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CRA IRB / Human Subjects Study Set

Terms in this set (49)

The Nuremberg Trials 1945-1946
Brought Nazis to trial for having performed medical experiments without consent of prisoners
Thalidomide Experiments 1962
Thalidomide Experiments 1962
Drug not approved by FDA
Caused severe birth defects
Out of this came declaration of Helsinki
Declaration of Helsinki
Declaration of Helsinki
June 1964 - revised 6 times
Built upon Nuremberg code
Recommendations:
Research with humans should be based on
lab and animal experiments
Should be conducted by medically/scientifically qualified individuals
Risk should not exceed benefits
Set of ethical principles• Developed by WMA for medical community - human experimentation• Followed Nuremberg Code (1947)• Regarded as cornerstone document of human research ethics• Included within clinical trial protocols
Syphilis study at Tuskegee 1932-1972
No informed consent
Largely African American
Recruited by being told hot meals would be provided
Life magazine article exposed study and it was shut down
Not given medical care
History summary here: https://www.history.com/news/the-infamous-40-year-tuskegee-study
National Research Act of 1974
Established the Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

Identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects

Another important provision that came out of the National Research Act was the requirement that all human subjects' research must be reviewed and approved by an Institutional Review Board (IRB). IRBs remain a critical component of the clinical research process

http://www.imarcresearch.com/blog/the-national-research-act-1974
Belmont Report - 1979
Influenced by Nuremberg Code and Declaration of Helsinki

-
The result of the Commission for the Protection of Human Subjects of Biomedical and Behavioral Research's work was summarized in what is now known as The Belmont Report. The Belmont Report gets its name from the location where the commission held their initial four day summit in February of 1976 to discuss the ethical concepts, which took place at the Smithsonian Institute's Belmont Conference Center. The commission met numerous times after the initial summit to expand and revise their ideas, until the final Belmont Report was ultimately released in 1979. The end result was a new set of 3 underlying ethical principles that were to guide biomedical and behavioral research conducted on human subjects:

Respect for Persons - Individuals should be treated as autonomous agents
- Persons with diminished autonomy are entitled to protection

Beneficence
- Human Subjects should not be harmed
- Research should maximize possible benefits and
minimize possible harm

Justice
The benefits and risks of research must be distributed
fairly
The Common Rule
The Common Rule is a federal policy regarding Human Subjects Protection that applies to 20 Federal agencies and offices. It does not apply to federal agencies that have not signed the agreement. The main elements of the Common Rule include:

Requirements for assuring compliance by research institutions

Requirements for researchers' obtaining and documenting informed consent

Requirements for Institutional Review Board (IRB) membership, function, operations, review of research, and record keeping.

The Common Rule includes additional protections for certain vulnerable research subjects.
Subpart B provides additional protections for pregnant women, in vitro fertilization, and fetuses

Subpart C contains additional protections for prisoners

Subpart D does the same for children.

DHHS Regulations are provided in 45 CFR, Part 46.
http://www.access.gpo.gov/nara/cfr/waisidx_99/45cfr46_99.html

FDA Regulations are detailed in 21 CFR, Part 50, and 21 CFR, Part 56.
You can review these at
http://www.access.gpo.gov/cgi-bin/cfrassemble.cgi?title=199945
45 CFR 46
Basic DHHS Policy for the Protection of Human Research Subjects
OHRP
Office of Human Research Protection
entity within the Dept of Health and Human Services in charge of implementing the regulations
DHHS
Department of Health and Human Services
IRB definition
Institutional Review Boards

a specially constituted review body established or designated by an entity to protect the welfare of human subjects recruited to participate in funded biomedical or behavioral research
IRB function
established to protect the welfare of human subjects recruited to participate in funded biomedical or behavioral research
Members of IRB
minimum of 5 members
at a minimum, one member whose primary concerns are in scientific areas, one member whose primary concerns are in nonscientific areas, numerous members representing more than a single profession, and at least one individual not affiliated with institution
No affiliation with research or institution
experts in the field-scientific background
community residents / representatives-nonscientific background
diversity -balanced by gender, culture, race
2 types of IRBs
internal - committees at academic institutions and medical facilities to monitor research studies involving human participants

external - independent or commercial irbs with identical responsibilities to academic or medical institution IRBs.
IRBs want to know
purpose of the research
study details
funding source
benefits, risks, and precautions
types of review
full
expedited
exempt
Exempt review
non invasive - poses no more than minimal risk
educational settings
educational tests
document review

6 eligible categories
- review of research already conducted
- normal educational practices
- normal educational tests or survey procedures, not on
children
- taste tests

Research and demonstration projects which are conducted by or subject to the approval of department or agency heads, and which are designed to study, evaluate, or otherwise examine:
(i) Public benefit or service programs;
(ii) procedures for obtaining benefits or services under those programs;
(iii) possible changes in or alternatives to those programs or procedures; or
iv) possible changes in methods or levels of payment for benefits or services under those programs
expedited review
no more than "minimal risk"
interviews, focus groups
surveys
specimens, non-invasive

