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Responsible Conduct of ResearchFall-1, 2012
Delia Y. Wolf, MD, JD, MSCI
Assistant Dean, Regulatory AffairsDirector, Human Research AdministrationAssistant Professor, Health Policy and ManagementHarvard School of Public Health
Email: [email protected]
Website: www.hsph.harvard.edu/ohra
RCR Lecture-1, September 7, 2012
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Topics to be Covered Regulations and guidelines governing research
involving human subjects Historical background Ethical Principles Definitions Relevant regulations and guidelines governing human
research General responsibilities of the IRB and investigators How to avoid/correct violations
Collaborative research
Human Research andRegulatory RequirementsCase 1: For his dissertation project in psychology, Antonio is
studying new approaches to strengthen memory. He can apply these techniques to create interactive Web-based instructional modules. He plans to test these modules with students in a general psychology course, for which he is a teaching assistant. He expects that student volunteers who use the modules will subsequently perform better on examinations than other students. He hopes to publish the results in a conference proceeding on research in learning…1. Should Antonio seek IRB approval for his project? 2. If yes, what type of IRB review would be appropriate?3. Can this protocol be exempted? Why or why not?4. Do student volunteers need to give formal informed consent? If so,
what information needs to be included in the consent document?
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Past Scandals and Tragedies
Nazi human experimentation after WWII Brooklyn Jewish Chronic Disease Hospital
case in 1963 – inject live cancer cells into elderly patients without their consent
Willowbrook study – exposed children and adolescents with disabilities to hepatitis at a New York state facility
The Tuskegee Syphilis study – over 400 men enrolled
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Recent Scandals & Tragedies
Jesse Gelsinger, September 1999 Gene Therapy Study at U-PENN
Ellen Roche, May 2001 Johns Hopkins Medical Institution
“Administrative failings”, 1999 Duke University IRB did not keep
adequate documentation
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Landmark Documents The Nuremberg Code of 1947
“Permissible Medical Experiments” Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No.10, 1949
Declaration of Helsinki World medical association (1964, ‘75, ‘83, ‘89, ‘96,
’00, ‘08) Belmont Report of 1979
Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, DHEW, April, 1979
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Ethical Principles & Regulations
Ethical Principles
Federal Regulations
BASIS
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Relevant Regulations
Code of Federal Regulations (CFR) Title 45 Part 46: Protection of Human Subjects
CFR 21, Parts 50 Protection of Human Subjects 56 Institutional Review Boards 312 Investigational new drug 812 Investigational device exemptions
Applications of Ethical Principles
PRINCIPLE REQUIREMENTRespect For
PersonsInformedConsent
BeneficenceRisk/Benefit
Ratio
JusticeSubject
Selection
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Know Your ABC’s DHHS: Dept. of Health and Human Services OHRP: Office for Human Research
Protection NIH: National Institutes of Health FWA: Federal Wide Assurance FR: Federal Register ICH: International Conference on
Harmonisation GCP: Good Clinical Practice
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Know Your ABC’s (cont.)
CFR:Code of Federal Regulations IND: Investigational New Drug NDA: New Drug Application IDE: Investigational Device
Exemption DSMB: Data Safety and Monitoring
Board IB: Investigator’s Brochure
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Definitions
RESEARCH: A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge
HUMAN SUBJECTS: A living individual about whom an investigator conducting research obtains data through intervention or interaction with the individual, or identifiable private information
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Definitions (cont.) PRIVATE INFORMATION: information about
behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (i.e., medical records).
INTERACTION: Communication or interpersonal contact between investigator and subject.
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Definitions (cont.) INTERVENTION: both physical procedures by
which data are gathered (i.e., blood draw, x-ray) and manipulations of the subject or the subject's environment that are performed for research purposes.
IRB (Institutional Review Board): A specially constituted review body established or designated by an entity to protect the welfare of human subjects recruited to participate in biomedical or behavioral research.
Definitions (cont.) MINIMAL RISK: the probability and magnitude of
harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests
ANONYMOUS: Samples or data that were obtained and stored without any identification that may link to a specific individual. Anonymous samples may have population information (e.g., the samples may come from patients with diabetes)
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Definitions (cont.) ANONYMIZED/DE-IDENTIFIED: Samples or data
that may have been acquired from identified humans subjects, but all identifiers or codes have been removed and destroyed
CODED: Samples labeled with a code (e.g., a number), rather than a person’s name or other personal identifier. Such code can be traced or linked back to sample donor by an investigator, who usually keeps the key to the code. As long as a link exists, data are considered indirectly identifiable and therefore, not anonymized
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IRB Membership At least five members, with varying backgrounds No IRB consists entirely of men or women At least one scientist, one non-scientist and one
non-affiliated member No IRB may have a member participate in the
IRB's initial or continuing review of any project in which the member has a conflicting interest, except to provide information requested by the IRB
Use of consultant is permissible, but such person may not vote
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IRB Authority
To approve, require modification in research to secure approval, defer action, or disapprove all research activities, including proposed changes in ongoing, previously approved, human subject research.
