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KELVIN OGHOGHO
ID 13022217
Records-Based Research
Center for Bioethics and Research (CBR), Nigeria - Group 1 - Investigators
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Records-Based Research
Content Author
Judy Matuk, MS
HRP Consulting Group
This module was revised and adapted from the original module authored by Barbara
Young.
Introduction
Researchers can make important advances in the fields of education, medicine,
psychology, and public policy without any in-person interaction with human
subjects. Rather, hypotheses can be posed and answered by analyzing documented
information in various types of paper or electronic records (such as medical, motor
vehicle, criminal justice, or school records).
Each person conducting scientific research based on records should:
Before collecting information from records for research purposes, a researcher

should consult with:
The Institutional Review Board/Independent Ethics Committee (IRB/IEC) at his/her

organization to determine the type of review required (if any)
The applicable administrator at the organization where the actual records are owned
or maintained to ensure ability to access them for research purposes
In addition, the researcher needs to determine if there are other regulations
affecting the record-review. Examples include the Health Insurance Portability and
Accountability Act’s (HIPAA) Privacy Rule for medical records research, or the
Family Educational Rights and Privacy Act (FERPA) for student education records.
Learning Objectives
By the end of this module, you should be able to:
Discuss the risks associated with conducting records-based research.

Identify the types of review that apply to records-based research.
Risks of Records-Based Research: Privacy and Confidentiality
Risks associated with records-based research stem from possible invasion of privacy
and breaches of confidentiality.
For example, the possibility that disclosure of the information could reasonably
place the subject at risk of criminal or civil liability and/or damage the
subject's financial standing, employability, or reputation.
Privacy can be defined in terms of having control over the extent, timing, and
circumstances of sharing oneself (physically, behaviorally, or intellectually) or
information about oneself with others.
In the context of research, privacy risk pertains primarily to the methods used to
obtain information about subjects. Privacy risks are very low when subjects
actually consent to provide personal information. However, privacy risks are much
higher when researchers obtain information for research purposes without the
subjects’ consent, which is often the case in records-based research.
Confidentiality pertains to the actual handling of the personal information once it

is obtained.
In other words, now that the researcher has obtained private information, how will
it be used, stored, and reported in a way that is consistent with the manner under
which it was originally obtained from the individual? Information from public
records and information obtained under a relationship of trust, as in the doctor-
patient relationship, will require different considerations for protecting
confidentiality.
Records-based research must balance the possible benefits of answering important

research questions with the possible risks of using information about individuals,
especially if information is used without their consent. Information about
individuals should be protected from disclosure because of the potential risks of
harm when shared inappropriately.
For instance, individuals may provide certain information about drug addiction or
mental illness to their medical doctors. However, they may experience certain
consequences if this information were revealed to law enforcement officials or
their employers. The IRB/IEC carefully reviews the procedures that are described by
the researcher to protect the confidentiality of the information being accessed,
including identification of all individuals or groups who may also be able to
access that information. For example, a university's audit office or a research
sponsor may require access to the information to ensure that the research activity
is being conducted appropriately.
Minimizing Risks
There is an ethical and regulatory responsibility to minimize research risks to

human subjects. The risks of invasion of privacy can be minimized by obtaining
informed consent from subjects. However, for a variety of reasons, obtaining
informed consent may be impracticable, may compromise the goal of the research, or
may actually put the subject at greater risk. In these circumstances, the IRB/IEC
may waive the necessity for informed consent if specific regulatory criteria at 45
CFR 46.116(f)(3) are met:
The research involves no more than minimal risk to the subjects;

The research could not practicably be carried out without the requested waiver or
alteration;
If the research involves using identifiable private information, the research could
not practicably be carried out without using such information in an identifiable
format;
The waiver or alteration will not adversely affect the rights and welfare of the
subjects; and
Whenever appropriate, the subjects or legally authorized representatives will be
provided with pertinent information after participation.
The risks of breach of confidentiality associated with records-based research are
necessarily tied to the sensitivity of the requested information. If the
information is recorded without identifiers, the sensitivity of the information is
less of a concern. If the information is both identifiable and sensitive, methods
to protect confidentiality must be carefully considered by the researcher and
approved by the IRB/IEC.
Therefore, in considering the research hypothesis, the researcher must assess how
important it is to be able to associate the individual with his/her information.
Whenever possible, and to the greatest extent possible, only de-identified or

anonymous information should be recorded. Assuming the research cannot be conducted
anonymously, the following questions speak to protection of the collected
information. Based on a researcher's answers, an IRB/IEC will carefully assess
whether possible risks from breaches of confidentiality have been minimized:
Certificates of Confidentiality
Researchers may obtain additional protection for certain research data by receiving
a study-specific Certificate of Confidentiality (CoC) from the National Institutes
of Health (NIH), Food and Drug Administration, or other HHS agency.
Specifically, the research data in question must constitute identifiable, sensitive

information, defined as “information that is about an individual and that is
gathered or used during the course of biomedical, behavioral, clinical, or other
research and:
Through which an individual is identified; or

For which there is at least a very small risk, as determined by current scientific
practices or statistical methods, that some combination of the information, a
request for the information, and other available data sources could be used to
deduce the identity of an individual.” (NIH 2018)
Once issued, a CoC prohibits disclosure of research data by the researcher if
requested to do so through civil, criminal and other types of legal proceedings,
and also prohibits disclosure to any other person not connected with the research,
unless certain conditions are met (for example, request is made with consent of the
subject).
If a study is funded by the NIH, the issuance of a CoC is automatic. If a study is

not funded by NIH, the issuance of a CoC depends on a successful application to the
funding agency.”
For more information, visit the NIH’s “Certificates of Confidentiality (CoC)”

webpage.
What Type of Review is Required for Records-Based Research?

