pwc b carleton college october 10, 2002 tom puglisi, phd protecting human subjects -- what everyone...

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Carleton College

October 10, 2002

Tom Puglisi, PhD

Protecting Human Subjects --

What Everyone Needs to Know

The Protection of Human Subjects in Research

Medical Research Summit

Michele Russell-Einhorn, JD

Tom Puglisi, PhD

May 5, 2003

©2002 PricewaterhouseCoopers. PricewaterhouseCoopers refers to the individual member firms of the world-wide PricewaterhouseCoopers organisation. All rights reserved.

PricewaterhouseCoopers


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


Research Involving Human Subjects

Human Research Halted at Major Institutions– Deficient Informed Consent– Inadequate Initial and Continuing IRB Review– Multiple Areas of Concern

Death in Gene Transfer Research– Conflicts of Interest– Unreported Deaths and Injuries

Media Attention – Congressional Hearings – Distrust


Research Involving Human Subjects

“What’s at Stake is the Integrity of Research

and

Public Confidence in Research”

-- HHS Secretary, Donna Shalala, May 2000

Historical Overview


Historical Overview

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

Dr. Henry Beecher’s Review of Medical Literature

Radiation Experiments

Cancer Cell Injections

“Tea Room Trade” Study

Kansas City “Jury Deliberations” Research

Social Psychology Research – Conformity / Authority

Historical Overview


Historical Overview

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

Historical Overview -- 1974


Historical OverviewHistorical Overview:The Belmont Report – April 18, 1979

Ethical Principles and Guidelines for the Protection of Human Subjects of Research

Respect for PersonsInformed Consent

Capacity to Consent

BeneficenceDo no Harm

Maximize Benefit

JusticeEquitable Selection of Subjects

Equitable Burdens and Benefits


Roles and Responsibilities

Institutions

Institutional Review Boards (IRBs)

Research Investigators

Sponsors

Data Safety Monitoring Boards (DSMBs)


Roles and Responsibilities:Institutional Responsibility

Institutional Commitment and Infrastructure

Authorized Institutional Official

IRB Chair, IRB Members, IRB Staff

Other Institutional Committees

Research Investigators and Co-Investigators

Study Coordinators and Research Staff

Everyone Else Involved in the Research Enterprise


Roles and Responsibilities:Authorized Institutional Official

Legal Signatory for Institution (e.g., Assurance)

Overall Organizational Responsibility

Ensure Adequate placement of IRB within Institutional Structure

Ensure Adequate resources for IRB (staff, computers, office space, etc.)

Inspire and Enforce Institutional Culture of Respect and Compliance (e.g., Oversight and Monitoring of Research)


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 and Documented– Privacy and Confidentiality Protections Adequate– Safety Monitoring is Adequate– Protections for Vulnerable Subjects are Adequate

Exercise Continuing Oversight of Research


Roles and Responsibilities:Principal Investigators

General Responsibilities of Principal Investigators:

Accept and exercise 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, IRB requirements, and protocol requirements

Ensure adherence to enrollment criteria Monitor and report unanticipated problems and

adverse events to sponsor and IRB


Federal Oversight of Human Subject Research

HHS Regulations – Revised 1981

FDA Regulations– Revised 1981

Federal Policy for the Protection of Human Subjects (Common Rule)– Adopted 1991


DHHS Regulations: 45 CFR Part 46

Subpart A – Basic Protections (“Common Rule”)– IRB Review– Informed Consent– Institutional “Federalwide Assurance” (FWA)

Subpart B - Protections for Pregnant Women, Fetuses, and Neonates

Subpart C - Protections for Prisoners

Subpart D - Protections for Children


Federal Policy (Common Rule)for the Protection of Human Subjects

17 Federal Agencies Adopted HHS Subpart A

Some Agencies Required Additional Protections– VA requires compensation for research – related

injuries

Some Agencies Never Adopted the Federal Policy– Department of Labor - Miners and Coal Dust– Appalachian Regional Commission – Telemedicine– Department of Transportation - Sleepy Truck Drivers

No Federal Regulation for Research Not Covered Under The Common Rule or FDA Regulations


DHHS Federalwide Assurance (FWA)

