Human Subjects Do You or Do You Not Have Human Subject Involvement

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Human Subjects Do You or Do You Not Have
Human Subject Involvement?
Carlos E. Caban, Ph.D., M.P.H. NIH Extramural
Program Policy Officer Office of Extramural
Programs Office of Extramural Research, OD,
NIH [phone] (phone) cc25a_at_nih.gov
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(No Transcript)
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Outline

• HHS Regulations 45 CFR part 46
• Protection of Human Research Subjects
• NIH Policies Human Subjects/Clinical Research
• Definitions
• Case Studies
• SF424(RR) Application Instructions
• Resources/References

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Office for Human Research Protections (OHRP)
Responsibilities

• OHRP is in Office of the Assistant Secretary for
  Health, DHHS
• http//www.hhs.gov/ohrp/
• OHRP is responsible for
• Issuing Assurances to institutions engaged in
  federally-funded human research and registering
  IRBs which provide approval and oversight for
  human subjects research
• http//www.hhs.gov/ohrp/assurances/
• Developing and updating policy and guidance
  documents
• Education
• Compliance with HHS Human Subjects Protections
  Regulations
• http//www.hhs.gov/ohrp/humansubjects/guidance/45c
  fr46.htm

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HHS Regulationshttp//www.hhs.gov/ohrp/humansubje
cts/guidance/45cfr46.htm

• 45 CFR part 46 Protection of Human Research
  Subjects
• Subpart A--Federal Policy for the Protection of
  Human Subjects
• Subpart B --Additional Protections for Pregnant
  Women, Human Fetuses and Neonates
• Subpart C --Additional Protections for Prisoners
• Subpart D --Additional Protections for Children
  in Research

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Q When is an institution considered to be
engaged in research?

• A In general, when its employees or agents
• (1)obtain data about living individuals for
  research purposes through intervention or
  interaction with them, or
• (2) obtain individually identifiable private
  information for research purposes.
• An institution is automatically considered to be
  engaged whenever it receives a direct HHS award
  to support such research, even if all of the
  human subjects activities will be performed by
  agents or employees of another institution.

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OHRP FAQS (New)

• FAQs on Assurances
• http//www.hhs.gov/ohrp/assurances/assurances_inde
  x.html
• FAQs on IRB Registration
• http//www.hhs.gov/ohrp/assurances/

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Definition of Risk

• the probability of
• harm
• or
• discomfort
• Extracted from
• http//ohrp.osophs.dhhs.gov/humansubjects/guidance
  /45cfr46.htm46.102

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Definition of Research

• a systematic investigation designed to develop
  or contribute to generalizable knowledge
• research development
• testing, and
• evaluation
• http//www.hhs.gov/ohrp/humansubjects/guidance/45
  cfr46.htm46.102

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Definition of Human Subject

• a living individual
• about whom an investigator conducting research
  obtains
• Data through intervention or interaction with the
  individual,
• or
• Identifiable private information
• http//www.hhs.gov/ohrp/humansubjects/guidance/45c
  fr46.htm46.102

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Case Study 1 Research with autopsy specimens

• An application describes the following proposed
  research activities
• An investigator receives autopsy specimens from a
  pathologist.
• The investigator will receive and record
  identifiable private information about the
  individuals from medical records.

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Case 1 Is the investigator conducting human
subjects research?

• No Research involving only specimens and data
  from deceased individuals is not human subjects
  research
• Investigator is neither interacting nor
  intervening with living individuals for research
• Definition of human subject is not met

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Case 1 What information should appear in Human
Subjects section?

