Ethical issues in human studies with biomarkers

1. Ethical issues in human studies with biomarkers IRCCS San Raffaele Pisana, Rome, Italy,28 February - 2 March 2018

2. Epidemiologic research potentially raises many ethical questions and issues. The use of biomarkers in such research may raise further issues, because biomarkers are obtained from the individual person and have the potential for providing important information about exposures, biological effects of exposures, and susceptibility for disease for that individual (Grandjean, 1991; Schulte, 1992; Van Damme et al, 1995).

3. Ethical issues come into play from the moment biomarkers are considered for a study.

4. Biomarkers are usually more resource and labor intensive than other measures of exposure, outcome or risk. Key in the design of transitional, etiological or applied studies is the need to identify the driving scientific or public health questions and determine whether they could be answered by some other approach (Rothman, 1993). Protocol development and study design Ethical and social problems must be anticipated and actions planned This may include repeat testing, counseling, or diagnostic evaluations.

5. Obtaining participation I • How subjects are recruited into studies can involve serious ethical and social issues. These issues hinge on what potential subjects are told about the study and whether they can truly give informed consent. If subjects are deceived or coerced into participating in a study or are given false expectations (e.g., we can tell if you are sick or well, new anticancer drugs) with respect to the value of the study to the participant, ethical principles are violated.

6. With regard to informing participants of risks, general practice has been to identify only medical risks; however, it has been argued that truly informed consent should include reference to nonmedical risks that might affect participants. Obtaining participation II A broad spectrum of opinion exists about what obtaining informed consent entails and when it is achieved. Some believe that for markers whose meaning is not known at the time of the study, a subject or worker in an occupational study cannot give truly informed consent. This implies a much higher standard of interpretation for biomarker information than for other information routinely obtained by questionnaires, environment monitoring, or record linkage.

7. Interpretation and notification of test and study results I • Biomarker research yields individual test (assay) and study results (Schulte and Singal, 1989). • Research participants may want or have a right to these results and an interpretation of them. • Interpretation of these results is the responsibility of investigators(Some institutions require investigators to provide individual test results to subjects as well as overall study results, while others may advise them not to communicate results of assays that have no clinical relevance)

8. One area of interpretation that is problematic is what is called "individual risk assessment." Generally, epidemiological studies (with or without biomarkers) yield group results. The risk pertains to the group as a whole and not necessarily to individual members of the group. It is possible to compute an individual risk using risk function equations, however, if the marker being used has not been validated for disease, the calculation will be meaningless. Thus far, for the current generation of molecular biomarkers, there are practically no markers with the exception of a few genetic mutations linked to high risk of disease in cancer family syndromes, for which an individual risk can be determined based on the level of the marker. Interpretation and notification of test and study results II

9. The ethical use of biomarkers in research involves attention to the "rights" of subjects to appropriate information before, during and after studies so that they can make informed decisions. Failure to plan or budget adequately for these efforts can lead to these rights not being met.

10. Many of the issues of recruiting and informing subjects of test and study results have varied depending by study design. • Consider three examples, • a cross-sectional study involving occupational exposure and a biomarker of early effect (e.g. cytogenetic effects), • a cancer case-control study evaluating the impact of common polymorphisms of metabolizing enzymes, and • a prospective cohort study with banked biological specimens.

11. Cross-sectional studies of healthy workers are completed in a short period of time with the expectation that the biomarkers under study may provide some insight into the potential risk of an exposed group as a whole, or possibly for an individual's risk for subsequent cancer development. Notifying workers of their results of these studies is common

12. The case-control study involves subjects who are already sick along with randomly selected controls who are not definable in an a priori sense, to be at risk. These subjects are generally not notified of results

13. In a prospective cohort study everyone is healthy. Samples are provided with the expectation that results will not be available for a relatively long time. Cohort studies in the general population usually are not in identified high-risk groups. In other cohort studies of identified high-risk individuals, such as workers, the tendency is more likely to inform subjects of results.

14. Ethical issues for stored • specimens relate to whether • consent for use of the • specimens in research was originally given, • (ii) this consent was generic or specific to the hypothesis to be tested, • (iii) the consent obtained when the specimens were collected still meets the standards of informed consent.

15. (i) consent for use of the specimens in research was originally given, Frequently in clinical settings, a wide variety of tests are ordered without any consultation with the patient. It has been long held as ethically acceptable practice to conduct some types of research on "discarded" blood or tissues, i.e. specimens left over after the clinical tests are performed. Access to these tissues has been critical to development of new clinical markers such as histologic or immunochemical markers of cancer prognosis. It would seem a natural extension of this tradition that new biomarkers of genetic susceptibility or prognosis would also be evaluated in this way. However, because of the potential high predictive value of some of these tests, as well as the implications for family members, this tradition is being challenged. A recent statement from a working group of the Ethical, Legal, and Social Implications of the Human Genome Project, suggested that informed consent should usually be obtained before testing for genetic susceptibility on clinical specimens although the statement acknowledged that research involving "minimal risk", and for which reconsenting subjects would be impracticable, could be exempted (national laws).

