Responsibility in Human

1
Welcome

• Responsibility in Human
• Subject Research
• IRB-101
• Pat W. Myrick, CCRP, CIP
• Director
• IRB Administration Office of Research and
  Sponsored Programs
• East Tennessee State University

2
Who are the Key Personnel ? . .

• Members of the Institutional Review Board
• The listed Principal Investigator
• Sub- or Co-Investigators named on an Application
  for Research
• All listed investigators on FDA Form 1572 for
  FDA-regulated investigations

3
More key personnel . . .

• A member of the group of key personnel on a Grant
  Application (e.g. NIH)
• A subcontractor or consultant associated with a
  NIH-sponsored study

4
More key personnel . . .

• A clinical Research Coordinator involved in any
  direct interactions with research subjects,
  including involvement in the process whereby
  Informed Consent is acquired from potential
  research subjects
• Departmental Administrative and/or support staff
  directly involved with the completion of required
  forms or the support of thesis and doctoral
  students.

5

• If it isnt documented, it did not happen

6
The Neuremberg Code (1947)

• As part of the verdict in the Nuremberg War
  Crimes Trials of 23 German doctors, the Court
  enumerated some rules for permissible Medical
  Experiments, now known as the Nuremberg Code.
  These rules include
• Voluntary consent
• Benefits outweigh risks
• Ability of the subject to terminate participation

7
Declaration of Helsinki

• Recommendations Guiding Medical Doctors in
  Biomedical Research involving Human Subjects
• Adopted by the 18th World Medical Assembly,
  Helsinky, Finland, 1954 and as revised by the
  World Medical Assembly in Tokyo, Japan in 1975,
  in Venice, Italy in 1983, and in Hong Kong in
  1989 and the 48th General Assembly, Somerset
  West, Republic of South Africa, October 1996,
  Japan 2000
• Concern for the interest of the subject must
  always prevail over the interests of science and
  society.

8
What is an Assurance?

• A promise to conduct the research in compliance
  with the HHS regulations for the protection of
  human subjects of research as found in 45 CFR 46.
• Establishes a partnership to protect the rights
  and welfare of the human subjects of research.
• Identifies a signatory official.

9
What Constitutes Ethical Human Research?

• A valid and important question
• Valid methodology
• Balance between risks/benefits
• Independent ethical review
• Informed consent

10
Fundamental Ethical Constructs Guiding Human
Research (The Belmont Report)

• Beneficence an obligation (do no harm, and
  maximize benefits/minimize harms)
• Justice (who ought to receive the benefits of the
  research and bear its burdens)
• Respect for persons (individuals should be
  treated as autonomous agents and those with
  diminished autonomy are entitled to protection)

11
The Buck Stops here!

• Principal Investigator
• Conduct of study
• Personnel supervision
• Protecting the rights,
• safety and welfare of
• research subjects . . .

12
Regulatory Alphabet Soup

• Food and Drug Administration FDA
• Office for Human Research Protections OHRP
• Assoc. for the Accreditation of Human Research
• Protection Programs AAHRPP
• National Committee for Quality Assurance NCQA
• Department of Health and Human Services DHHS
• Public Health Services PHS
• Veterans Affairs Research Development VA RD
• Institutional Review Board IRB
• National Institutes of Health NIH
• Health Insurance Portability and Accountability
  Act HIPAA

13
What Regulations Apply?

• Common Rule 56 FR 28003 (Subpart A, 45 CFR 46)
• 45 CFR 46
• 45 CFR 160, 164
• 38 CFR 16 (Veteran Affairs)
• OHRP regs for all research in FWA institutions
• OHRP regs applied for the sake of consistency in
  many non-FWA institutions
• Institutional policies
• 21 CFR 50, 54, 56, 312, 314, 812
• Statutes
• Ethical codes

14
Scientific Misconduct

• Public Health Service (PHS) regulations
• Misconduct in science means fabrication,
  falsification, plagiarism or other practices that
  seriously deviate from those that are commonly
  accepted within the scientific community for
  proposing, conducing and reporting research. It
  does not include honest error or honest
  differences in interpretations or judgments of
  data.
• Retaliation against a whistle-blower who made
  an allegation of misconduct in good faith, may
  itself, be construed as an act of misconduct.

