OHRP Doing it right … together! OFFICE FOR HUMAN RESEARCH PROTECTIONS, DHHS

OHRPOHRP Doing it right … together!Doing it right … together!

OFFICE FOR HUMAN RESEARCH PROTECTIONS, DHHSOFFICE FOR HUMAN RESEARCH PROTECTIONS, DHHS

((http://ohrp.osophs.dhhs.gov/http://ohrp.osophs.dhhs.gov/))

SBIR/STTR: HUMAN SUBJECT REQUIREMENTSSBIR/STTR: HUMAN SUBJECT REQUIREMENTS((http://ohrp.osophs.dhhs.gov/educmat.htm))

Clifford C. Scharke, D.M.D., M.P.H.Clifford C. Scharke, D.M.D., M.P.H.

Last Revised May 20, 2002Last Revised May 20, 2002

Introduction and Overview

Why - ConceptsWhy - Concepts When - Applicability When - Applicability What - ProcessWhat - Process How - ResourcesHow - Resources Who - Human AssistanceWho - Human Assistance Wow - Things That Can Go WrongWow - Things That Can Go Wrong

Concepts

Volunteers - Human SubjectsVolunteers - Human Subjects Permission - Informed ConsentPermission - Informed Consent Oversight - Institutional Review BoardsOversight - Institutional Review Boards Documentation - Assurance and RecordsDocumentation - Assurance and Records Self-Interest - What’s it to you?Self-Interest - What’s it to you?

Volunteers - Human Subjects

Other people and their private Other people and their private information don’t belong to the PI information don’t belong to the PI

The sheer value of the research does not The sheer value of the research does not automatically trump rights of people automatically trump rights of people

Ask before you take unless IRB approvesAsk before you take unless IRB approves Definition of a human subjectDefinition of a human subject

Definition of a Human Subject

Human subjectHuman subject means a living individual means a living individual about whom an investigator (whether about whom an investigator (whether professional or student) conducting professional or student) conducting research obtains:research obtains: data through data through interventionintervention or or interactioninteraction with the individual, or with the individual, or identifiable private informationidentifiable private information

Permission - Informed Consent

From the Nuremberg Code on, the right to From the Nuremberg Code on, the right to say “no” is the first right of a subjectsay “no” is the first right of a subject

Permission of a duly informed volunteer is Permission of a duly informed volunteer is required unless the IRB says otherwiserequired unless the IRB says otherwise

Volunteers who are not of legal age for the Volunteers who are not of legal age for the intended procedure must also grant intended procedure must also grant permission (if they’re able to do so)permission (if they’re able to do so)

Definitions of consent and assentDefinitions of consent and assent

Definitions of Consent and Assent ConsentConsent - - legally effectivelegally effective agreement of the agreement of the

subjectsubject or the or the subject's legally authorized subject's legally authorized representativerepresentative based on based on informationinformation that is that is given to the subject or the representative in given to the subject or the representative in language that is language that is understandableunderstandable

AssentAssent - child’s - child’s affirmative agreementaffirmative agreement to to participate in researchparticipate in research

PermissionPermission - agreement of - agreement of parent(s) or parent(s) or guardianguardian to the participation of their to the participation of their child child or wardor ward in research in research

Oversight - Institutional Review Boards

An objective review panel under 45 CFR 46An objective review panel under 45 CFR 46((http://ohrp.osophs.dhhs.gov/humansubjects/guidance/http://ohrp.osophs.dhhs.gov/humansubjects/guidance/

45cfr46.htm#46.10245cfr46.htm#46.102)) Competent for review of science & ethicsCompetent for review of science & ethics

Adequate in number and compositionAdequate in number and composition Voting members are free of conflictVoting members are free of conflict Suitably composed for involved human subjectsSuitably composed for involved human subjects Sufficient knowledge of local contextSufficient knowledge of local context

((http://ohrp.osophs.dhhs.gov/humansubjects/guidance/local.htmhttp://ohrp.osophs.dhhs.gov/humansubjects/guidance/local.htm))

Documentation - Assurance and Records

Prior written promise to meet minimum Prior written promise to meet minimum Federal standards to protect subjectsFederal standards to protect subjects

IRB minutes in required detailIRB minutes in required detail Ongoing IRB certification and enduring Ongoing IRB certification and enduring

records of all required reportable eventsrecords of all required reportable events If it isn’t documented, it didn’t happenIf it isn’t documented, it didn’t happen Definitions of Assurance and RecordsDefinitions of Assurance and Records

