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Applicable Requirements for Human Research

Regulatory applicability

Patchwork of laws and regulations Common rule (HHS, DOD) FDA ICH-GCP

Impossible to have one standard

Impossible to apply HHS regulations to all research

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Applicable requirements for IRBs

HHS & 18 other federal departments and agencies 45 CFR 46

Subpart A “Common Rule” Subparts B-D Subpart E

FDA 21 CFR 50 (Informed consent) 21 CFR 56 (IRB review)

ICH-GCP (E6)

Activity must meet the HHS definition of “research”

“Research” must involve “human subjects” as defined by HHS

“Research involving human subjects” must be “subject to regulation”:

Covered “research involving human subjects” “subject to regulation” must engage the institution (http://wwwhhsgov/ohrp/policy/engage08.html)

Covered “research involving human subjects” “subject to regulation” that “engages” the institution must be non-exempt

45 CFR 46 Subpart A applicability

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HHS Definition of “Research”

A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. About behavior Not about intent Not about publication Not about outcome

HHS Definition of “Human Subject”

A living individual about whom an investigator conducting research obtains data through intervention or

interaction with the individual, or identifiable private information.

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HHS Definition of “Human Subject”

A living individual about whom an investigator conducting research obtains data through interventionor interaction with the individual

Intervention Physical procedures by which data

are gathered Manipulations of the subject or the

subject’s environment that are performed for research purposes

Interaction Communication or interpersonal

contact between investigator and subject

Research

Human subject Subject to regulation

Engaged

Non-Exempt

HHS Definition of “Human Subject”

A living individual about whom an investigator conducting research obtains identifiable privateinformation.

Identifiable The identity of the subject is or may

readily be ascertained by the investigator or associated with the information

Private Information about behavior that occurs in

a context in which an individual can reasonably expect that no observation or recording is taking place

Information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public

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HHS Definition of “Subject to regulation”

Conducted by a federal department or agency that has taken action to adopt 45 CFR 46 Subpart A (listed on next slide)

Supported by a federal department or agency Monetary or non-monetary

Otherwise subject to regulation by a federal department or agency “Checking the box” EPA

I love it when clients check the box!

They never negotiate fees when OHRP is walking in the door.

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HHS & 18 other federal departments and agencies

7 CFR §1c Agric

10 CFR §745 DOE

14 CFR §1230 NASA

15 CFR §27 Commrce

16 CFR §1028 CPSC

22 CFR §225 AID

24 CFR §60 HUD

28 CFR §46 DOJ

32 CFR §219 DOD

34 CFR §97 Education

38 CFR §16 VA

40 CFR §26 EPA

45 CFR §690 NSF

45 CFR §46 HHS

49 CFR §11 DOT

Policy OSTP

PL 108-458 DHS

PL 103-296 SSA

EO 12333 CIA

HHS definition of “engaged”

http://www.hhs.gov/ohrp/policy/engage08.html

Employees or agents gather information about living individuals for research purposes by: Interaction Intervention

Employees or agents gather private identifiable information about living individuals for research purposes

Employees or agents obtain consent

Direct federal awardee

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HHS definition of “employees or agents”

Individuals who: Act on behalf of the institution, Exercise institutional authority or

responsibility, or Perform institutionally

designated activities

Up to institution to define when these are true

HHS exceptions to definition of “engaged”

Commercial services

Research related clinical care

One time or short term care

Inform subjects

Use of facilities

Release of information

Coded data or specimens

Visiting professor

Audit

FDA reporting

Authorship

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HHS exempt categories

“… research activities in which the only involvement of human subjects will be in one or more of the following categories are exempt from this policy:”

Six categories Education research Communication Public figure communication Retrospective reviews Federal demonstration projects Taste and food

Research

Human subject

Subject to regulation

Engaged

Non-Exempt

Subpart BPregnant Women

Subpart CPrisoners

Subpart DChildren

DHS Regulation Regulation Regulation

DOD Guidance Guidance Guidance

ED Regulation

EPA Regulation Regulation Regulation

HHS Policy Policy Policy

VA Guidance Guidance Guidance

Common Rule agencies and the subparts

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Agencies with additional regulations and guidance

DOD

DOE

DOJ

EPA

ED

VA

HHS exempt categories

Consider each item in order

Follow regulatory definitions

Consult regulatory agency because they have the final word

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FDA applicability

Any experiment that involves a test article and one or more human subjects, and that either must meet the requirements for prior submission to the FDA under section 505(i) or 520(g) of the FD&C Act, or need not meet the requirements for prior submission to the FDA under these sections of the act, but the results of which are intended to be later submitted to, or held for inspection by, the FDA as part of an application for a research or marketing permit.

