Disruptive Influences on Research in Academic Pathology Departments Biospecimens and Consent and 2xR 3, Oh My! University of Michigan November 16, 2015.

Disruptive Influences on Research in Academic Pathology Departments

Biospecimens and Consent and 2xR3, Oh My!

University of MichiganNovember 16, 2015

Biospecimens and Consent and 2xR3, Oh My!

R3 Research Rigor and Reproducibility R3 Return of Research Results Biospecimens and Informed Consent

Notice of Proposed Rule Making – Common Rule

Disclosure and Disclaimer

Mark E. Sobel MD, PhDExecutive Officer

American Society for Investigative [email protected]

http://www.asip.org/about/executive_officer.cfm

I have no relevant financial disclosure

Some content of this presentation represents my personal views, which have been influenced by my conversations with members of the ASIP Research and Science Policy Committee, but they have not been officially endorsed by ASIP.

Congratulations

Asma Nusrat:Aldred S. Warthin Professor and Director of

Experimental Pathology

Kathy Cho:Member of the National Academy of Medicine

Disruptive Influences on Clinical Service Reimbursement and Funding Synergize with other departments

Radiology Nuclear Medicine Clinical Informatics Personalized Medicine Centers

Adaptation to Affordable Care Act Disruptive Technologies

Next-generation sequencing Microchip-based equipment

Commercial Direct-to-Consumer FDA Draft Guidance on Laboratory Developed Tests

Next-Generation Sequencing (NGS)

Research Rigor and Reproducibility

Allegations of the inability to reproduce published biomedical research Distinguish from scientific fraud Poor methodological detail

NIH announced new requirements Effective January 25, 2016 (pending OMB)

NIH Requirements

Effective January 25, 2016 (pending OMB) New grant proposals must:

Consider strength of the body of work that the proposed work will be built upon

Design experiments that are unbiased and rigorous Consider sex and other biological variables (age,

weight, underlying health conditions in vertebrate animals)

Authenticate key biological and/or chemical resources Antibodies Cell lines

Return of Research Results

Secretary’s Advisory Committee on Human Research Protections

Lack of harmony between HIPAA and CLIA HIPAA: Health Insurance Portability and

Accountability Act CMS: Centers for Medicare and Medicaid Services

Interprets the Clinical Laboratory Improvement Act (CLIA) Laboratories providing patient care should be CLIA-certified

COMMENTS TO SACHRP: LACK of HARMONY BETWEEN CLIA and HIPAA

and RETURN of RESEARCH RESULTS

Mark E. Sobel MD, PhDExecutive Officer

American Society for Investigative [email protected]

Secretary’s Advisory Committee on Human Research ProtectionsJuly 22, 2015

The Path to Clinical Implementation from Translational Research

•Analytical validity - Technical feasibility and optimization – does the test measure what we say?•Clinical validity – Diagnostic accuracy - does the test measure a value associated with a clinical condition?

•Sensitivity (false negatives)•Specificity (false positives)

•Clinical utility •will the test improve making a healthcare decision?•Will the test be cost effective?

Core Principles

• Laboratories providing patient care should be CLIA-certified. • Different laboratory standards for patient care and for

research are appropriate.• Patient care standards are designed to ensure that the right result is

provided to the right patient, addressing analytic, test, and clinical validity standards.

• The goal of research laboratory testing is to expand upon generalizable knowledge. Research sample testing procedures are designed to accurately capture data from specimens in aggregate.

• The National Institutes of Health and the National Science Foundation have recently expressed concern about the lack of research reproducibility and rigor in preclinical research.

• CLIA values the difference between reporting of patient test results and research.

American Society for Investigative Pathology

Core Principles

• Regardless of whether research is conducted in a HIPAA-covered institution or in a non-covered institution, IRBs should carefully consider the issues involved in approving a consent that informs the subject of potential risks and benefits.• The responsibility of the IRB should be independent of whether an

institution is covered under HIPAA. • Obligations to research subjects should not vary depending upon the

nature of the laboratory (CLIA-certified or non‒CLIA-certified) conducting the research.

• Instead, the nature of the research should be the focus.


Core Principles

• Research proposals should proactively address contingencies for findings that may have implications for clinical care.

• Will re-contact be a possibility and under what circumstances?

• Best practice is to inform research participants in advance, through the informed consent process, whether individual laboratory test results will be made available to the participant.


Core Principles

• CLIA-certified laboratories should be the entities responsible for providing information that may, at some point in the future, be used in patient treatment.

• Non‒CLIA-certified laboratories, whether or not part of a HIPAA-covered entity, should not release findings to individual participants.

• The research proposal and the informed consent documents, which are reviewed and approved by the IRB, should clearly state whether individual findings will be released to participants.

• External review should take place in rare cases in which there is consideration of follow-up of a result from a non‒CLIA-certified laboratory.

