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DF/ HCC DANA-FARBER / HARVARD CANCER CENTER Beth Israel Deaconess Medical Center / Brigham and Women’s Hospital / Children’s Hospital Boston / Dana-Farber.

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Presentation on theme: "DF/ HCC DANA-FARBER / HARVARD CANCER CENTER Beth Israel Deaconess Medical Center / Brigham and Women’s Hospital / Children’s Hospital Boston / Dana-Farber."— Presentation transcript:

1 DF/ HCC DANA-FARBER / HARVARD CANCER CENTER Beth Israel Deaconess Medical Center / Brigham and Women’s Hospital / Children’s Hospital Boston / Dana-Farber Cancer Institute / Harvard Medical School / Harvard School of Public Health / Massachusetts General Hospital Review, Approval and Oversight of Cancer Research involving Human Subjects at the DF/HCC Office for Human Research Studies (OHRS) (617) 

2 Office for Human Research Studies 2 General Overview The 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 Office for Human Research Studies 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 Office for Human Research Studies 4 National Cancer Institute Cancer Center Support Guidelines require: 1. Scientific review for merit, feasibility, prioritization and accrual 2. 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 Office for Human Research Studies 5 Scientific Review vs. IRB Review There are differences between scientific review and IRB review, e.g., -conditional approvals -annual progress review

6 Office for Human Research Studies 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 Office for Human Research Studies 7 DFCI IRBs Information Relating to the Operation of IRBs

8 Office for Human Research Studies 8 DFCI IRBs IRBs 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 Office for Human Research Studies 9 DFCI IRBs IRBs 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 Office for Human Research Studies 10 DFCI IRBs IRB D:  meets twice monthly on Mondays from 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 Office for Human Research Studies 11 DFCI IRBs IRB E:  “rapid response IRB”  small number of members and can respond quickly to an emergent situation.

12 Office for Human Research Studies 12 DFCI IRBs IRB G:  Pediatric Panel  Meets 1 st and 3 rd Monday of each month  Expertise to review any pediatric matter

13 Office for Human Research Studies 13 Institutions in the News

14 Office for Human Research Studies 14

15 Office for Human Research Studies 15

16 Office for Human Research Studies 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 Office for Human Research Studies 17 Government Shutdowns Massachusetts Eye and Ear Infirmary UCLA VA Health Sys. Greater Los Angeles Rush Presbyterian St Luke’s Med Ctr. University of Illinois Chicago Duke University Med Ctr. Univ. Texas Medical Branch Galveston University of Oklahoma Tulsa Johns Hopkins University

18 Office for Human Research Studies 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) 18

19 Office for Human Research Studies Most Common FDA Findings Failure to obtain informed consent of subjects involved in research in accordance with 21 CFR 50 Legally effective informed consent not obtained from subject or representative (21 CFR , 50.20, 50.27) 19

20 Office for Human Research Studies Columbia University-FDA warning letter February 21,2014 Investigator Warning Letter Ralf Zimmerman 1. Enrolled 28 of 50 subjects prior to obtaining consent 2. Provided 10 subjects with investigational agent prior to obtaining consent 20

21 Office for Human Research Studies 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 Office for Human Research Studies 22 Weill Medical College, May 2004 OHRP Findings: (a) For protocol # , subjects were enrolled outside the protocol age range prior to IRB review and approval of the amended protocol. (b) Protocol # stated that subjects would be randomized between metformin and placebo. During our interview, the investigator stated that, among other things, the protocol was changed to a single arm study without prior IRB review and approval. (c) For protocol # , between August 12, 2002 and July 22, 2003, the protocol was changed from a double-blind study to a single blind study. OHRP could 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 Office for Human Research Studies 23 Weill Medical College, May 2004 OHRP Action  In 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 Office for Human Research Studies 24 Emory Emory halts enrollment in cancer clinical trials Action at Winship Cancer Institute follows critical audit of procedures By Craig SchneiderCraig Schneider The Atlanta Journal-Constitution Tuesday, June 16, 2009 Emory 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 Office for Human Research Studies OHRP Compliance Findings: Repeated Deficiencies in Human Subjects Research Unapproved Research Unapproved Protocol Changes Unreported Adverse Events Unreported Unanticipated Problems Conflicts of Interest Misleading or Deficient Informed Consent Inadequate Initial and Continuing IRB Review Avoidable Injuries & Deaths 25

26 Office for Human Research Studies 26 Historical Overview The development of protections for human subjects in research.

