Human Subjects Refresher Test Background Document 2-18-09

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Human Subjects Refresher Test Background Document

This program is designed to provide investigators and coordinators with a refresher course

in the ethics of research and the protection of human subjects. A primary focus is onDepartment of Health and Human Services (DHHS) regulations as they pertain to projects

funded by the National Institute of Health. However, the principles as they apply to human

subjects research are universal.

The program consists of:

1. A background document in a question and answer format2. An interactive test

Each question of the interactive test will reference the corresponding section of the

background document.


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A.Introduction

A1. What are the basic principles of ethics?

From 1966 until 1974, the Department of Health and Human Services (DHHS) operatedaccording to Policies for the Protection of Human Subjects issued by the Office of Human

Research Protection (OHRP). On May 30, 1974, these Policies were upgraded to Regulationsfor the Protection of Human Subjects.

On July 12, 1974, the National Research Act (Public Law 93348) was signed into law, thereby

creating the National Commission for the Protection of Human Subjects of Biomedical and

Behavioral Research.

One of the Commissions mandates was to identify the basic ethical principles that should

underline the conduct of biomedical and behavioral research involving human subjects and torecommend steps to improve the Regulations for the Protection of Human Subjects to ensure that

such research is conducted in accordance with these ethical principles.

Three basic principles of ethics are particularly relevant to the protection of human subjects in

biomedical and behavioral research.

These principles, which form the basis for the Belmont Report, are:

Respect for Persons: recognition of the personal dignity and autonomy of individualsand special protection of those persons with diminished autonomy

Beneficence: obligation to protect persons from harm by maximizing anticipatedbenefits and minimizing possible risks of harm

Justice: Fairness in the distribution of research benefits and burdensB. IRB

B1. What is the role of the Institutional Review Board?The IRB at an institution must review and approve all projects that meet the definition of

research involving human subjects.

This process is designed to ensure that the research protects the rights and welfare of humansubjects-for example:

By minimizing risks.

Selecting subjects equitably.

Obtaining informed consent and ensuring privacy and confidentiality.

IRB approval must precede initiation of any work involving human subjects. No NIH grant or

contract can be awarded until IRB approval is obtained.


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The IRB has the responsibility to review and approve not only the protocol and informed consent

form but also other materials provided to subjects (e.g., study brochure), recruitment methods,and payments to subjects.

If the research continues, the IRB must review and approve the project at least once a year.

When changes occur in the procedures with human subjects, the IRB must review and approvethese changes.

If human subjects are harmed, including physical injury, improper disclosure of private

information, economic loss or other harmful occurrences, the IRB must be notified.

C. Informed Consent

C1. What is the informed consent process?Federal regulations require that legally effective informed consent be obtained from the subject

or the subjects legally authorized representative. They also make an important distinction

between the process itself and the documentation of the process.

Informed consent is a process that begins with the recruitment and screening of subjects and

continues throughout the subjects involvement in the research. It includes:

Providing specific information about the study to subjects in a manner comprehensible tothem.

Answering questions to better ensure subjects understand the research and their role in it. Giving subjects adequate time to consider their decisions. Obtaining the voluntary agreement of subjects to participate in the study. The agreement

is only to enter the study, as subjects may withdraw at any time, or decline to answerspecific questions or complete specific tasks.

Proper education of patients about a study protocol is a critical function for a sites staff. Thistakes time and requires more than just handing the Informed Consent Form to the patient to read.

This can be a challenge when a patient is being evaluated for a study in the midst of a busy office

schedule. However, it is imperative that sufficient time be allotted to be sure that the patient hasbeen properly informed about the study.

Ensuring that the patient fully understands the protocol not only protects the patient but also

protects the study. A well-informed patient who consents to be part of the trial is more likely tocomply with the protocol than a patient who agrees to participate but does not fully understand

the study. If a patient is uncertain about participating, it is better to not enroll the patient rather

than trying to convince the patient to enroll. Patients should never be coerced to join a study.Signing of the Informed Consent Form by the parent (and assent form by the patient if required)

is the final step in the process of educating the patient about the study. The parent/patient should

not be asked to sign the form until the site staff is confident that the parent/patient understandsthe study and is likely to comply with the protocol.


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Ask the parent/patient to respond with a brief summary (2-3 sentences) of the study before

he/she signs the informed consent form.

The consent form must be signed before any testing that is not part of usual care is performed

and before any data are collected specifically for the study.

Ensure that the parent/patient properly signs and dates the form, and all witness/investigator

signatures and dates are properly completed. Also, be sure that the HIPAA consent is properlysigned and dated if it is being used.