Records-based research can fall into one of four review types. To identify the
appropriate type of review, consider the sequence of the following four questions:
Do the activities meet the federal definition of "human subjects research?" If yes:
Is the research eligible for exemption from the federal regulations? If no:
Is the research eligible for expedited review under the federal regulations? If no:
Does the records-based research need review by the full/convened IRB/IEC? Must be
yes!
Some organizations have criteria that are more stringent than the federal
regulations and guidance, so the information provided in this specific section may
not describe policies and procedures at the researcher’s organization. Check with
the applicable IRB/IEC office to find out how your organization makes such
determinations.
Do the activities meet the federal definition of "human subjects research?”
To determine if an activity constitutes human subjects research, one must break out
the individual definitions of ‘research’ and ‘human subject’.
Records-based research activities may not meet the federal definition of human
subjects research. HHS regulations at 45 CFR 46 (Protection of Human Subjects 2018)
define a human subject as "a living individual about whom an investigator (whether
professional or student) conducting research:
Obtains information or biospecimens through intervention or interaction with the

individual, and uses, studies, or analyzes the information or biospecimens; or
Obtains, uses, studies, analyzes, or generates identifiable private information or
identifiable biospecimens.”
According to the regulations, research is defined as “a systematic investigation,
including research development, testing, and evaluation, designed to develop or
contribute to generalizable knowledge” (Protection of Human Subjects 2018).
To determine if the proposed records-based project meets the regulatory definition

of “human subjects research,” the individual designated by the organization to make
this decision will consider:
The Common Rule specifically excludes certain activities from the definition of
research:
Scholarly or journalistic activities

Public health surveillance activities
Criminal justice activities (collection and analysis of information, biospecimens,
or records) conducted for criminal justice purposes
Authorized operational activities in support of intelligence, homeland security,
defense, or other national security missions
Check with your HRPP/IRB office to see if your records activity constitutes
research.
The researcher should check with the IRB/IEC to determine who has the authority to
make this decision whether the research constitutes human subjects research, or
whether the organization’s policy is more stringent.
If the research involves coded private information, please refer to OHRP’s Guidance
on Research Using Coded Private Information or Specimens.
Is the research eligible for exemption from the federal regulations?

If an activity constitutes human subjects research, it may be exempt from federal
regulations.
Records-based research may be exempt if any of the following apply:
The identifiable private information is publicly available (any person can obtain
the data).
The information is recorded by the researcher in such a manner that subjects cannot
be identified (directly or through identifiers linked to the subjects). Although
the researcher may actually see identifiers while reviewing the data set, he/she
cannot record any of them in any research record or data collection instrument. The
researcher also does not contact the subjects and will not re-identify the
subjects.
The research involves only information collection and analysis for the purposes of
“health care operations” or “research” (as defined at 45 CFR 164.501), or “public
health activities and purposes” (as described at 45 CFR 164.512[b]).
The research is conducted by, or on behalf of a federal department or agency using
government-generated or government-collected information obtained for non-research
activities.
The identifiable private information is being used for secondary research in which
broad consent was obtained and documented for the identifiable private information
for secondary research; a waiver of documentation of informed consent was obtained;
or an IRB conducts a limited IRB review and makes the determination that the
secondary research is within the scope of the broad consent and the research does
not include returning individual research results to subjects (unless legally
required).
OHRP recommends that researchers do not determine if their research qualifies as
exempt. Rather, the organization should designate an applicable institutional
official (or the IRB/IEC) to conduct this review. Organizations may have internal
rules and policies in addition to the federal regulations that will determine
whether to grant the exemption.
Is the research eligible for expedited review under the federal regulations?
If the records review activity constitutes human subjects research, and does not
qualify for exemption, it will then be subject to federal regulations.
Records-based research may qualify for expedited review if the research activity:
Poses no more than minimal risk of harm or discomfort to the subjects; and
Is described in one of the expedited review categories (OHRP 1998).
Records-based research that is eligible for expedited review generally falls under
Category 5, "Research involving materials (data, documents, records, or specimens)
that have been collected, or will be collected solely for non-research purposes
(such as medical treatment or diagnosis)."
Expedited Category 5 applies to prospective as well as retrospective research.
Does the record-based research need review by the full/convened IRB/IEC?
If the human subjects research does not qualify for exemption or expedited review,
then it must undergo full review by the IRB/IEC at a convened meeting.
When Health Information is Involved: Health Insurance Portability and

Accountability Act (HIPAA)
When records-based research requires access to individually identifiable

