© hrp associates, inc. required findings & determinations jeffrey m. cohen, ph.d. cip president...

© HRP Associates, Inc.

Required Findings & Determinations

Jeffrey M. Cohen, Ph.D. CIPPresidentHRP Associates, Inc.


Overview

Three types of required findings and determinations

Required findings for all protocols Required findings where appropriate to the

protocol Other determinations


Required Findings: All Protocols

For each protocol, the IRB must determine and document:– The research meets all of the criteria for approval

in 45 CFR 46.111– Additional safeguards to protect vulnerable

populations– The level of risk (minimal or more than minimal)– Approval period


Required Findings: Where Appropriate

When approving research that involves populations covered by Subparts B, C, or D of 45 CFR 46, the IRB must find and document that the research meets the criteria in the Subparts

When waiving consent, the IRB must find and document that the research meets the criteria in 45 CFR 46.116(d)

When waiving documentation of consent, the IRB must find and document that the research meets the criteria in 45 CFR 46.117(c)

Other Determinations

Investigator Conflict of Interest Serious or Continuing Noncompliance Unanticipated Problems Multi-site/Collaborative Research


Criteria for Approval

Criteria for IRB Approval of Research

45 CFR 46/21 CFR 56 §111(a)

“In order to approve research covered by these regulations the IRB shall determine that all of the following requirements are satisfied”


Criteria for IRB Approval

Risks to subjects are minimized

Risks are reasonable in relation to anticipated benefits

Selection of subjects is equitable

Informed consent is sought from each subject

Informed consent is appropriately documented


46.11146.111

When appropriate: data collection is monitored to

ensure subject safety privacy and confidentiality of

subjects is protected additional safeguards are

included for vulnerable populations

Criteria for IRB Approval


BENEFICENCE JUSTICE

RESPECT FOR PERSONS

Privacy & ConfidentialityVulnerable Populations

Informed consentSurrogate consent

Assent

Risk/Benefit AnalysisData Safety

Experimental DesignQualifications of PI

Subject selectionInclusion/exclusion

Recruitment

46.11146.111


Risk/Benefit

Identifying Risks

The term “risk” involves two dimensions– Magnitude of harm– Probability of harm

Assessing the level of risk involves taking both into account


Identifying Risks

Identifying risk requires scientific expertise on the part of the IRB

When the IRB does not have the necessary expertise it must use outside consultants

An IRB that reviews research without the necessary expertise is not in compliance with the regulations


Minimizing Risk

Three ways to minimize risk Alternatives

– other procedures that are less risky Precautions

– procedures to decrease the likelihood that harms will occur

Contingencies– procedures to deal with harms if they occur



Subject Selection & Recruitment

Subject Selection

Justice requires equitable distribution of both the burdens and benefits of research

– Individuals and groups that bear the burden should share in the benefits

– Individuals and groups that benefit from research should share in the burden

Selection of subjects should be justified by the science IRBs should not overprotect vulnerable populations so that they

are excluded from participating in beneficial research If the study is funded by NIH, exclusions of women, minorities

or children MUST be justified.


Subject Recruitment

Subject recruitment is part of the consent process – Information in recruitment should be consistent with

protocol– Recruitment should not be coercive or unduly enticing– Recruitment should clearly indicate that it is for research

and not make unfounded claims (e.g., “cure” or “free treatment”)

IRBs must review recruitment procedures, including any advertising

– Difference between FDA and OHRP guidance


Informed Consent


Beyond the Beyond the Consent Consent

FormForm

The Consent Process

Informed consent is not a single event or just a form to be signed -- rather, it is an educational process that takes place between the investigator and the prospective subject.

The basic elements of the consent process include: full disclosure of the nature of the research and the

subject's participation, adequate comprehension on the part of the potential

subjects, and the subject's voluntary choice to participate.


