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

DF/ HCCDANA-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) 632-3029 [email protected]

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.


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.


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.


Scientific Review vs. IRB Review

There are differences between scientific review and IRB review, e.g.,

-conditional approvals-annual progress review


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.


DFCI IRBs

Information Relating to the Operation of IRBs


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.


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.


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.


DFCI IRBs

IRB E: “rapid response IRB” small number of members and can

respond quickly to an emergent situation.


DFCI IRBs

IRB G: Pediatric Panel Meets 1st and 3rd Monday of each

month Expertise to review any pediatric

matter


Institutions in the News




JHU-FDA Warning Letter to PIMarch 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.”


Government Shutdowns

Massachusetts Eye and Ear InfirmaryUCLAVA 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

Office for Human Research Studies

Most Common FDA Findings

• Failure to obtain informed consent of subjects prior to administration of study drug (21 CFR 312.60; 21 CFR 50.20)

• Failure to provide informed consent information in language understood by the subject (21 CFR 50.20)

18


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 812.100, 50.20, 50.27)

19


Columbia University-FDA warning letter

February 21,2014Investigator Warning Letter Ralf

Zimmerman1. Enrolled 28 of 50 subjects prior to obtaining

consent2. Provided 10 subjects with investigational

agent prior to obtaining consent

20


Still happens… Weill Medical College, May 2004OHRP 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 #0204-165, 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 46.404). 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.


Weill Medical College, May 2004

OHRP Findings:(a) For protocol #0296-223, subjects were enrolled outside the protocol age

rangeprior to IRB review and approval of the amended protocol.(b) Protocol #0800-354 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 #0801-842, 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.”


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.


Emory

Emory halts enrollment in cancer clinical trialsAction 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.


OHRP Compliance Findings: Repeated Deficiencies in Human Subjects Research

Unapproved ResearchUnapproved Protocol ChangesUnreported Adverse EventsUnreported Unanticipated ProblemsConflicts of InterestMisleading or Deficient Informed ConsentInadequate Initial and Continuing IRB ReviewAvoidable Injuries & Deaths

25


Historical Overview

The development of protections for human subjects in research.


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)


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 (1932 -

1972)


Historical Overview:United States -- 1974

Congressional Hearings Senator Walter Mondale Senator Edward Kennedy

HHS RegulationsNational Research Act National Commission for the Protection

of Human Subjects of Biomedical and

Behavioral Research, July 12, 1974


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


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


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


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


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


Subpart A: Core Human Subject ProtectionsFederal 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


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)


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


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


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.


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 with All regulatory requirements All IRB requirements All protocol requirements

Ensure adherence to enrollment criteriaMonitor and report unanticipated problems and adverse events to sponsor and IRB


Roles and Responsibilities:Principal Investigators

University of Pittsburgh, FDA warning letter, September 15, 2009-John M Kirkwood

1. 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


Applying the Regulations to Research Involving Human Subjects


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


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


Manhattan Eye, Ear and Throat Hospital Incident


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, or2) identifiable private information

-- 45 CFR 46.102(f)


VCU Twin Study


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)

-- 45 CFR 46.102(f)


IRB Requirements and Procedures


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


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


IRB Approval (Initial or Continuing) Includes Findings That …

Risks are minimized through sound research designRisks are reasonable relative to anticipated benefitsSelection of subjects is equitable Informed consent will be obtained Informed consent will be documentedPrivacy and Confidentiality provisions are adequateData safety monitoring is adequateAppropriate safeguards are included for vulnerable subjects


Types of IRB Review

Determination whether activity is Human Subject ResearchVerification of ExemptionExpedited ReviewConvened (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


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 member Non-scientific memberOne member not otherwise affiliated with the institutionExpertise in vulnerable populations for regular review of such research


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


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


Types of IRB determinations

ApprovalConditional ApprovalDeferralDisapproval


Conditional ApprovalFrom 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.


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 46.110


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.


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.)


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.


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.


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; or

b) no subjects have been enrolled and no additional risks have been identified; or

c) remaining research activities are limited to data analysis.


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


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 researchInappropriate use for Continuing Review


Exempt Research


Six Exemptions:45 CFR 46.101(b)

1) Research conducted in: Established or commonly accepted

educational settings Involving normal educational

practices• Instructional strategy comparisons



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



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)



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



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


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.



