September 21, 2016
Does the NPRM Get
Biospecimens Right?
Applying the New Standards
to Challenging Ethical
Issues
Barbara Sampson Davidson, IRB Member,
Schulman IRB
Jamie Chalfin, Director, Quality Assurance,
Schulman IRB
About Schulman IRB
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Established in 1983
Superior audit history with FDA—five consecutive audits
with no findings
21 CFR Part 11 compliant electronic systems
Compliant with FDA, OHRP and Health Canada
requirements
Full Board meetings five days a week
Dedicated daily expedited review of qualifying minimal
risk protocols
About Schulman IRB
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Review outcome provided within one business day of
new study review
One business day turnaround for complete new site
submissions
Dedicated streamlined processes tailored to Phase I
timelines
Expert oncology IRB members experienced in all
phases of oncology research
̶ National IRB for Cancer MoonShot 2020 initiative
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Customized services for institutions
Experienced primary points of contact for sponsors,
CROs, institutions and sites
About Schulman IRB
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Clinical Quality Assurance (CQA) and Human Research
Protection (HRP) consulting services provided by
Provision Research Compliance Services
www.provisionrcs.com
schulmanirb.com
About Today’s Presenter
Barbara Sampson Davidson, MS, RN,
MSN, CCRC
IRB Member, Schulman IRB
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With Schulman since 2015
Scientific IRB Member, responsible for review
of amendments, Investigator Brochures and
new site submissions
Developed & managed Research Human Milk
Bank at Cincinnati Children’s Hospital Medical
Center, 2003-2015
Research Study & Laboratory Manager,
Center for Interdisciplinary Research in
Human Milk & Lactation, CCHMC, 2010-2015
MSN Community Health Nursing, MS Cell &
Molecular Biology, University of Cincinnati
About Today’s Presenter
Jamie Chalfin, BA, CCRP
Director, Quality Assurance and Training,
Schulman IRB
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With Schulman since 2013
Responsible for leading the Quality Assurance &
Training (QA) Team to provide ongoing improvements
to the efficiency and effectiveness of Schulman’s
human research protection program (HRPP)
Extensive experience in GCP, GLP and GDP auditing
and training
Former Project and Regulatory Manager for Cincinnati
Children’s Hospital (CCHMC) Institutional Repository
Helped achieve CAP accreditation for biobank at
CCHMC and published article on the challenges of an
opt-in biobank
Bachelor’s Degree in Psychology from Northern
Kentucky University
Presentation Objectives
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Describe the NPRM’s proposed changes for
biospecimen research
Analyze historical events within the context of the
NPRM’s changes
Identify how the NPRM’s changes do and do not
provide improved human subject protections while
supporting scientific inquiry
Biospecimen Regulations:
The Current Common Rule and NPRM’s
Proposed Changes
The Common Rule 45 CFR 46 subpart A
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Established 1991
Promotes uniformity, understanding,
and compliance with human subjects
protections
Creates a uniform body of regulations
across Federal departments and agencies
The Common Rule – Today
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Secondary use of biospecimens and data that have been
stripped of all identifiers is permissible without consent
̶ The non-identified biospecimens and data do not meet the
regulatory definition of human subject
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Human subject: a living individual about whom an
investigator (whether professional or student) conducting
research obtains data through intervention or interaction
with the individual, or identifiable private information
45 CFR 46.102(f)
Advanced Notice of Public Rulemaking
ANPRM 2011
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Request for comment on how current
regulations for human subject protections
might be modernized to be more effective
Specific attention to improving human subject
protections while facilitating research by
reducing burden, delay, and ambiguity for
investigators
Preferred balance of protections for research
participants among the 3 Belmont principles
̶ Respect for persons, beneficence, and justice
NPRM 2015 – Biospecimens
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Consensus – active partners
Most public comments supported consent
requirements for use of their biospecimens
regardless of identifiability
NPRM 2015 – Biospecimens
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Some researchers supported the idea of
requiring consent for research use of all
biospecimens
Several researchers stated that if all
biospecimens are covered under the Common
Rule regardless of identifiability, there still might
be some activities involving biospecimens that
should be considered exempt from coverage
NPRM 2015 – Biospecimens
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Many researchers felt the existing regulatory
framework is adequate and that current practices
should be maintained
Several researchers noted the likelihood of