15
Compliance Audits

• ETSU and the ETSU/VA IRB
• Quality Improvement Program for Human Subject
  Research (QIP)
• FDA
• OHRP
• NCQA or AAHRP
• Sponsor/Cooperative Group Monitoring
• Internal Auditing Mechanisms

16
TRUSTBut VERIFY
17
Investigator Records

• Original signed ICDs
• Documentation of initial date of subject or
  patient enrollment
• Documentation of the initial procedure or
  treatment date for each subject or patient
• Refer to the Quality Improvement for Human
  Subject Research (QIP) program guidelines located
  on the IRB Website for program description and
  the specific documentation required for
  compliance and to achieve successful program
  audits

18
What Counts as Research?

• Several characteristics raise the red flag
  indicating that an activity may be research, and
  may therefore incur some consent and oversight
  burdens...

19
What Counts as Research?

• Quest for generalizable knowledge
• Organized data gathering
• Non-standard therapeutic or diagnostic approach
• Decisions made by computer or protocol, rather
  than by patient or caregiver
• Presence of risk (even soft risk) beyond that
  of standard care

20
OHRP Definition of Researchin Regs 45 CFR
46.102(e)

• 45CFR46.102(d) Research means a systematic
  investigation designed to develop or contribute
  to generalizable knowledge.
• Activities which meet this definition constitute
  research for purposes of these regulations,
  whether or not they are supported or funded under
  a program which is considered research for other
  purposes.

21
OHRP Definition of Human Subjectin Regs 45 CFR
46.102(f)

• Human subject means a living individual about
  whom an investigator (whether professional or
  student) conducting research obtains
• data through intervention or interaction with
• the individual, or
• (2) identifiable private information.

22
Risk/Benefit

• Risk - A probability of harm or injury
  (physical, psychological, social, or economic)
  occurring as a result of participation in a
  research study.
• Minimal Risk where the probability and
  magnitude of harm or discomfort in the study is
  not greater than those ordinarily encountered in
  daily life, in performance of routine physical or
  psychological testing.

23
Whats that in Practical Terms?When is a
Neighbor, Student or Patient also a Subject?

• Process or treatment being given is itself
  experimental
• Process or treatment not experimental, but is
  being evaluated in a formal way
• Extra tests or information are being gathered for
  research
• Medical (social or behavioral) decisions are made
  by protocol or computer
• Any risk is increased for the sake of data
  gathering or hypothesis testing

24
Vulnerable Subjects

• Additional protections are required (45CFR46,
  Subparts B,C,D)
• Children
• Some mentally disabled, individuals with dementia
• Cognitive disorders
• Prisoners
• Pregnant women

25
Are Soft Risks Important?

• Risks re confidentiality, stigmatization,
  embarrassment, social/legal risk are explicitly
  mentioned in FDA and OHRP documents as potential
  exclusions from categorization as minimal risk
• Once in awhile, the consequences can be severe
• Do not assume no physical risk means no risk.

26
Whats that in Practical Terms?Sometimes
Overlooked the Soft Risks

• Cost
• Convenience
• Confidentiality
• Embarrassment
• Social/legal risk exposure (e.g. labeling)
• Receipt of misinformation or unwanted information
  (e.g. misassigned paternity)

27
Privacy and Confidentiality

• This area creates more concern for behavioral
  research than for biomedical studies
• Subjects can be wronged even if they are not
  harmed
• Traditional risk/benefit somewhat changed because
  benefits rarely accrue to the subject, but rather
  to science and/or society
• Public exposure, perceived loss of control
• Sense of insecurity
• Breaches of privacy erode trust on all levels

28
Deception

• Deception interferes with the subjects ability
  to give informed consent
• Ethical concerns are increased whenever the
  protection of informed consent is compromised
• Use of deception must be scientifically AND
  ethically justified AND approved by the IRB
• It is not permissible to use deception to obtain
  enrollments

29
What is an IRB?

• An Institutional Review Board (IRB) is a board,
  committee, or other group formally designated by
  an institution to review, to approve the
  initiation of, and to conduct continuing review
  of biomedical and behavioral research involving
  the participation of human subjects in accordance
  with the regulations of the DHHS, FDA and OHRP.

30
IRB ResponsibilitiesCriteria for IRB approval of
research

• Risks to subjects are minimized
• Risks are reasonable in relation to anticipated
  benefit
• Selection of subjects is equitable
• Informed consent is sought from each subject
• Informed consent is appropriately documented.