- does not qualify for exemption - no additional risk
- only a select number of committee members review the protocol
- 7 categories for initial review, 2 additional categories for continuing review
full review
clinical trials
vulnerable population (children, prisoners)

- greater than minimal risk, or
- does not fit into 6 exempt or 9 expedited categories
- reviewed during monthly convened IRB meeting
Review Process
review for administrative concerns
assign protocols to the reviewers
confirm correct review type
committee may agree to approve, conditionally approve, table, or reject - what happens next:
letters or phone calls to confirm the outcome
two week timeline
requirements for approval
risks to the subjects are minimized

risks to the subjects are reasonable in relation to the anticipated benefits

selection of subjects is equitable

informed consent will be sought from each prospective subject or the subjects legally authorized representative

informed consent will be appropriately documented

research plan makes adequate provisions for monitoring the data collected to ensure the safety of subjects

there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data

when some or all subjects are likely to be vulnerable to coercion or undue influence, additional safeguards have been included in the study to protect their rights and welfare
IRBs role
Reviews and approves initial protocols
reviews modifications of existing protocols
continuing review of approved research
suspend or terminate previously approved research
- unanticipated harm
- not following IRB regulations
report issues to OHRP
Investigator Responsibilities
Has primary responsibilities for protecting the rights and welfare of human research subjects

conducts all research according to IRB approved protocol

ensures each potential subject understands the nature of research

Provides a copy of the IRB approved consent document to each subject

Retains all signed consent documents for at least 3 years

does not initiate any changes with IRB review and approval, unless it is necessary to eliminate an immediate hazard

reports progress to the IRB annually through continuing review

Promptly reports any unanticipated problems to the IRB
human subjects
a living individual about whom an investigator conducting research obtains:

1. data through intervention or interaction with the individual

2. identifiable private information

FDA definition - an individual on whom or on whose specimen a device is used (21 CFR 812.3) or an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. a subject may either be a healthy human or patient (21 CFR 50.3 (g))
Selection of Subjects
there must be fair procedures and outcomes in the selection of research subjects
Assessment of risks and benefits
the nature and scope of risk and benefits must be assessed in a systematic manner
informed consent
the consent process much include three elements:
1. information
2. comprehension
3. voluntariness

subjects, to the degree that they are capable, must be given the opportunity to choose what shall or shall not happen to them

describe overall experience, emphasize voluntary participation, selection procedures, risks and benefits, alternatives for treatment if applicable, confidentiality, explain compensation, explain rights to refuse and withdraw, explain why a subject might be expelled, costs to subjects, explain use and maintenance of data, permission to use data in future research
Agencies following the Common Rule
Common Rule Departments and Agencies:

Department of Homeland Security
Department of Agriculture
Department of Energy
National Aeronautics and Space Administration
Department of Commerce
(National Institute of Standards and Technology)
Social Security Administration
Agency for International Development
Department of Housing and Urban Development
Department of Justice
(National Institute of Justice)
Department of Labor
Department of Defense
Department of Education
Department of Veterans Affairs
(Office of Research Oversight)
(Office of Research and Development)
Environmental Protection Agency
(Research and Development)
Department of Health and Human Services
National Science Foundation
Department of Transportation
Office of the Director of National Intelligence
Central Intelligence Agency
Consumer Product Safety Commission
IND application
the means through which the sponsor technically obtains exemption from the FDA to transport or distribute a drug across state lines.

circumstance of this would be when investigator wants to ship drug to clinical investigators in other states
what is a clinical trial
generally considered to be biomedical or health - related research studies in human beings that follow pre-defined protocol
intervention study
those in which the research subjects are assigned by the investigator to a treatment or other intervention, and their outcomes are measured.
observation study
those in which individuals are observed and their outcomes are measured by the investigators
different types of clinical trials
treatment trials
test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy

prevention trials
look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. these approaches may include medicines, vaccines, vitamins, minerals, or lifestyle changes

diagnostic trials
are conducted to find better tests or procedures for diagnosing a particular disease or condition

screening trials
test the best way to detect certain diseases or health conditions

quality of life trials
explore ways to improve comfort and the quality of life for individuals with a chronic illness
phases of clinical trial
Phase I trials
researchers test an experimental drug or treatment in small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

Phase II
the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate the safety

Phase III
the experimental study drug or treatment is given to large groups of people (1000-3000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely

Phase IV
post marketing studies delineate additional information including the drug's risks, benefits and optimal use.
Nuremberg Code
ethical conduct of medical experimentation 10 Principles -
1.Required is the voluntary, well-informed, understanding consent of the human subject in a full legal capacity.