27 Office for Human Research Studies 27 Historical Overview: International Nazi Doctor Trials  Nuremberg Code – 1947  Informed Consent Declaration of Helsinki  World Medical Association, Ethical Principles for Medical Research Involving Human Subjects  1964 (revised 2000)

28 Office for Human Research Studies 28 Historical Overview Public Health Service (PHS) Policy  Prior Review of Research by “Institutional Associates” (PPO 129, February 8, 1966) United States Public Health Service  Syphilis Study at Tuskegee ( )

29 Office for Human Research Studies 29 Historical Overview: United States Congressional Hearings  Senator Walter Mondale  Senator Edward Kennedy HHS Regulations National Research Act  National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, July 12, 1974

30 Office for Human Research Studies 30 Historical Overview: The Belmont Report – April 18, 1979 Ethical Principles and Guidelines for the Protection of Human Subjects of Research Respect for Persons Informed Consent Capacity to Consent Beneficence Do no harm Maximize Benefit Justice Equitable Selection of Subjects Equitable Burdens and Benefits

31 Office for Human Research Studies 31 Federal Oversight of Human Subject Research Federal Policy for the Protection of Human Subjects (Common Rule)  Adopted 1991 HHS Regulations  Revised 1981, 1991 FDA Regulations  Revised 1981, 1991 No Mandatory Protections if not covered by above

32 Office for Human Research Studies 32 DHHS Federalwide Assurance (FWA) FWA requires compliance with 45 CFR 46 for Federally Funded/Supported Research All FDA regulated research must comply with applicable FDA regulations even in the absence of Federal Funding or Support

33 Office for Human Research Studies 33 Federal Policy (Common Rule) for the Protection of Human Subjects 18 Federal Agencies Adopted DHHS Subpart A Some Agencies Required Additional Protections  VA requires compensation for research-related injuries  DoD additional level of review (e.g., HSRRB) for certain types of research Some Agencies Never Adopted the Federal Policy  Department of Labor – Miners and Coal Dust  Appalachian Regional Commission – Telemedicine

34 Office for Human Research Studies 34 DHHS Regulations: 45 CFR Part 46 Subpart A  Core Protections  Common Rule  IRB Review  Informed Consent Subpart B  Additional Protections  Pregnant Women, Fetuses, and Neonates Subpart C  Additional Protections  Prisoners Subpart D  Additional Protections  Children

35 Office for Human Research Studies 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 Review  Prospective Review of All Changes  Reporting/Review of Unanticipated Problems  Reporting/Review of Adverse Events  Continuing Review at Least Annually Informed Consent (DHHS 45 CFR Part 46 and FDA 21 CFR Part 50)  Eight Required Elements  Written Documentation  Language Understandable to Subjects  No Coercion or Undue Influence  No Waiver of Subjects Rights

36 Office for Human Research Studies 36 Roles and Responsibilities: Institutional Responsibility Institutional Commitment and Infrastructure Authorized Institutional Official IRB Chair, IRB Members, IRB Staff Data Safety Monitoring Committees/Boards (DSMBs) Other Institutional Committees (Audit) Research Investigators and Co-Investigators Everyone Else Involved in the Research Enterprise (sponsors)

37 Office for Human Research Studies 37 Roles and Responsibilities: Institutional Review Board (IRB) Review and Approve Proposed Research  Risks Minimized through Sound Research Design  Risks Reasonable Relative to Benefits  Subject Selection Equitable  Informed Consent Obtained  Informed Consent Documented  Privacy and Confidentiality Protections Adequate  Safety Monitoring is Adequate  Protections for Vulnerable Subjects are Adequate Exercise Continuing Oversight of Research

38 Office for Human Research Studies 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 Office for Human Research Studies 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 Office for Human Research Studies 40 Roles and Responsibilities: Principal Investigators Accept responsibility for all aspects of the research Ensure adequate training for entire research team Ensure adequate supervision of entire research team Know and ensure compliance with  All regulatory requirements  All IRB requirements  All protocol requirements Ensure adherence to enrollment criteria Monitor and report unanticipated problems and adverse events to sponsor and IRB

