Ethical and legal issues in research involving human subject
Posted: 20 Apr 2012, 23:16
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J Clin Pathol 2006;59:335–339. doi: 10.1136/jcp.2005.030957
The conduct of biomedical research involving the
participation of human beings implicates a variety of
ethical concerns pertaining to such values as dignity, bodily
integrity, autonomy, and privacy. These ethical concerns
have been translated into a complex regulatory apparatus
in the USA, containing specific legal provisions concerning
such matters as participant safety, informed consent, and
confidentiality. A topic of particular interest for pathologists
is the handling of human tissue specimens that may be used
for present, or stored for future, research purposes. This
article examines the ethical and legal ramifications of
obtaining and storing tissue samples for research
purposes, with special attention to the issues of informed
consent and confidentiality.
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Correspondence to:
Marshall B Kapp, Garwin
Distinguished Professor of
Law and Medicine, School
of Law, Southern Illinois
University, 1150 Douglas
Drive, Carbondale, IL
62901-6804, USA;
kapp@siu.edu
Accepted for publication
18 January 2006
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The conduct of biomedical research involving
human participants raises a host of ethical
and legal issues that have concerned philosophers,
lawyers, policy makers, scientists, and
clinicians for many years.1 After briefly enumerating
several relevant ethical principles and the
legal apparatus that has been developed specifically
in the USA to effectuate those principles, I
will outline one matter of particular interest to
pathologists: the obtaining and retention of
human tissue samples for use in current or
future research projects.
UNDERLYING ETHICAL PRINCIPLES
Biomedical research is conducted for the purpose
of systematically collecting and analysing data
from which generalisable conclusions may be
drawn that may aid in improving the care of
currently unknown beneficiaries in the future.2
The chief role of human participants in research
is to serve as sources of needed data. This is a
different situation than ordinarily occurs in
clinical medicine, in which diagnostic or therapeutic
interventions are suggested or carried out
solely to benefit the current patient.3
Consequently, although many ethical issues
overlap between the realms of research and
clinical medicine, the ethics concerns in human
subjects research are not identical to those
arising in the diagnostic and therapeutic context.
The most salient ethical values implicated by
the use of human participants in research are
beneficence (doing good), non-maleficence (preventing
or mitigating harm), fidelity and trust
within the fiduciary investigator/participant
relationship, personal dignity, and autonomy
pertaining to both informed, voluntary, competent
decision making and the privacy of personal
information.4 These (as well as other) ethical
concerns are addressed by an extensive regulatory
structure pertaining to human subjects
research. The historical and philosophical background
culminating in the present American
system of governmental command and control
regulation in this arena has been extensively
chronicled elsewhere.5
GENERAL REGULATORY OVERSIGHT IN
THE USA
Based largely on the recommendations of the
National Commission for the Protection of
Human Subjects in Biomedical and Behavioral
Research (the Belmont Commission), established
by the 1974 National Research Act,
American regulations governing the conduct of
biomedical research involving human participants
were published in 1981 by the federal
Department of Health and Human Services
(DHHS) (at that time, the Department of
Health, Education and Welfare). Most US health
care institutions conducting research have now
agreed to apply these federal regulations to all of
their research protocols regardless of the funding
source for a particular study. Additionally,
numerous other federal agencies have adopted
the DHHS regulations, as subsequently
amended, as a Common Rule to protect human
participants in any research protocol that those
agencies sponsor.6 Research involving the testing
of investigational drugs or medical devices is
regulated concurrently by the federal Food and
Drug Administration (FDA)7; the Common Rule
and FDA requirements overlap considerably but
are not completely identical.
Research to which the Common Rule or FDA
regulations, or both, apply must be reviewed and
approved initially by an institutional review
board (IRB) recognised by the federal Office of
Human Research Protections (OHRP) within the
Office of the Secretary, DHHS. The research
activity is then subject to continuing IRB oversight
and at least annual reapproval thereafter.
To approve (and renew approval for) a protocol,
the IRB must determine that each of the
following requirements is satisfied:
Abbreviations: AAMC, Association of American
Medical Colleges; HIPAA, Health Insurance Portability
and Accountability Act; IRB, institutional review board;
OHRP, Office of Human Research Protections; PHI,
protected health information
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N Physical and psychological risks to subjects are minimised.
N Physical and psychological risks to subjects are reasonable
in relation to anticipated benefits to those subjects and to
the importance of the general knowledge that may
reasonably be expected to result.
N Selection of subjects is equitable
N Informed consent will be obtained, including at least the
following items being communicated to potential participants
or their authorised surrogates:
– purposes of the research, its expected duration, and the
nature of any interventions/experiments;
– anticipated risks and benefits of participation and the
reasonable alternatives to participation in the research
protocol;
– confidentiality provisions relating to the research
records;
– any compensation and/or treatment available for
research related injuries;
– the right to not participate and to discontinue participation
at any time without penalty.
N Informed consent will be documented appropriately.
The regulatory provisions for informed consent in research
are basically a codification and extension of the American
common law informed consent doctrine8 that was developed
by the courts in the therapeutic setting.
As a complement to the federal regulation, some individual
states have enacted statutes containing protections for
human participants, requiring some type of prior review
and oversight.9 The specific content of these state laws varies.
