Human Subjects Research

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Human Subjects Research

• Valery M. Gordon, Ph.D., M.P.H.
• NIH Extramural Human Subjects Research Policy
  Officer
• Office of Extramural Programs
• Office of Extramural Research, OD, NIH, DHHS
• [phone]
• vg10w_at_nih.gov
• http//grants.nih.gov/grants/policy/hs/index.htm

NIH Regional Seminar, 2005
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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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Why does NIH have requirements?

• Belmont Principles
• Respect for Persons
• Informed Consent
• Additional protections for vulnerable populations
• Beneficence
• Data Safety Monitoring for Clinical Trials
• Justice
• Inclusion of Women/Minorities/Children
• Valid Analyses for NIH-defined Phase III Clinical
  Trials
• HHS Regulations 45 CFR 46 Protection of Human
  Subjects
• 1993 Public Law 103-43

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NIH Policies Protection for Human Subjects from
research risks

• NIH is committed to the highest ethical and
  scientific standards for Human Subjects research
• NIH follows all parts of HHS regulations
• 45 CFR 46 Protection of Human Subjects
• NIH has additional policy requirements for
  research involving Human Subjects
• Human Subjects Education Requirement
• http//grants.nih.gov/grants/policy/hs_educ_faq.ht
  m

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NIH Policies Clinical Research

• Inclusion of Women and Minorities in Clinical
  Research
• Inclusion of Children in Clinical Research
• Valid Analyses for NIH-defined Phase III Clinical
  Trials

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Application (PHS 398) Human
Subjects Research

• Item 4 Human Subjects Research
• Item 4a Exemption number(s)
• Item 4b Institutional Assurance (FWA) number
• Item 4c Clinical Trial
• Item 4d NIH-defined Phase III Clinical Trial
• Required information must appear in the Research
  Plan in Section e. Human Subjects

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PHS 398 Part IIInstructions 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)

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Which Scenario matches?

• Questions to assist in identifying correct
  scenario
• Human Subjects?
• Exempt Human Subjects research?
• Clinical Research?
• Clinical Trial?
• NIH-defined Phase III Clinical Trial?

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Question 1 Human Subjects Research?

• PHS 398 Item 4 yes
• Non-exempt Human Subjects Research
• Research Plan Section E. Human Subjects
• Risks
• Adequacy of protections against risks
• Potential benefits
• Importance of knowledge to be gained
• http//grants.nih.gov/grants/funding/phs398/instru
  ctions2/phs398instructions.htm

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Certification of IRB Review and Approval

• The institution must certify that the research
  has been reviewed and approved by an IRB
  (includes all participating sites)
• 45CFR46103(b)
• Just-In-Time submission to NIH
• IRB approval is not required prior to NIH peer
  review of an application
• http//grants.nih.gov/grants/policy/policy.htm

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HHS RegulationsNIH v. IRB Responsibilities

• NIH Responsibilities
• Evaluation of proposed research involving human
  subjects for protections
• Delegated to peer review 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)
• 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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Question 2Exempt Human Subjects Research?

• Exempt Human Subjects Research
• Exemption Category
• Justification for exempt status
• Population sample
• Number
• Age range
• Health status
• Sources of research materials or data

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Determination of Exempt Human Subjects Research

• OHRP advises that investigators should not have
  the authority to make an independent
  determination that research involving human
  subjects is exempt.
• OHRP guidance states that Exemptions should be
  independently determined (http//www.hhs.gov/ohrp/
  humansubjects/guidance/irb71102.pdf).
• Institutions often designate their IRB to make
  this determination.
• Because NIH does not require IRB approval at time
  of application, the exemptions often represent
  the opinion of the Principal Investigator, and
  the justification provided by the Principal
  Investigator for the exemption is evaluated
  during peer review.

