This document discusses several ethical and legal issues related to human tissue biobanking, including: 1) Organizational structure and stakeholder engagement are important considerations for biobanks. Stakeholders like surgeons, pathologists, and researchers all have interests that must be addressed. 2) Informed consent is required for tissue donation, though some argue for an outright gift model without ongoing obligations. Consent for minors is obtained through parents. 3) Materials transfer agreements and privacy protections like de-identification are used to ensure samples and data are only used for approved purposes and maintain confidentiality. 4) The return of incidental research findings is debated, as researchers may find medically relevant information but are

1. Ethical and legal issues related to
human-derived tissues (I)
Soo-Yong Tan
Department of Pathology,
National University of Singapore
Standardization and ethical issues for biomedical collection
Bangkok, 2019

2. Ethical and legal issues related to
human-derived tissues (I)
• Scope
– Structure, stakeholders and governance
– Legislation
– Consent matters
– MTA
– Privacy and confidentiality
– Return of incidental findings

3. STRUCTURE OF BIOBANK
Ethical and legal issues related to human-derived tissues (I)

4. Organizational Structure
• Is the biobank a national, institutional or
departmental asset?
• Who does it serve?
• Who funds the biobank and who exerts
operational control?
• What is the relationship between the biobank
and its various stakeholders?
– Pathologists
– Surgeons
– Scientists
– Funding agency

5. Structure of biobank
• Central collection and central storage (NUHS TR,
TTSH TR)
• Central storage with satellite collection sites
(SingHealth)
• Virtual biobank with multiple, centrally-funded
biobanks based in hospitals (KNRRC)

6. ENGAGING THE STAKEHOLDERS
Ethical and legal issues related to human-derived tissues (I)

7. Biobanking
Funding
agency
Patients
SurgeonsPathologists
Researchers

8. Engaging the stakeholders
• The patients
– Will I become a guinea pig?
– Will you take more tissue from me than necessary?
– Will it affect my treatment if I say ‘no’?
– What does it mean to participate?
– What about my privacy?
– Will my insurance rates go up if you find something?
– Will you be contacting me each time you want to use
my samples for research?
– Will I know the results of your research on my
samples?

13. Engaging the stakeholders
• The surgeons
– What’s in it for me? You get your publications and fame
and I get ignored. I might as well dump everything into
formalin.
– If I allow you into MY Operating Theatre to harvest
samples from MY patients, then I should be able to
access MY samples for nothing
– I don’t want you to give away MY samples to all my
competitors, and when I want to do any research, all MY
tissues are gone
– If you collect clinical data directly from the hospital
records, how can I be sure you will not publish without
including me?
– What if the scientists play me out and leave me out of the
author list?

14. Clinician contributor’s interests are
protected
• Contributor always contacted before any tissue
release for a project
• STR does not keep clinical data but act as trusted
third party to provide them to researchers
• Invitation to participate in wider range of
research activities, more publications
• Publications from researchers are screened to
ensure collaborating clinician has been included
as author

16. Engaging the stakeholders
• The pathologists
– Will tissue harvesting compromise pathological
assessment?
– I don’t have time to harvest tissues for you. I am
very busy as it is.
– If I cannot make a diagnosis after tissue has been
harvested for research, what then?

17. Para 13.1.1.1.
“Where a tissue sample has been taken primarily for
the purposes of diagnostic procedures, no further
sub-sample should be taken from the main sample
for the purposes of research until the diagnostic
procedures are satisfied, or unless the diagnosing
pathologist certifies that the taking of the sub-
sample will not compromise the main diagnostic
purpose of the taking of the main tissue sample.”
Consultation Paper: Human Tissue Research. Singapore Bioethics Advisory
Committee. 27 Feb 2002.

19. Engaging the stakeholders
• The researchers
– I need a large number of samples. The reviewers say my
study is too small, but I cannot afford your charges
– Why must I include the surgeons as authors in my paper?
They are merely butchers.
– I need high-quality tissue samples
– Is the material I get from the biobank what it says it is?
– There is too much paperwork. There are so many
regulatory bodies to deal with: IRB, Tissue Access
Committee etc.
– How do I get the samples I need without any fuss?

21. RESEARCHER: HOW DO I GAIN
FROM THIS?
Ethical and legal issues related to human-derived tissues (I)

22. Advantages for the researcher
• Access to large quantity of research material
collected in accordance to ethical principles
and following best practices
• Quality assurance provided by research
pathologists under supervision of a Senior
Consultant in Department of Pathology, SGH
• Anonymized specimens linked to clinical data
(available through clinician collaborator)

23. Engaging the stakeholders
• The funding agency
– Can the biobank be self-sustaining by charging for
your services?
– Can you find other streams of revenue?
– Why can’t Pharma pay for the operations of the
biobank?
– How do you ensure data sharing, so that I get a
bigger bang for my buck?

