Subpart A Subcommittee
(SAS)
Elizabeth Bankert and Daniel Nelson
SAS Co-Chairs
with David Borasky, SAS Member
Presentation to the
Secretary’s Advisory Committee on Human Research Protections
(SACHRP)
October 19, 2010
Outline of Today’s Presentation
• Subcommittee charge and
membership
• Topic for consideration at this
meeting
• Biospecimen FAQs one loose end
• Update on ongoing work
• Informed consent Form & Process
Charge to the Subcommittee
• Review and assess
• All provisions of Subpart A of 45 CFR 46
• Relevant OHRP guidance documents
• Based on this review and assessment
• Develop recommendations for consideration by
SACHRP in three categories:
• Interpretation of specific Subpart A provisions
• Development of new or modification of existing OHRP
guidance
• Possible revisions to Subpart A
Based on memo to Subcommittee from E. Prentice, Chair of SACHRP, 1/14/05
and subsequent discussion by SACHRP
Charge to the Subcommittee
• Goals
• Enhance protection of human subjects
• Reduce regulatory burdens that do not
contribute to the protection of human
subjects
• Promote scientifically and ethically valid
research
Based on memo to Subcommittee from E. Prentice, Chair of SACHRP, 1/14/05
and subsequent discussion by SACHRP
Subpart A Subcommittee
Present Members
• Elizabeth Bankert,* Dartmouth College
• Laura Beskow, Duke University
• David Borasky, RTI International
• Bruce Gordon, University of Nebraska Medical Center
• Susan Kornetsky, Children’s Hospital Boston
• Gigi McMillan, We Can Pediatric Brain Tumor Network
• Daniel Nelson,* University of North Carolina - Chapel Hill
• Susan Rose, University of Southern California
• Michele Russell-Einhorn, Dana Farber Cancer Institute
• Ada Sue Selwitz, University of Kentucky
• With welcome input from
• SACHRP members who choose to affiliate
• Ex officio reps of Common Rule agencies
*co-chairs
Subpart A Subcommittee
Past Members
• Ricky Bluthenthal, RAND Corporation
• Gary Chadwick, University of Rochester
• Felix Gyi, Chesapeake Research Review, Inc
• Isaac Hopkins, Community Research Advocate (UMDNJ) †
• Nancy Jones, Wake Forest University NIH
• Moira Keane, University of Minnesota
• Ernest Prentice, University of Nebraska Medical Center
• Thomas Puglisi, PriceWaterhouse Coopers VA
• Lorna Rhodes, University of Washington
• David Strauss, New York State Psychiatric Institute
• Not shown are multiple SACHRP members who chose to
affiliate with SAS while members of parent committee
Subcommittee Meetings
• January 18, 2005 via teleconference • August 16-17, 2007 in Arlington, VA
• February 14, 2005 in Alexandria, VA • October 3, 2007 via teleconference
• May 20, 2005 via teleconference • February 21, 2008 in Rockville, MD
• July 20-21, 2005 in Alexandria, VA • May 15-16, 2008 in Rockville, MD
• October 4, 2005 via teleconference • September 22-23, 2008 in Rockville, MD
• January 9, 2006 via teleconference • January 26-27, 2009 in Rockville, MD
• January 30-31, 2006 in Rockville, MD • June 8 & 30, 2009 via teleconference
• May 11-12, 2006 in Gaithersburg, MD • July 8, 2009 via teleconference
• September 11, 2006 via teleconference • Sept 1 & 30, 2009 via teleconference
• October 4, 2006 via teleconference • Oct 21, 2009 via teleconference
• February 15-16, 2007 in Arlington, VA • Feb 24 & 26, 2010 via teleconference
(with retreat)
• Jun 1-2, 2010 in Rockville, MD
• March 9, 2007 via teleconference
• Jun 30, 2010 via teleconference
• May 31-June 1, 2007 in Arlington, VA
• Sept 27, 2010 via teleconference
• July 16, 2007 via teleconference
Supplemented by Working Group calls and e-mails
Secretarial Letters Incorporating SAS Recommendations
• 5th SACHRP letter to Secretary Leavitt 3/14/07
• Recommendations approved 2005-2006
• Continuing Review Federal Register notice on 11/06/09
• Expedited Review Federal Register notice on 10/26/07
• 6th SACHRP letter to Secretary Leavitt 6/15/07
• Recommendations approved March 2007
• Required Training Federal Register notice on 07/01/08
• 7th SACHRP letter to Secretary Leavitt 1/31/08
• Recommendations approved March & July 2007
• Waiver of Informed Consent
• Minimal Risk Analytical framework and examples
• 8th SACHRP letter to Secretary Leavitt 9/18/08
• Recommendations approved Oct 2007, March & July 2008
• Exemptions
• Alternative models of IRB review
• IRB membership rosters
• Waiver of documentation of informed consent
• Institutional Officials
• American Indians and Alaska Natives
• (Letter also addressed disaster research, and systems-level commentary)
• 10th SACHRP letter to Secretary Sebelius 7/15/09
• Recommendations approved March 2009
• Designation of IRBs within FWA
• 11th SACHRP letter to Secretary Sebelius 3/24/10
• Reaffirmation of previous rec on required education, after public RFI
Subpart A Subcommittee (SAS) Report and
Recommendations to SACHRP
Questions Relating to
Informed Consent and
Research Use of
Biospecimens
Biospecimen FAQs
Over the course of several SACHRP meetings, the
full set of FAQs on this topic (#1- 28) have been
presented and approved, modified or deleted.