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Scientific Review of Human Research Protections

• Acceptable or
• Unacceptable
• Human Subjects Concern
• Any actual or potential unacceptable risk, or
  inadequate protection against risk, to human
  subjects as described in any portion of the
  application.
• Summary Statement
• PROTECTION OF HUMAN SUBJECTS (Resume)
  UNACCEPTABLE -SRG concerns

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Question 3Clinical Research?

• Patient-oriented research
• Research conducted with human subjects or
• Material of human origin such as tissues,
  specimens and cognitive phenomena
• for which an investigator (or colleague)
  directly interacts with human subjects, including
• (a) mechanisms of human disease,
• (b) therapeutic interventions,
• (c) clinical trials, or
• (d) development of new technologies
• Patient-oriented research requires a
  direct interaction with living individuals for
  research purposes
• In vitro studies that utilize human tissues that
  cannot be linked to a living individual is not
  clinical research
• Exemption 4 research is not clinical research
• Epidemiologic and behavioral studies
• Outcomes research and health services research

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Applications (PHS 398) must address

• Proposed Composition of Study Population Using
  Proposed Enrollment Tables
• Data must be collected by self-report
• Two separate questions
• Ask about ethnicity
• Ask about race with option to select more than
  one racial designation
• Subject Selection Criteria Rationale
• Rationale for Any Exclusions
• Enrollment Dates (start and end)
• Outreach Plans for Recruitment

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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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Scientific Review of Inclusion Plans

• Scientific Reviewers will evaluate
• Inclusion -
• Whether proposed inclusion is appropriate for
  scientific objectives of study
• 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
• Acceptable or Unacceptable

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Question 4Clinical Trial?

• Prospective biomedical or behavioral research
  study of human subjects that is designed to
  answer specific questions about biomedical or
  behavioral interventions (drugs, treatments,
  devices, or new ways of using known drugs,
  treatments, or devices)
• Data and Safety Monitoring Plan required for all
  Clinical Trials
• General Description in Grant Applications
• Monitoring Entity
• Process for Adverse Event Reporting

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Question 5NIH-defined Phase III Clinical Trial?

• A broadly based prospective Phase III clinical
  investigation, usually involving several hundred
  or more human subjects
• Pharmacologic, non-pharmacologic and behavioral
  interventions, Community trials and other
  population-based intervention trials
• disease prevention,
• prophylaxis,
• diagnosis, or
• therapy
• Purpose
• evaluation of an experimental intervention in
  comparison with a standard or controlled
  intervention or
• Comparison of two or more existing treatments.
• Goal
• To provide evidence leading to a scientific basis
  for consideration of a change in health policy or
  standard of care.

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Requirements for NIH-defined Phase III Clinical
Trials

• Research plan must include one of the following
• If prior studies support significant differences
  between subgroups
• Need plans to conduct valid analyses to detect
  significant differences between sex/gender and/or
  racial/ethnic subgroups
• For the purpose of this policy, Significant
  Difference is
• a difference that is of clinical or public
  health importance based on substantial scientific
  data. This is not the same as statistically
  significant difference.
• For the purpose of this policy, Valid Analysis
  means an unbiased assessment that does not
  require high statistical power and should be
  conducted for both large and small studies.

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Requirements for NIH-Defined Phase III Clinical
Trials (cont)

• OR
• If prior studies support no significant
  differences between subgroups
• Representation as subject selection criterion is
  not required however, inclusion and analyses are
  encouraged
• OR
• If prior studies neither support nor negate
  significant differences in intervention effect
  between subgroups
• Need plans to conduct valid analyses of the
  intervention effect in sex/gender and/or
  racial/ethnic subgroups

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Awards Human Protections and Inclusion Issues

• Before award NIH staff require
• 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
• 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 Protections Issues
• Annual Progress reports from the grantee to the
  NIH and certification of continuing IRB review
  for non-exempt research
• Adverse Event Reports
• 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
• PHS 398 Instructions
• http//grants.nih.gov/grants/funding/phs398/phs3
  98.html
• PHS 2590 Instructions
• http//grants.nih.gov/grants/funding/2590/2590.h
  tm