Medical Research

Law & Policy

Report

Reproduced with permission from Medical Research Law &

Policy Report, 14 MRLR 686, 10/07/2015. Copyright 2015
by The Bureau of National Affairs, Inc. (800-372-1033) http://
www.bna.com

Proposed Changes to the Common Rule

Grapple With the Secondary Research Use of Biospecimens
years of deliberation following the July 26, 2011, Advance Notice of Proposed Rulemaking (ANPRM)2 published by the Department of Health and Human Services and the Office of Science and Technology Policy.
The revisions are intended to reflect the substantial increase in research involving human subjects since the
1991 publication of the Common Rule and the fact that
such research now often involves multiple sites; uses
new technologies, including genomics, imaging and informatics; and includes areas of study beyond biomedical research including health services and the social sciences.

BY MICHAEL J. VERNICK
n Sept. 8, 2015, the long-awaited proposal to update and modernize the Common Rule1 governing
research involving human subjects was published.
The proposed rule is the culmination of more than four

1
45 C.F.R. Part 46. The following departments and agencies are participating in the Notice of Proposed Rulemaking:
the departments of Homeland Security, Agriculture, Energy,
Commerce, Justice, Labor, Defense, Education, Veterans Affairs, Health and Human Services, and Transportation; the National Aeronautics and Space Administration; Social Security
Administration; U.S. Agency for International Development;
National Science Foundation; and Environmental Protection
Agency. In addition, the Office of the Director of National Intelligence and the Central Intelligence Agency will follow HHS
guidelines after promulgation of the final rule. Finally, the De-

Michael J. Vernick is a partner with Hogan

Lovells US LLP in Washington.

COPYRIGHT 2015 BY THE BUREAU OF NATIONAL AFFAIRS, INC.

A. Notice of Proposed Rulemaking

The Notice of Proposed Rulemaking (NPRM) recognizes that the Common Rule requires updating to more
effectively balance the protection of actual and potential research subjects against the need to facilitate continued scientific advances. The NPRM explains that its
goals:
are to increase human subjects ability and opportunity to
make informed decisions; reduce potential for harm and increase justice by increasing the uniformity of human subject protections in areas such as information disclosure
risk, coverage of clinical trials, and coverage of IRBs
[institutional review boards]; and facilitate current and
evolving types of research that offer promising approaches
to treating and preventing medical and societal problems
through reduced ambiguity in interpretation of the regulations, increased efficiencies in the performance of the repartment of Housing and Urban Development and the Consumer Product Safety Commission both intend to adopt a final
rule but will do so through a separate rule-making process.
2
76 Fed. Reg. 44,512 (July 26, 2011).

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view system, and reduced burdens on researchers that do
not appear to provide commensurate protections to human
subjects. It is hoped that these changes will also build public trust in the research system.3

Research using biospecimens, particularly in the genomics field, is one of the many areas where those competing interests are present. Among the primary
changes to the scientific landscape since the 1991
promulgation of the Common Rule are the staggering
advances in genomics and other similar cutting-edge research technologies. Indeed, the NPRM explains that it
seeks to facilitate cutting edge research in genomics
and other omics such as the transcriptome[4] and the
microbiome[5], which generate a wealth of data from
biospecimens designed to inform the development of
treatments and preventative measures for chronic diseases such as cancer.6 The NPRM also recognizes that
supporting research of this nature raises numerous
challenging ethical issues.
Not surprisingly, among the primary areas of change
to the current version of the Common Rule are the following:7
s With only limited exceptions, require informed
consent before biospecimens may be used for secondary research. For example, if part of a blood
sample taken for clinical use is left over, an investigator would generally need an informed consent before using that sample for research. This informed consent requirement would apply even if
the biospecimen cannot be identified. The consent
obtained for the secondary research use of biospecimens may, however, be broad inasmuch as it
may seek permission to store and use biosamples
for future, unspecified studies.
s Limit the ability of researchers to obtain waivers
or alter previously provided consent for research
involving biospecimens (regardless of identifiability).
The NPRMs approach would be a significant change
that would increase cost and the administrative burden
placed on investigators and their institutions. It may,
therefore, prove to be one of the more controversial aspects of the proposed changes to the Common Rule. For
that reason, and as discussed below, the NPRM offers
two alternative solutions to the secondary research use
of biospecimens. Collectively, these proposals should
trigger a lively debate during the comment period and
thereafter.