Also, private civil lawsuits may be brought by a particular
participant against researchers and protocol sponsors for
breach of common law tort standards of care (that is, medical
malpractice) in the conduct of research involving and
harming that participant.10
TISSUE SPECIMENS
Uses in research
Hakimian and Korn11 observed, ‘‘Human biological specimens
have been the foundation of pathological inquiry ever
since Rudolf Virchow propounded the cellular basis of disease
in 1858. Today, the study of human tissue affords unique and
increasingly sophisticated molecular and genetic insights that
progressively illuminate the detailed mechanisms and pathways
of human diseases.’’
Tissue specimens may be sought specifically for use in a
current research protocol from individuals who are either
undergoing non-experimental diagnostic or therapeutic
interventions for a medical problem, or who are currently
participating in a different research protocol. Also, with
increasing frequency, patients or current research participants
are being asked to donate bodily tissue for storage and
possible use at some future date as part of human genetic
studies whose precise details are not yet known or knowable.
12 It has been noted that the genetic analysis of human
tissue samples may result in highly useful information about
genetic explanations of human disease. In the light of
developments fuelled by the Human Genome Project, ‘‘both
the number of known target genes and the methods for rapid
and inexpensive genetic analysis are increasing, as is our
realization of the complexity of the genetic links of common
diseases.’’13 Research addressing complex diseases involving
many different genes will require the study of tremendous
amounts of data on both the genotypes and phenotypes of
numerous people. Researchers both in the USA and internationally
are looking enthusiastically at the creation of vast
database resources to house the human tissues collected to
supply this potentially valuable genetic material.
The ethical and regulatory debate
The collection of human tissue specimens for use in current,
and especially in potential future, research protocols raises a
panoply of ethical concerns about, among other things,
consent and confidentiality. These ethical issues manifest
themselves in a regulatory context. Debates about these
issues have been carried out for a considerable time.14 More
than a decade ago, the National Institutes of Health and the
Centers for Disease Control and Prevention jointly issued a
Consensus Statement on ‘‘Informed Consent for Genetic
Research on Stored Tissue Samples.’’15 In August of 1999, the
National Bioethics Advisory Commission published a report
that looked comprehensively at the uses of human biological
materials and issued 23 recommendations generally trying to
interpret the language of the existing Common Rule rather
than replace it.16
Informed consent
When a person is having tissue removed (with their consent)
as part of a treatment intervention and is asked for
permission to allow a piece of that tissue to also be available
for use in a related ongoing genetic study, valid consent for
the additional research use would require that the participant
be told clearly whether the genetic study is an integral part of
the treatment protocol or is an entirely separate investigation.
Only in the former situation could the investigator legitimately
condition receipt of the treatment on the participant’s
agreement to have tissue analysed for research purposes. If
the genetic study is separate, a volunteer may refuse to
donate tissue to it without giving up the chance to participate
in the treatment protocol.
Whether linked to present patient treatment or totally
separate, a current research project can be described to a
prospective tissue donor with enough precision to allow for
meaningful informed consent. By contrast, it is difficult, if
not impossible, for a participant in a research protocol to give
meaningful prospective consent to the use of tissue in a
possible future research protocol that cannot currently be
described. Common practice has been for IRBs to allow
investigators to ask patients receiving treatment to give a
generic approval for the current banking of tissue, but only
on the condition that use of the tissue in specific
research protocols in the future would require an additional
consent from the patient, based on specific information
conveyed about the particular genetic study at that later point
in time.
Recent events have fuelled the controversy over the ethical
and legal need to obtain a tissue donor’s informed consent for
the collection, storage, and use of the donor’s biological
specimen for research purposes. In an August 2004 guidance
document, the federal OHRP sought to clarify its position
regarding consent requirements when human biological
specimens are used in research by ‘‘reaffirm[ing] OHRP
policy (see OHRP guidance on repository activities and
research on human embryonic stem cells) that, under certain
limited conditions, research involving only coded private
information or specimens is not human subjects research.’’
(emphasis in original)17 Under this guidance, tissue collection
for present or future research purposes is not subject to the
IRB review and informed consent provisions of the Common
Rule, as long as there is no personally identifiable information
attached to the tissue specimens. The OHRP guidance
‘‘recommends that institutions have policies in place that
designate the individual or entity authorized to determine
whether research involving coded private information or
specimens constitutes human subjects research.’’
336 Kapp
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Some confusion remains, however, because, despite
OHRP’s interpretation exempting collection of non-identifiable
tissue specimens from application of the Common Rule,
FDA regulations mandating the obtaining of informed
consent for the collection and use of tissue specimens in
present or future research protocols involving the testing of
investigational drugs or medical devices still do apply with
full force. This disharmony in regulatory requirements has
been noted critically by commentators18 and groups representing
biomedical investigators.19 In a letter to OHRP dated
11 January 2006, the Association of American Medical
Colleges observed: ‘‘Discordant guidance from different
agencies puts institutions in an untenable position and
creates confusion and anxiety where none should exist.’’20
The problem results because the FDA regulatory definition of
human subject differs from the definition of human subject
under the Common Rule, with the former including within
the definition the use of unidentified tissue specimens.
