Presentation on theme: "(617) 632-3029 firstname.lastname@example.org Review, Approval and Oversight of Cancer Research involving Human Subjects at the DF/HCC Office for Human Research."— Presentation transcript:
1 (617) 632-3029 email@example.com Review, Approval and Oversight of Cancer Research involving Human Subjects at the DF/HCCOffice for Human Research Studies (OHRS)(617)
2 General OverviewThe DF/HCC scientific review committees and the DFCI IRBs review all adult and pediatric cancer-related research on behalf of BIDMC; BWH; CHB; DFCI and MGH.
3 National Cancer Center Grant DF/HCC Scientific Review Committees-five committees and an ongoing expedited review process that fall under the protocol review and monitoring system process for oncology research set out in the NCI Cancer Center Support Grant.The Cancer Center Grant requires that we keep the scientific review and IRB review functions separate and distinct.
4 National Cancer Institute Cancer Center Support Guidelines require:1. Scientific review for merit, feasibility, prioritization and accrual2. No guidelines for determining which post approval events such as amendments; deviations; violations; or adverse events require re-review by a scientific review committee.
5 Scientific Review vs. IRB Review There are differences between scientific review and IRB review, e.g.,-conditional approvals-annual progress review
6 Institutional Review Boards DFCI IRBs operate under a Federal Wide Assurance that we have with the U.S. Department of Health and Human Services.DFCI IRBs operate under Federal regulations that specifically dictate the operations and substantive review of the IRBs.DFCI IRBs, on behalf of the DF/HCC, currently have oversight of over 1750 open research protocols involving human subjects.
7 DFCI IRBsInformation Relating to the Operation of IRBs
8 DFCI IRBsIRBs A and B:meet on an alternating basis every Tuesday from 12-2 pm.expertise to review any matter, but focus on new protocols and amendments.
9 DFCI IRBsIRBs C and F:meet on an alternating basis every Thursday morning from 8-10 am.expertise to review any matter but focus on continuing reviews; amendments; adverse events; and other events.
10 DFCI IRBs IRB D: meets twice monthly on Mondays from 10-12 pm was known as the “social and behavioral IRB” or the “minimal risk IRB”, in fact…reviews any research that is not technically clinical intervention research as well as research that is greater than minimal risk.additional bone marrow aspirates;additional blood draws;tissue repository research etc.
11 DFCI IRBs IRB E: “rapid response IRB” small number of members and can respond quickly to an emergent situation.
12 DFCI IRBs IRB G: Pediatric Panel Meets 1st and 3rd Monday of each monthExpertise to review any pediatric matter
16 JHU-FDA Warning Letter to PI March 31, 2003 “Our records indicate that you are aware of your sponsor obligations…we note that on September 15, 1997, you submitted an IND application to the FDA…(FDA) notified you in writing on October 24, 1997, that you were prohibited from initiating any of the submitted protocols due to significant safety concerns and other protocol deficiencies… including inadequate chemistry, purity, and pre-clinical data; inadequate and confusing study procedures and protocols, lack of inclusion criteria, discontinuation criteria, and defined safety parameters; and lack of methodology for adverse event monitoring, treatment, and follow-up of subjects.”
17 Government Shutdowns Massachusetts Eye and Ear Infirmary UCLA VA Health Sys. Greater Los AngelesRush Presbyterian St Luke’s Med Ctr.University of Illinois ChicagoDuke University Med Ctr.Univ. Texas Medical Branch GalvestonUniversity of Oklahoma TulsaJohns Hopkins University
18 Most Common FDA Findings Failure to obtain informed consent of subjects prior to administration of study drug (21 CFR ; 21 CFR 50.20)Failure to provide informed consent information in language understood by the subject (21 CFR 50.20)
19 Most Common FDA Findings Failure to obtain informed consent of subjects involved in research in accordance with 21 CFR 50Legally effective informed consent not obtained from subject or representative (21 CFR , 50.20, 50.27)
20 Columbia University-FDA warning letter February 21,2014Investigator Warning Letter Ralf ZimmermanEnrolled 28 of 50 subjects prior to obtaining consentProvided 10 subjects with investigational agent prior to obtaining consent
21 Still happens… Weill Medical College, May 2004 OHRP Findings:OHRP’s review of IRB documents reveals evidence that the IRB does not always make the required findings when reviewing research involving children, and when the findings are made, they are sometimes inappropriate (e.g. for protocol # , which involved a dose-finding, safety study of a drug in pediatric hypertensive patients, the IRB found that the protocol was approvable under HHS regulations at 45CFR ). Based on OHRP’s discussions with the IRB chairperson and IRB members, OHRP is concerned that the IRB lacks a detailed understanding of HHS regulations at 45 CFR part 46, subpart D, which require specific IRB determinations related to the risks and potential benefits when children are involved as subjects of research.