For Federally-Supported Research– Common Rule Protections of HHS Subpart A– IRB Review & Informed Consent

For HHS-Supported Research– Protections of HHS Subparts A,B,C,D

MPA-FWA Institutions– Voluntary application of all HHS Subparts to all

research, regardless of funding source

Applying the Regulations toResearch Involving Human

Subjects


Definition of Research:45 CFR 46.102(d)

Research means:– a systematic investigation– designed to develop or contribute to generalizable

knowledge

Research includes:– research development, testing, evaluation,

i.e., pilot studies


Definition of Human Subject:45 CFR 46.102(f)

“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



“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)


Definition of Minimal Risk:45 CFR 46.102(i)

“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.

IRB Requirementsand Procedures


Institutional Review Board (IRB)

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 Review Board (IRB): Composition

Minimum of 5 members

Diverse in gender and racial background

Sufficiently qualified in experience and expertise

One scientific member

Non-scientific member

One member not otherwise affiliated with the institution

Expertise in vulnerable populations for regular review of such research


IRB Approval Includes Findings That . . .

Review, Approve (§46.111), Exercise Continuing Oversight: 1. Risks are minimized through sound research design2. Risks are reasonable relative to anticipated benefits3. Selection of subjects is equitable 4. Informed consent will be obtained 5. Informed consent will be documented6. Privacy and Confidentiality provisions are adequate7. Data safety monitoring is adequate8. Appropriate safeguards are included for vulnerable

subjects


IRB Oversight Includes...

Continued ethical evaluation of the research

Monitoring of the research

Monitoring of the informed consent process

Analysis (as received) of new information, adverse events, and unanticipated problems involving risks to subjects and others

Formal Continuing Review at intervals appropriate to the degree of risk and no less than annually


Oversight Issues for IRBs

Special oversight mechanisms:– Data & Safety Monitoring

Boards (DSMBs)– Consent Monitors– Random Audits of Research– Continuing Education


Types of IRB Review

• Verification of Exemption

• Expedited Review

• Convened (Full) Review

• Continuing Review

NOTE: Initial and Continuing Review Require Vote of the Convened IRB, Meeting All Quorum Requirements, Unless Specific Conditions for Use of Expedited Review are Satisfied


Convened (Full Board) Review

• Majority of Total Membership Must Be Present

• Non-Scientist Member Must Be Present

• Approval Requires a Majority of Those Members Present

• Vote Must Be Documented

• Same Requirements for Initial and Continuing Review


Expedited Review:Initial or Continuing Review

Conducted by Chair or IRB member designated by Chair

Only minimal risk research

Must fit into a category on November 1998 list

All other provisions and requirements apply

Can only approve research -- Cannot disapprove

Must be reported to full IRB


Expedited Review:Minor Changes to Approved Research

MINOR changes in previously approved research

During the established approval period

Conducted by Chair or IRB member designed by Chair

Must be reported to full IRB


Expedited Review 45 CFR 46.110

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.




(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.)




(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.

(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.




(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.




(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.


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


Continuing Review 45 CFR 46.109(e)

Required to occur within one year (no grace period)

IRB must review all relevant materials

Continuing review is opportunity to see what has happened once the research started. (NOTE: At initial review the research had not yet begun)

More than status reports should be reviewed -- review must be substantive and meaningful


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 recent approval of 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

Exempt Research


Six Exemptions:45 CFR 45.101(b)

(1) Research conducted in:– established or commonly accepted educational

settings– involving normal educational practices

e.g. instructional strategieseffectiveness 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



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



(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 officeor

– 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 codesdisqualifies the exemption



(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


Verification of Exemptions

Exemptions must be verified by a trained and qualified institutional official

Exemptions may not be determined by the investigator

Informed Consent


Informed Consent

Legally effective informed consent– Legally Authorized Representative (LAR) under State law

No coercion or undue influence (recruitment)

Obtained by Investigator/Staff trained and authorized by IRB

Language understandable to the subject

No exculpatory language

Eight required elements

Six additional elements


Eight Required Elements

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

(2)Reasonably foreseeable risks or discomforts

(3)Benefits which may be reasonably expected

(4)Alternative procedures

(5)How confidentiality will be maintained


Eight Required Elements (cont.)