24. Number and types of tumour collected in 2011 (vials)
CNS,
Skeletal + Soft Tissue
+ Spleen + LN (248)
Breast (904)
Colon (1050)
GIT, others (478)
Stomach (124)
Female + Male
Genital Organ (623)
Lung + Peritoneum
(228)
Abdomen,
Head&Neck, Face +
NPC + Skin (322)
Thyroid, Parathryoid
+ Adrenal Gland (94)
Urinary Tract (216)
Total number of samples collected = 4287 vials

25. Number and types of tumour withdrawn in 2011 (vials)
CNS + Skeletal + Soft
tissue + spleen + LN
(51)
Breast (231)
Colon (34)
GIT, others (920)
Stomach (355)
Female + Male
Genital Organ(94)
Lung +
Peritoneum(92)
Abdomen, Head &
Neck, Face + Skin (25)
Thyroid, adrenal
gland (26)
Urinary Tract(152)
Total number of samples withdrawn = 1980 vials

26. Data sharing policy
• Researchers will deposit copy of publications
with the Repository
• Published abstracts will be available online
• Upon completion of project and publication of
results, PI will provide list of data fields (not
data) collected in study e.g. expression
profiling, haematology/biochemical laboratory
results

28. http://www.asiabiotech.com/publication/apbn/16/english/preserved-
docs/1604/0040_0043.pdf
“Biobanking is an expensive long term Investment”
“It appeared that the cost recovery charges for specimens at the SBB may be
too high, thus discouraging the use of the service. Apart from cost concerns,
researchers needed sufficient assurance that the biobank would provide bio-
specimens of high quality, with reliable clinical information.”
“..most clinician scientists viewed approaching the patients directly to be more
accessible. They would also be able to control the quality and handling of the
bio-specimens and collect the necessary specific clinical information from each
subject”

29. Why did the STN fail?
• Failure to obtain buy-in from stakeholders
– Surgeons are not engaged as collaborators in studies
making use of samples contributed
– Pathologists excluded: no pathology data nor QC of
samples
– Physicians excluded: no treatment or survival data
• Funding for second set of samples in institutions
– No demand by clinician scientists
• Top-down initiative
– No buy-in by healthcare institutions

30. THE ISSUE OF CONSENT
Ethical and legal issues related to human-derived tissues (I)

31. Why do we need consent?
• In medical treatment, consent is a defence
against a charge of battery
• In a clinical trial, the same considerations
apply. In addition, there is an ethical element
involved in administering a treatment that is
randomised. The patient may not benefit from
the results of the research.

32. Why do we need consent?
• In human tissue biobanking, consent has already
been given for surgery. The specimen is removed as
part of necessary treatment.
• What is the purpose of consent in biobanking?
– Not necessary as defence against battery
– Ownership? No.
• Supreme Court of California ruling in Moore v. Regents of the
University of California (51 Cal. 3d 120; 271 Cal. Rptr. 146; 793
P.2d 479): A person could have no property rights in tissue taken
from his body during an operation to which he consented.

33. Why do we need consent?
• Consent for medical treatment and
participation in clinical trials is more of a legal
issue
• Consent for human tissue biobanking (unless
there is relevant legislation) is primarily an
ethical issue
• We ask consent for biobanking:
– Respect for autonomy: The patient should have a
right to decide what to do with the sample

34. Why do we need consent?
• Respect for autonomy
– In the Moore case, Justice Mosk stated that Moore had the
"right to do with his own tissue what the defendants did
with it."
– With regard to remnant material following pathological
assesment, the patient should be given the right to decide
how this material should be disposed of.
– Anomaly: it is not customary to consult the patient before
discarding the sample had there been no biobanking

35. Implications of the consent model in
biobanking
• Consent in biobanking
– May be conditional:
• Project-specific, excludes certain types of research,
continuous process and repeat consent, return of
research data
– May be withdrawn
• Tissue samples to be returned or discarded? Data
already collected to be discarded?

36. Tissue donation as an alternative
model
• Patient makes an absolute gift of remnant
surgical material to the biobank for all IRB-
approved research
• Declaration of donation
– Separate from consent for surgery
– Absolute gift, no possibility of return
– Not contacted with regard to research findings
• Gifting implies recognition of property rights

37. The issue of consent
• Informed consent is essential
– Pre-operative consent the rule
– Post-operative consent allowed where valid pre-
op consent is not possible ( respect for autonomy)
– Consent from parents in the case of minors
– Consent to allow access to relevant clinical records
for the purpose of research

38. 28 Mar 2012

39. The issue of consent
• Tissue donation treated as an outright gift
– Different concept from consenting to participate
in clinical trial
– Ownership held by institution (Singhealth)
– Terms of gifting: Purely for research, which may be
project-specific (Scheduled collection) or general
(Unscheduled collection)

40. Tissue
donation
treated as an
outright gift
28 Mar 2012

41. WHAT ABOUT MINORS?
Ethical and legal issues related to human-derived tissues (I)

42. Tissue Donation from Minors
• Age of majority in Singapore is 21
• Gillick competence recognized for medical
treatment, e.g. NS boys, abortion
• Contracts entered into by minors are voidable
• Parents donate on behalf of children