22 Weill Medical College, May 2004 OHRP Findings:(a) For protocol # , subjects were enrolled outside the protocol age rangeprior to IRB review and approval of the amended protocol.(b) Protocol # stated that subjects would be randomized betweenmetformin and placebo. During our interview, the investigator stated that, amongother things, the protocol was changed to a single arm study without prior IRBreview and approval.(c) For protocol # , between August 12, 2002 and July 22, 2003, theprotocol was changed from a double-blind study to a single blind study. OHRPcould find no evidence of IRB review and approval of this protocol modification.Further, the continuing review form reviewed by the IRB on July 22, 2003 stated“no changes since last continuing review.”
23 Weill Medical College, May 2004 OHRP ActionIn view of the above determinations and in order to ensure adequate protections for human subjects, OHRP hereby restricts the WMC assurance (FWA 93), pending satisfactory completion of the required corrective actions described below.
24 Emory Emory halts enrollment in cancer clinical trials Action at Winship Cancer Institute follows critical audit of proceduresBy Craig SchneiderThe Atlanta Journal-ConstitutionTuesday, June 16, 2009Emory University’s Winship Cancer Institute has stopped accepting new patients into clinical trials after a critical audit, even as it seeks to enhance its standing in the fight against cancer.The center voluntarily halted accepting new patients May 15 following a critical audit of record-keeping for research purposes. The audit was performed by the Eastern Cooperative Oncology Group, a cancer research group that works with Winship.The audit found deficiencies in the research files regarding patients, including missing test results and CAT scans, unreported vital signs such as blood pressure and heart rate, and unreported logs on how often a patient took his or her drugs.
25 Unapproved Protocol Changes Unreported Adverse Events OHRP Compliance Findings: Repeated Deficiencies in Human Subjects ResearchUnapproved ResearchUnapproved Protocol ChangesUnreported Adverse EventsUnreported Unanticipated ProblemsConflicts of InterestMisleading or Deficient Informed ConsentInadequate Initial and Continuing IRB ReviewAvoidable Injuries & Deaths
26 Historical OverviewThe development of protections for human subjects in research.
27 Historical Overview: International Nazi Doctor TrialsNuremberg Code – 1947Informed ConsentDeclaration of HelsinkiWorld Medical Association, Ethical Principles for Medical Research Involving Human Subjects1964 (revised 2000)
28 Historical Overview Public Health Service (PHS) Policy Prior Review of Research by “Institutional Associates” (PPO 129, February 8, 1966)United States Public Health ServiceSyphilis Study at Tuskegee ( )
29 Historical Overview: United States -- 1974 Congressional HearingsSenator Walter MondaleSenator Edward KennedyHHS RegulationsNational Research ActNational Commission for the Protection ofHuman Subjects of Biomedical and Behavioral Research, July 12, 1974
30 Historical Overview: The Belmont Report – April 18, 1979 Ethical Principles and Guidelines for the Protection of Human Subjects of ResearchRespect forPersonsInformed ConsentCapacity to ConsentBeneficenceDo no harmMaximize BenefitJusticeEquitable Selection of SubjectsEquitable Burdens and Benefits
31 Federal Oversight of Human Subject Research Federal Policy for the Protection of Human Subjects (Common Rule)Adopted 1991HHS RegulationsRevised 1981, 1991FDA RegulationsNo Mandatory Protections if not covered by above
32 DHHS Federalwide Assurance (FWA) FWA requires compliance with 45 CFR 46 for Federally Funded/Supported ResearchAll FDA regulated research must comply with applicable FDA regulations even in the absence of Federal Funding or Support
33 Federal Policy (Common Rule) for the Protection of Human Subjects 18 Federal Agencies Adopted DHHS Subpart ASome Agencies Required Additional ProtectionsVA requires compensation for research-related injuriesDoD additional level of review (e.g., HSRRB) for certain types of researchSome Agencies Never Adopted the Federal PolicyDepartment of Labor – Miners and Coal DustAppalachian Regional Commission – Telemedicine
34 DHHS Regulations: 45 CFR Part 46 Subpart A Core Protections Common RuleIRB ReviewInformed ConsentSubpart B Additional ProtectionsPregnant Women, Fetuses, and NeonatesSubpart C Additional ProtectionsPrisonersSubpart D Additional ProtectionsChildren
35 Subpart A: Core Human Subject Protections Federal Policy (Common Rule), DHHS, FDA IRB Review (DHHS 45 CFR Part 46 and FDA 21 CFR Part 56)Initial ReviewProspective Review of All ChangesReporting/Review of Unanticipated ProblemsReporting/Review of Adverse EventsContinuing Review at Least AnnuallyInformed Consent (DHHS 45 CFR Part 46 and FDA 21 CFR Part 50)Eight Required ElementsWritten DocumentationLanguage Understandable to SubjectsNo Coercion or Undue InfluenceNo Waiver of Subjects Rights
