Sep 21, 2016 - Clinical Quality Assurance (CQA) and Human Research. Protection .... to be provided to research subjects,
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
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
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
Customized services for institutions Experienced primary points of contact for sponsors, CROs, institutions and sites
About Schulman IRB
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
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
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
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
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
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
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
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
Consensus – active partners
Most public comments supported consent requirements for use of their biospecimens regardless of identifiability
NPRM 2015 – Biospecimens
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
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
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
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
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
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
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 ̶
AND 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
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
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
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
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
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
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
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: ̶ ̶
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
HeLa cells have led to several important scientific discoveries in the last 50 years ̶ ̶ ̶ ̶
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?
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
But it didn’t stop there…
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?
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
YES based on the informed consent process ̶
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
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…
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 ̶ ̶ ̶
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?
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
In 2004, the Havasupai Tribe filed a lawsuit against ASU ̶ ̶
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
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 ̶
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
YES and NO ̶
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: ̶ ̶
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
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
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