(6)For more than minimal risk, information on compensation for injuries

(7)Contact names -- at least one not associated with the research recommended

(8)Statement that participation is voluntary and the subject can withdraw at any time without penalty or loss of benefits to which the subject is otherwise entitled


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


Informed Consent Generally

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

Deception Research– Requires a formal waiver of consent


Risks to Subjects

A risk or problem is unanticipated if it is not in the protocol or consent document.

Risks discussed in the protocol should usually 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?


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 LAR

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 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


Waiver of Documentation of Informed Consent (Not Permitted by FDA Regs)

The Signed Consent Document Provides the Only Link the 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

Advanced IRB Issues


FDA Regulations

Informed Consent - 21 CFR 50

IRB Review - 21 CFR 56

Investigational Drugs - 21 CFR 312– Marketing Approval - 21 CFR 314

Biologics - 21 CFR 600– Biologics Licensing – 21 CFR 601

Investigational Devices - 21 CFR 812– PreMarket Approval – 21 CFR 814

Financial Disclosure – 21 CFR 54

Electronic Records – 21 CFR 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: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 and to Investigators

Maintaining 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:Investigational New Drug Application (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:Investigational Device Exemption (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]


Requirements for Reporting to the IRB

Required by HHS Human Subject Regs. [45 CFR 46.103(b)(5)] and FDA IRB Regs [21 CFR 56.108(b), 312.66]

– Unanticipated problems involving risks to subjects or others

– Serious or continuing noncompliance with Regs. or IRB

Adverse Events (required by FDA for devices only)– Local IRB Policy Determines Requirements

1) Any serious adverse events experienced by subjects

2) Any adverse events reported to the study sponsor


FDA Regulation Exceptions and 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

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 Regulation Brain Teasers: 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.


FDA Regulation Brain Teasers: “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


FDA Regulations Brain Teasers: “Standard of Care” Comparisons

Systematic comparison of FDA-approved products (i.e., marketed products) used for approved indications constitutes RESEARCH and requires IRB REVIEW

Systematic comparison of competing STANDARDS OF CARE constitutes RESEARCH and requires IRB REVIEW


FDA Regulation Brain Teasers: “Compassionate Use”

Does not Appear in IND Regulations or Guidance

Often Confused With:– Emergency Use of a Test Article (without IRB Review

and/or without Informed Consent)– Treatment Use of Investigational Drugs (with or

without a Treatment IND) Requires IRB Review and Informed Consent

– Use of Orphan Drugs (disease affects < 200,000 Americans) Requires IRB Review & Informed Consent

– Parallel Track Use Requires IRB Review & Informed Consent


FDA Regulation Brain Teasers: “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


FDA Regulation Brain Teasers: 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 Regulation Brain Teasers: 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


Vulnerable Research Subjects

Pregnant Women, Human Fetuses, and Neonates

Prisoners

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

Pregnant women or fetuses may be involved in research if all of the following conditions are met:

a) Where appropriate, preclinical studies on pregnant animals and clinical studies on nonpregnant women have provided data to assess potential risks

b) Risk to the fetus is caused solely by procedures holding out the prospect of direct benefit for the woman or the fetus or the risk to the fetus is no greater than minimal and the purpose is to develop important biomedical knowledge that cannot be obtained by other means



c) The risk is the least possible for achieving the objectives of the research

d) If the research holds out the prospect of direct benefit to the pregnant woman or to both the pregnant woman and fetus or the research holds out no prospect of direct benefit but present no more than minimal risk to the fetus as in (b) above, the informed consent of the pregnant woman is obtained



e) If the research hold out the prospect of direct benefit solely for the fetus, the informed consent of the pregnant woman and the father is obtained, except the father’s consent need not be obtained if he us unable to consent because of unavailability, incompetence, or temporary incapacity, or if the pregnancy resulted from rape or incest

f) Consenting individuals are fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate



g) For children who are pregnant, assent of the pregnant child and permission of the child’s parents are obtain in accordance with Subpart D

h) No inducements, monetary or otherwise, are offered to terminate a pregnancy

i) Individual engaged in the research have no part in any decisions as to the timing, method, or procedures to terminate a pregnancy

j) Individual engaged in the research have no part in determining viability of a neonate