While these recommendations have yet to be
finalized via Secretarial letter, one issue has
already arisen with regard to the formatting of a
single FAQ. This issue only is being revisited
today, for the sake of clarification.
Background on FAQ #3
• FAQ #3 described a scenario where researchers proposed to use
specimens for a purpose that was not compatible with the original
consent. This was a particularly controversial scenario, which
received much discussion.
• At the SACHRP meeting on October 27, 2009, the majority of the
response (the first 2 of 3 bullets) was approved, but the 3rd bullet
was returned for further consideration on the following day, after a
SACHRP member offered to rework that part of the response.
• On October 28, 2009, the 3rd bullet was reintroduced, discussed
and approved.
Background on FAQ #3
(continued)
• Despite being considered as “a separate recommendation” (per the
minutes), the 3rd bullet did not truly stand alone, based as it was on the
identical scenario described in FAQ #3. Nevertheless, when
documented in the archival compilation of all FAQs, the original
scenario was repeated as FAQ #3 and FAQ #3A.
• Because the scenarios in FAQ #3 and FAQ #3A are identical, this is
already leading to confusion among readers, and even among some
SACHRP members who are familiar with this background. The
separation of the two answers is, to a large extent, an artifact of the way
this scenario was resolved on two separate days. In reality, the
answers are parts of a whole and do not entirely make sense when
viewed on their own.
FAQ #3
(as revised and approved)
• Blood samples were obtained for research purposes, with
informed consent of the subjects, and the original study has
been completed. The samples remain under the control of
the original investigator. Another investigator wants to use
a portion of the remaining samples to perform research
completely unrelated to the original study.
• If the original consent stated that “…your sample will only
be used for research on colon cancer,” but the secondary
user is interested in studying Alzheimer’s disease, can the
samples still be used if provided to the secondary user in a
coded fashion?
FAQ #3 RESPONSE
(as revised and approved)
• The secondary use of de-identified or coded samples is not research
involving human subjects under 45 CFR 46. Nevertheless, the
original investigator and his/her institution have made an agreement
with the subjects about use of their specimens, and have an obligation
to honor that agreement.
• Institutions should establish mechanisms to determine whether
secondary uses are compatible with the original informed consent;
this could involve consultation with the IRB that approved the original
research, or review by some other body designated for these
purposes. Coding should not be used as a means to circumvent the
original terms of consent. This is ethically problematic, even if the
original project is over and the secondary use is no longer considered
to be research involving human subjects.
FAQ #3 COMBINED RESPONSE
(REVISED ON 10-19-2010)
• The secondary use of de-identified or coded samples is not research involving
human subjects under 45 CFR 46. In the case where secondary use of tissue
samples is not compatible with the original consent for tissues that are de-
identified, coded, or anonymized and are not readily identifiable, the samples
are no longer subject to human subject regulations. Thus, there is no regulatory
violation. Nevertheless, the original investigator and his/her institution have
made an agreement with the subjects about use of their specimens, and have
an obligation to honor that agreement.
• Institutions should establish mechanisms to determine whether secondary uses
are compatible with the original informed consent; this could involve
consultation with the IRB that approved the original research, or review by some
other body designated for these purposes. Coding should not be used as a
means to circumvent the original terms of consent. This is ethically problematic,
even if the original project is over and the secondary use is no longer
considered to be research involving human subjects.
FAQ #3A
(NOTE: Identical to FAQ #3)
• Blood samples were obtained for research purposes, with
informed consent of the subjects, and the original study has
been completed. The samples remain under the control of
the original investigator. Another investigator wants to use
a portion of the remaining samples to perform research
completely unrelated to the original study.
• If the original consent stated that “…your sample will only
be used for research on colon cancer,” but the secondary
user is interested in studying Alzheimer’s disease, can the
samples still be used if provided to the secondary user in a
coded fashion?
FAQ #3A RESPONSE
(as revised and approved)
• In the case where secondary use of tissue samples is not
compatible with the original consent for tissues that are
de-identified, coded, or anonymized and are not readily
identifiable, the samples are no longer subject to human
subject regulations. Thus, there is no regulatory violation.