36 Roles and Responsibilities: Institutional Responsibility Institutional Commitment and InfrastructureAuthorized Institutional OfficialIRB Chair, IRB Members, IRB StaffData Safety Monitoring Committees/Boards (DSMBs)Other Institutional Committees (Audit)Research Investigators and Co-InvestigatorsEveryone Else Involved in the Research Enterprise (sponsors)
37 Roles and Responsibilities: Institutional Review Board (IRB) Review and Approve Proposed ResearchRisks Minimized through Sound Research DesignRisks Reasonable Relative to BenefitsSubject Selection EquitableInformed Consent ObtainedInformed Consent DocumentedPrivacy and Confidentiality Protections AdequateSafety Monitoring is AdequateProtections for Vulnerable Subjects are AdequateExercise Continuing Oversight of Research
38 Roles and Responsibilities: Institutional Review Board (IRB) IRBs are also required to review HHS grants to ensure that the protocol submitted to the IRB is consistent with the grant application
39 Risks Minimized Through Sound Research Design Family of Subject who died in Gene Therapy Trial sponsored by Targeted Genetics is suing the company, the IRB and the principal investigator.The basis of the lawsuit is not so much objections to the informed consent document as the contention that “someone with a mild case of rheumatoid arthritis should not be enrolled in a gene therapy trial.”The science of the protocol could not justify enrollment of this type of subject in the research.
40 Roles and Responsibilities: Principal Investigators Accept responsibility for all aspects of the researchEnsure adequate training for entire research teamEnsure adequate supervision of entire research teamKnow and ensure compliance withAll regulatory requirementsAll IRB requirementsAll protocol requirementsEnsure adherence to enrollment criteriaMonitor and report unanticipated problems and adverse events to sponsor and IRB
41 Roles and Responsibilities: Principal Investigators University of Pittsburgh, FDA warning letter, September 15, 2009-John M Kirkwood1. failed to conduct procedures required by protocol2. changed protocol without going through the IRB and FDA3. failed to follow-up and collect adverse event information4. failed to report serious adverse events experienced by three subjects5. failed to prepare and maintain case histories6. failed to monitor the progress of the clinical investigation
42 Applying the Regulations to Research Involving Human Subjects
43 Definition of Research: HHS, Federal Policy (Common Rule) “Research” means:A systematic investigationDesigned to develop or contribute toGeneralizable knowledgeIncludes:Research developmentTestingEvaluationPilot Studies
44 Definition of Research “Research” means:A systematic investigation designed to develop or contribute to generalizable knowledgeWhat does “Systematic” mean?Carried out according to a planPermitting logical conclusions to be drawnWhat does “Generalizable” mean?Beyond the immediate situationBeyond the institution
45 Manhattan Eye, Ear and Throat Hospital Incident
46 Definition of Human Subject: “Human Subject” means:a living individualabout whom an investigator…conducting research obtains:data through intervention or interaction with the individual, oridentifiable private information-- 45 CFR (f)
48 Definition of Human Subject: “Private Information” means:Information about behavior in a context in which an individual can reasonably expect that no observation or recording is taking placeInformation, provided for specific purposes, that the individual can reasonably expect will not be made public (e.g., a medical record)-- 45 CFR (f)
50 Institutional Review Board (IRB): Mission, Duties, Authorities Mission To protect the rights and welfare of individuals participating in research involving human subjectsDuties To approve, disapprove, modify, suspend research as necessary to ensure protections for human subjects in researchAuthority To exercise final authority within the institution for ensuring adequate protections for subjects. Officials of the institution may not approve research if it has not been approved by an IRB.Institutional Authority Beyond Regulations Delegated to IRBEthical Issues on behalf of institutionSanctioning Investigators for noncomplianceUse of “tainted” data
51 IRB Review and Approval Routine oversight mechanisms:Initial ReviewContinuing ReviewReview of Adverse EventsReview of Unanticipated ProblemsSpecial oversight mechanismsData & Safety Monitoring Boards (DSMBs)Consent MonitorsRandom Audits of ResearchContinuing Education