31
When is IRB Review Not Needed?in Regs 45 CFR
46.101

• Research involving normal educational practices,
  such as instructional strategies, ...
• Research involving the use of educational tests
  (cognitive, diagnostic, aptitude, achievement),
  if ... subjects cannot be identified, directly
  or through identifiers linked to the subjects.
• Research involving survey or interview
  procedures, (if no identifiers and no
  confidentiality risk)

32
When is IRB Review Not Needed?in Regs 45 CFR
46.101

• Research involving the observation of public
  behavior, (if no identifiers and no
  confidentiality risk)
• Research involving the collection or study of
  existing data, documents, records, pathological
  specimens, or diagnostic specimens, if these
  sources are publicly available or if the
  information is recorded by the investigator in
  such a manner that subjects cannot be identified,
  directly or through identifiers linked to the
  subjects.

33
When is Consent Needed?in Regs 45 CFR 46.116

• Except as provided elsewhere in this or other
  subparts, no investigator may involve a human
  being as a subject in research covered by these
  regulations unless the investigator has obtained
  the legally effective informed consent of the
  subject or the subject's legally authorized
  representative.

34
When Can Consent be Waived?in Regs 45 CFR 46.116
(c,d)

• No more than minimal risk
• Research not practicable with consent
• Subjects rights not adversely affected, AND
• Information available later, if practicable
• Final determination is made by the IRB

35
21 CFR 56.106 Waiver of IRB Requirement

• On the application of a sponsor or
  sponsor-investigator, FDA may waive any of the
  requirements contained in these regulations,
  including the requirements for IRB review, for
  specific research activities otherwise covered
  by these regulations.

36
But FDA Cannot Waive

• An OHRP regulation
• A statute
• An institutional policy
• A fundamental ethical precept

FDA waiver is only one duck out of several that
need to be lined up in a row to do research
without IRB approval.
37
FDA Form 1572Hangin Papers

• Also called, Statement of Investigator
• IF YOU Sign a FDA Form 1572 YOU ARE AN
  INVESTIGATOR FULLY COMMITTED TO
• Personally conduct or supervise the
  investigation
• Ensure that all associates, colleagues, and
  employees assisting in study conduct are informed
  about their obligations
• Conduct the study in accordance with the protocol
• Comply with all requirements regarding
  obligations of clinical investigators

38
FDA Form 1572Hangin Papers

• Inform subjects that drugs are being used for
  investigational purposes and ensure informed
  consent and IRB requirements are met
• Report Adverse Events to the sponsor
• Read and understand the investigators brochure
  Delegation high risk
• FDA Form 1572 - Statement of Investigator, (See
  21 CFR 312.53(c))

39
Levels of IRB Review

• Exempt
• Expedited (Short Review)
• Full Review (Convened Meeting)

40

• If it isnt documented, it did not happen

41
Exempt Review

• Does not mean do NOTHING!

42
Exempt Review

• Risks to subjects are minimized Review is
  performed by IRB chairperson or designated
  experienced reviewer.
• Example anonymous survey of a healthy adult
  population.
• No signed consent document is required!

43
Exempt Review

• Research in established educational settings used
  to compare instructional techniques, curricula,
  or classroom methods
• Educational tests which are not damaging to the
  subjects standing or reputation
• Research involving the study of existing data,
  documents, if publicly available, or if data has
  been collected with anonymity.

44
Exempt Review

• Research which evaluates public service programs
• Taste and food quality evaluations

45
Expedited (Short Review)

• Minimal risk to human subjects and involves only
  procedure in the categories
• 1. Research on drugs for which an
  new investigational new drug application is not
  required.
• 2. Collection of blood samples by finger stick,
  heel stick, ear stick, or venipuncture from
• (a) healthy, non-pregnant adults weighing
  at least 110 pounds, not exceeding 550
• ml in an 8 week period, and no more
• than 2 times per week.

46
Expedited (Short Review)

• (b) Other adults and children, considering
  the age, weight, and health of subjects.
  Amount drawn may not exceed the lesser of 50
  ml or 3ml per kg in an 8 week period, with
  collection no more than 2 times per week.
• 3. Biological specimens by noninvasive means
  Hair and nail clippings, excreta, saliva,
  placenta after delivery, amniotic fluid
  obtained at time of rupture, subgingival plaque,
  mucosal and skin cells by scraping, swabbing,
  sputum.

47
Expedited (Short Review)

• 4. Collection of data through noninvasive
  procedures, excluding x-rays or microwaves.
  Examples physical sensors on the body
  surface moderate exercise testing of sensory
  acuity.
• 5. The study of existing data, documents,
  records, pathological specimens.

48
Expedited (Short Review)

• Collection of data from voice, video, digital, or
  image recordings made for research purposes.
• Research on individual or group characteristics
  or behavior.
• Continuing review of research previously approved
  by the convened IRB where (a) project is closed
  to accrual (b) the research remains active only
  for long-term follow-up. (c) remaining research
  activities are limited to data analysis.