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FDA applicability – explained

Any use of a drug in one or more humans other than the use of a marketed drug in the course of medical practice Or controls to above

Any evaluation of the safety or effectiveness of a device through its use in one or more humans or its use on human tissue specimens Or controls to above

Submission of data to FDA

FDA regulations

21 CFR 50 (Informed consent)

21 CFR 56 (IRB review)

21 CFR 11

21 CFR 54

21 CFR 312

21 CFR 314

21 CFR 812

21 CFR 820

Under FDA “sponsor” is the person who runs the trial, not the person who pays for the trial

IRB Requirements Requirements for sponsors

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FDA exemptions

Emergency use

Exemption from 21 CFR 56 (IRB review)

Not an exemption from 21 CFR 50 (informed consent)

ICH-GCP (E6)

“International Council on Harmonisation – Good Clinical Practices (E6)”

International standard

Force of law in many countries

Allows sponsors to submit data to regulators outside US

Not the same as what FDA refers to as “GCP” Is a safe harbor for FDA GCP

50% of protocols or contracts require ICH-GCP compliance

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EPA

Oversight of human research

Common standards defined by SOPs

FDA

ICH

Human Research Compliance Risks

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Risk of human research

Regulatory risk Liability risk

Regulatory risk

Who is at risk? Investigators IRB Institution

Causes of risk Minutes Consent documents Quorum Standard operating procedures No IRB approval

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Most IRBs documentation is not required by regulation

Including IRBs with regulatory citations

Common missing items in minutes

Actions taken by the IRB Votes for, against, or abstaining Attendance at the meeting Basis for requiring changes Written summary of controverted

issues and their resolution Approval period Names of members who leave the

meeting because of a conflict Rationale for significant risk/non-

significant risk device determinations

Determinations and protocol-specific findings for: Waiver or alteration of the consent

process Research involving pregnant women Research involving prisoners Research involving children

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Solution to minutes issues

Audit minutes Get someone who knows what

they are doing

Insist that unnecessary information be removed from minutes The greater the attention on

unnecessary information, the less the attention on necessary information

Forbid recording of meetings If the IRB staff cannot figure out

what is going on at meetings without listening to a recording, then IRB members don’t know what they are voting on

Consent documentsOmission of risks because of “standard of care”

If the protocol requires a procedure, that procedure is part of the research and needs to be included in the consent document!

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Solution to consent issues

Make IRB members use a checklist for elements of consent disclosure Not role of IRB staff

Limit boilerplate wording “It follows our standard

language, so it must be OK.”

Limit non-regulatory requirements The greater the attention on

unnecessary requirement, the less the attention on requirements

Remove “standard of care” from the IRB lexicon

Solution to quorum issues

Review roster for accuracy Who is “non-scientific”?

Must be clearly non-scientific

Who is “unaffiliated”? Immediate family must also be

unaffiliated

What is a “conflicting interest”?

Assign someone the responsibility to monitor quorum

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SOP requirements

Conducting initial and continuing review

Reporting its findings and actions to the investigator and the institution

Determining which projects require review more often than annually

Determining which projects need verification from sources other than the investigators that no material changes have occurred since previous IRB review

Ensuring prompt reporting to the IRB of proposed changes in a research activity

Ensuring that changes in approved research, not be initiated without IRB review

Ensuring prompt reporting to the IRB, appropriate institutional officials, and the Department or Agency head of Any unanticipated problems involving risks to

subjects or others

Any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB; and

Any suspension or termination of IRB approval.

Solution to SOP issues

Require operational SOPs

Get AAHRPP accredited

Borrow existing SOPs

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Solution to lack of IRB approval

Outreach to investigators Explain concept of research

Minimize IRB burden Be customer friendly Be prompt Use least restrictive approval

Survey literature periodically and match to approved research Handle non-compliance with a

velvet glove Half the problem is institutional

Create a safe confidential channel to report allegations of non-compliance

Liability risk

Who is at risk? Investigators IRB Institution

Causes of risk Obedience to authority Failure to use the regulatory

criteria for approval

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Obedience to authorityMilgram experiments

Obedience to authority in research

“I told the PI that the protocol required us to collect the investigational device from subjects after the research was done.”

“I told the PI that the IRB would probably want informed consent before drawing that blood.”

“I told the PI that Judy was doing something funny with the data.”

“I told the PI that I under ECOG criteria, the subject was performance status 2 not 3.”

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Solution to obedience to authority in research

Have centralized control of research staff

Establish safe, confidential, and well known channels for whistleblowers

Train investigators and research to work as a team Airline safety model is called

“Crew Resource Management”

Failure to use the regulatory criteria for approval

“Do inclusion criteria eliminate subjects at higher risk without affecting the soundness of the research design?”

“Does the data and safety monitoring board meet frequently enough?”

“Are the subjects in this study vulnerable to coercion or undue influence?”

“Is this study FDA-regulated?”

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Solution to use of regulatory criteria for approval issues

Train members on the regulatory criteria

Require use of a checklist by all members

Require all members to review the protocol

Require all changes and concerns to be justified by a regulatory criterion

Empower non-scientific members