HHS Subpart B: 45 CFR 46.205(a)Research Involving Neonates of Uncertain Viability and Nonviable Neonates

Neonates of uncertain viability and nonviable neonates may be involved in research if all of the following conditions have been met:

1) Where scientifically appropriate, preclinical and clinical studies have provided data for assessing potential risk to neonates

2) Each individual providing consent is fully informed regarding reasonably foreseeable impact of the research on the neonate

3) Individuals engaged in the research have not part in determining viability of the neonate


HHS Subpart B: 45 CFR 46.205(b)Research Involving Neonates of Uncertain Viability

Until viability is ascertained, neonates of uncertain viability man not be involved in research unless the additional conditions are met:

1.The IRB determines that (i) the research holds out the prospect of enhancing the survival of the neonate to viability and any risk is the least possible for achieving that objective or (ii) the purpose of the research is the development of important biomedical knowledge which cannot be obtained by other means and there will be no added risk to the neonate from the research


HHS Subpart B: 45 CFR 46.205(b)Research Involving Neonates of Uncertain Viability

2) The legally effective informed consent of either parent of the neonate If neither parent is able to consent because of

unavailability, incompetence, or temporary incapacity, the legally effective informed consent of either parent’s legally authorized representative is obtained

Consent of the father or the father’s legally authorized need not be obtained if the pregnancy resulted from rape or incest


HHS Subpart B: 45 CFR 46.205(c)Research Involving Nonviable Neonates

After delivery, nonviable neonates may not be involved in research unless all of the following conditions are met:

1) Vital function of the neonate will not be artificially maintained

2) The research will not terminate heartbeat or respiration of the neonate

3) There will be no added risk to the neonate from the research

4) The purpose of the research is to develop important biomedical knowledge that cannot be obtained by other means


HHS Subpart B: 45 CFR 46.205(c)Research Involving Nonviable Neonates

5. The legally effective informed consent of both parents is obtained.

The waiver provisions of Subpart A do not apply. If either parent is unable to consent because of

unavailability, incompetence, or temporary incapacity, the informed consent of one parent will suffice

The consent of the father need not be obtained if the pregnancy resulted from rape or incest

The consent of a legally authorized representative of either or both parents of a nonviable neonate will not suffice


HHS Subpart B: 45 CFR 46.205(d)Research Involving Viable Neonates

After delivery, a neonate that has been determined to be viable is a child and may only be included in research to the extent permitted by Subpart D.


HHS Subpart C: 45 CFR 46.303(c)Research Involving Prisoners

Definition of 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


Additional IRB DutiesHHS Subpart C: 45 CFR 46.305

Research is permissible within a 46.306 category

Advantages of participating are not coercive given the limited choice prison environment

Risks commensurate with those accepted by nonprisoner volunteers

Selection procedures are fair

Language is understandable to the subject population

Participation has no affect on parole, and prisoners are so informed

Adequate provisions will be made if there may be a need for follow-up care, and given varying lengths of sentences, and prisoners are so informed

If HHS-supported, institution (IRB) certifies to OHRP that it has carried out its duties under these sections


Categories of Permissible Research HHS Subpart C: 45 CFR 46.306(b)

(i)

The study of the possible causes, effects, and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects.

(ii)

The study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects.


Categories of Permissible Research HHS Subpart C: 45 CFR 46.306(b)

(iii)

Research on conditions particularly affecting prisoners as a class - ONLY AFTER DHHS CONSULTATION WITH EXPERTS AND PUBLICATION OF A NOTICE TO APPROVE IN THE FEDERAL REGISTER.

(iv)

Research on practices, both innovative and accepted, which have the intent and reasonable probability of involving the health or well-being of the subject. IF CONTROL GROUP WITH NO BENEFIT, CONSULTATION WITH EXPERTS AND FEDERAL REGISTER IS NOTICE REQUIRED.


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


HHS Subpart D & FDA Subpart D:Research Involving Children

Subpart D

IRB Category Determinations Required– Specific Approval Criteria for Each Category– Protocol-Specific Justification Required

Not greater than minimal risk research

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


Subpart D: 45 CFR 46.405 & 21 CFR 50.52:Greater than minimal risk but presenting the prospect of direct benefit to the 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, but likely to yield generalizable knowledge about the subject’s disorder or condition.