16. (ii) this consent was generic or specific to the hypothesis to be tested, The original consent form can only be as thorough as the original aims of the study and the state of knowledge at the time permit. Samples from participants in a study of cancer risk factors, for instance, may subsequently be useful in a study of cardiovascular disease or psychiatric illness. Even the best designed and informed consent process in a study of genetic susceptibility to cancer may be outdated with the discovery of a new susceptibility gene, or a new prognostic implication of an "old" gene. The obvious strategy of obtaining fresh consent has major problems. Due to the heterogeneity of study settings, and of social norms and responses, it is likely to be impossible to draft uniform rules on what constitutes ethical behavior in every application of biomarker research and every situation. Most issues are similar to those encountered in other types of research, and can be overseen by appropriately constituted ethics committees who are in the best position to be aware of the local and particularistic aspects of any proposed biomarker research.

17. Confidentiality of data Investigators need to maintain the confidentiality of biomarker data because of its potential for misuse or abuse leading to discrimination, labeling, and stigmatization. In some uses where specimens are identifiable or capable of being linked to databases where identification is possible, it may be difficult to assure confidentiality.

18. Further issues dealing with ethics in human studies with biomarkers: Informed consent in studies involving children Who supports the study ? Conflict of interest

19. Informed consent is the legal permission that a patient voluntarily agrees to participate in a research study. Informed consent must be signed by the legal guardian(s) of the child with the number of signatures needed, depending on the risk of the research (see Table 1-1). Informed consent must be written in a manner that satisfies the IRB standard that “the information must be provided in a form that is understandable.”

20. Ethical Considerations in Pediatric Research, Podany AT, Research and Study Design in Pediatrics, 2017

21. Guardianshipis a term used to describe someone who is either chosen or appointed to make legal decisions for another person unable to make these decisions on his or her own. If parenteral rights remain in the presence of alternative guardianship, it can be unclear to the investigator who can legally make decisions regarding a child’s involvement in pediatric research. For this reason, researchers often avoid approaching or enrolling pediatric patients when the guardianship is either involved or unclear. By doing so, large groups of pediatric patients often may not be well represented in pediatric clinical trials and pediatric research in general.

22. It Is possible to compensate participants to biomedical or epidemiological research ? Ethical Considerations in Pediatric Research, Podany AT, Research and Study Design in Pediatrics, 2017

23. Three fundamental values The investigator’s interest in the health and well being of the public is more important then any economic interest. Some economic interests of investigators, or their relatives, are substantial enough to be in conflict with this public interest. If a conflict of interest is present it must be managed in a manner that is in the best interest of the public.

24. Everyone discloses to PI/Institution in charge Continue with persons who disclose Implement a mechanism to identify and resolve conflicts of interest Standard 2: Resolution of Personal COI

25. Process • STANDARD 2:Resolution of Personal Conflicts of interest • The provider must have implemented a mechanism to identify and resolve all conflicts of interest prior to the education activity being delivered to learners.  Financial relationships may create actual conflicts of interest when individuals have both • A financial relationship with a commercial interest and • The opportunity to affect the content of their research about the products or services of that commercial interest. How do these circumstances create a conflict of interest? The potential for maintaining or increasing the value of the financial relationship with the commercial interest creates an incentive to influence the content/interpretation of the research– an incentive to insert commercial bias.

26.  Any amount…within the past 12 months… • Salary • Royalty • Intellectual property rights • Consulting fee • Honoraria • Ownership interest(e.g., stocks, stock options or other ownership interest, excluding diversified mutual funds) • Other financial benefit …Of person, spouse or partner. • Process • STANDARD 2:Resolution of Personal Conflicts of interest • The provider must have implemented a mechanism to identify and resolve all conflicts of interest prior to the education activity being delivered to learners.  Financial relationships may create actual conflicts of interest when individuals have both • A financial relationship with a commercial interest and • The opportunity to affect the content of their research about the products or services of that commercial interest.

27. Roles that may result in financial benefits… Employment Management position Independent contractor (including contracted research), Consulting, Speaking and teaching, Advisory committees or review panels, Board membership, Other activities from which remuneration is received, or expected.

28. COI may involve: Planners Faculty Managers Authors Staff Reviewers

29. Engagement by PI and collaborators in a process that goes beyond simple disclosure, with necessary interventions to resolve conflict of interest implemented before the activity. COI may involve: