Protecting Human Study Volunteers Human research regulations and the need to understand them

Protecting Human Study Volunteers

Human research regulations and the need to understand them

You’re not my patient, Mrs Quist, you’re my meat!

The reasons you are here

• 1. Human research horror stories– a. Nazi experiments– b. Tuskegee Syphilis Study– c. Radiation experiments– d. Willowbrook– e. Milgram experiment

The reasons you are here

• 1. Response to Tuskegee– a. Belmont Report– b. Federal regulations

The Belmont Report

• Principles for protection of human subjects

– 1. Respect for persons

– 2. Beneficence

– 3. Justice

Respect for persons

• The concept of informed consent– complete– accurate– understandable– in the preferred language of the subject

Beneficence

• Risks must be minimized

• Anticipated benefits must exceed anticipated risks

• Risk:benefit assessment

• “Do no harm”

Justice

• The selection of subjects is equitable

• Equal sharing of risk/equal sharing of benefit

• Recruitment from as wide a variety of subjects as possible to increase generalizability of results

Federal regulations

• 1. 45CFR46

• 2. 21CFR50 &56

• 3. OPRR/OHRP (Office of Human Research Protection)

State Regulations

• Health and Safety Code, Section 24170-24179.5– mirrors the Federal regulations– does not apply to an MPA institution, except:

• Experimental Subject’s Bill of Rights

• Fines and imprisonment for failure to obtain informed consent

Recent Federal Actions - OPRR/FDA

• 1. Duke University• 2. Rush-Presbyterian Hospital• 3. University of Illinois Chicago• 4. University of Colorado• 5. University of Alabama at Birmingham• 6. University of Oklahoma at Tulsa• 7. Virginia Commonwealth University• Etc etc etc

Local Actions

• 1. West Los Angeles VA Medical Center

• 2. UCLA

• 3. Charles Drew University of Medicine

REI response

What is research?

• Federal regulations definition: Research means a systematic investigation, including research development, testing and evaluation, designed to contribute to generalizable knowledge.

What is research?

• Operational rule of thumb definition: Do you intend to publish it?

• Exception: Case reports are anecdotal and hence not generalizable. Nor are they generally systematic.

What is NOT research

• Normal teaching and evaluation methods

• Quality assurance designed to improve patient care (unless you propose to publish it)

• Review of individual patient records for the purpose of managing individual patient’s care

What is NOT human research

• Human subject: a living individual about whom an investigator (whether professional or student) conducting research obtains:– data through intervention or interaction with the

individual or– identifiable private information

• Therefore, a dead body is not a human subject• but samples removed from a living human are by

extension human subject originated and hence covered by the research

The Assurance

• 1. Single Project Assurances

• 2. Multiple Project Assurances

• NEW!!! Federal Wide Assurance (replaces all other assurances)

• REI currently has an MPA with the Office of Human Research Protection (OHRP)

The Assurance

• Defines the relationship of the REI to the DHHS/OHRP, since it sets out our responsibilities and the procedures we will use to protect human subjects.

• It is a binding commitment by the institution on behalf of its investigators.

• It is the standard against which performance will be judged.

The Assurance

• Covers all research involving human subjects, regardless of sponsorship if the research :– is REI sponsored– is conducted by REI personnel or agents – is conducted using REI property or facilities– involves use of non-public information to

contact prospective subjects

The Assurance

• Mandates continued oversight of ongoing studies, including regular audits of studies to ensure compliance with regulations

• Research sponsored by REI but conducted elsewhere must be approved by the other site IRB (e.g., at REI)

The Institutional Review Board (IRB)

• At least five members

• Must include scientists and non scientists

• Cannot be all men or all women

• Cannot all be physicians

• Must have at least one member otherwise unaffiliated with the institution

• If vulnerable populations are being studied, must have members with special expertise

The Institutional Review Board

• The John F. Wolf Human Subjects Committees #1 and #2

• Chairs

• Associate Chairs

• Vice Chairs

• Members

• Staff support

Criteria for IRB approval of research

• Risks to subjects are minimized:> by using procedures which are consistent with

sound research design and which do not unnecessarily expose subjects to risk: and