("protected") health information (also referred to as PHI), additional requirements
of the federal Health Insurance Portability and Accountability Act (HIPAA) must be
met. This includes the need for written authorization from the patient above and
beyond informed consent requirements under the Common Rule.
Promulgated through the Office of Civil Rights (OCR), requirements under HIPAA vary
depending on the type and number of identifiers that are being associated with the
accessed health information.
If most, but not all, mandated identifiers are removed this is called a "limited
data set." Written patient authorization may not be required for research using
limited data sets, provided there is a data use agreement between the researcher
and the organization holding the medical records.
If any more identifiers are added to the set, either written patient authorization
is required, or a HIPAA Privacy Board can grant a waiver of authorization based on
similar criteria to those required for waiver of consent under 45 CFR 46. Health
information that is completely “de-identified” as defined under HIPAA, is not
subject to the privacy law.
When School Records are Involved: Family Educational Rights and Privacy Act (FERPA)
FERPA is a federal law that applies to educational records and control over how
this information is disclosed to third parties. FERPA applies to any educational
organization that receives funds from programs administered by the U.S. Department
of Education (ED). This includes public kindergarten through twelfth grade (K-12)
schools and postsecondary institutions. There may be instances when a records-based
research study is exempt from human subjects research regulations, but must comply
with FERPA. Researchers should be aware of FERPA, so they may comply with it if
conducting research with educational records.
Summary
Although there is no direct interaction with human subjects in records-based
research, there may be risks to those individuals who originally provided the
information used in such activities. Those risks must be minimized, informed
consent must be considered, and review and approval from the organization and
IRB/IEC must be obtained, per local, state, and/or federal regulations. Research
involving identifiable health information requires compliance with additional
federal requirements.
References
National Institutes of Health (NIH). 2021. “Notice of Changes to NIH Policy for
Issuing Certificates of Confidentiality.” Last updated December 2.
Protection of Human Subjects, 45 CFR § 46 (2018).
U.S. Department of Health and Human Services (HHS), Office for Human Research
Protections (OHRP). 1998. “OHRP Expedited Review Categories (1998).” Accessed March
15, 2016.
Additional Resources
National Institutes of Health (NIH). 2015. “Certificates of Confidentiality (CoC)
Kiosk.” Last updated October 28.
U.S. Department of Health and Human Services (HHS), Office for Human Research
Protections (OHRP). 2008. “Guidance on Research Using Coded Private Information or
Specimens.” Accessed March 15, 2016.
U.S. Food and Drug Administration (FDA). 2018. “Use of Electronic Health Record
Data in Clinical Investigations.” Accessed 17 August 2018.
Original Release: December 2010

Last Updated: May 2019
This module has a quiz.
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Question
In order to grant a waiver or alteration of the requirements of informed consent,
an IRB must find which of the following:
Your Answer The research could not practicably be carried out without the waiver of
consent.
Result Correct
Comment
In order for an IRB to grant a waiver of consent, it must ensure the following
federal criteria at 45 CFR 46.116 are met:
The research involves no more than minimal risk to the subjects;

The research could not practicably be carried out without the requested waiver or
alteration;
If the research involves using identifiable private information, the research could
not practicably be carried out without using such information in an identifiable
format;
subjects; and
Whenever appropriate, the subjects (or legally authorized representatives) will be
provided with pertinent information after participation.
Question 2
Question
An investigator obtains consent and HIPAA authorization from subjects to review
their medical records and HIV status. She plans to go back to the medical record,
so the HIV status information is stored along with subject identifiers in a
database that she keeps on her laptop computer. What are some safeguards she could
use to protect subject privacy and data confidentiality?
Your Answer All of the above

Result Correct
Comment
All of the listed safeguards could be employed to provide additional protections
for subject privacy and data confidentiality.
Question 3
Question
An investigator obtains consent and HIPAA authorization from subjects to review
their medical records and HIV status. He plans to go back to the medical record, so
the HIV status information is stored along with subject identifiers in a database
that he keeps on his laptop computer. His laptop is stolen. This incident
constitutes:
Your Answer A breach of confidentiality

Result Correct
Comment
Privacy is about people and their expectations. Privacy risk pertains primarily to
the methods used to obtain information about subjects. Confidentiality pertains to
the actual treatment of the personal information once it is obtained. In other
words, now that the researcher has obtained private information, how will it be
used, stored, and reported. Clearly, this event represents a breach of
confidentiality.
Question 4
Question
A researcher wants to conduct a secondary analysis using a Centers for Disease
Control and Prevention (CDC) database that was collected by the agency solely for
surveillance purposes from 1996-2006. The researcher did not participate in the
initial collection of the data. The database is publicly available. The database
does not include any identifiers. The IRB makes a determination that the
individuals whose records will be reviewed do not meet the federal definition of
human subjects.
Which of the following considerations was relevant to the IRB's determination that
this activity does not constitute research with human subjects?
Your Answer The researcher will not be interacting/intervening with subjects and
the data has no identifiers.
Result Correct
Comment
Records-based research activities may not meet the federal definition of “human
subjects” research. A human subject is “a living individual about whom an
investigator (whether professional or student) conducting research: (i) Obtains
information or biospecimens through intervention or interaction with the
individual, and uses, studies, or analyzes the information or biospecimens; or (ii)
Obtains, uses, studies, analyzes, or generates identifiable private information or
identifiable biospecimens. (Protection of Human Subjects 2018). In this case, the
investigator did not collect the data directly from the human subject and the
investigator cannot readily ascertain the identity of the subject; therefore, this
would not qualify as human subject research.
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KELVIN OGHOGHO
ID 13022217
Research Involving Prisoners
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Research Involving Prisoners
Content Author
Helen McGough, MA
The University of Washington (retired)
Introduction
A picture of a prison hospital ward from the 1930s.
In 1976, the U.S. National Commission for the Protection of Human Subjects issued a
report on the issues involved with performing experiments on prisoners. In 1978,
the U.S. Department of Health and Human Services (HHS) issued regulations
addressing prisoners as a vulnerable research population (45 CFR 46, Subpart C).
These regulations were developed as a result of the exploitation of prisoners to

test drugs and medical devices during the middle decades of the twentieth century.
For example, it is estimated that, until the early 1970s, nearly 90 percent of all
new pharmaceuticals were first tested in prison populations (Wiegand 2007). This
module addresses some of the important matters researchers should consider when
they are contemplating research with prisoners.
Note: The U.S. Department of Justice (which includes the National Institute of
Justice and the Federal Bureau of Prisons [BOP] and other agencies) complies with
the Common Rule. However, it is not a signatory to the revised Common Rule
(although it is expected to be in the future). Researchers should be aware of and
comply with any additional BOP, and specific BOP facility, rules and requirements.
This module does not address those rules and requirements.
Learning Objectives
Describe the regulatory definition of a prisoner.