It is noteworthy that, in recognition of the disruptiveness of
the Common Rule/FDA regulatory disharmony on this point,
the FDA had published,21 two days before the date of the
AAMC letter, a public notice that it is in the process of
preparing a new guidance document to be entitled ‘‘Guidance
on informed consent for in vitro diagnostic device studies
using leftover human specimens that are not individually
identifiable.’’ The regulations themselves would remain intact.
However, FDA indicated in its 9 January 2006 Federal Register
publication an intent to notify the public, through the issuance
of a guidance document, that FDA will ‘‘exercise enforcement
discretion [that is, refrain fromenforcing the regulations] as to
the informed consent regulations for clinical investigators,
sponsors, and IRBs’’ when:
N the study uses leftover specimens; that is, remnants of
specimens collected for routine clinical care or analysis
that would have been discarded if not used in the study;
N the specimens provided to the investigator are accompanied
by only minimal clinical information such as age, sex,
and existing laboratory results;
N the specimens are not individually identifiable;
N the specimens are provided to the investigator(s) without
identifiers and the supplier of the specimens has established
policies and procedures to prevent the release of
personal information;
N the individuals caring for the patients are different from,
and do not share information with, those conducting the
investigation; and
N the study has been reviewed by an IRB.
The August 2004 OHRP guidance on this subject has been
characterised by at least a few commentators not (as OHRP
explicitly claims) as merely a reaffirmation of existing policy,
but instead as ‘‘a dramatic shift’’ leaving ‘‘an enormous
regulatory gap in which, with a minimum of effort, the
majority of research involving databanks can be excluded
from the Common Rule.’’22 One argument in favour of
imposing substantial affirmative informed consent requirements
rather than allowing exemption altogether or substituting
presumed consent (with an opportunity to object)
would focus on the risks involved in donating tissue. This
argument is exemplified by the comment, ‘‘In human tissue
research, genomic technology has not only increased the
demand for human tissue, but it has also increased the
potential for tissue donors to be subjected to both psychosocial
and economic harms.’’23
However, most arguments supporting a specific consent
requirement for present or future research uses of human
tissue specimens, even if anonymised, rest more on the claim
that basic personal interests are at stake for the prospective
tissue donor. This is the contention: ‘‘There should be no
doubt about what is at stake in developing policy for the use
of stored samples: the fundamental right to decide whether
and how one’s body and its parts will be used in research.’’24
As explained by a proponent of requiring informed consent
for the conduct of research using non-identified tissue
specimens: ‘‘Informed consent is not just about enabling
people to decide whether or not to accept certain risks.
Seeking permission to use biobanks can be valuable for its
own sake as well. The process of asking acknowledges the
individual whose information and tissue are obtained
therein. In the case of research, informed consent is one
part of honoring the contribution that the person is making
to advancement of knowledge.’’25
Regulatory proponents additionally cite evidence that at
least a significant minority of patients polled want to be
informed in advance and afforded the opportunity to consent
to or refuse the use of their tissue for research purposes.26
This desire bolsters the argument that the storage and use of
tissue specimens in research protocols is a matter about
which people really care and, therefore, strongly want their
autonomy rights respected.25
This part of the proponents’ argument is weakened,
though, by a number of study findings to the contrary. For
instance, some studies of tissue donors’ preferences and
perceptions have been interpreted to show that most patients
do not share professional bioethicists’ concern about the
potential research related uses of their surplus tissues.
Responses to one questionnaire revealed that ‘‘only a small
number [of patients supplying tissue specimens] report their
information levels to be of particular importance when
biobank based research is assessed in relation to other issues
pertaining to research politics and ethics...This study calls for
reconsideration of the importance attributed to informed
consent in debates about ethics of biobanks and genomics
companies...’’27
Other surveys demonstrate that most individuals who have
had tissue removed for other purposes have no objection to
the unlimited use of excess tissue in future research studies.
These findings—as well as the position that the law appears
not to recognise donors’ personal ownership rights pertaining
to surplus tissue specimens taken from those individuals for
diagnostic or therapeutic purposes11—underpin the contention
by some that a patient’s valid consent for future research
uses of previously collected tissue specimens should be made
on the basis of a binary choice (either authorising all future
research uses or none at all) rather than requiring investigators
in every new research protocol to track down and
obtain specific consent from every tissue donor, even if the
specimen is identified only by a code.28 Other bioethics
scholars go further, arguing that the ‘‘data [regarding what
matters actually are important to patients] suggest applying a
tentative general framework for obtaining consent for
research using stored biological samples. Consent should be
required for research using clinically derived, identified
samples, but waived for additional research using research
derived, anonymized samples.’’29
An active ethical/social policy discussion about the parameters
of informed consent for research uses of surplus
human tissue specimens undoubtedly will persist in the USA
for the foreseeable future, as we delve ever further into the
genomic era of biomedical progress. For the time being, the
regulatory approach to this question has been resolved by
OHRP and FDA in the respective manners described above.
Whether the present approach of OHRP to exclude the
research use of coded tissue specimens from the classification
of human subjects research, subject to the requirements of
the Common Rule, constitutes a serious gap in legal
protection for vulnerable individuals, or whether a realistic
Ethical and legal issues in research involving human subjects 337
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recognition that the ability to give or withhold informed
consent in this context is not an especially important value to
most potential tissue donors remains to be seen.