Documentation - Assurance and Records

AssuranceAssurance - a - a legally binding written documentlegally binding written document that commits a public or private that commits a public or private entityentity to to compliance with applicable compliance with applicable Federal minimum Federal minimum standardsstandards for the protection of human subjects for the protection of human subjects prior to engagementprior to engagement in Department or Agency in Department or Agency conducted or supported research (i.e., conducted or supported research (i.e., prior prior binding promise to follow applicable rulesbinding promise to follow applicable rules) and ) and includes citation of includes citation of ethical principlesethical principles, , designated designated IRBIRB, list of , list of IRB membersIRB members, , IRB procedures,IRB procedures, and and institutional and investigator institutional and investigator responsibilitiesresponsibilities

Documentation - Assurance and Records

RecordsRecords - - An institution, or when appropriate an An institution, or when appropriate an IRB, shall prepare and maintain:IRB, shall prepare and maintain:

Copies of all Copies of all research proposalsresearch proposals reviewed, any reviewed, any scientific evaluationsscientific evaluations, , approved sample consent approved sample consent documentsdocuments, , progress reportsprogress reports submitted by submitted by investigators, and investigators, and reports of injuriesreports of injuries to subjects to subjects

Minutes of IRB meetingsMinutes of IRB meetings which shall be in sufficient which shall be in sufficient detail to show attendance; actions taken; the vote on detail to show attendance; actions taken; the vote on these actions; the basis for requiring changes in or these actions; the basis for requiring changes in or disapproving research; and a written summary of disapproving research; and a written summary of the discussion of controverted issues and their the discussion of controverted issues and their resolutionresolution

Documentation - Assurance and Records

RecordsRecords - - An institution, or when appropriate an An institution, or when appropriate an IRB, shall prepare and maintain:IRB, shall prepare and maintain:

Records of continuing review activitiesRecords of continuing review activities Copies of all Copies of all correspondencecorrespondence between the IRB and between the IRB and

the investigatorsthe investigators A A list of IRB memberslist of IRB members in the same detail as in the same detail as

described in §46.103(b)(3)described in §46.103(b)(3) Written procedures for the IRBWritten procedures for the IRB in the same detail as in the same detail as

described in §46.103(b)(4) and §46.103(b)(5).described in §46.103(b)(4) and §46.103(b)(5).

Self-Interest - What’s it to you?

Defensible research must be ethical researchDefensible research must be ethical research Rules that protect subjects protect the PIRules that protect subjects protect the PI PI integrity is measured by compliancePI integrity is measured by compliance The reputation of the PI’s institution is at stakeThe reputation of the PI’s institution is at stake Future funding can be jeopardizedFuture funding can be jeopardized Funding authority credibility can be questionedFunding authority credibility can be questioned As goes the public’s trust, so goes researchAs goes the public’s trust, so goes research

Applicability

ResearchResearch - a - a systematicsystematic investigation, including research development, investigation, including research development, testing and evaluation, testing and evaluation, designeddesigned to develop or contribute to to develop or contribute to generalizablegeneralizable knowledge (regardlesss of what it might be called) knowledge (regardlesss of what it might be called) ((http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.102http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.102))

45 CFR 46 applies if Human Subjects + DHHS Research - Exemptions 45 CFR 46 applies if Human Subjects + DHHS Research - Exemptions ((http://ohrp.osophs.dhhs.gov/humansubjects/guidance/decisioncharts.htmhttp://ohrp.osophs.dhhs.gov/humansubjects/guidance/decisioncharts.htm))

AwardeesAwardees of DHHS-supported human subject research and of DHHS-supported human subject research and all entitiesall entities that that interactinteract with, with, interveneintervene upon, or have potential access to upon, or have potential access to private private identifiable informationidentifiable information of of living personsliving persons are are engagedengaged and are required and are required to possess an applicable Assurance prior to human subjects to possess an applicable Assurance prior to human subjects ((http://ohrp.osophs.dhhs.gov/humansubjects/assurance/engage.htmhttp://ohrp.osophs.dhhs.gov/humansubjects/assurance/engage.htm))

Process

PreparationPreparation - it’s - it’s never too earlynever too early to consult to consult with the population, institutions, and IRB with the population, institutions, and IRB Chair(s) when planning the research designChair(s) when planning the research design

Pre-applicationPre-application - Assurance and IRB - Assurance and IRB approvals approvals are are notnot required required (needed prior to any award) (needed prior to any award)

PHS 398 ApplicationPHS 398 Application – – completecomplete instructions instructions

((http://grants.nih.gov/grants/funding/phs398/phs398.htmlhttp://grants.nih.gov/grants/funding/phs398/phs398.html))

Process SBIR/STTR Application Instructions - don’t miss:SBIR/STTR Application Instructions - don’t miss:

I.C.1 I.C.1 Face Page - Item 4 - Human SubjectsFace Page - Item 4 - Human Subjects No Human SubjectsNo Human Subjects Human Subjects InvolvedHuman Subjects Involved