List the categories of research permitted with prisoners.
Identify the IRB membership requirements required for approval of research with
prisoners.
Describe the items the IRB must determine in order to approve research involving
prisoners.
Why do prisoners need special protections?
The National Commission’s (1976) report on “Research Involving Prisoners” presented
several reasons that supported special protections for prisoners as research
subjects:
Who is a prisoner?
The word "prisoner" is defined in 45 CFR 46.303(c) (Protection of Human Subjects)
as follows:
"A Prisoner means any individual involuntarily confined or detained in a penal

institution. The term is intended to encompass individuals sentenced to such an
institution under a criminal or civil statute, individuals detained in other
facilities by virtue of statutes or commitment procedures which provide
alternatives to criminal prosecution or incarceration in a penal institution, and
individuals detained pending arraignment, trial, or sentencing."
This may be interpreted as:
Prisoners are people who are being held in a jail, prison, juvenile offender
facility, or treatment facility or who have been convicted or are awaiting
arraignment, trial, or sentencing. This includes those who are in hospitals,
alcohol, and drug treatment facilities under court order. The definition applies to
minors as well as to adults.
According to the Office for Human Research Protections (OHRP n.d.), some common
examples of the application of the definition of prisoner include:
Minimal risk is also defined differently for prisoners and non-prisoners.
Minimal Risk is defined in 45 CFR 46.102(j) as follows: 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
Prisoner Minimal Risk is defined in 45 CFR 46.303(d) as follows: Minimal risk is

the probability and magnitude of physical or psychological harm that is normally
encountered in the daily lives, or in the routine medical, dental, or psychological
examination of healthy persons.
According to OHRP (n.d.) Prisoner Research FAQs the difference between the minimal
risk definitions include:
What kinds of research with prisoners are allowed?

The regulations allow prisoners to be involved in four categories of research.
Category 1
Studies of the possible causes, effects, and processes of incarceration, and of
criminal behavior, provided that the study presents no more than minimal risk of
harm and no more than inconvenience to the subjects (examples of this kind of
research might involve demographic studies of rates of incarceration or records-
based studies of recidivism).
Category 2
Studies of prisons as institutional structures or of prisoners as incarcerated
persons, provided that the study presents no more than minimal risk of harm and no
more than inconvenience to the subjects (examples of this kind of research might
involve confidential surveys of prisoners regarding food service or educational
opportunities).
Category 3
Research on conditions particularly affecting prisoners as a class. An example is
vaccine trials and other research on hepatitis, that is much more prevalent in
prisons than elsewhere. Another example is research on social and psychological
problems such as alcoholism, drug addiction, and sexual assaults.
Category 4
Research on practices, both innovative and accepted, which have the intent and
reasonable probability of improving the health or well being of the subject
(examples of this kind of research might include studies on alternative sentencing
or clinical trials of cancer therapies that do not involve assignment to placebo).
Consultation by Secretary of HHS, OHRP Notifications, and Waivers

Most studies in categories 3 and 4 may proceed only after the Secretary of HHS has
consulted with appropriate experts, including experts in penology, medicine, and
ethics, and published notice in the Federal Register of the intent to approve such
research.
OHRP must be notified about the research in all categories if HHS funds the study.
The only exception for HHS secretary approval appears to be in category 4 if the
study holds out potential benefits for prisoner-subjects and does not include the
possibility of assigning them to a placebo or no treatment condition.
In addition to the aforementioned categories, there is also the HHS Secretarial

waiver for certain epidemiological research HHS conducts or supports.
What does the IRB have to do in order to review research involving prisoners?
A majority of the IRB members (excluding prisoner members) must have no association
with the prisons involved, apart from their membership on the board.
Additionally, at least one member of the IRB must be a prisoner, or a prisoner

representative with appropriate background and experience to serve in that
capacity. If a research project is being reviewed by more than one IRB only one IRB
must satisfy this requirement. Suitable individuals could include:
What must the IRB determine in order to approve research involving prisoners?
Pursuant to Subpart C (45 CFR 46.305), for research involving prisoners the IRB
must determine that (OHRP n.d.):
The research under review falls into one of the categories of research allowed
under Section 46.306(a)(2).
Any benefits to the prisoner which may result from being in the research, when
compared to the general living conditions, medical care, quality of food, amenities
and opportunity for earnings in the prison, do not impair his or her ability to
weigh the risks of the research against the benefits in the prison environment.
The risks involved in the research are commensurate with risks that would be
accepted by non-prisoner volunteers.
Procedures for the selection of subjects within the prison are fair to all
prisoners and control subjects must be selected randomly from the group of
available prisoners who meet the characteristics needed for that particular
research project.
The study information is presented in language that is understandable to the

subject population.
Parole boards will not take into account a prisoner's participation in the research
in making decisions regarding parole, and each prisoner is clearly informed in
advance that participation in the research will have no effect on his or her
parole.
Adequate provisions have been made for follow-up examination or care, taking into
account the varying lengths of individual prisoners' sentences, and for informing
participants of this fact.
What if an already enrolled subject becomes a prisoner?

The regulatory protections are applicable to all prisoner-subjects, regardless of
their status at the time of enrollment in a study. If a previously enrolled
research subject becomes a prisoner and the study was not reviewed and approved by
the IRB in keeping with Subpart C, then OHRP (2003) guidance requires immediate
suspension of research activities (including collection of identifiable private
information) until the study can be reviewed in keeping with the requirements of
Subpart C. The researcher should notify the applicable IRB promptly.
OHRP (2003) guidance includes one important exception to the requirement to suspend
activities. In special circumstances in which the researcher asserts that it is in
the best interests of the subject to remain in the research study while
incarcerated, the IRB chair may determine that the subject may continue to
participate in the research until the requirements of Subpart C are satisfied.
Once the IRB receives notice that the subject has become a prisoner, the IRB should
review the protocol promptly in keeping with the requirements of Subpart C if the
researcher wishes to have the subject continue in the research.
Can exempt research include prisoners?