> Wherever appropriate, by using procedures already being performed

• Risks are reasonable in relation to anticipated benefits

Criteria for IRB approval of research

• Selection of subjects is equitable

• Informed consent will be sought

• Informed consent will be documented

• When appropriate, adequate plans for monitoring research

Criteria for IRB approval of research

• When appropriate, adequate provisions for protecting confidentiality of data

• Additional safeguards for vulnerable populations

IRB Authority

IRB Authority• The IRB can:

– approve a research protocol– require modification of a protocol to obtain

approval– disapprove a protocol

• The IRB’s decisions are subject to review, except that:– it’s decision to disapprove a protocol cannot be

overturned.

IRB Authority

• Th IRB MUST conduct ongoing review of protocols, no less frequently than once per year, but sometimes more frequently

• The IRB approves the consent document to be used. Its approval stamp is the evidence of IRB approval of the form

• This approval is for NO MORE than one year; consent forms need to be renewed

IRB Authority

• IRB MUST approve all changes to protocols in advance - amendments, addenda, etc

• IRB MUST be informed PROMPTLY of adverse events, particularly those occurring at this site (in the case of multi-site studies)

• IRB MAY require audit and oversight of ongoing studies

IRB Authority

• IRB should review all instruments, questionnaires, surveys, etc to ensure that they conform to the approval with regard to identifiers, etc.

• IRB should review all advertising materials (fliers, print ads, etc) for content, as an extension of the consent process

IRB Authority

• For non-compliance with IRB decisions, investigators can be:> suspended from conducting research> told of the reasons for the suspension> have their grant and contract monies frozen> reported to the appropriate Federal authorities> given remedial options that will permit them to

resume research activities

Federal Authority

• In the event of an egregious violation of the regulations involving protection of human subjects by an investigator, Federal authorities may: choose to suspend the institution’s ability to

conduct research choose to withdraw permission to conduct

FDA trials post the investigator’s name on an internet

page

Recruitment

Recruitment

• Subjects should be recruited as widely as possible; unless there is a compelling scientific justification for restricting recruitment to narrower groups * recruiting men only for a study on male

contraception* restricting recruitment to adults for a disease

that does not occur in children

Recruitment

• Offering of incentives to participate is OK unless: – the incentive (e.g., cash) becomes a deciding

factor in the subject’s decision to participate– the incentive is withheld to ensure completion

of the study

• Recruitment must emphasize the voluntary nature of participation

Recruitment

• Non-financial coercion* Dual role of faculty/trainee investigators* Divided loyalty of faculty investigator between

patient care and project conduct* Potential coercive effect when enrolling

patients

Recruitment

• FDA views advertising as an extension of the informed consent process

• All advertising materials must be reviewed by the IRB

• Advertising materials include: fliers, posters, letters to subjects, newspaper ads, some types of internet websites, public service announcements

Informed Consent

Informed Consent

• It is a fundamental requirement that the consent of the subject being studied be obtained in advance unless:– specifically waived by the IRB

– specifically identified as not requiring consent

– the research is carried out under the emergency research exception

– the subject is deemed incapable of giving informed consent and an appropriate person signs on the subject’s behalf

Informed Consent

• Required elements> Statement that the study involves research > the purpose of the study> how long the subject will be involved> description of the procedures> identification of which procedures are

experimental

Informed Consent

• Required elements> Description of any reasonably foreseeable risks

or discomforts> description of any benefits to the subject or

others> disclosure of alternative treatments that might

be advantageous to the subject

Informed Consent

• Required elements> Statement describing the extent, if any, to which

confidentiality of records will be maintained

> Explanation of whether compensation or treatment are available in the event of injury

> who to contact re research and subjects’ rights or in the event of injury

> statement that participation is voluntary, refusal is not penalized and the subject can withdraw at any time

Informed Consent

• Additional elements> Unforeseeable risks> termination by investigator> additional costs to subjects> orderly procedures for withdrawal> new findings> number of subjects participating

Informed Consent

• In California> Subjects must receive a copy of the Human

Subjects Bill of Rights> This is attached to each consent form> It is available in both English and Spanish