41 Office for Human Research Studies 41 Roles and Responsibilities: Principal Investigators University of Pittsburgh, FDA warning letter, September 15, 2009-John M Kirkwood 1. failed to conduct procedures required by protocol 2. changed protocol without going through the IRB and FDA 3. failed to follow-up and collect adverse event information 4. failed to report serious adverse events experienced by three subjects 5. failed to prepare and maintain case histories 6. failed to monitor the progress of the clinical investigation

42 Office for Human Research Studies 42 Applying the Regulations to Research Involving Human Subjects

43 Office for Human Research Studies 43 Definition of Research: HHS, Federal Policy (Common Rule) “Research” means:  A systematic investigation  Designed to develop or contribute to  Generalizable knowledge  Includes: Research development Testing Evaluation Pilot Studies

44 Office for Human Research Studies 44 Definition of Research “Research” means:  A systematic investigation designed to develop or contribute to generalizable knowledge What does “Systematic” mean? –Carried out according to a plan –Permitting logical conclusions to be drawn What does “Generalizable” mean? –Beyond the immediate situation –Beyond the institution

45 Office for Human Research Studies 45 Manhattan Eye, Ear and Throat Hospital Incident

46 Office for Human Research Studies 46 Definition of Human Subject: “Human Subject” means:  a living individual  about whom an investigator…conducting research obtains: 1)data through intervention or interaction with the individual, or 2)identifiable private information CFR (f)

47 Office for Human Research Studies 47 VCU Twin Study

48 Office for Human Research Studies 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 place  Information, provided for specific purposes, that the individual can reasonably expect will not be made public (e.g., a medical record) CFR (f)

49 Office for Human Research Studies 49 IRB Requirements and Procedures

50 Office for Human Research Studies 50 Institutional Review Board (IRB): Mission, Duties, Authorities Mission  To protect the rights and welfare of individuals participating in research involving human subjects Duties  To approve, disapprove, modify, suspend research as necessary to ensure protections for human subjects in research Authority  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 IRB  Ethical Issues on behalf of institution  Sanctioning Investigators for noncompliance  Use of “tainted” data

51 Office for Human Research Studies 51 IRB Review and Approval Routine oversight mechanisms:  Initial Review  Continuing Review  Review of Adverse Events  Review of Unanticipated Problems Special oversight mechanisms  Data & Safety Monitoring Boards (DSMBs)  Consent Monitors  Random Audits of Research  Continuing Education

52 Office for Human Research Studies 52 IRB Approval (Initial or Continuing) Includes Findings That … Risks are minimized through sound research design Risks are reasonable relative to anticipated benefits Selection of subjects is equitable Informed consent will be obtained Informed consent will be documented Privacy and Confidentiality provisions are adequate Data safety monitoring is adequate Appropriate safeguards are included for vulnerable subjects

53 Office for Human Research Studies 53 Types of IRB Review Determination whether activity is Human Subject Research Verification of Exemption Expedited Review Convened (Full Board) Review NOTE: 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 Office for Human Research Studies 54 Institutional Review Board (IRB): Composition Minimum of 5 members Diverse in gender and racial background Sufficiently qualified in experience and expertise  (e.g., pediatric expertise required to review research involving children) One scientific member Non-scientific member One member not otherwise affiliated with the institution Expertise in vulnerable populations for regular review of such research

55 Office for Human Research Studies 55 Convened (Full Board) Review Majority of Total Membership Must Be Present Non-Scientist Member Must Be Present (not lay member) Approval Requires a Majority of Those Members Present Vote Must Be Documented Same Requirements for Initial and Continuing Review Important that documentation demonstrate that the IRB is making the appropriate regulatory determinations

56 Office for Human Research Studies 56 IRB Meetings and Record Keeping All members receive complete set of materials Adequate time to review materials Minutes of meetings must be comprehensive Attendance and votes should be recorded OHRP 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 Office for Human Research Studies 57 Types of IRB determinations Approval Conditional Approval Deferral Disapproval

58 Office for Human Research Studies 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 Office for Human Research Studies 59 Expedited Review: Minor Changes to Approved Research MINOR changes in previously approved research During the established approval period Conducted by Chair or IRB member designated by Chair Must be reported to full IRB No disapprovals, e.g., a decision to disapprove a requested deviation must be sent to the full board CFR

60 Office for Human Research Studies 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 Office for Human Research Studies 61 Expedited Review Minimal Risk Research in the Following Categories: 3) Prospective collection of biological specimens by noninvasive means 4) 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 Office for Human Research Studies 62 Expedited Review Minimal Risk Research in the Following Categories: 5) Research involving materials (data, documents, records, or specimens) that: have been collected will be collected for non-research purposes 6) Collection of data from voice, video, digital, or image recordings made for research purposes.