The original, signed consent form packet in its entirety should be filed at the study site. Thepatient should be given a copy of the signed Informed Consent Form packet.

Common errors that occur during the consent form process are: not obtaining informed consent

prior to performing study related procedures, not obtaining all required signatures on theconsent/assent forms, having the parent/patient sign the wrong or expired consent form and not

providing the patient with a signed copy of the informed consent.

C2. How can you provide study information?Guidelines for providing information include:

Advertising cannot be coercive or make false promises or claims. The information should be communicated in a manner and language that is clear and

understandable, be communicated in an organized fashion, and allow for questions the

subject may have to be answered.

The information communicated should not use exculpatory language either in the writtenconsent or in discussions about the research. No informed consent, whether oral or

written, may include any exculpatory language through which the subject is made towaive or appear to waive any of the subject's legal rights, or releases or appears to release

the investigator, the sponsor, the institution, or its agents from liability for negligence. ---45 CFR 46.116

Procedures to screen potential subjects for eligibility must protect the rights and welfareof prospective subjects.

C3. What is exculpatory language?Subjects may not be asked to waive or even appear to waive any of their legal rights. They may

not be asked to release an investigator, sponsor, or institution from liability for negligence.Institutions may provide information about how liabilities are covered.

C4. What are the elements to be included in the consent form?The federal regulations about informed consent list specific elements of information that must be

provided to subjects. Each IRB may have institutionally-specific wording for parts of the

consent form but all require the same essential elements in the consent form.


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a statement that the study involves research, an explanation of the purposes of the research and

the expected duration of the subject's participation, a description of the procedures to befollowed, and identification of any procedures that are experimental;

a description of any reasonably foreseeable risks or discomforts to the subject;

a description of any benefits to the subject or to others which may reasonably be expected from

the research; a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be

advantageous to the subject; a statement describing the extent, if any, to which confidentiality of records identifying the

subject will be maintained;

an explanation of the health information to be disclosed and to whom and for how long it is tobe provided; see section F. HIPAA Privacy Rule for further discussion on the HIPAA Privacy

Rule and its requirements;

an explanation of whom to contact for answers to pertinent questions about the research and

research subject's rights, and whom to contact in the event of a research-related injury to thesubject;

a statement that participation is voluntary, that refusal to participate will involve no penalty orloss of benefits to which the subject is otherwise entitled, and the subjectmay discontinue participation at any time without penalty or loss of benefits to which the

subject is otherwise entitled;

a statement that the particular treatment or procedure may involve risks to the subject (or to theembryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable;

a statement describing any anticipated circumstances under which the subject's participation

may be terminated by the research investigator without regard

to the subject's consent; a statement concerning any additional costs to the subject that may result from participation in

the research;

a statement to the consequences of a subject's decision to withdraw from the research andprocedures for orderly termination of participation by the subject;

a statement that significant new findings developed during the course of the research that may

relate to the subject's willingness to continue participation will be provided to the subject; the approximate number of subjects to be involved in the study.

C5. What is the consent procedure if the subject is a minor?

When a subject is a minor, written consent must be obtained from a parent or guardian.The consent of one parent or legal guardian is sufficient, according to the Jaeb IRB, when the

study does not involve greater than minimal risk or involves greater than minimal risk but

presents the prospect of direct benefit to the individual child. Other IRBs may have differentrequirements with regard to the signing by one or both parents.

In addition to this consent, the minor subject must give his or her assent to participate in thestudy unless the subject is below the age at which consent can effectively be given. This is

obtained by having the child sign a short Child Assent that is written at a level appropriate for the

child and explains the study. The Jaeb IRB requires children 7 to 17 years of age to sign theChild Assent. Other IRBs may have different age requirements.


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The need for child assent will be reviewed by the IRB for each applicable protocol. Any waiver

of child assent when the subject is capable of providing it -- must be requested and justified.Waiver of assent must meet the same criteria as a waiver of consent.

C6.Under what circumstances may documentation of informed consent be waived?

Documentation of the consent process is not always required.

Documentation may be waived under two circumstances:

1. The principal risks are those associated with a breach of confidentiality concerning thesubjects participation in the research, and the consent document is the only recordlinking the subject with the research. For example:

Research about women who have left abusive partners, which assesses factors thataffected their ability to leave.

Research on the black market capitalist economy in Cuba in which illicit vendorswill be interviewed in a safe space.

When the requirement for documentation is waived, the IRB may require theinvestigator to offer subjects information about the study in writing.