Policy makers in the USA also should closely monitor the
legal and ethical approaches of the international community
to the informed consent question in this context. In the
United Kingdom, the well publicised Alder Hey and Bristol
Royal Infirmary inquiries, revealing systematic retention of
postmortem organs from children for educational and
research purposes, without obtaining authorised informed
consent, engendered substantial debate about the role of
informed consent in research related tissue specimen collection.
12 30 31 Various informative surveys of relevant public and
professional attitudes have been conducted in Europe26 32 and
Asia.33 Pertinent laws and customs have been developed in
different countries to address this matter, accompanied by
various degrees of controversy about how they balance
patients’ rights and society’s interest in having research
conducted.34 Inconsistent national laws contribute to confusion
and inhibit collaborative research efforts,35 but conflicting
ethical, cultural, and religious perspectives will continue
to make international regulatory harmonisation a highly
difficult challenge.36
Medical privacy requirements
Because possible unfair discrimination against an individual
by a present or potential employer, insurer, educator, or other
party on the basis of genetic information derived from a
scientific analysis of the individual’s tissue specimen is a
major risk of allowing one’s tissue to be available for research
purposes, it is necessary to consider the confidentiality
implications of collecting and storing tissue to be used in
the research context. In the USA, medical confidentiality
rules derive from, and may be enforced under, common law
tort doctrine and any applicable state statutes and regulations.
However, the chief American source of pertinent legal
authority is the federal Standards for Privacy of Individually
Identifiable Health Information (Privacy Rule).37 This regulation
became effective in 2003 after being promulgated by
DHHS under the legislative authority of the Health Insurance
Portability and Accountability Act (HIPAA).38
The Privacy Rule requires specific written permission from
a patient before anyone may use or disclose ‘‘protected health
information’’ (PHI) about that person for non-routine
purposes such as research. PHI is defined as any ‘‘individually
identifiable health information’’ transmitted or maintained
by a ‘‘covered entity’’ (for example, a health care provider,
health insurance plan, or data processing firm).
In the context of research using stored tissue specimens,
the reach of the HIPAA Privacy Rule is somewhat constrained.
First, tissue repositories such as biobanks are not
‘‘covered entities’’ subject to the Rule unless they conduct
some other kind of activity that brings them within the
‘‘covered entity’’ definition. The Privacy Rule would be
implicated only with regard to a covered entity, such as a
hospital, that discloses PHI for the creation or stocking of the
research repository.39 ‘‘It is the act of the health care provider
sending a specimen to a commercial sponsor while knowing
that it will be retained in a repository that triggers the HIPAA
written authorisation form requirement, not the sponsor’s
actions in maintaining the repository.’’40
Moreover, the Privacy Rule would only apply to a covered
entity that sends to a repository tissue that is accompanied by
clinical information containing specific patient identifiers.
‘‘The Privacy Rule permits covered entities to release data
that have been de-identified without obtaining an
Authorization and without further restrictions upon use or
disclosure because de-identified data is not PHI and, therefore,
not subject to the Privacy Rule.’’39 ‘‘The Privacy Rule
permits covered entities under the Rule to determine that
health information is de-identified even if the health
information has been assigned, and retains, a code or other
means of record identification, provided that: (1) the code is
not derived from or related to the information about the
individual; (2) the code could not be translated to identify the
individual; and (3) the covered entity under the Privacy Rule
does not use or disclose the code for other purposes or
disclose the mechanism for re-identification.’’17
CONCLUSIONS
Pathologists everywhere involved in various aspects of
research involving human participants must be cognisant of
the regulatory environment impacting their activities in their
particular jurisdiction and the ethical principles underlying
the applicable local legal rules. In this article I have outlined
the salient boundaries of the regulatory environment for
biomedical research. I have devoted particular attention to
current approaches and controversies about informed consent
and the ramifications of medical confidentiality when
obtaining human tissue specimens for use in current research
protocols or storing them for use in future protocols, the
details of which cannot be predicted or described to the
potential tissue donors.
REFERENCES
1 Coleman CH, Menikoff JA, Goldner JA, et al. The ethics and regulation of
research with human subjects. Newark: Matthew Bender Co, 2005:3–50.
2 Code of Federal Regulations, Part 46.102(d)..
3 Sankar P. Communication and miscommunication in informed consent to
research. Med Anthropol Q 2004;18:429–46.
4 Veatch RM. The patient as partner: a theory of human experimentation ethics.
Bloomington: Indiana University Press, 1987:16–76.
5 Jonsen AR. The birth of bioethics. New York: Oxford University Press,
1998:125–65.
6 Code of Federal Regulations, Part 46..
7 Code of Federal Regulations, Parts 50, 56, 312, and 812..
8 Faden RR, Beauchamp TL. A history and theory of informed consent. New
York: Oxford University Press, 1986:114–50.
9 Gibbs JN. State regulation of pharmaceutical clinical trials. Food Drug Law J
2004;59:265–85.
10 Morreim EH. Litigation in clinical research: malpractice doctrines versus
research realities. J Law Med Ethics 2004;32:474–84.
11 Hakimian R, Korn D. Ownership and use of tissue specimens for research.
JAMA 2004;292:2500.