• No human subjects research is proposed in the
  application
• Required for PHS 398 applications
• Will not be required for SF 424 RR

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Definition of Obtain

• To receive or access individually identifiable
  human data or specimens
• Includes an investigators use, study, or
  analysis of human data or specimens already in
  investigators possession
• http//www.hhs.gov/ohrp/humansubjects/guidance/cde
  biol.pdf

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Definition of Investigator

• Includes anyone involved in conducting research
  involving human subjects
• Individuals who
• Provide coded human data or specimens and
  collaborate on other activities related to
  conducting the research are involved in HS
  research
• Solely provide coded human data or specimens are
  not involved in HS research
• http//www.hhs.gov/ohrp/humansubjects/guidance/cde
  biol.pdf

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Case Study 2 Discarded Surgical Specimens

• An application describes the following proposed
  research activities
• Investigators will obtain human specimens for
  basic research from a surgeon.
• The surgeon will collect surgical specimens, at
  the request of the investigators, that would
  otherwise be discarded and provide them in a
  coded fashion.
• The surgeon will have no other involvement in the
  proposed research.

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Case 2 Is the surgeon involved in human
subjects research?

• Yes The surgeon is involved in human subjects
  research because he is interacting with living
  individuals and collecting specimens for the
  proposed research.
• The surgeon meets the definition of an
  investigator.
• OHRP considers the term investigator to include
  anyone involved in conducting the research.
• The surgeons involvement may be limited to
  obtaining, coding, and providing the specimens,
  however, this activity is conducted specifically
  for this study.

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Case 2 Is the recipient investigator conducting
human subjects research?

• Yes The recipient investigator is conducting
  human subjects research, because
• an investigator involved in the research (the
  surgeon) is collecting specimens from living
  individuals for the specific study, and
• An investigator can readily link the specimens to
  the living individuals.

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Case 2 What information should appear in Human
Subjects section?

• Description of
• Risks
• protections against risks
• benefits to human subjects and others
• Importance of knowledge to be gained
• Inclusion of women and minorities or
  justification for exclusion of any groups
• Inclusion of children or justification for
  exclusion and
• Proposed/targeted enrollment tables

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NIH Requirements

• NIH Policies
• Human Research Protections
• Data and Safety Monitoring
• Human Subjects Education
• Clinical Research
• Inclusion of Women and Minorities
• Inclusion of Children
• Valid Analyses for NIH-defined Phase III Clinical
  Trials

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HHS RegulationsNIH vs. Responsibilities

• NIH Responsibilities
• Evaluation of proposed research involving human
  subjects for protections
• Delegated to peer review process and NIH staff
• On the basis of this evaluation NIH may
  approve or disapprove the application or enter
  into negotiations to develop an approvable one.
• Federal funds may not be expended for research
  involving human subjects unless the requirements
  have been satisfied.
• (46.120 122)

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HHS RegulationsNIH vs. IRB Responsibilities

• IRB Responsibilities
• Initial and continuing review of research
  involving human subjects
• To approve, require modifications in, or
  disapprove research (46.108)
• Ensure rights welfare of human subjects
• Protection of institution

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Key Application References

• SF424 (RR) Application and Electronic Submission
  Information
• http//grants.nih.gov/grants/funding/424/index.htm
  
• Grants.gov SBIR/STTR Application Guide SF424
  (RR)
• http//grants.nih.gov/grants/funding/424/SF424_RR_
  Guide_SBIR_STTR.pdf
• Part I, Instructions for Preparing and Submitting
  An Application
• Section 4.4 Other Project Information
  Component (p.I-53)
• Section 5. Completing PHS398 Components (pgs.
  I-83, I-85)
• Section 5.4 Research Plan Component, Human
  Subjects Sections (p.I-90, I-97)
• Attachments 6-10
• PART II Supplemental Instructions for Preparing
  the Human Subjects Section of the Research Plan
• OER Human Subjects Internet
• http//grants.nih.gov/grants/policy/hs/index.htm

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SBIR/STTR Application Guide SF424(RR) Part 1 -
4.4 Other Project Information Component (p.I-53)

• Research Related Other Project Information
• Are Human Subjects Involved Yes No
• 1.a. If Yes to Human Subjects
• Is the IRB review Pending? Yes No
• IRB Approval Date
• Exemption Number 1 2 3 4 5 6
• Human Subject Assurance Number

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SBIR/STTR Application Guide SF424(RR) Part 1 -
5.3 PHS 398 Cover Page Supplement (p.I-85)

• 2. Human Subjects
• Clinical Trial? No Yes
• Agency-Defined Phase III Clinical Trial? No Yes

