Current Topics in Human
Subjects Research 2012
Sandra L. Alfano, Pharm.D, CIP
Research Scientist, GIM
Chair, HIC II and IV
December 13, 2012
Objectives



Understand issues leading to problems with
compliance, including lapses in protocol approval, and
the need for clinical trials registration at inception of a
protocol
Be cognizant of issues thought of as ‘hot topics’,
including return of results from laboratory work on
donated tissues, and COI disclosure issues
Be aware of proposed changes to the human subjects
regulations embodied in the recent ‘Advanced Notice
of Proposed Rule Making (ANPRM)
December 13, 2012
Yale University Human Research
Protection Program (HRPP)
Formally implemented in September 2009. Seeks to:
• Create a culture of respect for, and awareness of, the rights
and welfare of human research participants while advancing
scientific knowledge and facilitating the highest quality
research.
• Facilitate compliance of researchers as they conduct research
with the federal regulations, and protection of research
participants.
• Develop new approaches that serve the overarching mission,
such as continuing education and training, ensuring scientific
integrity, tracking and monitoring research activities and
assessing the overall effectiveness of the HRPP.
• Assess the effectiveness and independence of the IRBs.
December 13, 2012
Yale University HRPP
December 13, 2012
Achieved
accreditation December, 2010
Enhanced
website, including all policies,
procedures, forms and guidance:
http://www.yale.edu/hrpp/
Implemented every three year training
requirements
Harmonized COI policy with University’s
Restructured
HICs into team structure
December 13, 2012
Recent compliance issues
Lapses in IRB approval

It is a violation of federal regulation and University
policy to continue to conduct research activities
once IRB approval for a study has lapsed unless
permission is granted by the Yale IRB to continue
research interventions. Such permission will be
granted by the IRB when discontinuing the research
interventions may jeopardize the health or welfare of
a participant.
December 13, 2012
Lapses, cont’d

Under no circumstances can federal funds
be expended on research and researchrelated activities during a lapse period. If the
study is federally funded, you must
immediately contact your Grant and Contract
Administration (GCA) and Grants and
Contract Financial Administration (GCFA)
representatives for more information.
December 13, 2012
Clinical Trial Registries
 Instituted
years ago in an effort to expand
public knowledge of, and access to,
clinical trials
 Clinicaltrials.gov is an example, run by the
NIH/NLM
 Currently over 135,000 studies are
registered, with locations in all 50 states
and 182 countries
December 13, 2012
Clinical Trial Registries

Registration of trial before subject enrollment
 Results posting now required as well
 Differing definitions used by FDA and ICMJE
 FDA required language for consent documents
informing participants that the trial is registered
and that additional information may be obtained
at clinicaltrials.gov
December 13, 2012
Two compliance issues with
registration
 Nationally,
very poor compliance with
posting of results according to
requirements
 Some
Yale researchers report being
denied publication because the trial had
not been registered prior to subject
enrollment
December 13, 2012
FDA definition
 ‘applicable
clinical trial’:
Controlled interventional studies with one or
more arms of drugs, or biologics if the trial
is a controlled clinical investigation, other
than a phase I investigation, of a drug
subject to FDA regulation
For devices, the trial prospectively compares
a device-based intervention against a
control
December 13, 2012
ICMJE definition
 Any
research study that prospectively
assigns human participants or groups of
humans to one or more health-related
interventions to evaluate the effects on
health outcomes

Health-related interventions include any
intervention used to modify a biomedical or
health-related measure including PK and AEs
December 13, 2012
Tissue and/or Data Banking
 Evolving
issues related to informed
consent, privacy, and definition of future
research.
 Attention to when donation is required for
participation versus when it may be
optional.
December 13, 2012
Ethical Issues in Tissue and Data
Banking

Respect for Persons





Beneficence



Informed consent
Autonomy
Withdrawal
Privacy, confidentiality
Mostly indirect or societal benefit
Need to Minimize risk
Justice

Ownership issues
December 13, 2012
Informed consent

Purpose of collection, use and any future
research must be specified
 Access to information



What identifiers will be released
Who will receive the information and
Under what conditions

Where human genetic research is anticipated,
consent must describe consequences
 Conditions whereby subjects may withdraw their
participation: destruction vs anonymization
December 13, 2012
Privacy/Confidentiality
 What
identifiers are linked to samples or
retained in data sets?
 If genetic testing is planned, can identities
really be protected?
 HIPAA RAF is limited to a single purpose
 Government, law enforcement use of DNA
biobanks (Patriot Act, Big Brother)
December 13, 2012
Risks
 Mainly



involve breach of confidentiality
Some public health data bases cite deductive
disclosure risks where releasing 5 data fields (or
more) has the potential to re-identify an
individual.(Add Health, PSI, ARIS/REDS)
Coded sets with coded donor sites may also lead
to deductive disclosure.
Effect on access to or retention of benefits or
entitlements, perceived harm of discrimination or
stigmatization. (health insurance, altered family
relationships, etc.)
December 13, 2012
Ownership issues

Courts seem to say subject forfeits ownership
upon donation (signing informed consent)
(Moore)
 Voluntary withdrawal from the research
(repository) does not equate to directing use or
transferring ownership (Catalona)
 Proprietary rights belong to the subject if cells
are still within the subject (Slavin)
 Bioethicists may be more conservative on the
issue than the general public
December 13, 2012
Unresolved issues
 Return
of information to subjects?
 Re-consent for future uses that were
unanticipated
 When is waiver for future or secondary
use not permissible?
 Tiered consent (how to track?)
 Assent/re-consent at age of majority for
minors
December 13, 2012
Tissue Conclusions
 Evolving
scenario
 Consent albeit broadly written should be
obtained for future research uses
 Put protections in place to minimize risks
 Check with HIPAA Security when storing
and sharing data sets
 Deal with ownership honestly
December 13, 2012
Disclosure of External Interests

Individuals must disclose all interests required
by University policy to the COI Office.