According to the HHS regulations, for research governed by the Common Rule (45 CFR
46, Subpart A), the exemptions at 46.104 “do not apply to research subject to
Subpart C, except for research aimed at involving a broader subject population that
only incidentally includes prisoners.”
This permits the exempt secondary research use of information or biospecimens from
subjects who are prisoners, if that analysis is not seeking to examine prisoners as
a population or subpopulation.
This also allows subjects to continue participating in exempt research if they

become prisoners during the course of an exempt study without IRB approval for
Subpart C.
Case StudyResearch Involving Prisoners
Summary
Regulatory protections exist for prisoner subjects. Researchers and IRBs should
include additional safeguards in research with prisoners as prisoners are a
population vulnerable to undue influence and coercion.
References
National Commission for the Protection of Human Subjects of Biomedical and
Behavioral Research (National Commission). 1976. “Research Involving Prisoners.”
Office for Human Research Protections (OHRP). 2003. “Prisoner Involvement in

Research.”
Office for Human Research Protections (OHRP). n.d. “Prisoner Research FAQs.”
Accessed May 24, 2019.
Wiegand, Timothy J. 2007. “Captive subjects: Pharmaceutical testing and prisoners.”

Journal of Medical Toxicology 3(1):37-9.
Original Release: August 2009

Last Updated: January 2019
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Research Involving Children
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Research Involving Children
Content Author
Bruce Gordon, MD
The University of Nebraska Medical Center
Introduction
This module presents an overview of the historical involvement of children in
biomedical research, as well as the development of 45 CFR 46, Subpart D. A
discussion of the permitted research, with examples, provides a detailed review for
biomedical researchers who are, or will be, conducting research with children.
Additionally, National Institutes of Health (NIH) guidelines as well as U.S. Food

and Drug Administration (FDA) guidance and regulation are included.
Learning Objectives
Describe the major historical events that influenced how research with children as
subjects is currently conducted.
Identify the types of research with children permitted under 45 CFR 46, Subpart D.
Discuss the assent and informed consent requirements for different types of studies
involving children.
Recognize the current efforts by the FDA to ensure the inclusion of children in
studies on the safety and efficacy of new drugs.
Historical Events That Have Influenced Research on Children
The history of research with human subjects includes medical experimentation on
children. That history has greatly influenced the research that is now permitted to
include children.
Early Medical Experiments

A picture of a painting showing Edward Jenner vaccinating a child.
In the 18th century, a number of early medical experiments involved the
immunization of children. They were deemed good subjects because they had no prior
experience with the disease and were convenient or in close proximity to the
researcher. Edward Jenner tested his theory that prior cowpox infection would
protect against smallpox by inoculating an 8-year-old boy with matter from a cowpox
lesion, then subsequently deliberately exposing him to smallpox.
Early American pediatrician Benjamin Waterhouse tested an initial shipment of

vaccine by vaccinating his own children, then exposing three of them to smallpox
patients. He subsequently commissioned a controlled trial in which 19 vaccinated
and two unvaccinated boys were exposed to smallpox, in order to determine the
vaccine’s efficacy.
The 19th century saw growth in a wide range of organizations for children (such as
orphanages, foundling homes, and hospitals), reflecting growing public concern for
the welfare of children. As these organizations became more common, the health
needs of institutionalized children encouraged pediatric experimentation, and these
organizations provided ideal conditions for these experiments.
Alfred Hess, the medical director of Hebrew Infant Asylum in New York, used his
charges to conduct seminal experiments on:
The anatomy and physiology of digestion
Pertussis, mumps, and varicella immunizations
Nutritional deficiencies
Hess (1914, 913-6) insisted, "conducting experiments in an asylum is ideal because
it approximated the conditions insisted on in studying experimental infection in
animals but which could rarely be controlled in a study of infection in man."
Some of these experiments were of benefit to the children involved. For example, in
1893-4 Louis Pasteur conducted large-scale tests of the new diphtheria vaccine in
children in Paris orphanages. Other vaccines were less beneficial or dangerous to
children. Karl von Ruck tested a "TB vaccine" on 262 children in a Baptist
orphanage in North Carolina. Experiments in guinea pigs (performed after the large
scale human tests) subsequently showed that the "vaccine" increased the risk of
developing TB.
National Research Act (1974)

Research excesses (including research on hepatitis using children with intellectual
and developmental disabilities at Willowbrook in the 1950s and 1960s) culminating
in the exposé of the U.S. Public Health Service (PHS) syphilis experiments, led to
the passage of the National Research Act in 1974.
The act established the National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research (The National Commission). Among the charges of
the National Commission was to "identify the requirements for informed consent to
participation in biomedical or behavioral research by children" (National Research
Act 1974).
The National Commission's report on research involving children was published in

1977, and largely translated into the regulations at 45 CFR 46, Subpart D -
Additional Protections for Children as Research Subjects.
National Commission Report and Federal Regulations

The National Commission's (1977) report described a "sliding scale" for research
involving children. Research was to be classified according to the risk and the
direct benefit to the child.
These categories were translated into 45 CFR 46.404-7. Research involving minors
must fit into one of these categories to be approvable by the Institutional Review
Board (IRB). Note: not all Common Rule departments and agencies adopted Subpart D.
Review a summary of National Commission's Analysis of Problematic Issues Involving

Children as Research Subjects.
Regulations and Guidance

Regulations and guidance provide a definition of children as well as a framework
for children’s assent and parental permission for participation in research.
Definition of Children
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” (Protection of Human Subjects
2018). This may vary based on location because of state or local law.
Assent and Permission in the Federal Regulations and Guidance