43. Re-consent is required in the following situations….
(b) If the tissue was collected when the individual was a
child, such that consent from a parent or guardian was
required, and there is ongoing contact. Once the child
attains the age of 21, his or her consent should be obtained
if research is to be conducted on the previously collected
tissue or information related to this tissue specimen. In the
event re-contact is not practicable, the IRB should have the
discretion to determine whether or not the stored material
or information can be used without re-consent
(para 5.16, “Ethics guidelines for Human Biomedical Research”, Singapore Bioethics
Advisory Committee, 20 June 2012, pg.35)

44. WHAT ABOUT CLINICAL DATA?
Ethical and legal issues related to human-derived tissues (I)

46. Consent to access to clinical data
• Patient Information Form:
“Therefore we ask for your consent (1) to retain in the
Repository your basic identification information
(NRIC/passport number, home address and date of birth)
(“ID Information”)and (2) access, where needed, to your
hospital medical records.”
“The researchers may be given access by the hospital to
relevant information in your medical records on the strict
condition that such information shall be used solely for the
purpose of the IRB Approved Research.”

47. MATERIALS TRANSFER
AGREEMENTS
Ethical and legal issues related to human-derived tissues (I)

48. MTA
• Specimens used for purpose as approved by
IRB
• Unused specimens cannot be used for second
project without approval
• Sending of specimens overseas
• Sending of data overseas and implications of
PDPA

49. PRIVACY AND CONFIDENTIALITY
Ethical and legal issues related to human-derived tissues (I)

50. Privacy and Confidentiality
• Repository retains basic information (identity card
number, date of birth, address)
• All biospecimens are de-identified but Repository
maintains link to patient records through identity card
number
• Access to medical data through attending physicians
who have duties to protect patient confidentiality
• STR staff covered by non-disclosure agreements

51. Ensure
employees
covered by
confidentiality
agreement
28 Mar 2012

52. Privacy and confidentiality
• Access to clinical data
– Patient consent form to cover clinical data
– PI to obtain IRB approval to access patient data
– PI requests clinical data
– PI submits list of clinical data required, STR
transmits list to clinician collaborator with NRIC and
TRID number
– Clinician collaborator provides de-identified clinical
data to PI with just the TRID number

53. RETURN OF RESEARCH DATA
Ethical and legal issues related to human-derived tissues (I)

54. Return of research data
• Modern research techniques often generate
incidental research findings of potential
clinical significance
– Wrong diagnosis
– Undiagnosed diseases
• Hyperglycaemia in blood sample
• Elevated PSA or HCG
– Hereditary genetic disorders
• Whole genome sequencing

55. Return of research data
• Some considerations
– Research labs not accredited for service and
research assays not subjected to vigorous
validation
– Clinicians and not researchers should interpret
and communicate results
– Do researchers have a duty to identify and report
‘significant’ findings?

56. Return of research data
• Patients have the right ‘not to know’
• Is it ethical or feasible to track the donors to return
research data?
• Are biobanks liable if researchers do not report
significant findings?
• Is the biobank/researcher obliged to inform relatives
of significant research findings that may impact
them, even if the donor has passed on?

57. “Donations of tissue samples for use in research should be
treated as outright gifts. Donors should not be paid any financial
incentives for the donation….. As a corollary of this principle,
donors should not expect any personal or direct benefit from the
donation of tissue, including information of any medical
condition or predisposition or likelihood of such discovered in
the course of research on the sample. Likewise, researchers and
tissue bankers should not be under any obligation to disclose
such information to the donors, unless they have agreed to do so
in advance of the donation.”
Consultation Paper, Singapore Bioethics Advisory Committee, 27 Feb 2002

59. “Where there is a possibility that the research may
yield clinically significant incidental findings,
participants should be allowed to decide whether or
not to be informed of the result, prior to the
commencement of the research. Participants should
also have an opportunity to express their preferences
about the sharing of such information with biological
relatives, or others.”
(para 3.37, proposed “Ethics guidelines for Human Biomedical Research”,
Singapore Bioethics Advisory Committee, 20 June 2012, pg.27)

60. Return of research data
• Some considerations
– Research labs not accredited for service and
research assays not subjected to vigorous
validation
– Clinicians and not researchers should interpret
and communicate results
– Do researchers have a duty to identify and report
‘significant’ findings?

61. Return of research data
• Patients have the right ‘not to know’
• Is it ethical or feasible to track the donors to return
research data?
• Are biobanks liable if researchers do not report
significant findings?
• Is the biobank/researcher obliged to inform relatives
of significant research findings that may impact
them, even if the donor has passed on?

62. Law vs Ethics
• Obtaining permission for tissue harvesting is often an
ethical rather than legal issue
• Law deals with rights and liability
– Strictly applied and avoidance of ambiguity
• Ethics deals with right and wrong
– Different ethical schools of thought
• Consent model satisfies the ethicists but introduces
serious concerns for the lawyers in the field of
biobanking
• Population sentiments may guide policy

63. Thank you
The Straits Times
Saturday, 4 June 2011