Procedures for Obtaining Consent

Subject has the legal and mental capacity to give consent

– legally authorized representative; Sufficient opportunity is provided to consider The possibility of coercion or undue influence is

minimized Language understandable to the subject No “exculpatory” language


46.11646.116

Documentation of Consent

Documentation of "legally effective informed consent" usually involves the use of a written consent form signed by the subject or the subject's legal representative.

The consent form is merely the documentation of informed consent and does not, in and of itself, constitute informed consent.

The fact that a subject signed a consent form does not mean that he/she understood what was being agreed to or truly gave their voluntary consent.


46.11746.117

Data Safety Monitoring


Safety Monitoring

Oversight and monitoring to ensure the safety of participants

Investigators need Data Safety Monitoring Plan– How subject reactions and data being monitored– Unanticipated Problems detected and reported– What to do in case of problems

Privacy and Confidentiality


Definitions

Privacy - having control over the extent, timing, and circumstances of sharing oneself (physically, behaviorally, or intellectually) with others.

Confidentiality - methods used to ensure that information obtained by researchers about their subjects is not improperly divulged.


Regulations

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.


Regulations

Private information - information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record).

Identifiable information – information where the identity of the subject is or may readily be ascertained by the investigator or associated with the information.


Confidentiality

Confidentiality and anonymity are not the same– Anonymous means no one, anywhere, ever can

identify individual subjects Names are not the only identifiers Subjects’ participation in the research may

need to be kept confidential as well as their data


Confidentiality

More elaborate procedures may be necessary for studies in which data are collected on sensitive matters such as sexual behavior or criminal activities.

Any written record linking subjects to the study can create a threat to confidentiality, including consent forms


Vulnerable Populations


Vulnerable Populations

Federal regulations involving human subjects in research include specific protections for children, pregnant women and fetuses (Subpart B), prisoners (Subpart C), and children (Subpart D).

In addition, the IRB expects the investigator to provide additional information regarding cognitively impaired individuals in research or others who are likely to be vulnerable to coercion or undue influence.


Conclusion

The IRB must be satisfied that all of the review criteria have been met before it approves a protocol

The IRB must have sufficient information upon which to base its decision– OHRP frequently cites IRBs for not having

enough information to make a decision



Risk Level

Risk Level

For each protocol the IRB must determine and document the level of risk– Minimal risk– More than minimal risk



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.”

45 CFR 46.102(i)


Approval Period


Continuing Review

“An IRB shall conduct continuing review of research covered by this policy at intervals appropriate to the degree of risk, but not less than once per year”

45 CFR 46.109(e)


Approval Period

Appropriate to the degree of risk and not less than once per year

Should be set for each protocol, not a routine annual review


Continuing Review

Must be substantive and meaningful– Criteria for approval still being met– Whether any new information has emerged, either from the

research itself or from other sources, that could alter the IRB’s previous determinations, particularly with respect to risk to subjects

At least one member should review entire protocol Full IRB reviews summary and progress report


45 CFR 46 Subparts


Subpart B -Pregnant Women, Human Fetuses and Neonates

Applies to all research involving pregnant women, human fetuses, neonates of uncertain viability, or nonviable neonates

For research where the risk to the fetus is no more than minimal and is not funded by DHHS, no additional safeguards are required and there are no restrictions on the involvement of pregnant women.

For research involving more than minimal risk to fetuses not funded by DHHS or research funded by DHHS, pregnant women or fetuses may be involved if the IRB must find and document that the following criteria are met.



Where appropriate, preclinical studies have been done

Direct benefit to woman or fetus If no direct benefit, no more than minimal risk to

fetus and knowledge can’t be obtained by other means (For DHHS-funded research: biomedical knowledge)

Any risk is the least possible for achieving the objectives of the research

If benefit is solely to fetus, then consent from father, if available, is required. Otherwise only mother’s consent required



Each individual providing consent is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate;

For children who are pregnant, assent and permission are obtained in accord with the provisions of subpart D of this part;

No inducements, monetary or otherwise, will be offered to terminate a pregnancy;

Individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy; and

Individuals engaged in the research will have no part in determining the viability of a neonate.