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SBIR/STTR Application Guide SF424(RR) Part 1 -
5.4 Research Plan Component (p.I-90)

• 2. Research Plan Attachments
• Human Subjects Sections (Attachments)
• 6. Protection of Human Subjects
• 7. Inclusion of Women and Minorities
• 8. Target/Planned Enrollment Table
• 9. Inclusion of Children
• 10. Data and Safety Monitoring Plan

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SBIR/STTR Application Guide SF424(RR)

• Part II
• Supplemental Instructions for Preparing the Human
  Subjects Section of the Research Plan

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Part II Instructions for Preparing the Human
Subjects Section

• All proposed research will fall into one of six
  scenarios
• A No Human Subjects
• B Human Subjects Research, Exemption 4
• C Human Subjects Research, Exemptions 1,2,3,5,6
• D Clinical Research
• E Clinical Trial(s)
• F NIH-defined Phase III Clinical Trial(s)
• (Page II-2)

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Scenario A No Human Subjects

• HUMAN SUBJECTS?
• NO
• Human Subjects Section

PHS 398 Section E. No Human Subjects research is
proposed
SF 424 Human Subjects No Human Subjects section
is required
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Scenario B or C Exempt Human Subjects Research

• Research activities in which the only involvement
  of human subjects will be
• Research in educational settings on educational
  practices
• Tests, Surveys, Interviews
• Tests, Surveys, Interviews with public officials,
  or if laws require confidentiality
• Collection/Study of existing data, specimens
  publicly available or unidentifiable
• Research approved/conducted by Federal Agencies
• Evaluation of taste or food quality

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Scenario B or C Exempt Human Subjects Research

• HUMAN SUBJECTS RESEARCH?
• YES
• Research Exempt
• YES, Exemption No. _____
• Human Subjects Section
• Exemption Category(ies)
• Justification for exempt status
• Population sample
• Number
• Age range
• Health status
• Sources of research materials or data
• For Scenario C Exemptions 1, 2, 3, 5, 6
• Address NIH Inclusion Policies

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Determination of Exempt Human Subjects Research

• Investigators should not determine that research
  involving human subjects is exempt
• OHRP guidance Exemptions should be independently
  determined (http//www.hhs.gov/ohrp/humansubjects/
  guidance/irb71102.pdf).
• Institutions often designate IRB to make
  determination
• NIH Policy Certification of IRB approval is
  Just-in-Time. http//grants.nih.gov/grants/policy/
  policy.htm

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Case Study 3 Archived Human Specimens

• An application describes the following proposed
  research activities
• An investigator is using archived, individually
  identifiable specimens from an NIH-funded
  clinical trial.
• The investigator removes identifiers from the
  specimens and does not maintain links to
  identifiers.
• The investigator then conducts research on the
  anonymized specimens.

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Case 3 Is the investigator conducting human
subjects research?

• Yes If the individuals from whom the specimens
  were obtained are living, then obtaining
  individually identifiable specimens is human
  subjects research.

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Case 3 Does the study involve exempt human
subjects research?

• Exemption 4
• Research involving the collection or study of
  existing
• data,
• documents,
• records,
• pathological specimens, or
• diagnostic specimens,
• from publicly available sources or
• if information is recorded by the investigator in
  such a manner that subjects cannot be identified,
  directly or through identifiers linked to the
  subjects.
• OHRP recommends that institutions adopt clear
  procedures under which the IRB (or some authority
  other than the investigator) determines whether
  proposed research is exempt from the human
  subjects regulations 45 CFR 46.101(b).

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Case 3 Does removing identifiers from existing
specimens meet the criteria for Exemption 4?

• Yes If all specimens are existing at the time
  the research is proposed to an institutional
  official or IRB for a determination of whether or
  not the research is exempt and
• If the investigator collects the specimens and
  then removes links to identifiers from the
  specimens then
• This research activity meets the criteria for
  Exemption 4.
• http//www.hhs.gov/ohrp/humansubjects/guidance/45
  cfr46.htm46.101

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Case 3 Does the research with anonymized
specimens involve human subjects?