52 IRB Approval (Initial or Continuing) Includes Findings That … Risks are minimized through sound research designRisks are reasonable relative to anticipated benefitsSelection of subjects is equitableInformed consent will be obtainedInformed consent will be documentedPrivacy and Confidentiality provisions are adequateData safety monitoring is adequateAppropriate safeguards are included for vulnerable subjects
53 Types of IRB ReviewDetermination whether activity is Human Subject ResearchVerification of ExemptionExpedited ReviewConvened (Full Board) ReviewNOTE: Initial and Continuing Review require votes of the convened IRB, meeting all quorum requirements, unless specific conditions for use of expedited review are satisfied
54 Institutional Review Board (IRB): Composition Minimum of 5 membersDiverse in gender and racial backgroundSufficiently qualified in experience and expertise(e.g., pediatric expertise required to review research involving children)One scientific memberNon-scientific memberOne member not otherwise affiliated with the institutionExpertise in vulnerable populations for regular review of such research
55 Convened (Full Board) Review Majority of Total Membership Must Be PresentNon-Scientist Member Must Be Present (not lay member)Approval Requires a Majority of Those Members PresentVote Must Be DocumentedSame Requirements for Initial and Continuing ReviewImportant that documentation demonstrate that the IRB is making the appropriate regulatory determinations
56 IRB Meetings and Record Keeping All members receive complete set of materialsAdequate time to review materialsMinutes of meetings must be comprehensiveAttendance and votes should be recordedOHRP permits teleconferencing if each participating member (i) has received all pertinent material prior to the meeting; and (ii) can actively and equally participate in the discussion of all protocols
57 Types of IRB determinations ApprovalConditional ApprovalDeferralDisapproval
58 Conditional Approval From OHRP Common Findings Contingent Approval of Research with Substantive Changes and no Additional Review by the Convened IRB.OHRP finds that the IRB frequently approves research contingent upon substantive modifications or clarifications without requiring additional review by the convened IRB.
59 Expedited Review: Minor Changes to Approved Research MINOR changes in previously approved researchDuring the established approval periodConducted by Chair or IRB member designated by ChairMust be reported to full IRBNo disapprovals, e.g., a decision to disapprove a requested deviation must be sent to the full board.-- 45 CFR
60 Expedited Review Minimal Risk Research in the Following Categories: 1) Clinical studies of drugs and medical devices where an IND (drugs) or IDE (devices) is not required.2) Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture:a) from healthy, non-pregnant adults weighing at least 100 lbs: 550 ml in 8-wk period, limited to 2 collections per week;b) from other adults and children, not more than 50 ml or 3 ml per kg in 8-wk period, limited to 2 collections per week.
61 Expedited Review Minimal Risk Research in the Following Categories: 3) Prospective collection of biological specimens by noninvasive means4) Collection of data through noninvasive procedures (not involving general anesthesia or sedation) employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed, they must be cleared/ approved for marketing. (Studies intended to evaluate the safety and effectiveness of the medical device are no generally eligible for expedited review, including studies of cleared medical devices for new indications.)
62 Expedited Review Minimal Risk Research in the Following Categories: 5) Research involving materials (data, documents, records, or specimens) that:have been collectedwill be collected for non-research purposes6) Collection of data from voice, video, digital, or image recordings made for research purposes.
63 Expedited Review Minimal Risk Research in the Following Categories: 7) Research on individual or group behavior or characteristics -- cognition, motivation, identity, language, communication, cultural beliefs/practices, social behavior; survey, interview, oral history, focus group, program evaluation, human factor, quality assurance methodologies.
64 Expedited Review Minimal Risk Research in the Following Categories: 8) Continuing review of research previously approved by the convened IRB wherea) the research is permanently closed to new enrollments, all subjects have completed all research-related interventions, and research remains active only for long-term follow-up of subjects; orb) no subjects have been enrolled and no additional risks have been identified; orc) remaining research activities are limited to data analysis.