Research involving neonates Neonates of uncertain viability

– Either research holds out prospect for enhancing viability or no added risk

– Consent from either parent allowed Nonviable neonates

– Vital functions not artificially maintained– Research will not terminate heartbeat or respiration– No added risk– Consent from both parents required

Viable neonates are children and come under Subpart D


Subpart C - Prisoners

Definition of Prisoner– Involuntarily confined or detained in a penal

institution as a result of sentencing– Detained in alternative institutions as a result of

sentencing– Detained pending arraignment, trial, or sentencing – Includes individuals who are prisoners at the time

of enrollment in the research or who become prisoners after they become enrolled in the research



IRB Findings: Research is in one of the permissible categories Advantages from research can’t be coercive Risks commensurate with risks acceptable to non-

prisoners Selection fair to all prisoners Information understandable to population Can’t have an effect on parole If applicable, provisions made for follow-up after release



Permissible Categories: 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;

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;



Research on conditions particularly affecting prisoners as a class (only after special panel)

Research which has the intent and reasonable probability of improving the health or well-being of the subject (control groups require special panel)



Waiver for Epidemiology Research: The categories of permissible research do not apply for epidemiology research where the IRB has approved the research and determined and documented that– The research presents no more than minimal risk

and no more than inconvenience to the prisoner-subjects, and

– Prisoners are not a particular focus of the research.


Subpart D - Children

Definition: "Children" are persons who have not attained

the 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. [46.402(a)]



Parental Permission: Adequate provisions are to be made to secure

permission from the parents or guardians of each child. – For minimal risk research or risk research with

direct benefit, the IRB may allow permission from one parent.

– For risk research without direct benefit, permission from both parents is required.

[46.408(b)]



Categories of Research Minimal Risk

– Assent & Parental Permission required[46.404]

Risk but with direct benefit to subjects– Risk justified by benefits– Risk/Benefit at least as favorable as alternatives– Assent & Parental Permission required

[46.405]



Categories of Research Risk but with no direct benefit

– Minor increase over minimal risk– Intervention or procedure reasonably

commensurate with what they already experience– Likely to yield generalizable knowledge about the

subject’s disorder or condition– Assent & Parental Permission required

[46.406]



Categories of Research Research not otherwise approvable which

presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children– can be approved if the Secretary consults

with panel of experts.[46.407]

Other Vulnerable Populations

Decisionally or cognitively impaired Non-English speaking Desperately ill Economically disadvantaged Educationally disadvantaged Students Employees


IRB Review

How should IRBs review vulnerability?– IRBs and investigators need to be sensitive to possible

vulnerabilities of subjects– IRBs need to ask detailed questions on the characteristics

of the potential populations– IRBs need to evaluate potential vulnerabilities– IRBs need to ask investigators what extra protections are in

place for vulnerable subjects– IRBs need to asses adequacy of extra protections


IRB Review

IRBs need sufficient expertise on vulnerable populations

– 46.107(a) If an IRB regularly reviews research that involves a vulnerable category of subjects, such as children, prisoners, pregnant women, or handicapped or mentally disabled persons, consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with these subjects

– Outside Consultation– Community Consultation



Consent Waivers


An IRB may approve a waiver or alteration of some or all of the consent requirements provided the IRB finds and documents that:

– The research involves no more than minimal risk to subjects;

– The waiver will not adversely affect the rights and welfare of subjects;

– The research could not practicably be carried out without the waiver; and

– Whenever, appropriate, the subjects will be provided with additional pertinent information after they have participated in the study.

Waiver of Consent 46.116(d)46.116(d)


An IRB may waive the requirement for the investigator to obtain a signed consent form for some or all subjects if it finds and documents that:– the research presents no more than minimal risk;and – the research involves procedures that do not

require written consent when performed outside of a research setting.