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.


Subpart D: 45 CFR 46.407 & 21 CFR 50.54:Research not otherwise approvable but presenting an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children

IRB finds the research presents opportunity as above

HHS Secretary / FDA Commissioner, after consultation with panel of experts and following 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


Research involving ChildrenSubpart D: Parental Permission Required

45 CFR 46.408 & 21 CFR 50.55

• Both Parents’ Permission Required If Greater than Minimal Risk

• Standard HHS Waiver Not Contained in FDA Regulations

• HHS Waiver in Interest of Child Not Contained in FDA Regulations


Research involving ChildrenSubpart D: Assent of Child Required

45 CFR 46.408 & 21 CFR 50.55

• Developmentally Appropriate as Determined by the IRB

• Documentation as Determined by the IRB

• Unless the Research Holds the Prospect of Direct Benefit Available Only in the Research or

• Unless Waived by the IRB per criteria at 45 CFR 46.116(d)


Research involving ChildrenSubpart D: Ward of the State

45 CFR 46.409 & 21 CFR 56

• Where greater than minimal risk and providing no direct benefit to the child, research with wards is permitted only if:

– Related to status as wardsor

– Conducted in settings where majority of children are not wards

• Child advocate required who is not otherwise associated with the research


Social and Behavioral Research:Recurring Controversy about Regulation

• Applicability to Social and Behavioral Research

• Compatibility with Social and Behavioral Research

• Applicability by Discipline?

• Review of Exempt Research

• Student Research


Definition of Research:45 CFR 46.102(d)

• Research means:– a systematic investigation– designed to develop or contribute to generalizable

knowledge

• Research includes:– research development, testing, evaluation, – i.e., pilot studies



“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


Social and Behavioral Issues –Institutional Evaluations / Quality Assurance

• Is the activity “Research” ?• Research means:

– A Systematic Investigation

– Designed to develop or contribute to generalizable knowledge

• What does “Generalizable” mean :– Beyond the immediate situation

– Beyond the institution


Social and Behavioral Issues –What if the Purpose / Intent Changes ?

• When did the purpose change ?

– After the investigation was completed

– IRB review of existing data

– Consent / Waiver of Consent

– During the investigation– IRB review for collected data

– IRB review for prospective data

– Consent / Waiver of Consent


Social and Behavioral Issues –“Secondary subjects”

• “Target” subjects vs “Secondary” subjects

• Who is a subject?

• A subject is a living individual about whom an investigator conducting research obtains:

– Identifiable Private Information


Social and Behavioral Issues –Existing Data Sets

• Data sets containing only non-coded, non-identifiable information do not involve human subjects

• Data sets “anonymized” before transfer to the investigator do not involve human subjects

• “Anonymized” means

– No codes or links of any kind, available to anyone, anywhere

– But note possible OHRP exception



• “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 nonresearch activities.



• “Publicly available” data sets are exempt• “Publicly available” means:

– Generally available to anyone

– Commercially available

– ?

• Access to data sets with identifiable private information is exempt if:

– Investigator does not record identifiers



• Other use of data sets containing identifiable private information requires IRB review

• IRB may determine that:

– Additional informed consent is needed

– Original informed consent covers the new research

– Informed consent requirements can be waived under 45 CFR 46.116(d)


Epidemiology Research

Epidemiology Research– May include medical records– May require linking of records from multiple

data sets– Investigator must have legitimate access

identifiable private information– Waiver of Informed Consent at 45 CFR

46.116(d) may be applicable


Social and Behavioral Issues –Research Involving Deception

• Requires waiver of informed consent requirement under 45 CFR 46.116(d)

• IRB must find and document that 4 criteria are met:– No greater than minimal risk to subjects– Waiver or alteration will not adversely affect the

rights and welfare of the subjects– Research could not practicably be carried out

without the waiver or alteration– Subjects will be provided with additional

pertinent information


Social and Behavioral Research:My IRB is Unreasonable ! !