12 Savulescu J. No consent should be needed for using leftover body material for
scientific purposes: against. BMJ 2002;325:649–51.
13 Greely HT. Breaking the stalemate: a prospective regulatory framework for
unforseen research uses of human tissue samples and health information.
Wake Forest Law Rev 1999;34:740.
14 Knoppers BM, Laberge CM. Research and stored tissues: persons as sources,
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15 Clayton EW, Steinberg KK, Khoury MJ, et al. Informed consent for genetic
research on stored tissue samples. JAMA 1995;274:1786–92.
16 National Bioethics Advisory Commission. Research involving human
biological materials: issues and policy guidance (1999), available at ,www.
bioethics.georgetown.edu/nbac...
17 Office of Human Research Protection, United States Department of Health
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18 Evans BJ, Meslin EM. Encouraging translational research through
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research with banked specimens. J Legal Med, (in press)..
19 Letter of Jordan J Cohen, President, Association of American Medical
Colleges to Michael J O’Grady, Assistant Secretary for Planning and
Evaluation, Department of Health and Human Services. Recommendations
for regulatory reform, November 3, 2005.
20 Letter of Jordan J Cohen, President, Association of American Medical
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J Clin Pathol 2006;59:335–339. doi: 10.1136/jcp.2005.030957
The conduct of biomedical research involving the
participation of human beings implicates a variety of
ethical concerns pertaining to such values as dignity, bodily
integrity, autonomy, and privacy. These ethical concerns
have been translated into a complex regulatory apparatus
in the USA, containing specific legal provisions concerning
such matters as participant safety, informed consent, and
confidentiality. A topic of particular interest for pathologists
is the handling of human tissue specimens that may be used
for present, or stored for future, research purposes. This
article examines the ethical and legal ramifications of
obtaining and storing tissue samples for research
purposes, with special attention to the issues of informed
consent and confidentiality.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . .
Correspondence to:
Marshall B Kapp, Garwin
Distinguished Professor of
Law and Medicine, School
of Law, Southern Illinois
University, 1150 Douglas
Drive, Carbondale, IL
62901-6804, USA;
kapp@siu.edu
Accepted for publication
18 January 2006
. . . . . . . . . . . . . . . . . . . . . . .
The conduct of biomedical research involving
human participants raises a host of ethical
and legal issues that have concerned philosophers,
lawyers, policy makers, scientists, and
clinicians for many years.1 After briefly enumerating
several relevant ethical principles and the
legal apparatus that has been developed specifically
in the USA to effectuate those principles, I
will outline one matter of particular interest to
pathologists: the obtaining and retention of
human tissue samples for use in current or
future research projects.
UNDERLYING ETHICAL PRINCIPLES
Biomedical research is conducted for the purpose
of systematically collecting and analysing data
from which generalisable conclusions may be
drawn that may aid in improving the care of
currently unknown beneficiaries in the future.2
The chief role of human participants in research
is to serve as sources of needed data. This is a
different situation than ordinarily occurs in
clinical medicine, in which diagnostic or therapeutic
interventions are suggested or carried out
solely to benefit the current patient.3
Consequently, although many ethical issues
overlap between the realms of research and
clinical medicine, the ethics concerns in human
subjects research are not identical to those
arising in the diagnostic and therapeutic context.
The most salient ethical values implicated by
the use of human participants in research are
beneficence (doing good), non-maleficence (preventing
or mitigating harm), fidelity and trust
within the fiduciary investigator/participant
relationship, personal dignity, and autonomy
pertaining to both informed, voluntary, competent
decision making and the privacy of personal
information.4 These (as well as other) ethical
concerns are addressed by an extensive regulatory
structure pertaining to human subjects
research. The historical and philosophical background
culminating in the present American
system of governmental command and control
regulation in this arena has been extensively
chronicled elsewhere.5
GENERAL REGULATORY OVERSIGHT IN
THE USA
Based largely on the recommendations of the
National Commission for the Protection of
Human Subjects in Biomedical and Behavioral
Research (the Belmont Commission), established
by the 1974 National Research Act,
American regulations governing the conduct of
biomedical research involving human participants
were published in 1981 by the federal
Department of Health and Human Services
(DHHS) (at that time, the Department of
Health, Education and Welfare). Most US health
care institutions conducting research have now
agreed to apply these federal regulations to all of
their research protocols regardless of the funding
source for a particular study. Additionally,
numerous other federal agencies have adopted
the DHHS regulations, as subsequently
amended, as a Common Rule to protect human
participants in any research protocol that those
agencies sponsor.6 Research involving the testing
of investigational drugs or medical devices is
regulated concurrently by the federal Food and
Drug Administration (FDA)7; the Common Rule
and FDA requirements overlap considerably but
are not completely identical.
Research to which the Common Rule or FDA
regulations, or both, apply must be reviewed and
approved initially by an institutional review
board (IRB) recognised by the federal Office of
Human Research Protections (OHRP) within the
Office of the Secretary, DHHS. The research
activity is then subject to continuing IRB oversight
and at least annual reapproval thereafter.