To suspend or terminate the approval of ongoing, previously approved research that is not being conducted in accordance with the IRB's requirements or that has been associated with unexpected, serious harm to subjects.
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IRB Responsibilities Conducting initial review Conducting continuing review Notifying the investigators about IRB decisions Determining which studies require review more
often than annually Review and approval of changes in research
activities Determining which device studies pose significant
or non-significant risk
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IRB Responsibilities (Cont.) Ensuring that changes in approved research are not
initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards to subjects
Ensuring prompt reporting to appropriate institutional officials, regulatory agencies and funding sources of: unanticipated problems involving risks to subjects or
others serious or continuing noncompliance with federal
regulations suspension or termination of IRB approval
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Criteria for IRB Approval
Risks to subjects are minimized Risks are reasonable in relation to anticipated benefits Selection of subjects is equitable Informed consent is sought from each subject Informed consent is appropriately documented Data collection is monitored to ensure subject safety Privacy and confidentiality of subjects is protected Additional safeguards are included for vulnerable
populations
Types of IRB Review
Full board review Initial and subsequent continuing review Others (i.e., major amendment, unanticipated
problem, serious or continuing non-compliance)
Expedited review – by IRB/IEC Chairs and/or designees Initial and subsequent continuing review Exemption determination (per US federal regulations) Amendment (minor changes to the protocol) Other reports from investigators, i.e., minor protocol
violations, adverse events
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Full Review a majority of the members of the Committee
must be present and at least one nonscientist must be present
if the required number of members is lost during a meeting, no action may be taken until it is restored
in order for research to be approved, it must receive the approval of a majority of those members present at the meeting
consultants with expertise in special areas may attend meeting, but they may not vote
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Full Review at HSPH The Office of Human Research Administration
(OHRA) processes all applications submit by the HSPH researchers: Deadline: completed submission must be
received by OHRA three weeks before the meeting date (www.hsph.harvard.edu/ohra)
Each submission under review is assigned to a Primary and a Secondary Reviewer
Although the IRB may request that an investigator attend a meeting or be available via phone. The investigator may not be present for the discussion and vote
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Expedited Review
An IRB may use the expedited review procedure to review either or both of the following: some or all of the research appearing on
the F.R. list and found by the reviewer(s) to involve no more than minimal risk,
minor changes in previously approved research during the period (of one year or less) for which approval is authorized.
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Expedited Review (cont.) Expedited review may be carried out by the IRB
chair or by one or more designated IRB members All of the requirements for IRB approval of
research apply equally to expedited review. Expedited review should not be viewed as a less rigorous review
Under expedited review, the reviewers may exercise all of the authorities of the IRB, except that the reviewers may not disapprove the research
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Expedited Review Categories Blood collection – within limits (i.e. from healthy, non-
pregnant adults who weigh at least 110 pounds) Prospective collection of biological specimens for
research purposes by noninvasive means, i.e. hair and nail clippings, buccal swab
Collection of data through noninvasive procedures such as moderate exercise, MRI, EKG
Research on existing data, specimens, materials collected solely for NON-research purposes
Collection of data from voice, video, digital, or image recordings made for research purposes
Research on Individual/group characteristics/behavior
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Expedited Review Categories Continuing review where
the research is permanently closed to the enrollment of new subjects; all subjects have completed all research-related interventions; and the research remains active only for long-term follow-up of subjects; or
no subjects have been enrolled and no additional risks have been identified; or
the remaining research activities are limited to data analysis, or
Other seven categories do NOT apply, BUT IRB determined and documented at a convened
meeting that the research involves no more than minimal risk
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Exemptions Determination Under Federal regulations, certain categories of
activity are considered human subjects research, but may be declared exempt from IRB review
Exemptions, however, must be granted by the IRB Chairperson or designee by reviewing the Exemption Application submitted by the principal investigator
The principal investigator may not make these determinations
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Exemption Determination
Category #1 The activities are normal educational practices
Practice would be expected to go on anyway Randomized designs/cross-over designs are suspect
The setting is an established or commonly accepted educational setting Schools, medical offices, hospitals, boot camps are
established or commonly accepted educational settings
Country fairs, shopping malls are not established or commonly accepted educational settings
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Exemption Determination (cont.)