2. Study participation presents minimal risk of harm to the subject and the research involvesno procedures requiring consent outside the context of participation in a research study,for example:

A telephone survey by environmental educators hypothesizing that knowledgeabout the exploration of oil reserves in Utahs Red Rock National Park is

positively related to proximity to the site and income level.

C7. How can you ensure comprehension of consent information?Researchers are required to provide information in a manner understandable to the subjects.

Some considerations regarding comprehension are discussed below.

Reading LevelConsider the following phrases that were included in actual consent forms:

"We are interested in the negotiation and articulation of gender roles within yourcommunity."

"We are studying the efficacy of dyadic modalities in problem solving exercises." "Goals are postulated to exist within hierarchies."

Although experts may understand these statements, most potential subjects would be baffled.Consent forms should avoid jargon and be written at a reading level that is appropriate for the

study population. It is estimated that the average reading level of Americans is the eighth grade;

however, many read at a much lower level.


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When a study is complex and/or the reading or educational level of the prospective studypopulation is low, the role of dialog and explanation becomes an even more crucial part of the

consent process. Investigators are obligated to ensure understanding to the best of their ability.

Techniques for gauging comprehension include both eliciting questions from subjects and asking

questions, for example, "Could you describe in your own words what the study is about and whatyou will be asked to do?"

Language IssuesThe consent process should be conducted in the subject populations primary language. The IRB

may require that they be presented a consent document written in a language understandable tothem. Alternatively, the IRB could determine that an oral presentation in a language

understandable to the subject in conjunction with a short form written consent document in that

language that summarizes the elements of the oral presentation is acceptable.

The Jaeb IRB has specific requirements for non- English speaking subjects. Other IRBs may

differ in their requirements.

According to the Jaeb IRB, since the consent form is to be provided in a language that the person

understands, the Spanish speaking subject or representative is to be consented with an IRB

approved Spanish translation of the consent form. Translations in other languages are notcurrently available. The IRB will revisit making them available when requests to consent

subjects who speak other foreign languages increase to such a degree that the potential subjects

present a significant statistical impact.

A qualified Spanish interpreter (i.e., someone other than a relative or friend, etc.) must be present

for the consent form process and must sign the consent form at the time that the investigator

signs it. The project must ensure that the Spanish speaking subject or representative has someonewho is Spanish speaking available at any time by phone or in person to answer questions or

concerns.

Cultural IssuesComprehension may be affected by cultural differences other than language, such as comfort in

asking questions of the researcher. For example, a doctoral student who had lived in Haiti for

years prior to becoming a researcher enlisted a community member to assist in the consentprocess. He knew that his potential subjects would be more comfortable asking questions of a

compatriot than of him, even though he was fluent in Creole. After the initial consent process, he

left the room for a period of time sufficient to allow questions to be asked.

C8. How can you ensure free choice?

The principle of respect for persons requires that participation in research be truly voluntary, free

from coercion or undue influence. Even when a study is innocuous, subjects must be informed

that they do not have to participate, they may choose not to answer particular questions orcomplete specific tasks, and they may choose to stop participating at any time.


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Investigators should consider ways in which the setting of the consent process might include

elements of coercion. Potential subjects might not feel entirely free to choose whether toparticipate in a research study if they are:

Adolescents whose parents are in the room. Adolescents in a group of other adolescents being recruited for the same study. Parents who receive a letter from the school principal asking them for permission to

enroll their children in a study.

Athletes recruited by their coach. Undocumented immigrants facing an official-looking person at their door. Employees asked to participate by their employer.

Subjects must be given adequate time to consider whether or not they wish to participate in a

study. This is particularly true if a study has more than minimal risk or will require subjects to

disclose sensitive information.

C9. How can research be performed in emergency situations where an individual is unable

to provide consent?There are certain emergency situations in which a waiver of the requirement for obtaining

informed consent is possible.

In general, the potential for a waiver exists for situations where human subjects are in need ofemergency therapy and for whom, because of the subjects' medical condition and the

unavailability of legally authorized representatives of the subjects, no legally effective informedconsent can be obtained.

The medical condition typically will be one that is life-threatening and for which availabletreatments are unproven or unsatisfactory, and the collection of valid scientific evidence is

necessary to determine the safety and effectiveness of particular interventions.

C10. What is a minimal risk study?"Minimal risk" means that 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.

General Waivers and Alterations are permissible if the IRB determines that:

1. The research involves no more than minimal risk to subjects.

For studies involving the collection of specimens or noninvasive information, the IRB isresponsible for determining whether or not informed consent is required from the subjects

from whom the specimens were obtained.