For a child to participate in research, permission of one or both parents is
required, and in most cases, the child’s assent is also needed. Assent means a
child's agreement to participate in research. Mere failure to object should not be
construed as assent. However, not all children are capable of assent, due to their
age, maturity, and psychological state. IRBs are responsible for making the
decision when assent is an absolute requirement.
Waiver or alteration of consent or assent is also allowed, as per the requirements

of 45 CFR 46.116(f). This only applies to studies approvable under 45 CFR 46.404,
as will be seen below, because these studies involve no more than minimal risk to
the subjects.
Categories of Allowable Research

The categories of allowable research separate research by risk level and potential
benefit from the research.
Research Involving No Greater Than Minimal Risk

To be approvable under 45 CFR 46.404 (Protection of Human Subjects 2018), research
must present no more than minimal risk to the subject.
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.
Examples of Minimal Risk Procedures

Venipuncture, bagged urine collection
Chest radiograph
Psychological tests
Classroom observation
No direct benefit to the child is needed for research to be approvable under 45 CFR
46.404.
Note: While a procedure may be minimal risk, it may not necessarily be approvable
by the IRB via expedited review procedure if it does not fit into one or more of
the expedited categories. Also, even if an activity fits into one or more
categories, the IRB must still make the determination that the proposed research
involves no more than minimal risk (OHRP 2019).
Examples of Research Projects Potentially Approvable Under 45 CFR 46.404

A study to determine the relationship between maternal age and head circumference
at birth. Measurement of head circumference is part of the normal newborn
examination, and is therefore minimal risk.
A study to determine the incidence of asymptomatic proteinuria in school age
children. The research involves the analysis of a voided urine collection, which is
minimal risk.
Research Involving Greater than Minimal Risk but Presenting the Prospect of Direct
Benefit
Research that presents greater than minimal risk to the subject may be approvable
under 45 CFR 46.405 if it holds the potential for direct personal benefit to the
child. The benefit must balance or outweigh the risks, and the risk-benefit
relationship must be at least as favorable as that seen with standard care.
Example of a Research Project Potentially Approvable Under 45 CFR 46.405

An example is a pilot study of a shorter duration of antibiotic treatment for
uncomplicated ear infection. The potential benefit associated with the shorter
duration of treatment is reduced cost, increased compliance, and a reduced rate of
antibiotic-related diarrhea. The risk associated with the shorter duration of
therapy is a higher likelihood of treatment failure.
The risks associated with this research appear to be greater than minimal, but
there is the prospect of direct benefit to the child (reduced cost, increased
compliance, and a reduced rate of antibiotic-related diarrhea). If the IRB decides
that the potential benefits balance or outweigh the risks, and the risk-benefit
relationship is as favorable as that seen with standard care, this research would
be approvable under 45 CFR 46.405.
Research Involving Greater than Minimal Risk and No Prospect for Direct Benefit
A picture of a doctor taking a child's blood pressure.
Research involving greater than minimal risk and no prospect for direct benefit to
the subject may be approvable under 45 CFR 46.406.
Under this section, the risks associated with the research must satisfy certain
specific criteria:
The risks must be no more than a "minor increase" over minimal risk. No definition
of minor increase is provided in the federal regulations. According to the National
Commission (1977, 139-40), "while [minor increase] goes beyond the boundaries of
minimal risk, it poses no significant threat to the child's health or well being."
Interventions that might constitute a minor increase include:
Catheterized urine collection
Skin biopsy or bone marrow biopsy
MRI scan with sedation
Sensitive survey
Risks must be commensurate with those inherent in the subject's actual medical
situation. According to the National Commission (1977, 9):
The requirement of commensurability of experience should assist children who can
assent to make a knowledgeable decision about their participation in research,
based on some familiarity with the procedure and its effects.
The research must be likely to yield knowledge of vital importance about the
child's disease or condition.
Example of A Research Project Potentially Approvable Under 45 CFR 46.406
An example is a study to determine the clinical relevance of a new technique to
quantitate minimal residual disease (MRD) during therapy for acute lymphoblastic
leukemia in children. The study requires one additional bone marrow aspirate be
performed during the course of treatment. Therapy for the subject will not be
altered based on the results of the assay. However, if it can be shown that the
presence of MRD predicts poor outcome, in the future, patients with MRD can receive
more intensive treatment and increase their chance of cure.
It can be argued that the risk of a bone marrow aspirate in a normal child is only
a minor increase over minimal risk. Further, the risk appears commensurate with
risks inherent in the subject's actual medical situation, and the research may
yield knowledge of vital importance about the child's disease (leukemia).
Therefore, this research may be approvable under 45 CFR 46.406.
Research Otherwise Not Approvable

Research not approvable under any of the previous sections, but that presents an
opportunity to understand, prevent, or alleviate a serious problem affecting the
health and welfare of children, may still be approvable under 45 CFR 46.407. A
panel of experts appointed by the Secretary of the U.S. Department of Health and
Human Services (HHS) must review the research. The research must be conducted in
accordance with sound ethical principles.
Inclusions of Wards
Remembering the exploitation of orphans as medical research subjects, the National
Commission also specifically addressed the inclusion of wards of the state. They
noted that it is important to "learn about the effects of the settings in which
children who are wards of the state may be placed...in order to improve the care
that is provided for such children" (The National Commission 1977, 139-40).
Further, they found it important to avoid embarrassing these children by excluding
them from research in which their peers in a school, camp, or other group setting
might be participating. To these ends, the National Commission (1977, 20) notes
that the IRB should "evaluate the reasons for including wards of the state as
research subjects and assure that such children are not the sole participants in a
research project unless the research is related to their status as orphans,
abandoned children, and the like."
The regulation at 45 CFR 46.409, reflecting the National Commission report,

restricts the involvement of wards in research that is:
Greater than minimal risk and without direct subject benefit (research approvable
under 45 CFR 46.406); or
Research not otherwise approvable, which presents an opportunity to understand,
prevent, or alleviate a serious problem affecting the health or welfare of children
(research approvable under 45 CFR 46.407).
Wards may only be enrolled in such research if the research is related to their
status as wards, or is conducted in schools, camps, hospitals, organizations, or
similar settings in which the majority of children involved as subjects are not
wards. Further, the regulations require that each child have an advocate appointed
who has the background and experience to act in, and agrees to act in, the best
interests of the child, and who is not associated in any way with the research,
researchers, or guardian organization. It is important to note that it is the IRB’s
responsibility to appoint the guardian and not the researcher.
Who Provides Permission?