65 Expedited Review Minimal Risk Research in the Following Categories: 9) Continuing review of research… where… the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk, and no additional risks have been identified.Critical Catchall Provision – Note documentation requirement
66 Expedited Review: Compliance Problems Inappropriate use of expedited reviewgreater than minimal riskno appropriate categoryfailure to document category and determinationGreater than minor changes to approved researchInappropriate use for Continuing Review
68 Six Exemptions: 45 CFR 46.101(b) 1) Research conducted in:Established or commonly accepted educational settingsInvolving normal educational practicesInstructional strategy comparisons
69 Six Exemptions: 45 CFR 46.101(b) 2) Research involving the use of:Educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behaviorUNLESSinformation is recorded in an (directly or indirectly) identifiable manner (NOTE: Coded = identifiable)ANDdisclosure would place subject at risk of criminal or civil liability or be damaging to financial standing, employability, or reputation
70 Six Exemptions: 45 CFR 46.101(b) Special Consideration involving ChildrenSurvey and Interview Research Involving Children IS NOT ExemptPassive Observation of Public Behavior Involving Children IS ExemptParticipant Observation of Public Behavior Involving Children IS NOT ExemptIRB Needs Copy of All Surveys and Interview Scripts (unless standard test known to IRB)
71 Six Exemptions: 45 CFR 46.101(b) 3) Research involving the use of:Educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behaviorWHEREsubjects are elected or appointed public officials or candidates for public officeorFederal statutes require confidentiality without exception
72 Six Exemptions: 45 CFR 46.101(b) 4) Research involving the collection or study of:existing data, documents, records, specimens, if:the sources are publicly availableorthe information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.NOTE: Even brief recording of identifiers or codes disqualifies the exemption
73 Definition of “Existing” “Existing” means:All data has been collected (i.e., on the shelf) prior to the researchFor a purpose other than the proposed researchIncludes data (or specimens) collected in research and non research activities.
74 Six Exemptions: 45 CFR 46.101(b) 5) Research and demonstration programs designed to study, evaluate, or examine (Federal) Public Benefit or Service Programs6) Taste and food quality evaluation and consumer acceptance studies involving:wholesome foods without additivesadditives, chemical, contaminants below safe levels determined by FDA, EPA, USDA
76 Eight Required Elements: 45 CFR 46.116(a) Statement that study is research and information on purposes/duration/procedures/experimental proceduresReasonably foreseeable risks or discomfortsReasonably expected benefitsAlternative procedures (including availability off-protocol where applicable)How confidentiality will be maintainedInformation on compensation for injuries (unless minimal risk)Contact Persons for info on research, injury, subjects’ rightsVoluntary participation, no penalty or loss of benefits for refusal or withdrawal
77 Six Additional Elements Statement that there may be risks which are unforeseeableUnder what circumstances investigator could terminate subject’s participationAdditional costs to subjectConsequences of subjects withdrawal from researchStatement that will be told of new findingsApproximate number of subjects in study
78 The Support TrialConducting research on the current standard of care
79 Informed Consent: Special Issues There is no such thing as “passive consent”consent is required unless formally waiveddocumentation is required unless formally waivedThere is no such thing as a “secondary subject”if an investigator obtains “identifiable private information” about a living individual, the individual is a human subject, regardless of the source
80 Waiver of Informed Consent (Not Permitted Under FDA Regulations) IRB must find and document that 4 criteria met:Minimal risk researchWaiver or alteration will not adversely affect the rights and welfare of the subjectsResearch could not practicably be carried out without the waiver or alterationSubjects will be provided with additional pertinent information
81 Documentation of Informed Consent Written consent documentIn language understandable to the subject or the subject’s Legally Authorized Representative (LAR)Verification of translated consent documentSigned by subject or subject’s LARCopy SHALL be given to subjectOpportunity to read before signing
82 Documentation of Informed Consent Short form written consent document requires :oral presentationwitness to oral presentationan IRB approved written summarygiven to subjectsigned by witnesssigned by person obtaining consentshort form documenting oral presentationsigned by subject or LAR
83 Waiver of Documentation of Informed Consent (Not Permitted by FDA Regs) The Signed Consent Document provides the only link to the subject’s identity and principal risk is breach of confidentialityThe research presents no greater than minimal risk of harm to subjects and involves no procedures requiring consent in a non-research contextIRB may require a subject information sheet
85 Adverse Events v. UPIRSO FDA Regulatory TermsAdverse EventsUnanticipated Problems Involving Risks to Subjects and OthersReportable eventsHHS Regulatory LanguageUnanticipated Problems Involving Risks to Subjects and OthersReportable Events
86 Risks to Subjects Adverse events vs. unanticipated problems A risk or problem is unanticipated if it is not in the protocol or consent document.Risks discussed in the protocol should be included in the consent documentQuestions raised as a result of an unanticipated risk:Does the informed consent form need to be amended?Do previously enrolled subjects need to be re-consented?Does a report need to be made to any government office?