63 Office for Human Research Studies 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 Office for Human Research Studies 64 Expedited Review Minimal Risk Research in the Following Categories: 8) Continuing review of research previously approved by the convened IRB where a) 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; or b) no subjects have been enrolled and no additional risks have been identified; or c) remaining research activities are limited to data analysis.

65 Office for Human Research Studies 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 Office for Human Research Studies 66 Expedited Review: Compliance Problems Inappropriate use of expedited review  greater than minimal risk  no appropriate category  failure to document category and determination Greater than minor changes to approved research Inappropriate use for Continuing Review

67 Office for Human Research Studies 67 Exempt Research

68 Office for Human Research Studies 68 Six Exemptions: 45 CFR (b) 1) Research conducted in:  Established or commonly accepted educational settings  Involving normal educational practices Instructional strategy comparisons

69 Office for Human Research Studies 69 Six Exemptions: 45 CFR (b) 2) Research involving the use of:  Educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior UNLESS information is recorded in an (directly or indirectly) identifiable manner (NOTE: Coded = identifiable) AND disclosure would place subject at risk of criminal or civil liability or be damaging to financial standing, employability, or reputation

70 Office for Human Research Studies 70 Six Exemptions: 45 CFR (b) Special Consideration involving Children  Survey and Interview Research Involving Children IS NOT Exempt  Passive Observation of Public Behavior Involving Children IS Exempt  Participant Observation of Public Behavior Involving Children IS NOT Exempt IRB Needs Copy of All Surveys and Interview Scripts (unless standard test known to IRB)

71 Office for Human Research Studies 71 Six Exemptions: 45 CFR (b) 3) Research involving the use of:  Educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior WHERE subjects are elected or appointed public officials or candidates for public office or Federal statutes require confidentiality without exception

72 Office for Human Research Studies 72 Six Exemptions: 45 CFR (b) 4) Research involving the collection or study of:  existing data, documents, records, specimens, if: the sources are publicly available or the 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 Office for Human Research Studies 73 Definition of “Existing” “Existing” means:  All data has been collected (i.e., on the shelf) prior to the research  For a purpose other than the proposed research  Includes data (or specimens) collected in research and non research activities.

74 Office for Human Research Studies 74 Six Exemptions: 45 CFR (b) 5) Research and demonstration programs designed to study, evaluate, or examine (Federal) Public Benefit or Service Programs 6) Taste and food quality evaluation and consumer acceptance studies involving:  wholesome foods without additives  additives, chemical, contaminants below safe levels determined by FDA, EPA, USDA

75 Office for Human Research Studies 75 Informed Consent

76 Office for Human Research Studies 76 Eight Required Elements: 45 CFR (a) 1. Statement that study is research and information on purposes/duration/procedures/experimental procedures 2. Reasonably foreseeable risks or discomforts 3. Reasonably expected benefits 4. Alternative procedures (including availability off- protocol where applicable) 5. How confidentiality will be maintained 6. Information on compensation for injuries (unless minimal risk) 7. Contact Persons for info on research, injury, subjects’ rights 8. Voluntary participation, no penalty or loss of benefits for refusal or withdrawal

77 Office for Human Research Studies 77 Six Additional Elements Statement that there may be risks which are unforeseeable Under what circumstances investigator could terminate subject’s participation Additional costs to subject Consequences of subjects withdrawal from research Statement that will be told of new findings Approximate number of subjects in study