• No Conducting research using anonymized
  specimens is not human subjects research because
  the specimens cannot be linked to individually
  identifiable living individuals.
• Criteria for human subject not met

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Case 3 What information should appear in Human
Subjects section?

• Description of
• Risks
• protections against risks
• benefits to human subjects and others
• Importance of knowledge to be gained
• Inclusion of women and minorities justification
  for exclusion of any groups
• Inclusion of children or justification for
  exclusion and
• Proposed/targeted enrollment tables

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Scientific Review of Human Research Protections

• Acceptable or Unacceptable
• Human Subjects Concern
• Actual or potential unacceptable risks, or
  inadequate protections OR
• Insufficient information
• Summary Statement
• PROTECTION OF HUMAN SUBJECTS (Resume)
  UNACCEPTABLE

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Common Concerns (FY2005)

• Inadequate Human Subjects section (30)
• Risks (24)
• Issues related to Informed Consent (15)
• Issues related to Confidentiality (10)
• Missing/inadequate Data and Safety Monitoring
  (8)
• Inequitable recruitment (7)
• Other (5)

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TWO Definitions for Children

• Children protections from risks in research are
  defined as persons who have not attained the
  legal age for consent to treatments or procedures
  involved in the research, under the applicable
  law of the jurisdiction in which the research
  will be conducted. (46.402)
• Children for the purposes of the requirement to
  address inclusion are defined as individuals
  under the age of 21.
• (NIH Policy and Guidelines on the Inclusion of
  Children as Participants in Research Involving
  Human Subjects)
• Try not to get confused!

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Inclusion of Children

• NIH policy requires that children must be
  included unless there are clear and compelling
  reasons not to include them
• Children are defined as individuals lt21 years
• http//grants.nih.gov/grants/guide/notice-files/
  not98-024.html

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Scenario D Clinical Research

• HUMAN SUBJECTS RESEARCH?
• YES
• Research Exempt?
• YES or NO
• Inclusion information not required for Exemption
  4 (Scenario B)
• Human Subjects Section

• Risks
• Adequacy of protections against risks
• Potential benefits
• Importance of knowledge to be gained

• Identification of Exemption
• Justification for Exempt Status

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Definition of Clinical Research

• Patient-oriented research
• Epidemiologic and behavioral studies
• Outcomes research and health services research
• Exemption 4 research is not clinical research

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Clinical Research Inclusion of Women and
Minorities

• Each study must have plans for
• Distribution by ethnicity/race and
• Distribution by sex/gender
• Rationale for Exclusions
• Outreach
• Outreach Notebook http//orwh.od.nih.gov/inclusio
  n/incloutreach.html

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Scientific Review of Inclusion Plans

• Inclusion -
• If proposed inclusion is appropriate for
  scientific objectives
• Rationale for selection of subjects and
  composition of study population
• Exclusion -
• Justification for exclusion when representation
  is limited or absent
• Based on risks to health of participants /or
  inclusion inappropriate with respect to the
  research topic
• Assessment Acceptable or Unacceptable

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Scenario E Clinical Trial

• Prospective biomedical or behavioral research
  study designed to answer questions about
  biomedical or behavioral interventions
• Applicants should
• Provide information required for Scenario D
  Clinical Research
• PLUS
• Data and Safety Monitoring Plan
• General Description in Grant Applications
• Monitoring Entity
• Process for Adverse Event Reporting

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Scenario FNIH-Defined Phase III Clinical Trial

• A broadly-based, prospective Phase III clinical
  investigation
• Purpose
• Evaluate an experimental intervention in
  comparison with standard or control intervention
  or to compare existing treatments
• For disease prevention, prophylaxis, diagnosis,
  or therapy

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Requirements for NIH-defined Phase III Clinical
Trials

• All information required for Scenario E
  Clinical Trial
• PLUS
• Research plan must include consideration of one
  of the following
• 1. Prior Studies support significant differences
  between subgroups OR
• 2. Prior studies support no significant
  differences between subgroups OR
• 3. Prior studies neither support nor negate
  significant differences in intervention effect
  between subgroups

