Responsible Conduct of ResearchSpring-1, 2014

Delia Y. Wolf, MD, JD, MSCI

Associate Dean

Regulatory Affairs and Research Compliance

Harvard School of Public Health (HSPH)

Email: dywolf@hsph.harvard.edu

RCR Lecture-1, January 31 2014

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Topics to be Covered Regulations and guidelines governing research

involving human subjects Ethical Principles Definitions Relevant regulations and guidelines governing human

research General responsibilities of the IRB and investigators How to avoid/correct violations

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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Applications of Ethical Principles

PRINCIPLE REQUIREMENTRespect For

PersonsInformedConsent

BeneficenceRisk/Benefit

Ratio

JusticeSubject

Selection

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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

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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 & HMS The Office of Human Research Administration

(OHRA) processes all applications submit by the HSPH/HMS/HSDM 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 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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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!