87 Protocol Deviations Very detailed protocol Missing a dose Intervention on the wrong dayAll become protocol deviationsWrite protocols more broadlyRange for dosingRanging for timingLess likely that differences in regimen will become a protocol deviation
88 Protocol DeviationsUniversity of Oklahoma – July 2000 suspension of researchTesting of a vaccine on subjects with melanomaThree year trialNumerous violations of study protocolshipping vaccine to subjects for self-injectioninadequate staffinginadequate supervision of sponsor’s manufacturing facilities
89 Protocol Deviations Univ. of Oklahoma June 29, 2000 letter from OHRP to Univ. OK“OHRP finds that the principal investigator implemented substantive changes to the research project without IRB approval. The changes made without IRB approval included, but are not limited to the following:(a) The investigator deviated from the IRB-approved inclusion and exclusion criteria. In specific, 11 of the first 18 subjects enrolled in the protocol did not satisfy all IRB-approved inclusion/exclusion criteria. Of note, the IRB Chair unilaterally approved these deviations retroactively…”
90 Protocol Deviations Univ. of Oklahoma (cont.) (b) Sample size was increased above the total subject number approved by the IRB (15 for phase I and 25 for phase II); by November 17, 1999, total subject enrollment had increased to more than 90.(c) The study vaccine was shipped to some subjects’ homes for self-administration by the subjects. Of note, the IRB-approved protocol prior to November 19, 1999 stated the following:the Nurse Coordinator will give all injections. She will record any transient erythematous reactions and refer patients with any other side effects… to Dr. McGee… Patients will be required to remain in the physician’s office for 30 minutes afterward.”
91 Protocol Deviations Univ. of Oklahoma (cont.) (d) Some subjects were allowed to self-monitor for adverse local reactions following vaccine administration.(e) The investigator added several remote study sites and co-investigators.(f) Non-physicians were used to perform some protocol-stipulated physical exams that were to have been performed by a physician under the IRB-approved protocol.”
93 FDA Regulations Informed Consent - 21 CFR Part 50 IRB Review - 21 CFR Part 56Investigational Drugs - 21 CFR Part 312Marketing Approval - 21 CFR Part 314Biologics - 21 CFR Part 600Biologics Licensing – 21 CFR Part 601Investigational Devices - 21 CFR Part 812Pre-Market Approval – 21 CFR Part 814Financial Disclosure – 21 CFR Part 54Electronic Records – 21 CFR Part 11
94 FDA Regulations Informed Consent -- 21 CFR 50 IRB Review -- 21 CFR 56 Eight Required ElementsWritten DocumentationLanguage Understandable to SubjectsNo Coercion or Undue InfluenceNo Waiver of Subjects RightsIRB Review CFR 56Initial ReviewProspective Review of All ChangesReporting/Review of Unanticipated ProblemsReporting/Review of Adverse EventsContinuing Review at Least Annually
95 FDA Regulations Drugs and Biologics Devices Investigational New Drug Application (IND)21 CFR Part 312DevicesInvestigational Device Exemption (IDE)21 CFR Part 812
96 FDA Regulations: When is an IND Needed? Any use in which a marketed or un-marketed drug is administered or dispensed to, or used involving, one or more human subjects, except for:Use of a marketed drug in course of medical practice, orInvestigation of a marketed drug where there is:No intent to support a new indication for use or other significant change in labeling;No intent to support a significant change in advertising;No factor such as route of administration, dosage, or patient population that increases or decreases the acceptability of risks associated with the product;Compliance with FDA Informed Consent and IRB Review requirements; andNo promotion or representation of the drug as safe or effective for the purpose under investigation.
97 FDA Regulations: Responsibilities of Sponsors Maintaining the INDObtaining Qualified Investigators and MonitorsProviding Necessary Information/Training for InvestigatorsMonitoring the InvestigationControlling the Investigational AgentReporting Significant Adverse Events to FDA/InvestigatorsMaintaining and Retaining Accurate Records
98 FDA Regulations: Responsibilities of Investigators Specific Responsibilities:Ensuring Conduct of the Research per the Investigator Agreement, Investigational Plan, and All Applicable RegulationsProtecting the Rights, Safety, and Welfare of the Research SubjectsControlling access to and use of the test article (drug / biologic / device)Monitoring and Reporting Adverse EventsMaintaining and Retaining Accurate Records