identifying an individual from their non-identified
biospecimens remains remote enough to argue
against the presumption that the sources of all
biospecimens are identifiable
̶ Cited a study showing that risk of re-identification
from a database system is only 0.22%
NPRM 2015 – Biospecimens
Broad consent: Informed consent for secondary use
even if biospecimens are non-identified
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Waivers rarely granted
Grandfathering of samples already banked or collected
for clinical pathology
Compliance 3 years from the date of publication
of the new rule
NPRM 2015 – Exemption from IRB
Review
1. Storage or maintenance of biospecimens or identifiable
private information for secondary research use for which
broad consent will be obtained using the HHS template
̶ Limited IRB review will be conducted to determine the broad
consent process
2. Secondary research use of biospecimens or identifiable
private information for which broad consent will be obtained
for the storage, maintenance, and secondary use
If individual research results are to be provided to
research subjects, then exemption no longer applies
NPRM 2015 – Elements of Consent
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Identifiers may be removed
Non-identifiable data may/may not be used or
disclosed for secondary research
Use for commercial profit
Whether profits will be shared with participants
Disclosure of clinically relevant results
Option for re-contacted
NPRM 2015 – Elements of Consent
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Types of secondary research that might be done and
information obtained
Types of biospecimens/information
Types of institutions that might conduct the research
Time period for collection: no more than 10 years
from date of consent
For children: collection no more than 10 years or the
date of legal age (whichever is first)
NPRM 2015 – Elements of Consent
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Withdrawal without penalty or loss of benefits
Subject may/may not know details of research
Specimen/data may or may not be used by multiple
researchers at multiple institutions
Option to opt out of having HIPAA non-identified data
listed on public database (may not be an issue)
NPRM 2015 – Alternative Proposal A
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Instead of considering all research using biospecimens
as human subjects research:
̶ Definition of human subjects would include whole genome
sequencing (WGS) data or any part of data generated as a
consequence of WGS
̶ Definition applies regardless of individual identifiability of
biospecimens used to generate such data
Regulations would then apply to:
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Research that would generate WGS data
The use of any part of the generated data
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Research involving secondary use of any part of WGS that
was originally generated for other purposes than the
proposed research
NPRM 2015 – Alternative Proposal A
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A new exemption would be created that allows such
research to be exempt if broad consent to secondary
future research use were obtained
Waiver of consent would be permitted
̶ BUT would be modeled on the more stringent waiver criteria
proposed for research involving biospecimens
Secondary research use of non-identified information
or non-identified biospecimens
would continue to fall outside Common Rule’s scope
NPRM 2015 – Alternative
Proposal B
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Expand definition of human subjects to include research
use of information produced using a technology applied
to a biospecimen that generates information unique to an
individual
̶ Possible that in combination with publicly available information
the individual could be identified
̶ Information that meets this standard would be referred to as
bio-unique information
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Consent for genomic sequencing of even small portions
of a person’s genome would be required
̶ Also would be required for use of other technologies that might
be developed that can generate information unique to a person
NPRM 2015 – Notable Objections
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ISBER: International Society for Biological and
Environmental Repositories
̶ International organization addressing the technical, legal,
ethical, and managerial issues relevant to repositories of
biological and environmental specimens
̶ Concern about the impact on important research using
archival clinical biospecimens collected after the
compliance date
NPRM 2015 – Notable Objections
Grandfathering specimens collected prior to the
compliance date does not solve the problem
New prospective studies would need to be
initiated, requiring years to complete
Hospitals and clinics would have to initiate
institution-wide approaches to broad consent
from all patients
NPRM 2015 – Notable Objections
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NPRM does not balance the 3 Belmont Principles
NPRM does not allow autonomy to be balanced
with social value of research that will lead to
improvement in medical care and health of the
public
“Respecting autonomy at the
expense of patient lives is a
significant ethical concern.”