• Re-contact to obtain additional samples should be allowed, and not considered, in and of itself, a returnable finding.


Summary of HIPAA – CLIA Issue

• Only CLIA-certified laboratories should release information that may be used in patient care.

• Researchers should proactively address whether or not individual research results will be made available to participants.• Communicate clearly in the research proposal to the IRB. • Approval by the IRB.• Communication to the research participants through the

informed consent process.


Biospecimens and Informed Consent

Precision Medicine in Context: A Transformative Event

A Primer on Ethical Issues of Human Biospecimens Impact of New Molecular Technologies on

Research Utilizing Human Biospecimens Next-Generation Sequencing (NGS)

Notice of Proposed Rule Making – Common Rule

A Primer on Ethical Considerations

1974 – National Research Act

Created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

Impetus: a series of scandals involving abuse of human subjects Nazi experiments Radiation experiments (US) Tuskegee Syphilis Study (US) Taking advantage of vulnerable populations

A Primer on Ethical Considerations

The Belmont Report (1979)http://

www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

Respect for persons (autonomy) Beneficence

Justice

http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html



The Common Rule

"Code of Federal Regulations - Title 45 Public Welfare CFR 46

"

A baseline standard of ethics by which any government-funded research in the United States is held, and nearly all academic institutions hold their researchers to these statements of rights

regardless of funding.

As of October, 2015, 19 Federal Agencies

http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm



The Common Rule

A rule of ethics regarding biomedical and behavioral research involving human subjects (US).

Regulations governing Institutional Review Boards (IRBs) for oversight of human research came.

Went into effect in 1981 following the 1975 revision of the Declaration of Helsinki and the Belmont Report of 1979

Revised in 1991 Advanced Notice of Rule Making – 2011 Notice of Proposed Rule Making – Sept. 7, 2015

The Common Rule

Rights in addition to autonomy, beneficence, and justice Privacy Right to withdraw Informed consent

Identification of Specimens

• Anonymous- the sample was collected without the identity of the donor.

• Anonymized – the sample was collected with the known identity, but the identification was removed

• Coded (Linked) – the sample is given a unique identifier that cannot be easily deciphered

• Identified – the sample has a common identifier (name, hospital number)

Identification of Specimens (Current)

• Any human biospecimen that can be identified by any one person, anywhere, is an identifiable sample

• If a sample is coded, and any investigator keeps a key to the code, the sample is identifiable.

• Exception (Office of Human Research Protections): If the recipient (i.e., the researcher) of the human biospecimen signs an agreement that there is no intent to identify the sample, the sample may be considered unidentifiable.

Current Definition of a Human Subject Does NOT Include:

• Deceased persons (autopsy specimens)• Publicly available information• Non-identifiable samples

The Common Rule (Current)

An IRB may grant a waiver of informed consent under the Common Rule if four criteria are met: Minimal risk Respect for autonomy and the rights of the

individual Impracticable Notification

The Common Rule (Current)

Waivers are rarely granted for identified samples

Waivers are usually granted for collecting anonymous samples

Waivers are usually granted for using anonymous or anonymized samples

Waivers are occasionally granted for coded (linked) samples

And then 12 years ago, along came HIPAA

Health Insurance Portability Authorization Act – April 2003

http:www.hhs.gov/ocr/hipaa There are inconsistencies (lack of

harmonization) between HIPAA and the Common Rule

Privacy of information extends to the family and survives beyond the death of the donor (50 years).

Affects clinical treatment and research

Biospecimens in a Human Biobank

•Tissue samples•Biopsy•Resection of tissue (surgery)•Dissection of tissue (autopsy)

•Blood, sputum, urine, bone marrow•Associated data

•Clinical history•Environmental history•Family history•Demographics (gender, age)•How the sample was collected

Biospecimens in a Human Biobank

•Freshly obtained•Frozen•Fixed

•Formalin-fixed paraffin-embedded (FFPE)•Alcohol-fixed•Other fixatives

Types of Biobanks

•Freezer banks or Cold storage rooms•Glass slide collections•Tissue blocks (FFPE)•Liquid specimens (blood, urine…)•Buccal (cheek) swabs•Extracted analytes (DNA, RNA, protein, etc)

Confidentiality and Privacy

•Confidentiality- the principle in medical ethics that the information a patient reveals to a health care provider is private and has limits on how and when it can be disclosed to a third party

•Privacy - culturally specific concept defining the extent, timing, and circumstances of sharing oneself