78 Office for Human Research Studies The Support Trial Conducting research on the current standard of care 78

79 Office for Human Research Studies 79 Informed Consent: Special Issues There is no such thing as “passive consent”  consent is required unless formally waived  documentation is required unless formally waived There 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 Office for Human Research Studies 80 Waiver of Informed Consent (Not Permitted Under FDA Regulations) IRB must find and document that 4 criteria met: 1.Minimal risk research 2.Waiver or alteration will not adversely affect the rights and welfare of the subjects 3.Research could not practicably be carried out without the waiver or alteration 4.Subjects will be provided with additional pertinent information

81 Office for Human Research Studies 81 Documentation of Informed Consent Written consent document  In language understandable to the subject or the subject’s Legally Authorized Representative (LAR) Verification of translated consent document  Signed by subject or subject’s LAR  Copy SHALL be given to subject  Opportunity to read before signing

82 Office for Human Research Studies 82 Documentation of Informed Consent Short form written consent document requires : 1.oral presentation 2.witness to oral presentation 3.an IRB approved written summary given to subject signed by witness signed by person obtaining consent 4.short form documenting oral presentation signed by subject or LAR signed by witness

83 Office for Human Research Studies 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 confidentiality The research presents no greater than minimal risk of harm to subjects and involves no procedures requiring consent in a non-research context IRB may require a subject information sheet

84 Office for Human Research Studies 84 After IRB Approval

85 Office for Human Research Studies 85 Adverse Events v. UPIRSO FDA Regulatory Terms Adverse Events Unanticipated Problems Involving Risks to Subjects and Others Reportable events HHS Regulatory Language Unanticipated Problems Involving Risks to Subjects and Others Reportable Events

86 Office for Human Research Studies 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 document Questions 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 Office for Human Research Studies 87 Protocol Deviations Very detailed protocol Missing a dose Intervention on the wrong day All become protocol deviations Write protocols more broadly Range for dosing Ranging for timing Less likely that differences in regimen will become a protocol deviation

88 Office for Human Research Studies 88 Protocol Deviations University of Oklahoma – July 2000 suspension of research Testing of a vaccine on subjects with melanoma Three year trial Numerous violations of study protocol  shipping vaccine to subjects for self-injection  inadequate staffing  inadequate supervision of sponsor’s manufacturing facilities

89 Office for Human Research Studies 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 Office for Human Research Studies 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 Office for Human Research Studies 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.”

92 Office for Human Research Studies 92 FDA Issues

93 Office for Human Research Studies 93 FDA Regulations Informed Consent - 21 CFR Part 50 IRB Review - 21 CFR Part 56 Investigational Drugs - 21 CFR Part 312  Marketing Approval - 21 CFR Part 314 Biologics - 21 CFR Part 600  Biologics Licensing – 21 CFR Part 601 Investigational Devices - 21 CFR Part 812  Pre-Market Approval – 21 CFR Part 814 Financial Disclosure – 21 CFR Part 54 Electronic Records – 21 CFR Part 11

94 Office for Human Research Studies 94 FDA Regulations Informed Consent CFR 50  Eight Required Elements  Written Documentation  Language Understandable to Subjects  No Coercion or Undue Influence  No Waiver of Subjects Rights IRB Review CFR 56  Initial Review  Prospective Review of All Changes  Reporting/Review of Unanticipated Problems  Reporting/Review of Adverse Events  Continuing Review at Least Annually

95 Office for Human Research Studies 95 FDA Regulations Drugs and Biologics  Investigational New Drug Application (IND)  21 CFR Part 312 Devices  Investigational Device Exemption (IDE)  21 CFR Part 812

96 Office for Human Research Studies 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, or  Investigation 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; and No promotion or representation of the drug as safe or effective for the purpose under investigation.

97 Office for Human Research Studies 97 FDA Regulations: Responsibilities of Sponsors Maintaining the IND Obtaining Qualified Investigators and Monitors Providing Necessary Information/Training for Investigators Monitoring the Investigation Controlling the Investigational Agent Reporting Significant Adverse Events to FDA/Investigators Maintaining and Retaining Accurate Records

98 Office for Human Research Studies 98 FDA Regulations: Responsibilities of Investigators Specific Responsibilities:  Ensuring Conduct of the Research per the Investigator Agreement, Investigational Plan, and All Applicable Regulations  Protecting the Rights, Safety, and Welfare of the Research Subjects  Controlling access to and use of the test article (drug / biologic / device)  Monitoring and Reporting Adverse Events  Maintaining and Retaining Accurate Records