49
Expedited (Short Review)

• 9. Continuing review of research that is not
  greater than minimal risk, but had to undergo
  initial review by a convened IRB because it
  did not meet the criteria of categories 2
  through 7.
• Special Note Related grant protocol packet must
  be included in the original submission.

50
Full Review (Convened Meeting)

• If a study does not fit in the short review
  scenario, it, by default, must have full review.
• Requires the attention of an official meeting of
  the IRB with an operating quorum.
• Investigator(s) must attend the meeting to
  present the project parameters, explaining the
  subjects involvement.

51
Types of Review

• Initial Review
• Continuing Review
• Study Closure
• Amendment Review (Minor Modifications)
• Includes any deviation from the original
  approval amendments, revisions modifications
  and requires IRB approval prior to implementation
• Adverse Event / Unanticipated Problems Review

52
Adverse Events

• Unanticipated Problems
• Information that impact on the risk/benefit ratio
  should be promptly reported to, and reviewed by
  the IRB to ensure adequate protection of the
  welfare of the subjects. (FDA (1998) Information
  Sheets)
• All investigators are required to report to the
  IRB any injury (harm caused by involvement in
  research), deaths and unexpected serious adverse
  experiences.
• When reporting, the Investigator must determine
  the relationship between the event and the study
  (definite, possible, probable, doubtful, unknown,
  not related)

53
Emergency Use

• Granted by the IRB chair
• Used primarily in life-threatening situations.
• Single patient use.
• A consultation with a non-related physician is
  required.
• When feasible, informed consent is required.
• Documentation must be submitted before the next
  IRB meeting.
• Contact the Compliance Manager or Chair for
  assistance.

54
Study Methods

• Surveys, interviews, questionnaires, record
  reviews
• Oral History
• Database access for aggregate data
• Observation
• Case Studies
• Various psychological and social interventions in
  field settings
• Drug / Clinical trials
• Medical chart reviews

55
Informed Consent

• Informed consent is not a document, it is a
  process. The informed consent document (ICD)
  provides documentation of the process.
• Telephone Consent (DONT DO IT!)
• Requirements are the same for both short and full
  review (less copies for short review)
• Confidentiality
• Data/Safety Monitoring
• Use 2nd person (you), rather than 1st person (I).
• Use well defined headings for each section.

56
The Process of Informed Consent

• An exchange of information between the subject
  and the investigator (or qualified designee)
  before, during and sometimes even after
  participation.

57
Elements of the Consent Form

• http//www.etsu.edu/irb.htm
• Document must be written non-technical terms,
  understandable by a 7th grade reading level.
• Format includes header with project title and
  investigator name, version date mm/dd/yy
• Footer must include page number in of total
  and an area for initial of subject for each page.
• No less than 12 pt. font
• Written to the potential subject
• Use of standard format is required unless a
  waiver under 45 CFR 46.116 has been granted.

58
Required Elements of the Consent Form

• Introductory paragraph stating
• 1. Invitation to participate in research
• 2. Admonishment to read the document and ask
  questions.
• 3. Make it clear that it is his decision to
  become involved.

59
Elements of Consent Form

• Purpose
• Specific purpose of the project, how it is
  related to other knowledge.
• Duration
• Subjects time commitment to the project.
  

60
Elements of Consent Form

• Procedures Describe what the subject will do,
  see, where he will go, what equipment will be
  used and how. If specimens are collected,
  explain when, where, and how much will be needed
  for the project.
• Hold all technical language to a minimum and when
  used, explain in lay-language the difficult terms.

61
Elements of Consent Form

• Possible Risk/Discomforts
• State in lay-terms any known risk, side effect
  or inconvenience that this project may cause.
  Also state there may be unanticipated risk or
  discomforts that are unknown.

62
Elements of Consent Form

• Possible Benefits
• Describe potential benefits that may occur due
  to their participation. If there is no expected
  benefit, clearly state this fact.
• Compensation in the form of payments
• If there is compensation for the subject, state
  clearly the amount for the amount of
  participation e.g. prorating

63
Elements of Consent Form

• Financial Costs
• List any financial responsibility that the
  subject might incur during the project duration.
• Explain what parts of the study will be at no
  charge.

64
Elements of Consent Form

• Alternative Procedures/Treatments
• Provide information about other choices that be
  available to the subject. If there are no
  alternatives, state explicitly.