99 FDA Reporting Requirements: IND - Adverse Event Reporting Investigator must report promptly (immediately if alarming) to the Sponsor any adverse effect that may reasonably be regarded as caused by the drug (21 CFR )Sponsor must notify FDA of any adverse experience associated with the drug that is both serious and unexpectedSerious Adverse Drug Experience = death, life-threatening, hospitalization, persistent /significant disability / incapacity, congenital anomaly / birth defect (21 CFR )Unexpected Drug Experience = any adverse drug experience, the specificity or severity of which is not consistent with the current investigator brochure or IND application (21 CFR )
100 FDA Reporting Requirements: IDE - Adverse Event Reporting Investigator must report any unanticipated adverse device effect to Sponsor and the IRB as soon as possible and within 10 working days [21 CFR ]Sponsor must report any unanticipated adverse device effect to FDA, all reviewing IRBs, and investigators [21 CFR ]Unanticipated Adverse Device Effect = any serious adverse effect on health or safety, or any life-threatening problem or death, caused by or associated with a device if not previously identified in nature, severity, or degree of incidence in the investigational plan or application [21 CFR 812.3]
101 FDA Regulation Exceptions & Exemptions: Emergency Use of a Test Article Without Informed Consent – 21 CFR 50.23(a)Life Threatening Situation Necessitating the UseInability to Communicate with Subject for Legal ConsentInsufficient Time to Obtain Consent from Legally Authorized Representative (LAR)No Alternative Therapy AvailableCertification in Writing from Investigator and an other Nonparticipating Physician of the AboveReport to IRB Within 5 Working Days
102 FDA Regulation Exceptions & Exemptions: Emergency Use of a Test Article (cont.) No IRB Review – 21 CFR (c)Life Threatening Situation Necessitating the UseNo Alternative AvailableInsufficient time for IRB reviewReport to IRB Within 5 Working DaysSubsequent Use Requires IRB Review
103 FDA Regulations: Single Patient IND Commonly referred to as compassionate useRequires Informed Consent and IRB review 21 CFRSee OHRS website for guidance
104 FDA Device Regulations: “Compassionate Use” Compassionate Use of an Unapproved Device may be approved by FDA when it is the only option for a patient with a serious conditionRequires as many of the following as possible:Informed ConsentInstitutional ApprovalConcurrence of IRB Chair (but NOT IRB APPROVAL)Independent Assessment of Uninvolved PhysicianAuthorization of the Sponsor
105 FDA Regulations: Devices SR Devices vs. NSR Devices IRB Must Make a Specific DeterminationSignificant Risk Device = Investigational device that presents a potential for serious risk to the health, safety, or welfare of subjects, including implantsNon-Significant Risk Device = Investigational devices that does NOT present the potential for serious risk to the health, safety, or welfare of subjectsNon-Significant Risk is NOT the same as Minimal RiskOnce IRB-approves the research as not involving a Significant Risk Device, the research is considered to have an approved IDE, unless the FDA has notified the sponsor otherwise.
106 FDA Regulations: “Off-Label Use” FDA-approved products (i.e., marketed products) may be used by physicians outside of labeled indications FOR THE PRACTICE OF MEDICINESuch use in RESEARCH (i.e., as part of a systematic investigation designed to develop or contribute to generalizable knowledge) requires IRB REVIEWSuch use intended to support a CHANGE in labeling requires IRB REVIEW and an IND / IDE
107 FDA Regulations: Humanitarian Device Exemption (HDE) Humanitarian Use Device (HUD)Device tested but not profitable for marketingRequires:IRB Review (Limited) and ApprovalNo Research Informed Consent
108 FDA Regulations: Planned “Emergency” Research Ordinarily Requires IRB Review and Informed Consent of Subject or Subject’s Legally Authorized Representative (as determined by State Law for Research Contexts)Exception from Informed Consent Requirement Involves Many Specific IRB Determinations and Approval by FDA or OHRP
109 Protections for Vulnerable Subjects Under SectionsVulnerable to Coercion or Undue Influenceeg: Handicapped, Disabled, Economically or Socially Disadvantaged PersonsHHS Subpart BPregnant Women, Human Fetuses, and NeonatesHHS Subpart CPrisonersHHS Subpart DChildren
110 HHS Subpart B: Research Involving Pregnant Women, Human Fetuses, and Neonates Subpart B -- Revised December 2001Research involving pregnant womenResearch involving fetusesResearch involving neonates of uncertain viability, nonviable neonates, or viable neonates
111 HHS Subpart B: 45 CFR 46.204 Research Involving Pregnant Women or Fetuses Any research that TARGETS pregnant women or fetuses requires a special and specific regulatory review.Any such research should be submitted directly to senior staff at OPRS since the IRB will need special training for the review and approval of this type of research.