B. Secondary Research Use of Biospecimens

Investigators may obtain biospecimens through a variety of means, including collection for clinical pur3

80 Fed. Reg. 53,933, 53,936 (Sept. 8, 2015).

The human genome consists of DNA that contains the instructions needed to build and maintain cells. Those instructions are carried out by transcribing them into RNA. A transcriptome is therefore a collection of all the gene instructions in a given cell.
5
The microbiome is the ecosystem of organisms that live
in and on the human body, e.g., bacteria, viruses and fungi.
6
80 Fed. Reg. at 53,942.
7
Other significant changes related to the secondary research use of biospecimens are also relevant, including new requirements addressing informed consent forms, exclusions
and exceptions to the Common Rule and privacy safeguards.
4

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poses, removal during a surgery or a specific research

purpose. The issue of secondary research use of such
specimens perfectly raises the competing interests the
NPRM is trying to balance. On one hand, is what the
NPRM refers to as the principle of autonomy,8 which in
this instance addresses the interest of the individual in
knowing what his or her genetic material will be used
for and in ensuring that personal information (genetic
and otherwise) is adequately safeguarded. The NPRM
notes that literature studies suggest, not surprisingly,
that individuals prefer to maintain control over the use
of their own biological materials. The NPRM also cites
a 2012 publication of the Presidential Commission for
the Study of Bioethical Issues, which recommended the
prohibition of unauthorized whole genome sequencing
without consent.9 On the other hand, and in a sense
competing with the idea of individual autonomy, is the
concept of beneficence, which here could weigh in favor of creating a regulatory regime that would limit the
need for informed consent so that society as a whole
would benefit from the potential scientific advances
that may occur by maximizing the secondary research
use of biospecimens.

1. The Current Rule

With respect to the secondary research use of biospecimens, the current version of the Common Rule focuses on whether the biospecimen is identifiable. Specifically, the current definition of a human subject explains that a human subject is a living individual about
whom the investigator has obtained (i) data through
some sort of intervention or interaction, or (ii) identifiable private information.10 The current rule goes on to
explain that [p]rivate information must be individually
identifiable (i.e., the identity of the subject is or may
readily be ascertained by the investigator or associated
with the information) in order for obtaining the information to constitute research involving human subjects.11 Given the current definition of a human subject, if there is an absence of intervention or interaction,
then coverage by the Common Rule will depend on
whether the researcher has obtained individually identifiable private information. Thus, if the biospecimens
were collected for some purpose other than the currently proposed research, an investigator may use those
specimens if they have had their identifiers removed
without seeking consent because the non-identified12
8
The Belmont Report uses the term Respect for Persons,
which encompasses the concept of autonomy. See National
Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (1979). Belmont Report. Washington, D.C.: U.S. Department of Health and Human Services.
Available
at:
http://www.hhs.gov/ohrp/humansubjects/
guidance/belmont.html.
9
Privacy and Progress in Whole Genome Sequencing.
(2012). Washington, D.C.: Presidential Commission for the
Study of Bioethical Issues. Retrieved from http://bioethics.gov/
sites/default/files/PrivacyProgress508_1.pdf.
10
45 C.F.R. 46.102(f).
11
Id.
12
The term non-identified is used here for conformance
with the NPRM, which explains that the terms nonidentified or non-identifiable are used to refer to biospecimens or data that have been stripped of identifiers such that
an investigator cannot readily ascertain a human subjects
identity. The term de-identified maintains its specific meaning under the Health Insurance Portability and Accountability
Act (HIPAA).

COPYRIGHT 2015 BY THE BUREAU OF NATIONAL AFFAIRS, INC.