How to ensure subjects’ understanding of the information provided

• Provide a consent form written at an appropriate level of language

• Explain the project clearly and answer all questions in a dialogue with the subject

• Question the subject• Provide sufficient time for the subject to be able to

make a reasoned decision• Continue to question the subject during

participation and provide feedback

How to ensure subjects’ understanding of the information provided

• If the subject’s primary language is not English> the consent process should occur in the primary

language, via relatives, interpreters, bilingual staff

> the consent form should be provided in the primary language (e.g., typically Spanish at this institution)

How to ensure subjects’ understanding of the information provided

> the translation of the consent form should be performed under the direction of the IRB; alternatively, a translated consent form should be back-translated by the IRB to ensure the information is correct

> If you can’t communicate effectively, the subject should NOT be enrolled

How to ensure subjects’ understanding of the information provided

• For individuals who are mentally disabled, either temporarily or permanently:> Some patients with psychiatric problems may

still be able to give informed consent; otherwise> consent can be obtained from the person with

durable power of attorney (caution: some powers of attorney are limited in scope)

> the appointed conservator

Risks

Risks

• Minimal risk:

• “...the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests”

Risks

• Risk of physical harm e.g., reaction to a drug, injury due to a procedure

• Risk of psychological harm e.g., distress caused by answering sensitive questions

• Risk of legal harm e.g., revelation of illegal activities

• Risk of social harm e.g., revelation of intimate information to other persons

• Risk of economic harm e.g., revelation of private information, such as HIV status

Risks

• Breach of confidentiality can lead to serious consequences to a subject’s social, legal or economic status

• Procedures must be in place to protect subjects’ privacy> retention of data without identifiers> use of coding to restrict access to subject ID> Certificate of Confidentiality

Vulnerable Populations

• Fetuses/Pregnant Women/In Vitro Fertilization - 45CFR46 Subpart B

• Prisoners - 45CFR46 Subpart C

• Children - 45CFR46 Subpart D

• Persons with altered mental capacity

• Economically disadvantaged persons

Special Protections for Vulnerable Groups

Children in research

Examples:

Research in schools

Adolescent and child psychiatry

Surveys

Interviews

Children in Research

• “Children” are persons who have not attained he legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted

Special Protections for Children

• 45CFR46 Subpart D– Investigator and IRB must determine the

level of risk from four categories:– .404 Research not involving greater than

minimal risk– .405 Research involving greater than

minimal risk but presenting the prospect of direct benefit to the individual subject

Special Protections for Children• 45CFR46 Subpart D

– .406 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

– .407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children

Special Protections for Children

• Although a child may not be mature enough to give informed consent, generally, their assent should be sought, particularly if the proposed research offers no direct benefit to the child (e.g., a PK study)

• The consent of the child’s parent(s) must also be obtained

Special Protections for Children

• In the event the child does not assent, even if the parent(s) consent, the child’s views must prevail

• Parental consent can, however, be sufficient, even if the child does not assent, if the IRB determines that the research offers the prospect of direct benefit only available in the context of the research

Behavioral Research

Behavioral Research

• Surveys

• Interviews

• Questionnaires

• Record reviews

• Observation (participatory, overt or covert)

• Psychological or social interventions

Behavioral Research

• Surveys, questionnaires, interviews, etc. are all superficially benign

• They may pose subtle risks to subjects including, but not limited to, emotional distress, stress, revelation of sensitive private information

Behavioral Research

The role of deception

Deception

• Humans act differently if they know they are being observed

• Deception in research must be carefully justified, scientifically and ethically

• IRB must approve in advance

• Missing information should not increase the risks

• Subjects should be debriefed afterwards

Deception

• Subjects must be given the opportunity to withdraw from study and have their data removed also

• Deception is not permissible to enroll subjects

Privacy

Privacy• Patient records are private documents• Access by investigators is appropriate for the

purposes of managing a patient’s medical treatment• Investigators do not have carte blanche to review

medical records• Review of medical records can involve Information

Systems personnel time and effort and must be carefully justified

• Use of investigator’s personal patient records is no different from use of hospital records

Privacy

• Access to databases must be made via the IRB

• Investigators must be sensitive to the private nature of the information in student records

• Publication must avoid any identifiers

Privacy

• After IRB review and approval of records review requests, investigators may review patient records

• If patients are identified as possible recruits, an approach to the patient should be made only through the patient’s primary caregiver.