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


Informed Consent


Eight Required Elements:45 CFR 46.116(a)

1. Statement that study is research and information on purposes/duration/procedures/experimental procedures

2. Reasonably foreseeable risks or discomforts3. Reasonably expected benefits4. Alternative procedures (including availability off-

protocol where applicable)5. How confidentiality will be maintained6. Information on compensation for injuries (unless

minimal risk)7. Contact Persons for info on research, injury, subjects’

rights8. Voluntary participation, no penalty or loss of benefits for

refusal or withdrawal


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


The Support Trial

Conducting research on the current standard of care

78


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


Waiver of Informed Consent(Not Permitted Under FDA Regulations)

IRB must find and document that 4 criteria met:1. Minimal risk research2. Waiver or alteration will not adversely

affect the rights and welfare of the subjects3. Research could not practicably be carried

out without the waiver or alteration4. Subjects will be provided with additional

pertinent information


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


Documentation of Informed Consent

Short form written consent document requires :1. oral presentation2. witness to oral presentation3. 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


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


After IRB Approval


Adverse Events v. UPIRSO

FDA Regulatory TermsAdverse EventsUnanticipated Problems Involving Risks to Subjects and OthersReportable events

HHS Regulatory Language

Unanticipated Problems Involving Risks to Subjects and OthersReportable Events


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?


Protocol Deviations

Very detailed protocolMissing a doseIntervention on the wrong dayAll become protocol deviations

Write protocols more broadlyRange for dosingRanging for timingLess likely that differences in regimen will become a protocol deviation


Protocol Deviations

University of Oklahoma – July 2000 suspension of researchTesting of a vaccine on subjects with melanomaThree year trialNumerous violations of study protocol shipping vaccine to subjects for self-injection inadequate staffing inadequate supervision of sponsor’s

manufacturing facilities


Protocol DeviationsUniv. 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…”


Protocol DeviationsUniv. 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.”


Protocol DeviationsUniv. 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.”


FDA Issues


FDA Regulations

Informed Consent - 21 CFR Part 50IRB Review - 21 CFR Part 56Investigational 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 54Electronic Records – 21 CFR Part 11


FDA Regulations

Informed Consent -- 21 CFR 50 Eight Required Elements Written Documentation Language Understandable to Subjects No Coercion or Undue Influence No Waiver of Subjects Rights

IRB Review -- 21 CFR 56 Initial Review Prospective Review of All Changes Reporting/Review of Unanticipated Problems Reporting/Review of Adverse Events Continuing Review at Least Annually


FDA Regulations

Drugs and Biologics Investigational New Drug Application

(IND) 21 CFR Part 312

Devices Investigational Device Exemption

(IDE) 21 CFR Part 812


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.


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


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


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 312.64)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 312.32)

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 312.32)


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 812.150]

Sponsor must report any unanticipated adverse device effect to FDA, all reviewing IRBs, and investigators [21 CFR 812.150]

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]


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


FDA Regulation Exceptions & Exemptions:Emergency Use of a Test Article (cont.)

No IRB Review – 21 CFR 56.104 (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


FDA Regulations: Single Patient IND

Commonly referred to as compassionate useRequires Informed Consent and IRB review 21 CFR 312.34See OHRS website for guidance


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 Consent Institutional Approval Concurrence of IRB Chair (but NOT IRB

APPROVAL) Independent Assessment of Uninvolved

Physician Authorization of the Sponsor


FDA Regulations: DevicesSR 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.


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


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


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


Protections for Vulnerable Subjects

Under Sections 46.111 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


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


HHS Subpart B: 45 CFR 46.204Research 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.


HHS Subpart C: 45 CFR 46.303(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


HHS Subpart C:Research Involving Prisoners

Subpart C Prisoner representative on OHRP

approved roster Additional duties under 46.305 Finding of permissible category

under 46.306 Certification to OHRP Concurrence from OHRP


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


Research involving Children


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


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.


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


Subpart D: 45 CFR 46.404 & 21 CFR 50.51 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


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….


Subpart D: 45 CFR 46.405 & 21 CFR 50.52Greater 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.


Subpart D: 45 CFR 46.406 & 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.


Fenfluramine Study

New York State Psychiatric InstituteMount 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.


Fenfluramine Study

Since the study did not provide any benefit, was it likely to yield generalizable knowledge about an underlying condition or disorder?


Subpart D: 45 CFR 46.407 & 21 CFR 50.54: 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 aboveHHS 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


Subpart D: Research Involving ChildrenParental 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 RegulationsHHS Waiver in Interest of Child Not Contained in FDA Regulations

45 CFR 46.408


Subpart D: Research Involving Children— Assent of Child Required

Developmentally Appropriate as Determined by IRBDocumentation 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 46.116(d)

45 CFR

46.408


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 requirements otherwise, investigators have to re-

consent the individuals


Conflicts of Interest


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


DF/HCC Additional Oversight

MCCDSMCDSMBAudit Committee

131


Questions?

Documents

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