• Exemptions from RegulationsExemptions from Regulations

• Human Subject Assurance NumberHuman Subject Assurance Number

• NIH-Defined Phase III Clinical TrialNIH-Defined Phase III Clinical Trial**

I.C.1I.C.1 Face Page - Item 15 - Organization CertificationFace Page - Item 15 - Organization Certification Human SubjectsHuman Subjects Transplantation of Human Fetal TissueTransplantation of Human Fetal Tissue NIH Women and Minority Inclusion PolicyNIH Women and Minority Inclusion Policy** NIH Inclusion of Children PolicyNIH Inclusion of Children Policy** Use of Embryonic Stem CellsUse of Embryonic Stem Cells

I.C.8 I.C.8 Research Plan – 8.e - Human Subjects ResearchResearch Plan – 8.e - Human Subjects ResearchNote:Note: These are policies to which questions are best addressed to NIH These are policies to which questions are best addressed to NIH

Process

SBIR/STTR Application Highlights - don’t miss:SBIR/STTR Application Highlights - don’t miss:

I.C.1. Item 4 - Face PageI.C.1. Item 4 - Face Page – enter “yes” or “no” for human – enter “yes” or “no” for human subjects and exemptions; if yes for both, then enter E1-6 subjects and exemptions; if yes for both, then enter E1-6 ((http://grants1.nih.gov/grants/funding/phs398/section_1.html#e_humansubshttp://grants1.nih.gov/grants/funding/phs398/section_1.html#e_humansubs) ) -see footnote to 46.101(b) for limitations to exemptions -see footnote to 46.101(b) for limitations to exemptions

I.C.1. Item 4 - Face PageI.C.1. Item 4 - Face Page - do - do notnot enter Assurance number enter Assurance number for the institution with the designated IRB (enter for the institution with the designated IRB (enter “None”); if “None”); if applicantapplicant possesses a Multiple Project possesses a Multiple Project Assurance (MPA) or Federalwide Assurance (FWA), then Assurance (MPA) or Federalwide Assurance (FWA), then enter number - check OHRP Website if not sure enter number - check OHRP Website if not sure (select link to MPA or FWA from (select link to MPA or FWA from http://ohrp.osophs.dhhs.gov/irbasur.htmhttp://ohrp.osophs.dhhs.gov/irbasur.htm))

Process SBIR/STTR Application entries - don’t miss:SBIR/STTR Application entries - don’t miss:

Research Plan/Item 8e – Human Subjects Research*Research Plan/Item 8e – Human Subjects Research*

Follow PHS 398 instructions carefully to Follow PHS 398 instructions carefully to avoid your avoid your application from being designated incomplete:application from being designated incomplete: Human Subject/Exemption/Clinical/Clinical Trial StatusHuman Subject/Exemption/Clinical/Clinical Trial Status

• Exemption Categories – 1 through 6 (select as applicable)Exemption Categories – 1 through 6 (select as applicable) Risks/Protections/Benefits/ImportanceRisks/Protections/Benefits/Importance

• Certificates of Confidentiality Certificates of Confidentiality ((http://grants.nih.gov/grants/policy/coc/index.htmhttp://grants.nih.gov/grants/policy/coc/index.htm and and

http://ohrp.osophs.dhhs.gov/humansubjects/guidance/cert-con.htmhttp://ohrp.osophs.dhhs.gov/humansubjects/guidance/cert-con.htm)) Collaborating SitesCollaborating Sites

• Engagement of sites in human subject research Engagement of sites in human subject research ((http://ohrp.osophs.dhhs.gov/humansubjects/assurance/engage.htmhttp://ohrp.osophs.dhhs.gov/humansubjects/assurance/engage.htm))

*Note*Note: Scenarios are given in the instructions to assist.: Scenarios are given in the instructions to assist.

Process Assurance to Comply with 45 CFR 46 Before AwardAssurance to Comply with 45 CFR 46 Before Award

Applicant will be notified by NIH in writing of awardApplicant will be notified by NIH in writing of award Award conditioned on Assurances to OHRP from:Award conditioned on Assurances to OHRP from:

AwardeeAwardee All sites engaged in human subject researchAll sites engaged in human subject research

Funding authority identifies the need for and seeks Funding authority identifies the need for and seeks Assurances through the awardee for all engaged sitesAssurances through the awardee for all engaged sites

Each site without a Federal-wide Assurance files an Each site without a Federal-wide Assurance files an FWA, designates a registered IRB; sends to OHRP FWA, designates a registered IRB; sends to OHRP (see instructions at (see instructions at http://ohrp.osophs.dhhs.gov/irbasur.htmhttp://ohrp.osophs.dhhs.gov/irbasur.htm))

OHRP advice required for options other than FWAOHRP advice required for options other than FWA Awardee/PI may but need not contact OHRPAwardee/PI may but need not contact OHRP