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The IRB may waive the requirement for informed consent if the risk to the subjects is

minimal and if certain other conditions are met.

You should not assume that your research poses minimal risk just because it involves no

physical risk.

Loss of confidentiality can cause harm and the IRB has an obligation to consider whether

privacy and confidentiality protections are adequate.

2. The waiver or alteration will not adversely affect the rights and welfare of the subjects.

In the absence of specific legal rights, this criterion is often difficult to apply because

rights and welfare are not defined in the regulations. Also, the parties involved in the

research process (researchers, IRBs, and the community of subjects) may not always

agree on how to define subjects rights and welfare. When a waiver is required becausethe research involves deception, this requirement is usually interpreted to mean that

subjects are not "tricked" into participation that they would find objectionable.

3. The research could not practicably be carried out without the waiver or alteration.

Not practicable does not mean time-consuming, expensive, or inconvenient.Researchers will have to provide acceptable evidence to their IRBs that securing consent

is not feasible, regardless of cost and time.

4. Whenever appropriate, the subjects will be provided with additional pertinentinformation after participation.

This process is often referred to as debriefing. The debriefing process is an opportunityto provide subjects with information not disclosed during the initial consent process. It

also provides an opportunity for subjects to withdraw and not have their data included in

the research.

C11. For what types of projects may verbal consent be acceptable or waived?

According to the FDA and the DHHS, an IRB may allow waiver of a signed consent document.

An IRB may waive the requirement for the investigator to obtain a signed informed consent for

some or all subjects if it finds the research presents no more than minimal risk of harm to thesubjects and involves no procedures for which written consent is normally required outside of the

research context.

Where informed consent is obtained by means other than a written form, the investigators are

responsible for documenting and maintaining records of the procedures used and the response of

each subject.


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In cases where the written informed consent requirement is waived, the IRB may require the

investigator to provide subjects with a written statement summarizing the research.

Verbal approval does not satisfy the FDAs requirement for a signed consent document.

However, it is acceptable to send the informed consent document to the legally authorized

representative (LAR) by facsimile and conduct the consent interview by telephone when theLAR can read the consent as it is discussed. If the LAR agrees, he/she can sign the consent and

return the signed document to the clinical investigator by facsimile.

D. Miscellaneous Human Subject Issues

D1. Can a subject withdraw from a study after written consent has been given?A subject has the right to withdraw from a study at any time without sacrificing any benefits or

loss of medical care.

An investigator may encourage a subject to remain in the study and note the reasons to do so but

cannot place undo pressure on a subject who requests to withdraw.

A formal statement of withdrawal may be requested from the subject.

D2. Can a subject be paid for participation in the study?Subjects can be paid for participation in a study.

This is particularly the case when there is no direct benefit for the subject to participate.

Payments are usually acceptable if they cover a subject's expenses for participation in the study

including the time that is required.

The IRB must be informed of payments to be made to subjects and this should be clearly

indicated in the consent form.

The IRB will make a judgment as to whether the amount of the payment is appropriate to thecommitment required by the subject and to the expenses the subject is likely to incur, and that

it is not so great as to be an inappropriate inducement for a subject to consent to participate.

Payments to subjects typically are referred to as remuneration in distinction from compensationwhich refers to payment or medical care provided to subjects for research-related injuries.

D3. What is meant by "clinical equipoise"? How can it be considered ethical to determine apatient's treatment randomly and possibly be giving the patient a placebo?

The decision to participate in a study in which the patient's treatment will be determined by arandom selection can be a difficult one for a physician.

Physicians have a potential ethical conflict between their commitment to provide the bestpossible individualized care for a patient and their desire to further medical knowledge through

clinical trials, knowing that the latter may ultimately have a great benefit for their patients.


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Physicians must feel convinced that one treatment is clearly not more beneficial than another (orwhen the other treatment is a placebo, that one treatment is clearly not more beneficial than no

treatment) and that randomized treatment assignment is in fact an ethical way to manage the

condition under study.

A quote from Thomas Chalmers that is germane:

it may even be that trials of new and potentially toxic drugs are not ethical unless half the

patients are assigned by chance to conventional treatment...One has only to review the

graveyard of discarded therapies to discover how many patients might have benefited from being

assigned to a control group... A carefully designed therapeutic trial is not only more scientific

but also more ethical than the treatment of consecutive patients with a new drug of unproved

value.

D4. What are the requirements for including or excluding children from research?It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all

human subjects research, conducted or supported by the NIH, unless there are scientific andethical reasons not to include them.