Waiver of Documentation 46.117(c)(2)46.117(c)(2)


An IRB may waive the requirement for the investigator to obtain a signed consent form for some or all subjects if it finds and documents that:– the principle risks are those associated with a

breach of confidentiality concerning the subject’s participation in the research;

and – the consent document is the only record linking

the subject with the research

Waiver of Documentation 46.117(c)(1)46.117(c)(1)


Other Determinations

Conflict of Interest

Initial review made by Chair or designee Chair makes recommendation that the

disclosed financial interest is:– not acceptable (in which case the financial interest must be

divested or other action taken); or– acceptable with some form of management (such as

disclosure, restrictions on the activities of the investigator, or such other form as determined appropriate); or

– acceptable without any need for management.


Conflict of Interest

IRB makes final determination regarding COI management.

Possible management plans:– Disclosure to subjects through the consent process– Modification of the research protocol or safety monitoring plan– Monitoring of research by independent reviewers– Disqualification of the conflicted party from participation in all or a portion of the

research– Appointment of a non-conflicted Principal Investigator– Divestiture of significant financial interests– Severance of relationships that create actual or potential conflicts.– Prohibition of the conduct of the research at the hospital


Noncompliance

Definition– failure to comply with or adhere to rules,

regulations, policies and standards of conduct that govern human subject research,

– failure to follow the determinations of the IRB,– failure to follow institutional policies.

Noncompliance may be minor or serious, or it may be sporadic or continuing.

Noncompliance

Serious noncompliance. – Noncompliance which increases risks to

participants, decreases potential benefits, or compromises the integrity of the human research protection program.

– Research being conducted without prior IRB approval is always considered serious noncompliance.

Noncompliance

Continuing noncompliance. – A pattern of noncompliance that suggests a

likelihood that without intervention instances of noncompliance will continue.

– Failure to respond to a request to resolve an episode of noncompliance.

Noncompliance

The IRB makes a determination about whether the incident is serious or is part of a pattern of non-compliance.

The IRB then makes a determination about what action is warranted, including taking any additional action it deems necessary to protect the rights and welfare of the research subjects involved in the study.

Noncompliance

Possible actions– Corrective action plan– Education– Modification of protocol– Increased monitoring– Informing subjects– Suspension or termination of research


Unanticipated Problems

Unanticipated Problems involving risk to subjects or others, include any incident, experience, or outcome that meets ALL of the following criteria: – Unexpected– Related to the research– Increased risk of harm


Not all Adverse Events are Unanticipated Problems– Some are not unanticipated

Depressed subject commits suicide

– Some are not relatedChild falls out of bed and is injured


Not all Unanticipated Problems are Adverse Events– Determined by risk of harm, not actual

harmLost laptopNew risk in literature



Not all Unanticipated Problems involve the subjects – “…risk to subjects or others.”– Researcher injured by subject– Family member “outed” by subject



IRB makes final determination as to whether an event is an unanticipated problem

Possible actions– Change protocol– Change consent form– Inform subjects– Suspension or termination of research


Multi-site/Collaborative Research

For multi-site or collaborative research, the IRB must determine that the procedures for dissemination of protocol information (IRB initial and continuing approvals, relevant reports of unanticipated problems, protocol modifications, and interim reports) between all participating institutions are adequate.


Multi-site/Collaborative Research

If McLean Hospital is the coordinating facility, the Principal Investigator must document (and the IRB approve) how important human subject protection information (such as safety information or information affecting an individual’s willingness to participate or continue in the study) will be communicated to the other participating facilities engaged in the research study.



Documentation of Required Findings


Documentation

For each of the required findings the IRB must provide protocol-specific information justifying why the IRB considers the research to meet each criterion or the IRB’s agreement with the findings and justifications as presented by the investigator on IRB forms.

For full-review protocols the findings must be documented in the IRB minutes

For expedited-review protocols the findings must be documented in the record along with the reviewer’s signature

© hrp associates, inc. required findings & determinations jeffrey m. cohen, ph.d. cip president...

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