To approve (and renew approval for) a protocol,
the IRB must determine that each of the
following requirements is satisfied:
Abbreviations: AAMC, Association of American
Medical Colleges; HIPAA, Health Insurance Portability
and Accountability Act; IRB, institutional review board;
OHRP, Office of Human Research Protections; PHI,
protected health information
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N Physical and psychological risks to subjects are minimised.
N Physical and psychological risks to subjects are reasonable
in relation to anticipated benefits to those subjects and to
the importance of the general knowledge that may
reasonably be expected to result.
N Selection of subjects is equitable
N Informed consent will be obtained, including at least the
following items being communicated to potential participants
or their authorised surrogates:
– purposes of the research, its expected duration, and the
nature of any interventions/experiments;
– anticipated risks and benefits of participation and the
reasonable alternatives to participation in the research
protocol;
– confidentiality provisions relating to the research
records;
– any compensation and/or treatment available for
research related injuries;
– the right to not participate and to discontinue participation
at any time without penalty.
N Informed consent will be documented appropriately.
The regulatory provisions for informed consent in research
are basically a codification and extension of the American
common law informed consent doctrine8 that was developed
by the courts in the therapeutic setting.
As a complement to the federal regulation, some individual
states have enacted statutes containing protections for
human participants, requiring some type of prior review
and oversight.9 The specific content of these state laws varies.
Also, private civil lawsuits may be brought by a particular
participant against researchers and protocol sponsors for
breach of common law tort standards of care (that is, medical
malpractice) in the conduct of research involving and
harming that participant.10
TISSUE SPECIMENS
Uses in research
Hakimian and Korn11 observed, ‘‘Human biological specimens
have been the foundation of pathological inquiry ever
since Rudolf Virchow propounded the cellular basis of disease
in 1858. Today, the study of human tissue affords unique and
increasingly sophisticated molecular and genetic insights that
progressively illuminate the detailed mechanisms and pathways
of human diseases.’’
Tissue specimens may be sought specifically for use in a
current research protocol from individuals who are either
undergoing non-experimental diagnostic or therapeutic
interventions for a medical problem, or who are currently
participating in a different research protocol. Also, with
increasing frequency, patients or current research participants
are being asked to donate bodily tissue for storage and
possible use at some future date as part of human genetic
studies whose precise details are not yet known or knowable.
12 It has been noted that the genetic analysis of human
tissue samples may result in highly useful information about
genetic explanations of human disease. In the light of
developments fuelled by the Human Genome Project, ‘‘both
the number of known target genes and the methods for rapid
and inexpensive genetic analysis are increasing, as is our
realization of the complexity of the genetic links of common
diseases.’’13 Research addressing complex diseases involving
many different genes will require the study of tremendous
amounts of data on both the genotypes and phenotypes of
numerous people. Researchers both in the USA and internationally
are looking enthusiastically at the creation of vast
database resources to house the human tissues collected to
supply this potentially valuable genetic material.
The ethical and regulatory debate
The collection of human tissue specimens for use in current,
and especially in potential future, research protocols raises a
panoply of ethical concerns about, among other things,
consent and confidentiality. These ethical issues manifest
themselves in a regulatory context. Debates about these
issues have been carried out for a considerable time.14 More
than a decade ago, the National Institutes of Health and the
Centers for Disease Control and Prevention jointly issued a
Consensus Statement on ‘‘Informed Consent for Genetic
Research on Stored Tissue Samples.’’15 In August of 1999, the
National Bioethics Advisory Commission published a report
that looked comprehensively at the uses of human biological
materials and issued 23 recommendations generally trying to
interpret the language of the existing Common Rule rather
than replace it.16
Informed consent
When a person is having tissue removed (with their consent)
as part of a treatment intervention and is asked for
permission to allow a piece of that tissue to also be available
for use in a related ongoing genetic study, valid consent for
the additional research use would require that the participant
be told clearly whether the genetic study is an integral part of
the treatment protocol or is an entirely separate investigation.
Only in the former situation could the investigator legitimately
condition receipt of the treatment on the participant’s
agreement to have tissue analysed for research purposes. If
the genetic study is separate, a volunteer may refuse to
donate tissue to it without giving up the chance to participate
in the treatment protocol.
Whether linked to present patient treatment or totally
separate, a current research project can be described to a
prospective tissue donor with enough precision to allow for
meaningful informed consent. By contrast, it is difficult, if
not impossible, for a participant in a research protocol to give
meaningful prospective consent to the use of tissue in a
possible future research protocol that cannot currently be
described. Common practice has been for IRBs to allow
investigators to ask patients receiving treatment to give a
generic approval for the current banking of tissue, but only
on the condition that use of the tissue in specific
research protocols in the future would require an additional
consent from the patient, based on specific information
conveyed about the particular genetic study at that later point
in time.
Recent events have fuelled the controversy over the ethical
and legal need to obtain a tissue donor’s informed consent for
the collection, storage, and use of the donor’s biological
specimen for research purposes. In an August 2004 guidance
document, the federal OHRP sought to clarify its position
regarding consent requirements when human biological
specimens are used in research by ‘‘reaffirm[ing] OHRP
policy (see OHRP guidance on repository activities and
research on human embryonic stem cells) that, under certain
limited conditions, research involving only coded private
information or specimens is not human subjects research.’’