• Alternatively, patients may be recruited by general advertising

Privacy

• Research data is confidential • Research data will contain private information

about individuals• Procedures must be in place to protect the

confidentiality of the data• Data should not be used except for the purpose

for which it was collected without prior additional consent

• Likewise, clinical data

Research Defined as Exempt

45CFR46.101(b)(1-6)

Research Defined as Exempt

• Educational studies, e.g., comparison of methods

• Educational tests, except if identifiers and sensitive**

• Educational tests, public officials or candidates

• Existing data, if publicly available or without identifiers

• Agency sponsored demonstration studies

• Taste and food quality evaluation and consumer preference studies

Educational research

• Conducted in established or accepted educational settings

• Involves normal educational practices:– research on regular and special education

instructional strategies; or– research on the effectiveness of, or the

comparison among instructional techniques, curricula, or classroom management methods

Educational tests

• Tests - cognitive, diagnostic, aptitude, achievement

• Survey procedures

• Interview procedures

• Observation of public behavior

Educational tests

• Educational tests in adults may be exempt from further IRB review unless:– a) the information obtained is recorded in such a manner

that the human subjects can be identified, directly or through identifiers linked to the subject; AND

– b) any disclosure of the human subjects’ responses outside the research could reasonably place the subject at risk of criminal or civil liability or be damaging to the subjects’ financial standing, employability, or reputation

**Exempt Research in Children

• Research involving children: all the same categories are exempt EXCEPT for: “research involving survey or interview procedures or observations of public behavior, except for research involving observation of public behavior when the investigator(s) do not participate in the activities being observed”

**Exempt Research in Children

• For interviews, surveys and participational observation of public behavior, the consent of parents must be sought and the assent of the children obtained, if appropriate.

• This must be determined by the IRB ahead of time

Analysis of existing data or specimens

• The Federal regulations exempt from IRB review

• “Research involving the collection or study of existing data, documents, records, pathological specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects”

Analysis of existing data or specimens

• “Existing” means that it was in existence PRIOR TO proposing the research

• “Identifiers linked to the subjects” means any way in which the information gathered could be linked to an individual subject. Examples include, names, SS#, student ID#, code lists, etc.

Analysis of existing data or specimens

• “publicly available” does NOT mean that the data are in the hospital chart; does NOT mean that they are in the physician’s or psychologist’s patient progress notes

Expedited Categories of Research

• Defined in the Federal Register

• Usually minimal risk studies

• Generally require a consent form

• Can be approved on an interim basis by a designated IRB member but subsequently are ratified by the IRB

Food and Drug Administration

21CFR50

21CFR56

21CFR312

21CFR812

Studies under FDA oversight

• The aim of studies conducted under FDA oversight is to obtain safety and efficacy data on drugs and devices in support of an application for marketing of the drug or device

• The emphasis in FDA studies is therefore more on the evaluation of these criteria in the context of a clinical trial.

Studies under FDA oversight

• FDA studies include– studies of new drugs or devices – studies of approved drugs and devices for new

indications– studies altering the approved dosage, dosing

schedule, method of delivery, target population, etc.

Studies under FDA oversight

• Studies of new drugs or new indications generally require that an Investigational New Drug (IND) application be filed

Studies under FDA oversight

• Investigators involved in an IND study must submit a Form 1572 with the FDA

• Under penalty of imprisonment, the investigator must fill this form out truthfully

• Records of FDA studies must be retained for at least two years after marketing approval or at least two years after last drug shipment

Genetics Research Issues

Genetics Research

• Increasingly common in psychiatry and psychology research

• Fraught with the possibility of generation of sensitive information, affecting subjects’ employment or insurability and of the subjects’ relatives

• Fraught with ethical dilemmas regarding provision of experimental findings to the subjects

Genetics Research

• Use of identifiers must be considered carefully• Issue of future use of specimens• Additional language in consent forms to reveal

and give options regarding future use• Additional language to consent forms re

confidentiality• Concerns about privacy of relatives