NPRM 2015 – Notable Objections
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More stringent requirements for research using biospecimens
than for research using clinical/phenotypic data or WGS data
Too much reliance on broad consent and not enough on
governance and oversight of research on biospecimens
Questions IRB exemptions and risk to sub-populations that
may be stigmatized by certain research approaches or findings
Concern for negative impact on international collaborations
where many countries may not find the regulations adequate
Applying the Proposed Regulations:
Does the NPRM Get It Right?
#1: The Case of Henrietta Lacks
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In 1951, an African American woman received
treatment for cervical cancer at Johns Hopkins
During treatment, two samples were taken from her
cervix without her permission or knowledge:
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One sample was of “healthy tissue”
The other sample was “cancerous”
These samples were “given” to George Otto Gey, a
physician and cancer researcher at Johns Hopkins
This cell line would be known as the
HeLa Immortal Cell Line
Importance of the HeLa Cell Line
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HeLa cells have led to several important scientific discoveries in the
last 50 years
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HeLa cells were the first cells to be observed dividing multiple times without dying
(“immortal”)
HeLa cells were the first human cells to be successfully cloned
Since 1950s, scientists have grown roughly 20 tons of her cells
⋄ There are over 11,000 patents involving HeLa cells
HeLa cells have been used in important experiments around the world
⋄ Examples include polio vaccine development, cancer research and AIDS research
It is believed that her immortal cell line was one of the most important
discoveries in science and medicine
Her cell line is still used today
All of this without her family’s
knowledge or consent
How Did the Family Find Out?
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Early 1970s: Large portion of HeLa cells became
contaminated by other cell cultures
Numerous researchers contacted family members for
samples of their blood to replace the contaminated cells
The Lacks family was obviously confused by the
solicitations as they were unaware that Henrietta’s
cells had been used for research purposes
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But it didn’t stop
there…
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In the 1980s, family medical records
were published without the family’s
consent
In 2013, a German researcher published
Henrietta’s genome without the
family’s permission
Question:
What Are the Ethical Concerns
With This Case?
What Did the Regulations Say Then?
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At time of her treatment, permission was NOT required or
frequently sought when tissue was removed from patients
These regulations went into effect well after the
samples were taken without her permission
Federal Policy for the
Genetic Information
Henrietta loses her
Protection of Human
Health Insurance Portability Nondiscrimination Act
battle to cervical
Subjects (the “Common
Henrietta
(GINA) passed
and Accountability Act
cancer
Rule”) published
receives
(HIPAA) passed
Belmont Report
treatment
published
1950
1951
1979
1991
1996
2008
Question:
Would the NPRM have prevented
the Henrietta Lacks case?
NPRM and Henrietta Lacks
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YES based on the informed consent process
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In the case of Henrietta Lacks, there was no consent
Enhancements to the informed consent document and process in
NPRM:
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Informed consent documents would be required to make it clear to the
subjects about the commercial use of specimens and whether profits
would be shared with subjects
The option to be recontacted by researchers
A broad informed consent would be required for storing biospecimens
and identifiable information
Specimen/data may or may not be used by multiple researchers at
multiple institutions
Option to opt out of having HIPAA non-identified data listed on public
database
#2: The Case of the Havasupai Tribe
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Members of the Havasupai Tribe were documented to have high
rates of Type II Diabetes
In 1989, researchers at Arizona State University built a research
partnership with the tribe to study this disease
This became known as the Diabetes Project and consisted of:
− Disease education for participants
− Blood draws
− Genetic association testing (looking
for a link between genetics and risk
for developing the disease)
The project lasted for many years but
was unsuccessful at finding a genetic
link to diabetes
Young girls in the Havasupai Tribe. Image Credit: University of Southern
California Libraries and the California Historical Society.