Category #2 Use of educational tests, survey procedures,
interview procedures (i.e. focus groups) or observation of public behavior – no identifiers recorded
If human subjects can be identified, directly or through identifiers linked to the subjects, any disclosure of the human subjects' responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, or reputation
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Exemption Determination (cont.)
Category #4 Research involving the collection or study of
existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or recorded with no identifiers (no links) Examples of links to identifiers make a study not
exempt: Hospital number Student ID Phone number
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Exemption Determination (cont.)
Category #6 Taste and food quality evaluation and
consumer acceptance studies, if wholesome foods without additives are
consumed or if a food is consumed that contains a food
ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by relevant government agencies
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IRB Review Actions Approval
No additional action required
Require Modification The IRB provides the investigator with specific
modifications to study-related materials
Investigator’s response can be reviewed by an IRB Chair
or his/her designee
The investigator may not start any study-related
activity until all modifications required by the IRB are
made AND the IRB final approval is granted
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Deferral The IRB needs additional information or
clarification from the investigator If the research was initially reviewed by the full
board, the PI's response and revised materials must be reviewed at a subsequent convened meeting
Disapproval The Investigator may not re-submit the same
protocol for review
IRB Review Actions (cont.)
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Investigator Responsibilities Assuring IRB review and approval
Obtaining informed consent
Financial disclosure
Conducting study according to signed investigator statement, protocol, and applicable regulations and institutional requirements
Controlling of investigational drugs/devices
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IRB Review and Approval
No study activity can be initiated without IRB
final approval
Conducting research in accordance with IRB-
approved protocol
Continuing review and approval by the IRB
Implementing amendment to the protocol only
after receiving IRB approval
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Informed Consent
Obtaining INFORMED consent from each subjects
Elements of informed consent Eight basic elements Six additional elements
Documentation of informed consent Sign and date A signed and dated copy to each subject
Elements of Informed Consent
1) a statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental;
2) a description of any reasonably foreseeable risks or discomforts to the subject;
3) a description of any benefits to the subject or to others which may reasonably be expected from the research;
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Elements of Informed Consent4) a disclosure of appropriate alternative procedures
or courses of treatment, if any, that might be advantageous to the subject;
5) a statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained;
6) for research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained;
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Elements of Informed Consent7) an explanation of whom to contact for answers to
pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject; and
8) a statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.
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Proper Study Conduct Selecting qualified investigators/study staff Conducting study according to protocol
Obtaining protocol exception from the IRB and sponsor Reporting protocol violations to IRB and sponsor
Ensuring proper record keeping and retention Investigator reports
Progress reports Safety reports/AE reports Final report Financial disclosure
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Control of investigational products
An investigator shall administer/use the investigational drug/device only to subjects under the investigator’s personal supervision
An investigator must not supply an investigational drug/device to any unauthorized person
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Why Do We Care?
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Common Violations/Deficiencies
Informed consent
Investigator responsibilities
Protocol deviations
Study records
IRB approval
Regulatory documentation
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Warning Letter Citations “Subject signed the consent form on …; however, the
witness signed the consent on [redacted].” “You did not ensure that the witness dated the signature.” “Subjects signing the informed consent in most cases did
not complete dates. It appears that the study coordinator…completed the date.”
“The original consent forms could not be located for 18…subjects enrolled in the study. Copies were available in study binders and subject charts.”
“You failed to provide study subjects with a copy of their signed informed consent document.”
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Warning Letter Citations “You did not personally conduct or supervise this study.” “You misrepresented your presence at the institution by
signing and dating source documents and consent forms on days you were, in fact, absent from the institution.”
“Staff who were delegated the authority to perform certain functions were not adequately credentialed, trained, or monitored.”
“An ultrasound was not done at six months for subject.” “You did not conduct certain follow up visits or document
efforts to locate missing subjects.”
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Warning Letter Citations “There is no record of who administered the study drug…
Without a record of who administered the study drug, you cannot assure that these injections were performed by a member of the blinded study team.”
“Source data for various assessments could not be located.” “The CRF contained blank fields.” “Records…were written in pencil, and many entries are
illegible.” “There is no documentation of the name or initials of the
person making entries in the records.” “All medical records/case reports audited had numerous
write-over corrections which lacked dates and initials.”
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Warning Letter Citations “Your IRB requires that a written report of the death of
any research subject be made within 5 business days…five or more subject deaths have not been reported to the IRB.”