The regulations at 45 CFR 46.408 lay out the requirements for permission by parents
or guardians and assent by children. In accordance with consent requirements from
46.116 of Subpart A, adequate provisions must be made for soliciting permission
from each child’s parents or guardians. The IRB can determine whether one or both
parents must give their permission.
Who provides permission?
Category
Parental Permission
45 CFR 46.404
At least one parent*
45 CFR 46.405
At least one parent*
45 CFR 46.406
Both parents**
45 CFR 46.407
Both parents**
* The IRB may find that permission of one parent is sufficient.
** Research falling under 46.406-7 requires permission to be obtained from both

parents, unless one parent is deceased, unknown, incompetent, or not reasonably
available, or when only one parent has legal responsibility for the care and
custody of the child.
Note about Assent by Children: The IRB shall determine that adequate provisions are
made for soliciting the child’s assent, when in the IRB’s judgment the child is
capable of providing assent. The child’s assent is not a necessary condition for
proceeding with the research if the IRB determines that:
The capability of some or all of the children is so limited that they cannot
reasonably be consulted; or
The intervention or procedure involved in the research holds out a prospect of
direct benefit that is important to the health or well-being of the child (45 CFR
46.405) and is available only in the context of the research.
Case StudyVulnerable Subjects - Research Involving Children
Other Guidelines on the Inclusion of Children in Research Involving Human Subjects

There are additional compliance requirements (as applicable) on the inclusion of
children as research subjects, including NIH guidelines and FDA guidance and
regulations.
NIH Guidelines
Although the adoption of 45 CFR 46, Subpart D marked a high point in the protection
of children, there were concerns that children would also be denied the potential
benefits of medical research.
In 1977, the American Academy of Pediatrics (AAP) agreed that children capable of
providing assent have the right to refuse research participation. However, the AAP
also pointed out that exclusion of children from drug studies was more unethical
than clinical testing and could lead to devastating results.
The antibiotic chloramphenicol was released in the 1950s without adequate testing
in infants and children. As use of the drug became more common, reports of a
serious and often fatal reaction called the Grey Baby Syndrome surfaced. This
reaction was related to slow clearance of the drug in infants as compared to
adults, due to deficiency in hepatic glucuronyl transferase in infants. Similarly,
though less devastating, widespread use of tetracycline in children was
subsequently shown to be associated with dental dysplasia.
Nonetheless, children continued to be excluded from drug testing. A survey of the

1991 Physician's Desk Reference showed that 81 percent of listed drugs contained
language disclaiming use in children or restricting use to certain age groups.
In March 1998, the NIH published Guidelines on the Inclusion of Children as

Participants in Research Involving Human Subjects, to answer some of these
concerns. The guidelines state children must be included in all human subjects
research, conducted or supported by the NIH, unless there are scientific or ethical
reasons not to include them (NIH 1998).
Possible justifications for the exclusion of children from NIH-funded studies

include:
The research topic is irrelevant to children.

Knowledge sought is already available in children or will be obtained from another
ongoing study.
A separate age-specific study is warranted and preferable.
Insufficient data are available in adults to determine potential risks in children.
In addition, the NIH (1998) guidelines state, "inclusion of children must be in
compliance with all applicable subparts of 45 CFR 46." In October 2015, the NIH
(2015) published an update to the definition of the age of children from under 21
to 18 years old.
FDA Guidance and Regulation

A picture of a doctor and a young patient.
In 2001, in response to the Children's Health Act of 2000, the FDA adopted
Additional Protections for Children in Clinical Investigations (21 CFR 50, Subpart
D). In 2013, the FDA issued a Final Rule formally amending its regulations.
It should be noted that while the FDA regulations are largely equivalent to 45 CFR
46, Subpart D, some differences exist with respect to the waiver of consent.
Specifically, the FDA regulation does not allow waiver of parental permission
except in emergency research in keeping with 21 CFR 50.23 and 50.24.
However, FDA (2017) issued guidance that states it will not object when IRBs
approve a waiver or alteration of consent for clinical investigations involving no
more than minimal risk to subjects if certain criteria are met and documented. The
FDA also stated that they plan to revise the regulation to include the waiver and
alteration of informed consent for no more than minimal risk research in the
future.
The FDA has attempted to answer concerns regarding the exclusion of children, by
taking a "carrot and stick" approach. The Best Pharmaceuticals for Children Act
(2002) extends marketing exclusivity for pharmaceutical companies who test new
drugs in children. The Pediatric Research Equity Act (2004) enables FDA to require
testing of drugs for pediatric use.
Exempt Research with Children