•Physical•Behavioral•Medical

Biomedical Research and Biobanks:Translational Research involves interactions

between the laboratory bench and patient’s bed

•Increase knowledge•Understand biological processes•Improve public health

•New diagnostic tests•New prognostic tests•New or improved therapy

The Translational Research Cycle The Biobank is Essential to Provide Solutions

Adapted from Dr. Bruce McManus, UBC

Translational Research

Cycle

Investigative ModelsPatients as Partners

Models of Human Disease

BiobankTissues, Cells, Fluids, & Products and Dry Data

Pathophysiological and Sociobiological

Processes

Identification of Novel Markers and Targets

Biomarker or Target Validation

Multi-population Assessment, High-

throughput ScreeningClinical Trials

Technology Transfer

ToolsGenetics, Genomics, Proteomics, Imaging, Physiology, Biophysics, Biochemistry, Nanotechnology,

Informatics, Sociology, Epidemiology, Statistics

Research Questions

Informed Consent and Ethical Considerations

The capacity to perform large-scale sequencing on the human genome presents unique challenges regarding the provision of informed consent, particularly in deciding on the level of detail that needs to be shared.

No specific guidance exists, and each institution offering such testing is deriving its own policies.

With genome testing by NGS, the perceived and real potential risks are magnified compared with genetic tests that target only one gene at a time.

The Research Paper That Broke the Anonymized Sample’s Back

Gymrek M, McGuire AL, Golan D, Halperin E, Erlich Y: Identifying personal genomes by surname inference. Science 2013, 339:321

Research using anonymous or anonymized samples in which a significant portion of the genome is sequenced may result in the specimen being considered identifiable and thus worthy of appropriate protections under human subjects research regulations.

Presidential Commissionfor the Study of Bioethical Issues

Washington, DCOctober 2012

http://www.bioethics.gov

The Question

Does the ability to inexpensively and rapidly sequence the genome of an individual from a single cell of a biospecimen nullify the concept of an anonymous or anonymized sample?

Is the anonymized sample an endangered species?

Notice of Proposed Rule MakingCommon Rule

Comments due December 7, 2015

Emphasis on AUTONOMY Non-identified biospecimens are human

subjects: informed consent required Broad consent templates Less concern about minimal risk Reduce administrative burden on individual

researchers

Significant Changes: Activities Excluded from IRB Review

Activities deemed “not research” Program improvement (data collection) Oral history, journalism, biography, historical

scholarship Criminal justice (data collection)

Activities that have non-research purposes Quality assurance and quality improvement Public health surveillance Intelligence surveillance

Significant Changes: Activities Excluded from IRB Review

Low-risk activities already subject to independent controls Educational tests, survey procedures, interview

procedures, observation of public behavior Research involving collection or study of

information that has or will be collected Activities regulated by HIPAA Research conducted by a government agency using

government-generated or –collected data

Significant Changes: Single IRB Review

Mandate that multi-institutional cooperative research rely on a single IRB

Significant Changes: Continuing Review

Eliminate the continuing review requirement for studies that Undergo expedited review Have completed study interventions

Analyzing data Observational follow-up in conjunction with

standard clinical care

Significant Changes: Extend Application of the Common Rule

Extend the scope of the policy to cover all clinical trials, regardless of funding source, conducted at a U.S. institution that receives (any) federal funding for non-exempt human subjects research

Significant Changes: Exempt Research

Add additional categories of exempt research: Accommodate changes in the scientific

landscape Better calibrate the level of review to the level

of risk involved in the research Online tool to determine exempt studies without

requiring administrative or IRB review


Certain research involving benign interventions with adult subjects

Research involving educational tests, surveys, interviews, observations of public behavior

Secondary research use of identifiable private information originally collected as part of a non-research activity


Storing or maintaining biospecimens and identifiable private information for future, unspecified secondary research studies Broad consent is used Consent template to be developed by DHHS Information and biospecimen privacy

safeguards Limited IRB approval of the consent process

Significant Changes: Informed Consent

Improve informed consent by increasing transparency and imposing stricter new requirements regarding the information that must be given to prospective subjects

Significant Changes: Waiver of Consent

Waiver of consent for research involving biospecimens will only occur in very rare circumstances

Research must have compelling scientific purpose Research must not be able to use biospecimens for

which consent was or can be obtained This will necessitate obtaining informed consent

for the vast majority of biospecimen research

Significant Changes: Broad Consent

Broad consent template to be developed by DHHS Gather biospecimens in a research setting- durable

over time Gather biospecimens in a clinical setting – for 10

years Once broad consent is signed, biospecimens

can be collected for 10 years, and they can be used indefinitely

Ten years after signing broad consent, no more collection of biospecimens unless new consent is signed

Significant Changes: Use of Biospecimens

The definition of a human subject is modified to include all uses of biospecimens by an investigator conducting research, including non-identified (anonymized or de-identified) biosepcimens

Estimates cost burden of $12 billion over ten years

Use of Biospecimens: Cost Burden Faulty Assumptions

Assumes only federal wide assurance institutions will store and maintain biospecimens

Assumes 5 minutes to obtain consent in a research setting and 10 minutes in a clinical setting