(emphasis in original)17 Under this guidance, tissue collection
for present or future research purposes is not subject to the
IRB review and informed consent provisions of the Common
Rule, as long as there is no personally identifiable information
attached to the tissue specimens. The OHRP guidance
‘‘recommends that institutions have policies in place that
designate the individual or entity authorized to determine
whether research involving coded private information or
specimens constitutes human subjects research.’’
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Some confusion remains, however, because, despite
OHRP’s interpretation exempting collection of non-identifiable
tissue specimens from application of the Common Rule,
FDA regulations mandating the obtaining of informed
consent for the collection and use of tissue specimens in
present or future research protocols involving the testing of
investigational drugs or medical devices still do apply with
full force. This disharmony in regulatory requirements has
been noted critically by commentators18 and groups representing
biomedical investigators.19 In a letter to OHRP dated
11 January 2006, the Association of American Medical
Colleges observed: ‘‘Discordant guidance from different
agencies puts institutions in an untenable position and
creates confusion and anxiety where none should exist.’’20
The problem results because the FDA regulatory definition of
human subject differs from the definition of human subject
under the Common Rule, with the former including within
the definition the use of unidentified tissue specimens.
It is noteworthy that, in recognition of the disruptiveness of
the Common Rule/FDA regulatory disharmony on this point,
the FDA had published,21 two days before the date of the
AAMC letter, a public notice that it is in the process of
preparing a new guidance document to be entitled ‘‘Guidance
on informed consent for in vitro diagnostic device studies
using leftover human specimens that are not individually
identifiable.’’ The regulations themselves would remain intact.
However, FDA indicated in its 9 January 2006 Federal Register
publication an intent to notify the public, through the issuance
of a guidance document, that FDA will ‘‘exercise enforcement
discretion [that is, refrain fromenforcing the regulations] as to
the informed consent regulations for clinical investigators,
sponsors, and IRBs’’ when:
N the study uses leftover specimens; that is, remnants of
specimens collected for routine clinical care or analysis
that would have been discarded if not used in the study;
N the specimens provided to the investigator are accompanied
by only minimal clinical information such as age, sex,
and existing laboratory results;
N the specimens are not individually identifiable;
N the specimens are provided to the investigator(s) without
identifiers and the supplier of the specimens has established
policies and procedures to prevent the release of
personal information;
N the individuals caring for the patients are different from,
and do not share information with, those conducting the
investigation; and
N the study has been reviewed by an IRB.
The August 2004 OHRP guidance on this subject has been
characterised by at least a few commentators not (as OHRP
explicitly claims) as merely a reaffirmation of existing policy,
but instead as ‘‘a dramatic shift’’ leaving ‘‘an enormous
regulatory gap in which, with a minimum of effort, the
majority of research involving databanks can be excluded
from the Common Rule.’’22 One argument in favour of
imposing substantial affirmative informed consent requirements
rather than allowing exemption altogether or substituting
presumed consent (with an opportunity to object)
would focus on the risks involved in donating tissue. This
argument is exemplified by the comment, ‘‘In human tissue
research, genomic technology has not only increased the
demand for human tissue, but it has also increased the
potential for tissue donors to be subjected to both psychosocial
and economic harms.’’23
However, most arguments supporting a specific consent
requirement for present or future research uses of human
tissue specimens, even if anonymised, rest more on the claim
that basic personal interests are at stake for the prospective
tissue donor. This is the contention: ‘‘There should be no
doubt about what is at stake in developing policy for the use
of stored samples: the fundamental right to decide whether
and how one’s body and its parts will be used in research.’’24
As explained by a proponent of requiring informed consent
for the conduct of research using non-identified tissue
specimens: ‘‘Informed consent is not just about enabling
people to decide whether or not to accept certain risks.
Seeking permission to use biobanks can be valuable for its
own sake as well. The process of asking acknowledges the
individual whose information and tissue are obtained
therein. In the case of research, informed consent is one
part of honoring the contribution that the person is making
to advancement of knowledge.’’25
Regulatory proponents additionally cite evidence that at
least a significant minority of patients polled want to be
informed in advance and afforded the opportunity to consent
to or refuse the use of their tissue for research purposes.26
This desire bolsters the argument that the storage and use of
tissue specimens in research protocols is a matter about
which people really care and, therefore, strongly want their
autonomy rights respected.25
This part of the proponents’ argument is weakened,
though, by a number of study findings to the contrary. For
instance, some studies of tissue donors’ preferences and
perceptions have been interpreted to show that most patients
do not share professional bioethicists’ concern about the
potential research related uses of their surplus tissues.
Responses to one questionnaire revealed that ‘‘only a small
number [of patients supplying tissue specimens] report their
information levels to be of particular importance when
biobank based research is assessed in relation to other issues
pertaining to research politics and ethics...This study calls for
reconsideration of the importance attributed to informed
consent in debates about ethics of biobanks and genomics
companies...’’27
Other surveys demonstrate that most individuals who have
had tissue removed for other purposes have no objection to
the unlimited use of excess tissue in future research studies.