After the Diabetes Study Ended…
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Researchers continued to use DNA samples from the Havasupai
Tribe for unrelated studies
To make matters worse, the topics investigated were
considered taboo in the Havasupai and other
Native American tribes
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Schizophrenia: many tribes (but not all) stigmatize mental illnesses
Migration: problematic because these studies sometimes contradict oral
histories told by the Tribal Elders
Inbreeding: while not actually about inbreeding behavior, the true intent of
the study was not effectively communicated to the tribal members
Some of these researchers also gained access to medical
records of the tribe members without permission
How Did Participants Find Out?
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In 2003, Carletta Tilousi, a member of the Havasupai Tribe and
participant in the Diabetes Project, attended a lecture at ASU
She found out that the samples given for the Diabetes Project were
also used for later studies without her knowledge or the
knowledge of other Havasupai Tribe members
The Havasupai Tribe Lawsuit
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In 2004, the Havasupai Tribe filed a lawsuit against ASU
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The lawsuit claims the researchers misused the DNA samples taken during the
Diabetes Project
The Havasupai expressed concern about:
⋄ Lack of informed consent
⋄ Violation of their civil rights through mishandling of the samples
⋄ Unapproved use of data
⋄ Violation of medical confidentiality
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The lawsuit was dismissed due to a procedural error
Eventually the Arizona court of appeals reinstated the lawsuit as a civil case
and a settlement was reached
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The tribe received compensation, funds for a clinic and a school, and the unused DNA
samples were returned to the Havasupai
Because the lawsuit was dismissed, there is no legal precedent
established in this case for how informed consent issues
should be handled
Question:
Would the NPRM have prevented
the Havasupai Tribe case?
NPRM and the Havasupai Tribe
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YES and NO
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The samples were used without complete informed consent
But wait! The participants did provide some level of consent
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Informed consent was obtained first by oral statements, and then the Havasupai
were given the consent forms to sign
All tribal members who gave blood were told that the samples would be used for
genetic studies on diabetes
The consent forms mentioned that samples would be used for research on
“behavioral and medical disorders”
⋄ However, it was not clear to the Havasupai this would include schizophrenia
Medical records were also reviewed to collect information about mental health
and other information unrelated to Type II Diabetes
⋄ This occurred without their consent
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Consent would be required for any use of specimens
Important information would no longer be “buried”
deep within the consent forms
Summary of the NPRM Changes
1. Improve the informed consent process to ensure that subjects are
appropriately informed before they decide to enroll in research by:
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Increasing transparency
Imposing stricter requirements regarding the information given to prospective
subjects, and the manner in which it is given to them
2. Require informed consent for the use of stored biospecimens in
secondary research even if the investigator is not being given
identifying information
In Conclusion
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PROS
The NPRM could have many positive changes to the
informed consent document and process
The NPRM also gives participants a voice with respect to
how their biospecimens are used
CONS
The NPRM could be an impediment to medical progress,
depriving society of important health benefits
The NPRM’s effort to honor autonomy seems superficial,
albeit not by design
References
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Skloot, R., & Turpin, B. (2010). The immortal life of Henrietta Lacks.
Watson, D. (2010). Cancer cells killed Henrietta Lacks–then made
her immortal. The Virginian Pilot, 10.
Kwok P et al. Harder Than You Think: A Case Study of ReIdentification Risk of HIPAA-Compliant Records. NORC at The
University of Chicago and Office of the National Coordinator for
Health Information Technology. 2011.
http://www.amstat.org/meetings/jsm/2011/onlineprogram/AbstractDet
ails.cfm?abstractids=302255.
Garrison, Nanibaa'A. "Genomic Justice for Native Americans: Impact
of the Havasupai Case on Genetic Research." Science, technology,
& human values 38.2 (2013): 201-223.
Abdullah, T., & Brown, T. L. (2011). Mental illness stigma and
ethnocultural beliefs, values, and norms: An integrative review.
Clinical psychology review, 31(6), 934-948.
NPRM 2015 – Summary
ISBER
September 21, 2016
Does the NPRM Get
Biospecimens Right?
Applying the New Standards
to Challenging Ethical
Issues
Barbara Sampson Davidson, IRB Member,
Schulman IRB
Jamie Chalfin, Director, Quality Assurance,
Schulman IRB