65
Elements of Consent Form

• Contact for Questions
• Two individuals with appropriate phone numbers
  must be included. The subject may questions
  concerning the research or research-related
  injuries.
• A statement as to questions about rights as a
  participant, with IRB phone number.

66
Elements of Consent Form

• Confidentiality
• Verbatim paragraph, tailored to fit the realm of
  specific project
• Compensation for Medical Treatment
• Verbatim paragraph, tailored to fit the realm of
  specific project. Remember that research related
  injury might be physical, psychological, social,
  financial or other!
• Additional Elements (if applicable) per
  45CFR46.116(8)(b)(1)-(6)

67
Elements of Consent Form

• Drugs and Devices Under FDA Regulation
• This verbatim paragraph require only when
  investigational drugs or devices are involved.
• Voluntary Participation
• This does have to be a verbatim paragraph, but
  all elements must be present.
• (No penalty or loss of benefits by not
  participating or withdrawing from the study)

68
Elements of Consent Form

• Signature Area
• Volunteer
• Parent (guardian), if applicable
• Investigator or presenter of consent
• Witness (if applicable)

69
Child Assent

• A short, easy to understand Assent (agreement)
  document may be adapted to allow the minor to
  sign. This does not negate the required formal
  ICD signed by the parent(s) or legal guardian in
  which permission is given for the unemancipated
  minor to participate in the study.

70
Narrative Description Guidelines

• Project Title
• Placed to be conducted
• Objective
• Summary
• Methods of Recruitment
• Research Data
• Specific Role of Human Subjects
• Specific Risk to Subjects

71
Narrative Description Guidelines

• Benefits to Subjects
• Inducements
• Subjects confidentiality
• Informed Consent
• Adverse Reaction Reporting
• Pertinent literature (bibliographic listing)
• Location of Records

72
Reviewer Evaluation

• Education
• Investigators and key personnel
• Scientific Issues
• Clearly formulated hypothesis
• Reasonable experimental design
• Inclusion and Exclusion Criteria appropriate

73
Reviewer Evaluation

• Human Participant Issues
• Participant Selection appropriate
• Compensation appropriate
• Adequate safety monitoring of subjects
• Consent Form Elements
• Risk/Benefit
• Special considerations for vulnerable populations

74
IRB Committee Organization

• Membership established under 45 CFR 46.107
  Authority approve, suspend, terminate, modify,
• request records, audit sites/records
• Membership and Attendance requirements
• IRB as PARTNERS
• Institutional Considerations
• Regulatory Reporting

75
IRB Meeting

• Schedule
• Packet dissemination
• Incomplete packets will not be reviewed
• Presentation of full review and non-minor
  modifications
• Committee deliberations and votes
• Conflict of Interest

76
Points to Consider

• Minimize the potential for stress, discomfort and
  other harms
• Use deception only when absolutely necessary then
  follow with complete debriefing
• Respect subjects privacy and minimize intrusion
• Design mechanisms to protect confidentiality of
  data
• Guard against factors leading to undue influence
• Provide adequate safeguards when studying
  vulnerable populations

77
Submission Guidelines

• Full Review
• Face Sheet, Narrative, ICD, Investigator
  Curriculum Vitae or other statement of
  qualifications and (if applicable) Protocol
  Investigators Brochure
• Expedited Review
• Exempt
• Compliance Education components MUST be completed
  PRIOR to submission
• For all reviews, (if appl.) the GRANT PACKET will
  also be reviewed by the IRB

78
File Maintenance

• IRB Administration 3 yrs.
• Investigator 10 yrs.
• Database or other management systems
• IRB Number designation

79

• If it isnt documented, it did not happen

80
Compliance Requirements

• Supplemental Training (IRB 101)
• On-line module completion (OHRP)
• Assessment Post-Test (85 pass rate required)
• Course evaluation
• (submit before leaving today)
• IRB Office will release letter of compliance and
  certificate.
• Online Course Registration
• http//www.etsu.edu/irb/RegistrationForm.htm

81
Acknowledgements

• Dale E. Hammerschmidt,MD, Associate Professor of
  Medicine, University of Minnesota, Editor of
  Journal of Laboratory Medicine, Dir. Of Education
  in Research Ethics and Compliance
• Dunn, C., Chadwick, G. (1999) Protecting Study
  Volunteers in Research,CenterWatch, Inc., Boston,
  MA
• Selwitz, A., Dir., Office of Research Integrity,
  University of Kentucky
• Office for Human Research Protections (OHRP)
• National Institutes of Health (NIH)
• Food and Drug Administration (FDA)
• Office of Research Compliance Assurance (ORCA)

82

• Thank you for participating!