Academic freedom gives me the right to conduct my research

This research is harmless and shouldn’t need IRB review

Requiring informed consent will lower participation rates

Having to sign a consent form will scare subjects away

Individual consent is meaningless among my subjects

College students are adults

“Subject Pool” requirements are an educational prerogative

“Passive Consent” is traditional in my field

Mom, dad, and sibs aren’t subjects my research

My use of these data sets shouldn’t need IRB review


Dealing with the “Unreasonable” IRB

Regulations Require Professional Competence (§46.107):

– IRBs must have the Scientific and Professional Competence to understand the research they review (including Social and Behavioral research)

– IRBs must understand regulatory options so as to apply them appropriately

Possible Solutions– Increase Academic Diversity of Existing IRB– Create Social and Behavioral Sciences IRB– Educate IRB Members (and investigators)

OHRP Compliance Determinations

Analysis of Common Concerns


OHRP Compliance Determinations:Letters Issued 10/01/1998 to 06/30/2002

• 269 Letters to 155 Institutions

• 18 Institutions Site-Visited

• 1,120 Citations of Noncompliance or Deficiency

• 142 Institutions (92%) Had at Least One Citation

– Median = 4

– Range: 0 - 53


OHRP Compliance Findings:Common Areas of Noncompliance

• Initial and continuing IRB review

• Expedited IRB review procedures

• Reporting of unanticipated problems

• IRB review of protocol changes

• Informed consent

• IRB membership, expertise, staff, support, and workload

• Documentation of IRB procedures, activities, and findings


All Site-Visited Institutions Institutions

Cited Deficiency (N = 155) (N = 18)

Research conducted without IRB review 17% 22% Deficiency in IRB initial review process 55% 94% Deficiency in IRB continuing review process 45% 72% Deficiency in use of expedited IRB review procedure 17% 61% Deficiency in satisfying reporting requirements 17% 39% Deficiency in IRB review of protocol changes 25% 39% Deficiency in application of exempt categories of research 6% 28% Failure to obtain informed consent of subjects 16% 11% Deficiency in documentation of informed consent 8% 6% Deficiency in IRB-approved informed consent docs/process 51% 78% Deficiency in IRB membership 11% 61% IRB members lack sufficient understanding of regulations 7% 44% Indequate IRB meeting space, staff, and resources 8% 50% Overburdened IRB 5% 28% Deficiency in IRB records, including IRB minutes 37% 78% Deficiency in written IRB policies and procedures 55% 72%


Number of Percent of Category of Deficiency Citations Citations

Deficiency in IRB initial review process 277 25%

Deficiency in IRB-approved informed consent documents/process 304 27%

Deficiency in IRB continuing review process 109 10%

Deficiency in written IRB policies and procedures 88 8%

Deficiency in IRB records, including IRB minutes 70 6%

Deficiency in IRB membership/training/support/workload 49 4%

Deficiency in IRB review of protocol changes 45 4%

Deficiency in use of IRB expedited review procedure 46 4%

Deficiency in satisfying reporting requirements 35 3%

Research conducted without IRB approval 25 2%

Failure to obtain informed consent of subjects 26 2%

Other miscellaneous deficiencies 46 4%

Total 1120 100%

Distribution of Noncompliance Findings (269 Letters)OHRP Compliance Oversight Data - 10/1998 to 6/2002

Table 2: Distribution of OHRP-Cited Deficiencies for All Institutions


Number of Percent of Category of Deficiency in IRB Initial Review Citations Citations

Deficiency related to criteria required for IRB approval 88 32%

Deficiency related to findings for research involving children 39 14%

Contingent approval with substantive changes/clarifications 33 12%

without further review by convened IRB

Deficiency related to findings for waiver of informed consent requirements 30 11%

IRB review without quorum 25 9%

Failure to review federal grant applications 16 6%

Deficiency related to findings for research involving prisoners 14 5%


Total 277 100%


Table 3: Distribution of OHRP-Cited Deficiencies Related to Initial IRB Review


Number of Percent of Category of Deficiency Related to Informed Consent Citations Citations