Justifications for exclusions include the following:

1. The research topic to be studied is irrelevant to children.2. There are laws or regulations barring the inclusion of children in the research.

3. The knowledge being sought in the research is already available for children or will be

obtained from another ongoing study, and an additional study will be redundant.

4. A separate, age-specific study in children is warranted and preferable.5. Insufficient data are available in adults to judge potential risk in children.

E. Miscellaneous Administrative Issues

E1. Is a drug that has been approved by the FDA for one indication considered to be

investigational if it is studied for a different indication?

Federal regulations require investigators to submit an application for approval of a new

indication for, or other change from, a listed drug.

The applicant must certify in the application that he/she is seeking approval only for a new

indication and not for the indications approved for the listed drug on which the applicant relies.

An IND (Investigative New Drug) application is warranted if:

the new study is using an increased dose of the approved drug the new study uses a different method of administering the approved drug

the approved drug is being used for a longer duration

the research population is considered "vulnerable", e.g. children, older subjects there is reason to believe that this population has different pharmacokinetic or

pharmacodynamic responses from the indicated population

E2. What is meant by scientific misconduct?


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Scientific misconduct is defined as fabrication, falsification, plagiarism, or other practices that

seriously deviate from the standards that are commonly accepted within the scientificcommunity.

Examples include:

(1) altering information collected from a patient that would have excluded the patient so that thepatient appears to be eligible for the study

(2) randomization of patients prior to obtaining informed consent and changing the date on theinformed consent form to conform with the randomization date

(3) changing examination dates so that they appear as being in the time windows specified in the

protocol(4) altering outcome measurements.

Scientific misconduct does not include honest error or honest differences in interpretation of

data.

Each institution will have reporting requirements for situations where scientific misconduct issuspected. The institution will have procedures for investigation of the report and for informingthe Office of Research Integrity.

F. HIPAA Privacy Rule

F1. What is identifiable information and why is it important?

Identifiable information is significant, because it relates to a patient whose privacy the researcher

is responsible for maintaining. Although the FDA Protection of Human Subjects Regulationsdoes not specifically address identifiable information, the HHS Protection of Human Subjects

Regulations does. Human subject research is based on whether or not information is individually

identifiable. If it is individually identifiable, then it equates to being research on human subjects.Identifiable information includes names; all geographic subdivisions smaller than a state (street

address, city, county, precinct, zip code); all elements of dates (excluding year) for dates that

directly relate to a subject, including birth date, admission date, discharge date, death date, andall ages over 89 and all elements of dates indicative of age; phone numbers, fax numbers, e-mail

addresses, social security numbers, medical record numbers, account numbers, health plan

beneficiary numbers, certificate/license numbers; vehicle identifiers (including license plate

numbers); device identifiers and serial numbers, web universal resource locators (URLs);internet protocol (IP) address numbers, biometric identifiers, full-face photographic images and

any comparable images; any other unique identifying number, characteristic, or code unless

otherwise permitted by the Privacy Rule for re-identification.

Any de-identified health information is not considered protected health information (PHI) and is

not protected by the Privacy Rule.

The HIPAA Privacy Rule builds on the importance of identifiable information in order to protect

the privacy of research patients. Under the HIPAA Privacy Rule, individually identifiable healthinformation transmitted by electronic media, maintained in electronic media, or transmitted or

maintained in any other form or medium, is known as protected health information. Any de-


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identified health information is not considered protected health information (PHI) and is not

protected by the Privacy Rule.

The HIPAA Privacy Rule affects research, because it places certain controls on how a researcher

can use protected health information. Since the April 14, 2003 compliance deadline, covered

entities have applied the principles of the HIPAA Privacy Rule to the research environment.

G1. What government entities require reporting of financial disclosures?Under U.S. Public Health Service regulations, investigators receiving NIH funds must identify

and manage, reduce, or eliminate financial interests related to research supported by this federal

agency. By accurately reporting your relevant financial interests to the Network, you enable the

Network to comply with these regulations. If you are an investigator in a clinical study whoseresults are being submitted to FDA for marketing approval, the sponsor would need you to

complete a disclosure form so it can comply with FDA regulations.

In some cases, failure to disclose, eliminate, or manage conflicts of interest with research has led

to investigative and legal action by plaintiffs, the Securities and Exchange Commission, and the

Office for Human Research Protections (OHRP).

G2. Why is disclosure required?

Financial disclosure reporting aims to eliminate, diminish, and/or manage potential andperceived risks to study subjects, integrity of research results, colleagues, and trainees.

Human Subjects Refresher Test Background Document 2-18-09

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