• MERGED WITH FIRST RESPONSE
RECOMMENDATION
Regarding the “packaging” of FAQ #3:
• In order to minimize confusion by future
readers of the SACHRP FAQs on research
use of biospecimens, it is proposed that the
scenarios currently labeled and presented
individually as FAQ #3 and FAQ #3A be
recombined into a single FAQ, with a multi-part
response.
SAS WORK IN PROGRESS:
Improving the Form and
Process of Informed
Consent
Problem Statement
The goal of the informed consent process is to
ensure an individual’s voluntary informed
decision to participate in research. Although the
regulations that govern informed consent are
designed to promote flexibility and the basic and
additional elements of consent have remained
unchanged, the level of detail provided in
consent forms has grown steadily since the
regulations were enacted.
Problem Statement (2)
Current approaches to consent forms and
processes are falling short of the goal of promoting
voluntary decision making based on adequate
understanding. Anecdotal and empirical evidence
indicates that potential participants may fail to
understand critical aspects of the research, and
that an overemphasis on the inclusion of detail has
led to lengthy and complex documents, a lack of
attention to process, and problems with
comprehension.
Problem Statement (3)
Factors that contribute to the problem include:
• IRB review of consent documents that is increasingly focused
on editorial review rather than a more meaningful review of
the process by which consent will be obtained;
• Form has become the catch-all vehicle for related information
that may not be central to the decision to participate (e.g.,
HIPAA; GINA; protocol registries; sponsor and institutional
liability concerns);
• Over-interpretation of regulatory requirements combined with
a fear of omitting important information;
• Current education on human subjects protections typically
stops short of training investigators and their staff on how to
promote and implement an effective informed consent
process.
SAS Work to Date
Review discussions about informed consent in
federal register documents no big surprises
• IC form is only a part of the larger process
• “The consent form, thus, should not be viewed as an
end point.”
• “The ‘form’ itself cannot substitute for the
communicative process that it represents….”
• Language should be “understandable”
• “The agency already requires consent documents to
describe, in language that is understandable to
subjects, all relevant information about the study.”
SAS Work to Date (2)
Review the current informed consent regulations
(45 CFR 116 & 117)
• Are the regulations clear and do they IRBs with
provide sufficient flexibility?
• 46.116(a)(4) – appropriate alternative procedures or
courses of treatment: When the only alternative is not
to participate? Off-label use?
• 46.116(a)(6) – research-related injury: Applicability to
non-physical risks, i.e., when the main risk is to
privacy/confidentiality, is this section supposed to
apply somehow?
SAS Work to Date (3)
Review the current informed consent regulations
(45 CFR 116 & 117)
• 46.116(b) – optional elements: Not immediately clear
when inclusion of these elements would be appropriate
and when not appropriate.
• 46.116(d)(3) – waiver/alteration: The “could not
practicably be carried out” criterion is not commonly
understood Many IRBs default to leaving unnecessary
information in the form because difficult to argue that the
research “could not practicably be carried out” without
the waiver or alteration.
SAS Work to Date (4)
Identify words/phrases in the regs that might
require clarification, guidance, etc?
• “Language understandable to the subject”
• Is this about translations or need to describe things in
non-technical terms?
• “legally effective”
• Does this mean that the IC form is a contract? What
is the legal status of IC?
SAS Work to Date (5)
Review of existing OHRP guidance on Informed
Consent
• Emergency Research (‘96)
• Exculpatory Language (‘96)
• Informed Consent Tips (‘93)
• Informed Consent Checklist (‘98)
• Informed Consent, Legally Effective and Prospectively
Obtained (‘93)
• Informed Consent, Non-English Speakers (’95)
• Informed Consent Requirements for In Vitro Medical
Device Clinical Investigations Conducted Under FDA’s
Interim Final Rule at 21 CFR 50.23(e) (‘06)
Review of existing OHRP Informed Consent FAQs
SAS Work to Date (6)
Conclusions from review of guidance and FAQs
• Generally clear, well-written
• Many answer the questions by quoting the regulations
• Others provide useful model language (e.g.,
exculpatory language)
• Some guidance documents appear quite dated (e.g.,
OPRR, MPAs)
• May be a need for additional guidance or FAQs on
issues/topics identified by SAS
SAS To-Do List
• Review FDA guidance (e.g., information sheets;
supervisory responsibilities)
• Identify common misperceptions that impact
consent form and process
• Catalog extra-regulatory information that ends up in
informed consent documents
• Misinterpretations that become “requirements” by
IRBs
• Toolkit repository for information and materials
that were developed to improve the consent
form and process
SAS Next Steps
• Complete the To-Do list
• Develop recommendations for SACHRP
consideration. Under consideration:
• Convene stakeholders’ meeting on IC
• Training requirement for research staff who obtain IC
• Additional guidance/FAQs on IC topics
• Develop model language / form based on required
elements re-order to emphasize what is most
important; make the form conducive to good process
• Identify and promote best practices for process
Stay tuned... there is always
more to come from SAS!