Specific Resources

OHRP Web-based FWA Filing and IRB OHRP Web-based FWA Filing and IRB Registration; review in detail and act when timely Registration; review in detail and act when timely ((http://ohrp.osophs.dhhs.gov/irbasur.htmhttp://ohrp.osophs.dhhs.gov/irbasur.htm))

Options to finding an IRB to designate:Options to finding an IRB to designate: Establish your own (potential conflicts) Establish your own (potential conflicts) Rely on suitable IRB of a collaborating siteRely on suitable IRB of a collaborating site Locate willing MPA institution near subjects Locate willing MPA institution near subjects

((http://ohrp.cit.nih.gov/search/asearch.asphttp://ohrp.cit.nih.gov/search/asearch.asp))

Identify suitable independent IRB (see next slide)Identify suitable independent IRB (see next slide) Designated IRB must perform “local” review Designated IRB must perform “local” review

((http://ohrp.osophs.dhhs.gov/humansubjects/guidance/local.htmhttp://ohrp.osophs.dhhs.gov/humansubjects/guidance/local.htm))

General Resources OHRP Website OHRP Website

((http://ohrp.osophs.dhhs.gov/index.htmhttp://ohrp.osophs.dhhs.gov/index.htm) - ) - seek, find, and fill needsseek, find, and fill needs

Belmont Report (ethical principles)Belmont Report (ethical principles) IRB Guidebook and Investigator 101 CDIRB Guidebook and Investigator 101 CD Training Videotapes and WorkshopsTraining Videotapes and Workshops Common Findings in NoncomplianceCommon Findings in Noncompliance Links to Other WebsitesLinks to Other Websites

Independent Institutional Review Boards Independent Institutional Review Boards (for a listing see (for a listing see http://www.advamed.org/solutions/reviewboards.shtmlhttp://www.advamed.org/solutions/reviewboards.shtml) - ) -

Note: URL Note: URL notnot endorsed by OHRP endorsed by OHRP - provided solely as a courtesy; - provided solely as a courtesy; not all listed IRBs necessarily conform to OHRP “local” not all listed IRBs necessarily conform to OHRP “local” IRB and conflict-free requirements (see previous slide)IRB and conflict-free requirements (see previous slide)

Human Assistance

IRB ChairIRB Chair Pre-protocol planning to enhance and prevent problemsPre-protocol planning to enhance and prevent problems Arrange for investigator training to preserve integrityArrange for investigator training to preserve integrity Advice on exemptions and expedited reviewAdvice on exemptions and expedited review Expertise on human subject issuesExpertise on human subject issues Referral to other sources of expertiseReferral to other sources of expertise

OHRP Assurance Staff OHRP Assurance Staff ((http://ohrp.osophs.dhhs.gov/dpa-staff.htm#Table1http://ohrp.osophs.dhhs.gov/dpa-staff.htm#Table1)) General SBIR/STTR questions - Assurance CoordinatorsGeneral SBIR/STTR questions - Assurance Coordinators** IRB Registration questions - Helen GordonIRB Registration questions - Helen Gordon Federalwide Assurance negotiations - Assurance CoordinatorsFederalwide Assurance negotiations - Assurance Coordinators**

((http://ohrp.osophs.dhhs.gov/dpa-staff.htm#Table2http://ohrp.osophs.dhhs.gov/dpa-staff.htm#Table2) )

*Note: Click on geographic location of awardee for correct AC*Note: Click on geographic location of awardee for correct AC

Things That Can Go Wrong

Doesn’t see PI and subject interests are sameDoesn’t see PI and subject interests are same Investigator waits too long for IRB inputInvestigator waits too long for IRB input Underestimates the value added by the IRB to Underestimates the value added by the IRB to

the integrity of the process and reputation of allthe integrity of the process and reputation of all PI’s unaware of accrual restrictions or is not PI’s unaware of accrual restrictions or is not

informed by funding authority until it’s too lateinformed by funding authority until it’s too late PI falls victim to miscellaneous investigator PI falls victim to miscellaneous investigator

shortcomings (e.g., special protections, protocol shortcomings (e.g., special protections, protocol

revisions, adverse events, and progress reports)revisions, adverse events, and progress reports) ((http://ohrp.osophs.dhhs.gov/references/findings.pdfhttp://ohrp.osophs.dhhs.gov/references/findings.pdf))

Conclusions

Volunteers grant permission with IRB Volunteers grant permission with IRB oversight that is assured in advanceoversight that is assured in advance

Prepare early for human subject issuesPrepare early for human subject issues Know when and from where to get helpKnow when and from where to get help Prepare your application with confidencePrepare your application with confidence Let the system work for you; know when Let the system work for you; know when

it isn’t & confirm with funding authorityit isn’t & confirm with funding authority What’s good for subjects is good for you!What’s good for subjects is good for you!