Deficiency in description of purpose, procedures, and duration 63 19%

Deficiency in description of risks and discomforts 56 17%

Deficiency in description of benefits 20 6%

Deficiency in description of alternatives 20 6%

Deficiency in description of other elements of informed consent 61 18%

Language too complex 31 9%

Use of exculpatory language 7 2%

Failure to obtain informed consent of subjects 26 8%

Deficiency in documentation of informed consent 12 4%


Total 330 100%


Table 4: Distribution of OHRP-Cited Deficiencies Related to Informed Consent


Managing Complaints and Site Visits

Managing internal complaints– Types of complaints– Managing investigation of complaints– Reporting to regulatory authorities

Managing a government site visit– Corrective action plan– IRB operations assessment

Related Issues


Health Insurance Portability and Accountability Act (HIPAA)

• HIPAA Passed by Congress and Signed by President in 1996

• Required HHS to Issue a Rule or Congress would legislate.

• History of Privacy Rule:

– December 28, 2000: Final Rule

– March, 2001: Rule Opened for Additional comment

– August 14, 2002 Regulations Amended

• Compliance Deadline: April 14, 2003


HIPAA Privacy RuleIn General --

HIPAA covers the Use and Disclosure of “Protected Health Information” by “Covered Entities”

• Protected Health Information (PHI) is:– Individually identifiable health information

• A “Covered Entity” is:– Health Care Provider, Plan, or Clearinghouse

• Consent is not required to use or disclose PHI for treatment, payment, or health care operations

• Other use or disclosure of PHI, including Research, generally requires “Authorization”



Use or Disclosure of “Protected Health Information”for research purposes requires either:

• A written Authorization from the subjector

• Verification that the research involves:=> De-Identified Information=> Limited Data Sets=> Reviews Preparatory to Research=> Decedents’ Informationor

• A Waiver approved by the Privacy Board / IRB



• The Privacy Rule permits Use and Disclosure of Protected Health Information as required under applicable statute or regulation

• The Privacy Rule provides individuals with:=> The right to Access Protected Health Information about themselves=> The right to obtain an Accounting of Disclosures of their Protected Health Information

• Does not supercede more stringent State requirements


Authorization

Generally, uses and disclosures of protected health information in research must be conducted pursuant to a valid Authorization….

• 6 Core elements

• 3 Required statements

• 2 Additional requirements


Authorization = Most Advantageous Route to Research

• No Representations (Assurances) Required

• No Privacy Board Review Required

• No Accounting of Disclosures Required

• No “Minimum Necessary” Limitations


Conflict of Interest in Research: Current Requirements and Recent Guidance

Conflict of Interest:

• Any situation in which financial, professional, or personal obligations

• May compromise or appear to compromise

• Professional judgment in designing, conducting, analyzing, reporting, or supporting research.


Types of Conflict of Interest

• Financial

– Consulting fees

– Stock ownership

– Honoraria

– Salary

– Intellectual property rights

– Enrollment bonuses

– Spouse / dependent finances

• Professional

– Pressure to publish

– Professional rivalries

– Career advancement

• 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


What Prompted the Recent Focus on Financial COIs in Research?

• Researchers and Institution held equity interest in research technology significantly above FDA requirements

• Two prominent research institutions involved–Gene-transfer research–Cancer research

center

• Results– NIH Conference to examine

the issue of financial COIs– Development of recent

guidance, including draft interim recommendations from DHHS

– Authorship and sponsorship of research (statement by the International Council of Medical Journal Editors)


Current Regulations

• IRB Regulations– 45 CFR 46.107(e)– 21 CFR 56.107(e)

• If an institution has an IRB, conducts research involving FDA-regulated test articles, and receives PHS funding, all three sets of regulations must be followed.

• FDA– 21 CFR Part 54– Investigator Disclosure to

Sponsors

• Public Health Service (PHS)– 42 CFR Part 50, Subpart F– Responsibilities for

institutions receiving research funds from PHS Agencies (NIH, etc.)