99 Office for Human Research Studies 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 unexpected  Serious 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 Office for Human Research Studies 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 Office for Human Research Studies 101 FDA Regulation Exceptions & Exemptions: Emergency Use of a Test Article Without Informed Consent – 21 CFR 50.23(a)  Life Threatening Situation Necessitating the Use  Inability to Communicate with Subject for Legal Consent  Insufficient Time to Obtain Consent from Legally Authorized Representative (LAR)  No Alternative Therapy Available  Certification in Writing from Investigator and an other Nonparticipating Physician of the Above  Report to IRB Within 5 Working Days

102 Office for Human Research Studies 102 FDA Regulation Exceptions & Exemptions: Emergency Use of a Test Article (cont.) No IRB Review – 21 CFR (c)  Life Threatening Situation Necessitating the Use  No Alternative Available  Insufficient time for IRB review  Report to IRB Within 5 Working Days  Subsequent Use Requires IRB Review

103 Office for Human Research Studies 103 FDA Regulations: Single Patient IND Commonly referred to as compassionate use Requires Informed Consent and IRB review 21 CFR See OHRS website for guidance

104 Office for Human Research Studies 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 condition Requires as many of the following as possible:  Informed Consent  Institutional Approval  Concurrence of IRB Chair (but NOT IRB APPROVAL)  Independent Assessment of Uninvolved Physician  Authorization of the Sponsor

105 Office for Human Research Studies 105 FDA Regulations: Devices SR Devices vs. NSR Devices IRB Must Make a Specific Determination  Significant Risk Device = Investigational device that presents a potential for serious risk to the health, safety, or welfare of subjects, including implants  Non-Significant Risk Device = Investigational devices that does NOT present the potential for serious risk to the health, safety, or welfare of subjects Non-Significant Risk is NOT the same as Minimal Risk  Once 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 Office for Human Research Studies 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 MEDICINE Such use in RESEARCH (i.e., as part of a systematic investigation designed to develop or contribute to generalizable knowledge) requires IRB REVIEW Such use intended to support a CHANGE in labeling requires IRB REVIEW and an IND / IDE

107 Office for Human Research Studies 107 FDA Regulations: Humanitarian Device Exemption (HDE) Humanitarian Use Device (HUD)  Device tested but not profitable for marketing Requires:  IRB Review (Limited) and Approval  No Research Informed Consent

108 Office for Human Research Studies 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 Office for Human Research Studies 109 Protections for Vulnerable Subjects Under Sections Vulnerable to Coercion or Undue Influence  eg: Handicapped, Disabled, Economically or Socially Disadvantaged Persons HHS Subpart B  Pregnant Women, Human Fetuses, and Neonates HHS Subpart C  Prisoners HHS Subpart D  Children

110 Office for Human Research Studies 110 HHS Subpart B: Research Involving Pregnant Women, Human Fetuses, and Neonates Subpart B -- Revised December 2001  Research involving pregnant women  Research involving fetuses  Research involving neonates of uncertain viability, nonviable neonates, or viable neonates

111 Office for Human Research Studies 111 HHS Subpart B: 45 CFR 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 Office for Human Research Studies 112 HHS Subpart C: 45 CFR (c) Research Involving Prisoners Definition of a Prisoner  Any individual involuntarily confined or detained in a penal institution under a criminal or civil statute  Individuals detained in other facilities as an alternative to criminal prosecution or incarceration in a penal institution  Individuals detained pending arraignment, trial, or sentencing

113 Office for Human Research Studies 113 HHS Subpart C: Research Involving Prisoners Subpart C  Prisoner representative on OHRP approved roster  Additional duties under  Finding of permissible category under  Certification to OHRP  Concurrence from OHRP

114 Office for Human Research Studies 114 Lawsuit Involving Prisoners DOJ funded research in Pennsylvania prison:  mandatory drug testing (urine vs. hair)  no consent  solitary confinement for refusal to be tested  facts of case not contested Acres of Skin  Dow, U Pennsylvania, City of Philadelphia  Prisoners told experiments were harmless

115 Office for Human Research Studies 115 Research involving Children

116 Office for Human Research Studies 116 Definition of Minimal Risk Definition impacts:  Pediatric Studies  Important for determining whether a research protocol or change in research can be expedited or must go to the full board.  Waiver of Consent  Document of Consent

117 Office for Human Research Studies 117 Definition of Minimal Risk: FDA, HHS, Federal Policy “Minimal Risk” means:  The probability and magnitude of harm or discomfort  Are not greater than those ordinarily encountered in daily life; or  During the performance of routine physical or psychological examinations or tests.

