years." or: e.g. "The remains of the unused samples are sent back to the hospital biobank (address x) and stored there for y years."
If it is planned to reuse the biological material and associated personal data for future, not yet defined, research projects in Switzerland or send them abroad, the donors must be informed accordingly and give their written consent (a template for writing an informed consent is available on the swissethics webpage).
Bundesgesetz über den Datenschutz (DSG); Loi fédérale sur la protection des données (LPD); Legge federale sulla protezione dei dati (LPD).