“Revised case report forms identifying additional data to be collected…, for which IRB approval was not documented, were used after initiation of the study.”
“The sponsor provided a log sheet, on which all study personnel are required to provide their signature, initials, title, responsibility for the study, and start and stop dates. The log is incomplete in that the start and stop dates were not recorded for several of the study personnel.”
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Avoid and Correct Violations
Informed consent Do not date for subjects All individuals must sign and date the consent
form for themselves If someone forgets to date the consent form,
write a signed and dated note-to-file explaining how and when the subject was consented
Write a signed and dated note-to-file explaining why dates are different
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Avoid and Correct Violations
Informed consent Always give subjects a copy of the signed and
dated consent form
Document what was done
Always maintain the original signed and dated
consent form in the subject file
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Avoid and Correct Violations
Investigator Responsibilities - Stay involved
Only delegate responsibilities to appropriate individuals who are qualified and trained
Maintain documentation of training for all staff
ALL study staff must be approved by the IRB
Take credit – document investigator's involvement, including monitoring activities
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Avoid and Correct Violations
Protocol Deviations - Obtain protocol exception prior to
implementation
Report all protocol violations to the IRB
Develop and implement an adequate corrective action plan to avoid future violations
Modify the protocol if necessary
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Avoid and Correct Violations
Study Records All information entered on a CRF or data collection
sheet must be supported by source documents
A signed and dated note-to-file can be used to explain: How information was obtained
Who obtained information
Any discrepancies
Missing or incomplete data
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Avoid and Correct Violations
IRB Requirements/Approval Obtain IRB approval prior to initiating study
Obtain IRB approval for any changes made during the course of the study
Do not allow study to lapse. Submit continuing review prior to IRB-approval expiration
Report all adverse events according to institutional reporting requirements
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Key to Research Compliance
Knowing what research is subject to regulation
Understanding applicable rules/requirements
Following the rules and approved protocol
Getting appropriate training
Accepting continuing responsibility for compliance through all stages of a project
Document, document, document
Report, report, report
Utilize institutional resources, such as IRB!
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Collaborative Research
Types of collaborative research
Points to consider before, during and
after collaboration
Case studies
Types of Collaborative Research
Within institution
With institutions/hospitals
Multicenter – within the US
Multicenter – transnational
Collaborations with industry
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Points to Consider Before any work is undertaken
Clear understanding of the nature of the collaboration Roles and responsibilities
Sufficient resources Time, space
Written agreement (between/among collaborators) Who does what Who owns what Criteria to identify and rank contributing authors
Necessary review and approval from institution Grants/contracts Technology transfer IRB/IACUC
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Points to Consider (cont.) During the course of collaboration
Following research plan/study protocol Communication
Report Progress Share findings Discuss problems
Documentation If it is not documented, it is not done!
Training and supervision Verification Good record keeping
Time and effort
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Points to Consider (cont.) After the completion of a collaborative
research project Submit final report/closure to relevant
offices at researcher’s institution IRB office
Be aware if record keeping requirements Institutional requirements Sponsor requirements Government agency requirements
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Case A Amber, Ben and Carol have just received funding from a small
pharmaceutical company to test one of its imaging agent. Amber is a neuro-radiologist at BIDMC, who will be the PI, as
well as the IND holder, Ben is a psychiatrist at MGH, and Carol is a biostatistician at HSPH. All three will serve as co-investigators.
Study is going to be conducted at BIDMC. Both Amber and Ben will be interact with research participants; Carol will not have direct contact with participants, but will have access to participants’ identifiable information. Which office(s) will they have to deal with Do all three need to get IRB approval from each of his/her
institution Do they need an agreement among themselves? If so, what should
be included in the agreement?
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Case B Dr. D is a biostatistician from HSPH. He is the
PI for a data coordinating center that oversees and analyzes all data collected from a multi-canter clinical trial involving 12 sites in the US and 10 sites outside of the US. What are Dr. D’s responsibilities in terms of meeting
regulatory requirement? Obtaining IRB approval Oversight of research conduct Reporting obligations
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Case C Dr. M is the overall PI for a multi-center Vitamin
A supplementation clinical trial that is sponsored by NIH. She is a faculty member at HSPH, but no study activities will be conducted in the US. There are a total of three sites in India, Tanzania and Botswana. Does Dr. M need to get HSPH IRB approval to work on
the study? Which country’s rules should be followed for
regulatory oversight? Since she only visits each site once a year, how can
she fulfill her responsibility as a PI?
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