118 Office for Human Research Studies 118 HHS Subpart D & FDA Subpart D: Research Involving Children Category Determinations Required Specific Approval Criteria for Each Category Protocol-Specific Justification Required  Not greater than minimal risk  Greater than minimal risk Prospect of direct benefit  Greater than minimal risk No prospect of direct benefit  Research not otherwise approvable

119 Office for Human Research Studies 119 Subpart D: 45 CFR & 21 CFR Research involving no greater than minimal risk Children may be involved in research where the IRB finds that:  The research presents no greater than minimal risk to the child  Adequate provision are made for obtaining The assent of the child The permission of the child’s parents or guardians

120 Office for Human Research Studies 120 NICHD Trial In 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 Office for Human Research Studies 121 Subpart D: 45 CFR & 21 CFR Greater than minimal risk but presenting prospect of direct benefit to individual subjects Children 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: a)The risk is justified by anticipated benefit to subjects; b)The relation of anticipated benefit to risk is at least as favorable as available alternatives; c)Assent of child and permission of parents are sought.

122 Office for Human Research Studies 122 Subpart D: 45 CFR & 21 CFR 50.53: Research involving greater than minimal risk and no prospect of direct benefit to individual subjects Children 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 risk  Research presents situations reasonably equal to to those inherent in their actual situations  Research is likely to yield generalizable knowledge about disorder or condition  Adequate provisions for obtaining child assent and parental permission.

123 Office for Human Research Studies 123 Fenfluramine Study New York State Psychiatric Institute Mount Sinai School of Medicine Queens College The 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 Office for Human Research Studies 124 Fenfluramine Study Since the study did not provide any benefit, was it likely to yield generalizable knowledge about an underlying condition or disorder?

125 Office for Human Research Studies 125 Subpart D: 45 CFR & 21 CFR : Research not otherwise approvable but presenting opportunity to understand, prevent, or alleviate a serious problem affecting health or welfare of children IRB finds the research presents opportunity as above HHS Secretary, after consultation with panel of experts & public review and comment, determines:  The research presents reasonable opportunity as above  The research will be conducted in accordance with sound ethical principles  Adequate provisions are made for obtaining child assent and parental permission

126 Office for Human Research Studies 126 Subpart D: Research Involving Children Parental Permission Required Permission of Both Parents Required If Greater than Minimal Risk, unless:  One parent not reasonably available  One parent has sole custody Standard HHS Waiver Not Contained in FDA Regulations HHS Waiver in Interest of Child Not Contained in FDA Regulations 45 CFR

127 Office for Human Research Studies 127 Subpart D: Research Involving Children — Assent of Child Required Developmentally Appropriate as Determined by IRB Documentation as Determined by IRB  Unless the Research Holds the Prospect of Direct Benefit Available Only in the Research Or  Unless Waived by IRB per criteria at 45 CFR (d) 45 CFR

128 Office for Human Research Studies 128 What happens if a child reaches the legal age of consent? Subject is a child enrolled in research Subject reaches the age of majority IRB can:  waive informed consent if can meet 4 regulatory requirements  otherwise, investigators have to re- consent the individuals

129 Office for Human Research Studies 129 Conflicts of Interest

130 Office for Human Research Studies 130 Types of Conflict of Interest Individual  Clinical investigators  Study coordinators  Research technicians  Research officials  IRB members Institutional  Financial holdings of the institution  Decisions regarding research funding or allocation of resources for research Financial  Consulting fees  Stock ownership  Honoraria  Salary  Intellectual property rights  Enrollment bonuses  Spouse / dependent finances Professional  Pressure to publish  Professional rivalries  Career advancement

131 Office for Human Research Studies DF/HCC Additional Oversight MCC DSMC DSMB Audit Committee 131

132 Office for Human Research Studies 132 Questions?


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