These findings—as well as the position that the law appears
not to recognise donors’ personal ownership rights pertaining
to surplus tissue specimens taken from those individuals for
diagnostic or therapeutic purposes11—underpin the contention
by some that a patient’s valid consent for future research
uses of previously collected tissue specimens should be made
on the basis of a binary choice (either authorising all future
research uses or none at all) rather than requiring investigators
in every new research protocol to track down and
obtain specific consent from every tissue donor, even if the
specimen is identified only by a code.28 Other bioethics
scholars go further, arguing that the ‘‘data [regarding what
matters actually are important to patients] suggest applying a
tentative general framework for obtaining consent for
research using stored biological samples. Consent should be
required for research using clinically derived, identified
samples, but waived for additional research using research
derived, anonymized samples.’’29
An active ethical/social policy discussion about the parameters
of informed consent for research uses of surplus
human tissue specimens undoubtedly will persist in the USA
for the foreseeable future, as we delve ever further into the
genomic era of biomedical progress. For the time being, the
regulatory approach to this question has been resolved by
OHRP and FDA in the respective manners described above.
Whether the present approach of OHRP to exclude the
research use of coded tissue specimens from the classification
of human subjects research, subject to the requirements of
the Common Rule, constitutes a serious gap in legal
protection for vulnerable individuals, or whether a realistic
Ethical and legal issues in research involving human subjects 337
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recognition that the ability to give or withhold informed
consent in this context is not an especially important value to
most potential tissue donors remains to be seen.
Policy makers in the USA also should closely monitor the
legal and ethical approaches of the international community
to the informed consent question in this context. In the
United Kingdom, the well publicised Alder Hey and Bristol
Royal Infirmary inquiries, revealing systematic retention of
postmortem organs from children for educational and
research purposes, without obtaining authorised informed
consent, engendered substantial debate about the role of
informed consent in research related tissue specimen collection.
12 30 31 Various informative surveys of relevant public and
professional attitudes have been conducted in Europe26 32 and
Asia.33 Pertinent laws and customs have been developed in
different countries to address this matter, accompanied by
various degrees of controversy about how they balance
patients’ rights and society’s interest in having research
conducted.34 Inconsistent national laws contribute to confusion
and inhibit collaborative research efforts,35 but conflicting
ethical, cultural, and religious perspectives will continue
to make international regulatory harmonisation a highly
difficult challenge.36
Medical privacy requirements
Because possible unfair discrimination against an individual
by a present or potential employer, insurer, educator, or other
party on the basis of genetic information derived from a
scientific analysis of the individual’s tissue specimen is a
major risk of allowing one’s tissue to be available for research
purposes, it is necessary to consider the confidentiality
implications of collecting and storing tissue to be used in
the research context. In the USA, medical confidentiality
rules derive from, and may be enforced under, common law
tort doctrine and any applicable state statutes and regulations.
However, the chief American source of pertinent legal
authority is the federal Standards for Privacy of Individually
Identifiable Health Information (Privacy Rule).37 This regulation
became effective in 2003 after being promulgated by
DHHS under the legislative authority of the Health Insurance
Portability and Accountability Act (HIPAA).38
The Privacy Rule requires specific written permission from
a patient before anyone may use or disclose ‘‘protected health
information’’ (PHI) about that person for non-routine
purposes such as research. PHI is defined as any ‘‘individually
identifiable health information’’ transmitted or maintained
by a ‘‘covered entity’’ (for example, a health care provider,
health insurance plan, or data processing firm).
In the context of research using stored tissue specimens,
the reach of the HIPAA Privacy Rule is somewhat constrained.
First, tissue repositories such as biobanks are not
‘‘covered entities’’ subject to the Rule unless they conduct
some other kind of activity that brings them within the
‘‘covered entity’’ definition. The Privacy Rule would be
implicated only with regard to a covered entity, such as a
hospital, that discloses PHI for the creation or stocking of the
research repository.39 ‘‘It is the act of the health care provider
sending a specimen to a commercial sponsor while knowing
that it will be retained in a repository that triggers the HIPAA
written authorisation form requirement, not the sponsor’s
actions in maintaining the repository.’’40
Moreover, the Privacy Rule would only apply to a covered
entity that sends to a repository tissue that is accompanied by
clinical information containing specific patient identifiers.
‘‘The Privacy Rule permits covered entities to release data
that have been de-identified without obtaining an
Authorization and without further restrictions upon use or
disclosure because de-identified data is not PHI and, therefore,
not subject to the Privacy Rule.’’39 ‘‘The Privacy Rule
permits covered entities under the Rule to determine that
health information is de-identified even if the health
information has been assigned, and retains, a code or other
means of record identification, provided that: (1) the code is
not derived from or related to the information about the
individual; (2) the code could not be translated to identify the
individual; and (3) the covered entity under the Privacy Rule
does not use or disclose the code for other purposes or
disclose the mechanism for re-identification.’’17
CONCLUSIONS
Pathologists everywhere involved in various aspects of
research involving human participants must be cognisant of
the regulatory environment impacting their activities in their
particular jurisdiction and the ethical principles underlying
the applicable local legal rules. In this article I have outlined
the salient boundaries of the regulatory environment for
biomedical research. I have devoted particular attention to
current approaches and controversies about informed consent
and the ramifications of medical confidentiality when
obtaining human tissue specimens for use in current research
protocols or storing them for use in future protocols, the
details of which cannot be predicted or described to the
potential tissue donors.
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