New regulations have prompted the University to
institute a branched policy and branched on-line
disclosure

Mandatory training is now required, and training
has been built into the on-line disclosure
December 13, 2012
Significant Financial Interests
(SFIs)





New PHS regulations used by NIH define an SFI
as income over $5K from a for-profit entity or
stock ownership
Many other entities are using the PHS rules, such
as AHRQ, ACS, AHA, CDC, JDRF
Travel must be disclosed and considered for PHS
NSF still defines SFI as income over $10K from a
for – profit entity
If a researcher has neither PHS or NSF funding,
University threshold is $10K
December 13, 2012
 Individual



profile must be:
Updated at least annually and whenever a
new interest is added, e.g., consulting for
industry or new ownership interests (stock).
On file with COIC BEFORE applying for NIH
funding
Kept current, especially when submitting a
human research protocol to the IRB where
there is a related interest.
December 13, 2012
HIC/COIC Harmonization Efforts
 IRB
will review annual disclosure status of
PI, co-investigator and those obtaining
consent for new studies (non exempt),
 IRB will also review at time of renewal and
when an amendment adds new PI, Co-I or
“responsible person”.
 No more disclosures to IRB, but must note
to PI and IRB, the names of researchers
with protocol-related interests
December 13, 2012
 IRB
will not process the submission when
the PI’s disclosure is expired or is pending.
 When the disclosure of a co-investigator or
person obtaining consent is not current or
is pending, then the person will be
removed from the research team and
cannot take part in the study until the COI
disclosure is updated.
 ENSURE DISCLOSURES ON FILE with
COIC PRIOR TO SUBMITTING TO THE
IRB!
December 13, 2012

IRB assesses the interest and determines if it is
a COI that must be managed


IRB needs to distinguish the risks that may
compromise the protection of subjects, a scientist’s
objectivity or challenge the integrity of the research.
May require a plan to manage, reduce or eliminate
the interest.
December 13, 2012
Disclosing Interests

Is it enough to inform research participants of
the investigator’s financial or potential financial
interests?
 Will disclosing the information to a research
volunteer affect their decision to participate?
 Will it make the process any safer for them?
 Can financial conflicts be managed or reduced
in a way that doesn’t adversely affect patient
safety or influence the objectivity of the research
conclusions?
December 13, 2012
Physician Payments Sunshine
Act
 Applicable
manufacturers of drugs,
devices, biologicals or medical supplies
must report annually to the secretary of
health and human services certain
payments or transfers of value to
physicians or teaching hospitals.
Government would then publish the
reported data on a public website
December 13, 2012
IOM Initiative

Creation of a harmonized conflict of interest
disclosure system that will be web-based to
allow a single, flexible mechanism allowing
physicians and researchers to disclose, and
institutions and relevant entities to request,
specific information
 Business plan being developed, with
deployment expected late 2013 or early 2014
JAMA 2012; 308:2093-4
December 13, 2012
Advance Notice of Proposed
Rule Making (ANPRM)
 First
revision of human subjects protection
regulations since they were written in 1981
 Advance
notice published Summer of
2011 for comment
 Next
step in process is still awaited
December 13, 2012
 Be
careful what you wish for:
It might come true!
December 13, 2012
Substantive changes proposed
 Good
news scenario: improvements on
several fronts that may lead to increased
efficiency (such as not requiring continuing
review for studies involving minimal risk)
 Bad
news scenario: some proposals not
thought through carefully and can have
significant unplanned repercussions
December 13, 2012
Broad categories of proposed
changes
 Risk
based protections: calibrate the type
of review to the risk posed by the
research, with resultant elimination of the
need for annual review of minimal risk
studies
 Revamp of informed consent, including
requiring consent up front for all samples
 Mandate use of a single IRB for multisite
studies
December 13, 2012
Single IRB for multisite studies





Great example of inadequate conceptualization
of entire issue
No universal model proposed/adapted
Resultant myriad of models which all differ
significantly and require new systems to be put
in place
Researchers will need to understand and
comply with multiple systems
Yale currently deals with 5 different models
December 13, 2012
 Strengthening
data protection
 Streamlining adverse event reporting and
cataloging via a website
 Extension of Federal Regulations to all
human subjects research regardless of
funding source
 Harmonization of guidance from myriad
federal agencies
December 13, 2012
Conclusions
 Conflicts
of interest, and tissue banking,
are evolving topics
 Lapses and clinical trials registration
present challenges for compliance
 Evolving landscape in human subjects
protections
December 13, 2012