2.The experiment should aim at positive results for society that cannot be procured in some other way.

3.It should be based on previous knowledge (e.g., an expectation derived from animal experiments) that justifies the experiment.

4.The experiment should be set up in a way that avoids unnecessary physical and mental suffering and injuries, except, in experiments where the experimental physicians also serve as subjects.

5.It should not be conducted when there is any reason to believe that it implies a risk of death or disabling injury.

6.The risks of the experiment should be in proportion to (that is, not exceed) the expected humanitarian benefits.

7.Preparations and facilities must be provided that adequately protect the subjects against the experiment's risks.

8.The staff who conduct or take part in the experiment must be fully trained and scientifically qualified.

9.The human subjects must be free to immediately quit the experiment at any point when they feel physically or mentally unable to go on.

10.Likewise, the medical staff must stop the experiment at any point when they observe that continuation would be dangerous.
intervention
includes both physical procedures by which data are gathered and manipulations of the subject or the subject's environment that are performed for research purposes
waiver of consent
FDA will not waive
DHHS will waive if
minimal risk
not practical to obtain
no rights adversely effected
alternate means to report new info would affect participation
control group
standard by which experimental observations are evaluated
given either the standard treatment or placebo
Tuskeegee Study
400 African males, no informed consent, 1930-1972

caused national commission for the protection of human subjects

which caused Belmont report

which became common Rule 45CFR46
Department of defense addenda
institutions that conduct human subjects research funded by DoD must sign addenda to their assurances and comply with additional regulations
research involving recombinant dna molecules
NIH guidelines apply to rDNA research that is
-funded by the NIH - term and condition of NIH funding
-performed at or sponsored by an institution that received any NIH funding for recombinant DNA research
-specify practices for constructing and handling
recombinant DNA molecules
organisms and viruses containing recombinant DNA molecules

definition
-constructed outside living cells by joining natural or synthetic DNA segments to dNA molecules that can replicate in a living cell
-molecules resulting from the replication of those described above
Institutional responsibilities under the NIH guidelines for recombinant dna
-establish and implement policies for the safe conduct of recombinant DNA research
-establish an institutional biosafety committee
-assist and ensure compliance with the NIH guidelines by inevestigators
-ensure appropriate training for IBC members and staff, PIs, laboratory staff
-determine necessity for health surveillance of personnel
-report any significant problems or violations to Office of Biotechnology Activities within 30 days
Joseph Mengele
Nazi doctor at Auschwitz who performed experiments on the Jews, especially twins. Claimed
that it was not his fault that Jews had to die at Auschwitz so he might as well take advantage of it for science
Revised Common Rule (Effective 7/19/19)
New Exempt Categories
The Common Rule defines three levels of review for human subjects research: exempt, expedited, and full (committee). The new Common Rule broadens the types of research that may be determined to be exempt from IRB review. For example, starting January 19, benign behavioral interventions conducted with adults may be determined to be exempt. Researchers must submit to the IRB program for a determination that activities are exempt from IRB review. Another example: the collection of identifiable, sensitive information from adults may also be exempt; however, this new category requires a limited IRB review to determine that appropriate privacy and confidentiality protections are in place.

Continuing Review Changes
Some minimal risk studies will no longer be required to renew their IRB approval on an annual basis (continuing review). Investigators conducting eligible studies will be informed of post-approval requirements at the time of initial approval.

Consent Form Changes
Consent forms will need to include a brief summary that explains the research to potential participants in an easy-to-understand and clear manner. It is now mandated that consent forms be concise while also giving the full context of a study, including its risks and benefits, so potential participants have all the information they need to make an informed decision. Consent forms will also need to include information regarding the potential for future use of de-identified data and biospecimens.

In addition, there is a new requirement that cooperative research studies involving more than one institution to use a single IRB for review. The implementation date for this requirement is January 19, 2020.
Single IRB
Multi-site projects with non-exempt human studies must conduct activities under a single IRB. Foreign research regulations must be at least equal to US Federal Policy.
Broad Consent
Human subjects consent to his/her sample being used once at the beginning of a research experiment - if additional analysis needs to be performed or new experiments are designed, the donor isn't contacted again, provided the new research isn't a significant deviation form what was agreed to initially.
Assurance
A documented commitment by an institution to comply with the requirements of 45 CFR 46
Data and Safety Monitoring Plan
Specifically required for multi-site clinical trials wit interventions that entail risk to participants.
DSMPs are generally required for Phase III clinical trials
A DSMP may be required for Phase 1,II or III if :
the clinical trial is blinded
the clinical trial involves high risk interventions
the clinical trial includes vulnerable populations
Human Subjects Training Requirement
All individuals involved in the design or conduct of the research must meet the education requirement. It is up to each institution to establish how often the investigators must complete the human subjects education. Documentation of completion of education must be submitted prior to each new award that involves human subjects.
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