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biospecimens do not met the current definition of a human subject.13

2. The ANPRM
The ANPRM posed a series of questions intended to
focus commenters on some of the key issues around the
secondary research use of biospecimens. First, the ANPRM asked the fundamental question of whether researchers should be required to obtain consent before
using non-identified biospecimens. Second, it asked the
related question of whether, if such consent were required, it could be obtained by having an individual provide a broad consent covering all future research or if
specific consent would have to be obtained each time a
secondary research use was contemplated. The ANPRM
also asked commenters to consider genomics specifically. For example, the NPRM states that the HHS does
not consider the whole genome analysis to produce individually identifiable information in and of itself but
acknowledges that at some point in the not-too-distant
future it may be possible to identify individuals from
their genetic information. Thus, the ANPRM sought
feedback on whether the rules should be changed to allow individuals to decide whether their specimens could
be used for research even if the biospecimens are not
considered individually identifiable. Finally, the ANPRM sought feedback on whether the Common Rule
should adopt the HIPAA Privacy Rules definition of
what constitutes individually identifiable information, a
limited data set and de-identified information.

3. Feedback on the ANPRM Questions

The NPRM explains that a majority of the comments
received were against requiring consent for the use of
all biospecimens, and were particularly opposed to imposing some sort of retroactive consent requirement
covering specimens collected before any new rule
might go into effect. The bases for these objections included, among others, a lack of evidence that using the
biospecimens for secondary research would cause
harm and that imposing consent requirements would
unduly slow research advances. Commenters also
raised concerns that requiring consent would create administrative burden and costs related to collecting, logging and tracking consent forms to ensure that the
wishes of individuals were respected. In contrast, the
NPRM states that most of the comments specifically
from individual members of the public were strongly in
favor of requiring consent, regardless of whether the
biospecimens are identifiable. There were also a number of comments suggesting that if the Common Rule
were changed to require consent for the use of all biospecimens without regard for identifiability, then certain activities that use biospecimens should be exempted from any consent requirements, including those
related to identifying markers for cancer prognosis or
prediction of response to cancer therapy and research
on rare conditions and diseases, among others. A majority of commenters were strongly against adopting
the HIPAA Privacy Rule standards.
13
The controversy around the secondary use of biospecimens is illustrated by the NPRMs statement that notwithstanding the current rule some IRBs require investigators to
seek consent anyway.

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4. The NPRMs Primary Proposal

With respect to secondary research use of biospecimens, the NPRM has, in general, favored individual autonomy. Indeed, the NPRM takes the view that to continue without a consent requirement would place the
publicly funded research enterprise in an increasingly
untenable position inconsistent with the desires of a
majority of the publics wishes. The NPRM, therefore,
proposes to revise the definition of a human subject
to cover obtaining, use, study, or analysis of biospecimens . . . regardless of identifiability. The NPRM explains that covering biospecimens regardless of identifiability allows the rule to avoid disputes around what
are identifiable data, such as decoding the whole genome. The NPRM does not, however, modify the current Common Rule standard of identifiability, i.e., the
test for whether a researcher has enough information
to readily ascertain the identity of an individual.
Thus, that test would continue to apply to information
derived from biospecimens. The NPRM would allow
IRBs to waive the consent requirement but only in very
limited, or rare, circumstances.
The NPRM does, however, recognize the need to
maximize efficiency and reduce administrative burden
and, therefore, would allow a broad consent covering
future unspecified research rather than requiring researchers to seek consent for each specific study. The
NPRM posits that this effort to balance individual autonomy with the need to facilitate continued scientific
advances will increase the trust of potential study subjects and hopefully increase participation rates in research.
Notably, the NPRM heard the concerns about imposing a retroactive consent requirement and instead
makes the proposed new requirement prospective, by
which it means that the new rule would reach only
those biospecimens collected in the future. The NPRM
also recognizes that the proposed new consent requirement will be a fundamental change in the research area
and consequently proposes to delay implementation of
the requirement until three years after publication of a
final rule.
Notwithstanding the broad consent requirement, the
NPRM will allow certain exclusions and exceptions.
First, research that is designed to generate information
about the study subject that is already known will be
deemed to be outside the scope of the Common Rule, or
excluded. Under this exception, for example, research
to develop a diagnostic test for a condition using specimens from individuals known to have the condition and
those known not to have the condition is excluded
from Common Rule coverage.14 Quality assurance and
control activities, and proficiency testing are also excluded. The basis for this exclusion is that if the research is not going to generate any new information,
but rather confirm something already known, then the
autonomy interest is relatively weak.15
14