112 HHS Subpart C: 45 CFR 46.303(c) Research Involving Prisoners Definition of a PrisonerAny individual involuntarily confined or detained in a penal institution under a criminal or civil statuteIndividuals detained in other facilities as an alternative to criminal prosecution or incarceration in a penal institutionIndividuals detained pending arraignment, trial, or sentencing
113 HHS Subpart C: Research Involving Prisoners Prisoner representative on OHRP approved rosterAdditional duties underFinding of permissible category underCertification to OHRPConcurrence from OHRP
114 Lawsuit Involving Prisoners DOJ funded research in Pennsylvania prison:mandatory drug testing (urine vs. hair)no consentsolitary confinement for refusal to be testedfacts of case not contestedAcres of SkinDow, U Pennsylvania, City of PhiladelphiaPrisoners told experiments were harmless
116 Definition of Minimal Risk Definition impacts:Pediatric StudiesImportant for determining whether a research protocol or change in research can be expedited or must go to the full board.Waiver of ConsentDocument of Consent
117 Definition of Minimal Risk: FDA, HHS, Federal Policy “Minimal Risk” means:The probability and magnitude of harm or discomfortAre not greater than those ordinarily encountered in daily life;orDuring the performance of routine physical or psychological examinations or tests.
118 HHS Subpart D & FDA Subpart D: Research Involving Children Category Determinations RequiredSpecific Approval Criteria for Each CategoryProtocol-Specific Justification RequiredNot greater than minimal riskGreater than minimal riskProspect of direct benefitNo prospect of direct benefitResearch not otherwise approvable
119 Children may be involved in research where the IRB finds that: Subpart D: 45 CFR & 21 CFR Research involving no greater than minimal riskChildren may be involved in research where the IRB finds that:The research presents no greater than minimal risk to the childAdequate provision are made for obtainingThe assent of the childThe permission of the child’s parents or guardians
120 NICHD TrialIn the minutes of the NICHD IRB, they noted that for one protocol, there was more risk to children in crossing the street than in spending two days in the hospital hooked up to an IV line….
121 Subpart D: 45 CFR & 21 CFR Greater than minimal risk but presenting prospect of direct benefit to individual subjectsChildren may be involved in research where the IRB finds that more than minimal risk to children is presented by (i) an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or (ii) a monitoring procedure that is likely to contribute to the subject’s well-being if:The risk is justified by anticipated benefit to subjects;The relation of anticipated benefit to risk is at least as favorable as available alternatives;Assent of child and permission of parents are sought.
122 Subpart D: 45 CFR & 21 CFR 50.53: Research involving greater than minimal risk and no prospect of direct benefit to individual subjectsChildren may be involved in research presenting more than minimal risk without the prospect of direct benefit or increased well being for the subject if:Risk is a minor increase over minimal riskResearch presents situations reasonably equal to to those inherent in their actual situationsResearch is likely to yield generalizable knowledge about disorder or conditionAdequate provisions for obtaining child assent and parental permission.
123 Fenfluramine Study New York State Psychiatric Institute Mount Sinai School of MedicineQueens CollegeThe study focused on 34 boys between the ages of 6 and 10 who had brothers with violent tendencies as reflected in court cases.The boys were given fenfluramine.Did children with siblings who were juvenile delinquents have a greater propensity towards juvenile delinquency.
124 Fenfluramine StudySince the study did not provide any benefit, was it likely to yield generalizable knowledge about an underlying condition or disorder?
125 IRB finds the research presents opportunity as above Subpart D: 45 CFR & 21 CFR 50.54: Research not otherwise approvable but presenting opportunity to understand, prevent, or alleviate a serious problem affecting health or welfare of childrenIRB finds the research presents opportunity as aboveHHS Secretary, after consultation with panel of experts & public review and comment, determines:The research presents reasonable opportunity as aboveThe research will be conducted in accordance with sound ethical principlesAdequate provisions are made for obtaining child assent and parental permission
126 Subpart D: Research Involving Children Parental Permission Required Permission of Both Parents Required If Greater than Minimal Risk, unless:One parent not reasonably availableOne parent has sole custodyStandard HHS Waiver Not Contained in FDA RegulationsHHS Waiver in Interest of Child Not Contained in FDA Regulations45 CFR
127 Subpart D: Research Involving Children — Assent of Child Required Developmentally Appropriate as Determined by IRBDocumentation as Determined by IRBUnless the Research Holds the Prospect of Direct Benefit Available Only in the ResearchOrUnless Waived by IRB per criteria at 45 CFR (d)45 CFR
128 What happens if a child reaches the legal age of consent? Subject is a child enrolled in researchSubject reaches the age of majorityIRB can:waive informed consent if can meet 4 regulatory requirementsotherwise, investigators have to re-consent the individuals
130 Types of Conflict of Interest IndividualClinical investigatorsStudy coordinatorsResearch techniciansResearch officialsIRB membersInstitutionalFinancial holdings of the institutionDecisions regarding research funding or allocation of resources for researchFinancialConsulting feesStock ownershipHonorariaSalaryIntellectual property rightsEnrollment bonusesSpouse / dependent financesProfessionalPressure to publishProfessional rivalriesCareer advancement