Estimates 1.0 database administrator FTE per institution

No allowance for developent of robust databases to track biospecimens

National Academy Reporthttp://www.nap.edu/21803

Optimizing the Nation’s Investment in Academic Research: A New Regulatory Framework for the 21st Century

“Concerns have been raised repeatedly that federal laws, regulations, rules, policies, guidances, and reporting requirements, while essential to a well-functioning, responsible system of research, have led over time to an environment wherein a significant percentage of an investigator’s time is spent complying with regulations, taking valuable time away from research, education, and scholarship… “

Optimizing the Nation’s Investment in Academic Research: A New Regulatory Framework for the 21st Century

“When effective and well coordinated, federal regulation protects the government, universities, investigators, and the public and helps prevent fraud, waste, and abuse. Today, however, there is a growing concern that the unintended cumulative effect of federal regulations undercuts the productivity of the research enterprise and diminishes the return on the federal investment in research.”

Overarching Findings

1. Effective regulation is essential to the overall health of the research enterprise, protecting both national investment and the various parties in the partnership:• Research participants• Investigators• Universities• Agencies


2. Continuing expansion of the federal regulatory system and its ever-growing requirements are diminishing the effectiveness of the nation’s research investment:• Investigators’ time is directed away from research

and training• Investigators’ time is directed toward overlapping

and incongruent administrative matters


3. Well-intended efforts of federal regulations to address important issues of accountability and performance associated with scientific integrity and the well-being of the people involved in research “often result in unintended consequences that needlessly encumber the nation’s investment in research.”


4. Many regulations fail to recognize the significant diversity of academic research institutions:• Geographic location• Public or private• Size• Financial and physical resources• Research capabilityThis diversity translates into widely varying capabilities to respond to increasing and overlapping regulations.


5. When regulations are inconsistent, duplicative, or unclear, universities may place additional requirements on research investigators, thereby diminishing the effectiveness of the national investment in research.


6. Some academic research institutions have failed to respond appropriately to investigators’ transgressions or failed to use effectively the range of tools available to create an environment that strongly discourages behaviors in conflict with the standards and norms of the scientific community.

Recommendation One

The regulatory regime … governing federally funded academic research should be critically reexamined and recalibrated• Direct federal agencies following the Common Rule

to institute a risk-stratified system of human subjects protections that substantially reduces regulatory burden on minimal-risk research.

• Direct agencies to align and harmonize their regulations and definitions concerning the protection of human subjects.

• Congress should instruct the US DHHS to ensure that research involving biospecimens is eligible for a waiver or modification of informed consent.

Recommendation Two

To advance the government-academic research partnership, research institutions must demand the highest standards in institutional and individual behavior.

Recommendation Three

Inspectors General responsibilities should be rebalanced so that appropriate consideration is given both to uncovering waste, fraud, and abuse and to advising on economy, efficiency, and effectiveness.

Recommendation Four

Create a new mechanism, to include an active public-private forum and a designated official within government, to foster a more effective conception, development, and harmonization of research policies: Regulations should be harmonized across all federal

research funding agencies Before proposing any new regulation, an agency

should determine whether the problem that the regulation is intended to address is systemic

Minor issues should not become cause for disproportionate regulatory response

Regulations should be framed with the recognition that risk levels will never be reduced to zero

Recommendation Four

New regulations should be piloted at a small number of institutions to determine whether they efficiently accomplish the intent of regulation.

Academic research institutions must take timely and appropriate action against members of their communities who violate the values of trust and integrity to which community standards and federal funding of research require strict adherence.

How Can We Safeguard Archived Pathology Resources?

Data confidentiality, integrity, security, and controlled access to information should be ensured.

The level of security should coincide with the sensitivity of the information.

Researchers, Institutional Review Boards (IRBs), and institutions providing support for research endeavors should oversee the consent requirement, maintenance, access, and use of archived pathology resources.


Investigative pathologists are well-positioned to assume a leadership role in addressing the concerns involved with archived pathology specimens, providing stewardship and ensuring that these specimens remain a vital resource.


Unless specific donor consent is granted, all individuals working with archived pathology samples should not attempt to identify previously unidentified (or anonymized) samples. Do not use advanced technologies to identify a

donor Do not access a research database for purposes of

identification


All individuals working with archived pathology samples should receive training in the applicable regulations. Health Information Technology for Economic and

Clinical Health Act (HITECH) Health Insurance Portability and Accountability Act

(HIPAA) Common Rule


Ethically conducted research is good research and helps build public

confidence to support participation in research and consent for research use

of biospecimens.Tenets of the Belmont Report

AutonomyBeneficence

Justice

Disruptive Influences on Research in Academic Pathology Departments Biospecimens and Consent and 2xR 3, Oh My! University of Michigan November 16, 2015.

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