80 Fed. Reg. 54,046 (proposed new __.101(b)(3)(i)).

Other exclusions are also potentially applicable, including certain (1) data collection and analysis activities, (2) quality assurance involving the implementation of an accepted
practice to improve the delivery or quality of care or services,
(3) public surveillance activities and (4) national security purposes. 80 Fed. Reg. 54,045 (proposed new __.101(b)(1)(i), (iii)(vi)).
15

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5. Alternative Proposals
In addition to its primary proposal that would require
informed consent for the secondary use of biospecimens in all but limited circumstances, the NPRM floats
two alternative proposals.

a. Whole Genome Sequencing

The first alternative would revise the definition of human subjects to include whole genome sequencing data
or any part of the data generated as a consequence of
whole genome sequencingwithout regard for identifiability. The NPRM explains that an investigator engaged in whole genome sequencing research would not
be able to avoid the Common Rule by removing identifiers because the whole genome sequence data themselves would already be subject to the Common Rule.
The NPRM says that is a notable difference between
this first alternative proposal and the primary proposal,
under which data produced from whole genome sequencing could be used for research without additional
consent so long as they were not identifiable private information. This first alternative proposal would also
create an exemption if researchers obtained consent to
secondary future research and adequately protected the
biospecimens.
The NPRM also explains that this first alternative
proposal places less emphasis on the autonomy of individuals because it would require consent for only the
limited area of whole genome studies. Moreover, the
NPRM notes that there is currently only a limited
amount of whole genome sequencing research and that
the proposal would therefore impose less of a burden
on the research community. That is, of course, also a
potential downside to the alternative inasmuch as the
Common Rule would cover only this one technology
and would perhaps have to be re-assessed as new technologies become more prevalent.

b. Classifying Cer tain Biospecimens Used in

Particular Technologies as Meeting the Criteria for
Human Subjects
Under this second alternative proposal, the definition
of human subjects would be revised to include:
the research use of information that was produced using a
technology applied to a biospecimen that generates information unique to an individual such that it is foreseeable
that, when used in combination with publicly available information, the individual could be identified.16

Such information would be designated bio-unique

information.
16

80 Fed. Reg. 53,945-6.

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The NPRM explains that this second alternative is

similar to the first alternative focused on whole genome
sequencing. According to the NPRM, the primary difference is that the scope of this second option is somewhat broader, namely that under the first alternative,
consent is required for whole genome sequencing but
here consent would be needed for sequencing of even
small portions of a persons genome and also for other
yet to be developed technologies that could generate information unique to a person. The NPRM recognizes
that a potentially significant drawback to this approach
is that the HHS would have to be in the business of continually evaluating new technologies to ensure that the
rule kept pace with technical and scientific developments.

C. Conclusion
If the primary NPRM proposal is promulgated, it will
effect a significant change in the use of biospecimens
inasmuch as investigators will need to obtain informed
consent in instances when it is now not necessary to do
so. The NPRM recognizes that many questions related
to the primary proposal remain open, including the fundamental question of whether the government should
define a biospecimen and if that definition should help
distinguish between biospecimens subject to the Common Rule and processing biological materials to create
commercial projects used for treatments. Likewise, the
primary proposal has rejected the concept of adopting
principles from the HIPAA Privacy Rule but posits that
additional guidance on how to define identifiable private information may be necessary. The primary proposal also leaves open several practical questions regarding how broad consents will be obtained. For example, will it become commonplace to seek that kind of
broad consent as part of routine clinical procedures?
Will individuals agree to such requests? If broad consents are not obtained, how practical will it be to seek
them after-the-fact? If it is not practical, will there be
substantially fewer opportunities to conduct secondary research?
As for the alternative proposals, both seem subject to
a similar critique inasmuch as they may create a regime
that is unable to keep pace with scientific developments. Given the amount of time and effort it has taken
to promulgate this NPRM, it seems reasonable to infer
that the ability to update the Common Rule to address
new technologies in a timely way is unlikely.
Ultimately, the secondary research use of biospecimens will likely remain a significant topic during the
comment period and for the HHS and the OSTP to consider as they develop a final rule.

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MRLR

ISSN 1539-1035