FDA Regulations

• Require:– Disclosure of potentially conflicting financial interests of investigator

(including spouse and dependent children)

• When to disclose?– Compensation depends on the outcome of the clinical study – Investigator has significant equity interest in the sponsor (in excess

of $50,000 during study and for 1 year after completion)– When investigator has a proprietary interest in the test product

(including patent, trademark, copyright, or licensing agreement) – When investigator has received significant payments of other sorts

(defined as a value of more than $25,000, exclusive of the costs of conducting the study, during the study and for 1 year after completion)


PHS Regulations:Investigator Requirements

• Disclosure of “significant financial interests” • Anything of monetary value • Salary and other payments for services• Equity interests• Intellectual property interests


PHS Regulations:Investigator Need Not Disclose

• Salary, royalties, or other remuneration from the institution

• Income from seminars, lectures, or teaching engagements sponsored by public or non-profit entities

• Equity interests (including spouse and dependent children) which do not exceed $10,000 and does not represent more than 5% ownership in any single entity

• Salary, royalties, and other payments, which when aggregated for the investigator, spouse, and dependent children, are not expected to exceed $10,000 over the next 12 months


PHS Regulations:Institutional Requirements

• Develop policies and procedures per PHS regulations

• Inform investigators of their responsibilities

• Designate an institutional official(s) to solicit and review financial disclosure statements

• Issue guidelines to identify, manage, reduce, or eliminate conflicts

• Allocate space for maintaining records for 3 years

• Establish enforcement mechanisms/sanction

• Certify in each PHS funding application that a written and enforced administrative process for financial COIs exists

• Assure PHS that any financial COIs will be managed, reduced, or eliminated before funds spent (or at least on an interim basis, for 60 days after initial report)


IRB Requirements:45 CFR 46.107(e) & 21 CFR 56.107(e):

• “No IRB member may participate in initial or continuing review of research in which they have a conflicting interest except to provide information requested by the IRB”

• Includes professional, personal, and financial conflicts.

• IRB members must recuse themselves


IRB “Best Practice” Standards

• IRB policies defines what might constitute a conflicting interest or has procedures for determining conflicting interest

• Conflicted IRB member absents self from meeting during IRB deliberation and vote

• IRB minutes document recusal and absence from deliberation and vote


Reporting of Conflicts of Interest to Regulatory Bodies

• FDA (=Investigator)– Investigator conducting

research on FDA-regulated test article discloses to research sponsor

– Disclosure applies to investigator, spouse, and dependent children

– If potential conflict, report steps taken to minimize bias using Form FDA 3455

– No financial interests, use Form FDA 3454

• PHS (=Institution)– Investigator supported by funds

from any PHS Agency discloses significant financial interest to the institution

–Disclosure applies to investigator, spouse, and dependent children

– Institution must certify to PHS Agency that significant financial interests have been eliminated, reduced, or managed


Recent Guidance

• Department of Health and Human Services (DHHS)– Draft Interim Guidance

(January 10, 2001)

• American Association of Medical Colleges (AAMC)– Task Force on Financial

Conflicts of Interest in Clinical Research (December 2001)

• General Accounting Office– Report GAO-02-89,

November 2001)

• Association of American Universities– Task Force on Research

Accountability: Individual and Institutional Financial Conflict of Interest (October 2001)

• American Medical Association– Council on Ethical and Judicial

Affairs Report 3-I-00, Managing Conflicts of Interest in the Conduct of Clinical Trials (December 2000)


Management Decisions for Conflicts of Interest Policy Development

• Who’s covered by the Policy?– Institutions may wish to cover

other individuals involved in research, research decisions, research oversight, and the institution’s financial holdings.

• Disclosure thresholds– FDA and PHS policies have

different disclosure thresholds.– For consistency and simplicity,

institutions may chose to adopt a single disclosure threshold.

• Examples of management plans:– Public disclosure of financial

interests– Divestiture of the interest– Monitoring of the research by

independent reviewers– Modification of research plan– Disclosure in informed consent

documents, manuscripts, oral presentations based on the research


Conflict of Interest Recommendations Distilled from Recent Guidance

• Conflict of interest committee– More representation from lay

public

• Administrative positioning of the IRB high within the organization.– IRB should not be the sole locus

of responsibility for conflicts of interest

• Design educational programs for all research staff, IRB, institutional officials with research and finance decision-making responsibilities

• Make policies, procedures, and documents available on-line

• Expand scope to include all research, regardless of funding for the sake of fairness and consistency

• Establish “firewall” between offices responsible for financial and research decisions

• “Rebuttable presumption” and “compelling circumstances” as conflict standards


Billing Compliance

Institutional Responsibility

Patient Care vs. Research

National Coverage Decision

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