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Before Award

• Human Research Protections Issues
• OHRP Assurance Number for grantee institution
• Certification of IRB review and approval from IRB
  registered under grantees Assurance number
• Acceptable/Resolved Human Subjects Protections
• Certification of Human Subjects Education for Key
  Personnel
• Inclusion Issues
• Acceptable/Resolved Inclusion of
  Women/Minorities/Children
• Plans for Valid Analyses for NIH-defined Phase
  III Clinical Trials

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After Award

• Human Research Protections Issues
• Annual Progress reports from the grantee to the
  NIH and certification of continuing IRB review
  for non-exempt human subjects research
• Adverse Event Reports

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After Award

• Inclusion Issues
• Inclusion Enrollment Tables
• Part A All Human Subjects
• Part B Hispanics and Latinos
• Separate tables for each study
• Separate tables for domestic and foreign
  populations

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Resources and Getting Help

• NIH Guide for Grants and Contracts
• http//grants.nih.gov/grants/guide/index.html
• NIH Grants Policy Statement
• http//grants.nih.gov/grants/policy/nihgps_2003/i
  ndex.htm
• SF 424 (Research Related) http//grants.nih.gov
  /grants/funding/424/index.htm
• PHS 2590 Instructions
• http//grants.nih.gov/grants/funding/2590/2590.h
  tm
• Office of Extramural Research Grants Home Page
  http//grants.nih.gov/grants/oer.htm
• OER Human Subjects Web Site
• http//grants1.nih.gov/grants/policy/hs/index.ht
  m

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Thank you
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FAQs Human Subjects Research?

• Research involving Focus Groups
• NO, if research will involve consultants chosen
  for their expertise to improve research design
• NO, if research will involve individuals
  recruited to test a new product/survey instrument
  in order to identify problems (b-testing)
• YES, if research will involve small group
  representing target population and
  individually-identifiable information will be
  obtained, that could result in risks (pilot
  testing)

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Purpose of OHRP Guidance on Research Involving
Human Data or Specimens

• Directed toward IRBs, investigators, and funding
  agencies
• Provides clarification of terms in HHS
  regulations
• http//www.hhs.gov/ohrp/humansubjects/guidance/45c
  fr46.htm
• Describes when research with coded data or
  specimens is not human subjects research
• Indicates that coded data/specimens that are
  designated not human subjects may still be
  covered by HIPAA, so protection against
  disclosure of identifiable private information
  may be protected
• Effective date August 10, 2004

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Definition of Coded

• Identifying information that enables the
  investigator to readily ascertain the identity of
  the individual has been replaced with a
• number,
• symbol, and/or
• letter and
• A key to the code exists, enabling linkage of
  information to an individual

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Specific Information in Guidance

• Research with coded human data/specimens does not
  involve HS if
• Data/specimens not collected specifically for
  proposed study and
• PI(s) cannot readily ascertain identities of
  donors because
• Key to code destroyed before research begins or
• Non-disclosure agreement between provider and
  investigator (no requirement for IRB approval)
  or
• IRB policies prohibit release of key to code or
• Other legal requirements prohibit release of
  key to code

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Coded Data/Specimens Summary

• In order to determine whether research with coded
  data/specimens is human subjects research, you
  must determine
• Role of data/specimen provider
• Role of recipient
• What is being obtained

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Repositories and Databases

• Non-Research Repositories Databases
• IF samples or data collected for non-research
  purposes AND
• Samples or data submitted to the Repository
  without any links to identifiable private data or
  information THEN
• NOT HUMAN SUBJECTS RESEARCH

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Repositories and Databases

• Research Repositories Databases
• Samples or data collected for research purposes
• Sample or data collection is a research activity
• Repository Storage/Data Management is a research
  activity
• Use/Disclosure of Samples/Data is a research
  activity
• Each research activity is Human Subjects Research
  and receives IRB review and approval
• If archived samples/data are provided without
  links to individually identifiable information,
  then the research may meet the criteria for
  Exemption 4 or not meet the definition of human
  subjects research