Under the HHS regulations (Protection of Human Subjects 2018), research with
children is eligible for exemption in categories 1, 4, 5, 6, 7, and 8 listed in 45
CFR 46.104. Research with children may also be exempt under category 2; however,
there are some specific limitations:
If the research involves observation of public behavior, the researcher does not
participate in the activities being observed.
Aside from observation, with respect to children, research involving administering
educational tests is the only other activity permitted to be exempt under category
2.
Information obtained is recorded in such a way that the identity of subjects could
not be easily ascertained (directly or through identifiers linked to subjects).
Any disclosure of the subjects’ responses would not place the subjects at risk of
criminal or civil liability or be damaging to them.
Expedited Research with Children
Research subject to Subpart D may be approved via expedited IRB review. The only
limitation is Category 2 with respect to the amount and frequency of blood that may
be collected (OHRP 1998).
Summary
Early medical experiments involving children, especially institutionalized
children, lacked sound ethical research practices. Growing public concern over the
exploitation of children led to movements aimed at protecting the rights of
children and resulted in the establishment of ethical standards and federal
regulations. The National Research Act established the National Commission.
The National Commission’s 1977 report on research involving children provides a

sliding scale classifying research according to the risk and the direct benefit to
the child and provides the requirements for assent and informed consent for
participation in research involving children.
Research involving no greater than minimal risk requires the permission of one
parent and the child’s assent.
Research involving greater than minimal risk but presenting the prospect of direct
benefit requires:
The benefit must balance or outweigh the risks of harm.
The risk-benefit relationship must be at least as favorable as that seen with
standard care.
Permission of one parent and assent of the child.
Assent of the child, unless the research holds out a prospect of direct benefit to
the child, which is not available outside the research.
Research involving greater than minimal risk and no prospect for direct benefit
requires:
The risk is only a minor increase over minimal risk.
The risks of harm are commensurate.
The research will likely yield knowledge of vital importance.
Permission of both parents (unless the exceptions noted apply)
Assent of the child.
References
Alliance for Human Research Protections (AHRP). 2016. “1921: Alfred Hess & Mildred
Fish, orphan guinea pigs.” Accessed July 8.
Hess, Alfred F. 1914. “German Measles (Rubella): An Experimental Study.” The

Archives of Internal Medicine 13(6):913-6.
National Institutes of Health (NIH). 1998. “NIH Policy and Guidelines on the
Inclusion of Children as Participants in Research Involving Human Subjects.”
Accessed March 16, 2016.
National Institutes of Health (NIH). 2015. “Inclusion of Children in Clinical

Research: Change in NIH Definition.” Accessed April 16, 2018.
National Research Act, Pub. Law 93-348 (1974).
Office for Human Research Protection (OHRP). 1998. Expedited Review Categories.
Accessed December 11, 2018.
Office for Human Research Protections (OHRP). 2019. "Revised Common Rule Q&As."
Accessed April 23.
Secretary’s Advisory Committee on Human Research Protections (SACHRP). 2005.

“SACHRP Chair Letter to HHS Secretary Regarding Recommendations.” Accessed August
18, 2016.
The National Commission for the Protection of Human Subjects of Biomedical and
Behavioral Research. 1977. “Report and Recommendations: Research Involving
Children.” Accessed March 16, 2016.
U.S. Food and Drug Administration (FDA). 2017. “IRB Waiver or Alteration of
Informed Consent for Clinical Investigations Involving No More Than Minimal Risk to
Human Subjects.” July.
Grodin, Michael A., and Leonard H. Glantz, eds. 1994. Children As Research
Subjects: Science, Ethics, and Law. New York: Oxford University Press.
Jonsen, Albert R., Robert M. Veatch, and LeRoy Walters, eds. 1999. Source Book in
Bioethics: A Documentary History. Washington, DC: Georgetown University Press.
Lederer, Susan E. 1997. Subjected to Science: Human Experimentation in America
Before the Second World War. Baltimore, MD: Johns Hopkins University Press.
National Institutes of Health (NIH). 1998. “NIH Policy and Guidelines on the
Inclusion of Children as Participants in Research Involving Human Subjects.”
Accessed July 8, 2016.
U.S. Food and Drug Administration (FDA). 2013. “Additional Safeguards for Children
in Clinical Investigations of Food and Drug Administration-Regulated Products.”
Federal Register 78(38):12937-51.
Original Release: July 2003

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FDA-Regulated Research
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FDA-Regulated Research
Content Authors
Susan Kornetsky, MPH

Boston Children’s Hospital
David G. Forster, JD, MA, CIP
WIRB-Copernicus Group
Gary L. Chadwick, PharmD, MPH, CIP
University of Rochester (Emeritus) and HRP Consulting Group (Retired)
Introduction
The U.S. Food and Drug Administration (FDA) regulates drugs, biologics, and devices
used in the diagnosis, mitigation, treatment, or prevention of diseases.
This module addresses FDA-regulated clinical research and the responsibilities of

researchers, Institutional Review Boards (IRBs), and sponsors when they participate
in a study of an FDA-regulated product.
Learning Objectives
Recognize when an Investigational New Drug (IND) application is and is not

necessary.
Describe the role of Form FDA 1572.
Define what constitutes a medical device.
Identify the responsibilities of sponsors and researchers as they relate to FDA-
regulated research.
FDA Review
Before a product is marketed, the sponsor submits an application for approval to
the FDA.
This application contains a proposed "package insert" that may also be referred to
as "labeling." This insert summarizes what the FDA has determined to be a safe and
effective use of the product.
The FDA conducts a thorough review of drugs, biologics, and medical devices for
safety and effectiveness before granting approval for marketing.
The FDA bases its approval decision upon bioresearch data generated and reported to
the FDA by the sponsor to support the product’s marketing approval. These data are
collected by the sponsor during clinical research conducted under an IND
application or an Investigational Device Exemption (IDE).
Drugs and Biologics

It is important to know when an IND application is required when conducting
research with drugs and/or biologics.
Investigational New Drug (IND) Application
Research involving a drug or biologic that has not yet reached the marketplace or
that studies a new use of the marketed product requires an IND application per 21
CFR 312 (Investigational New Drug Application 2018).
The IND application is submitted by the sponsor to the FDA.
The sponsor is the “person who takes responsibility for and initiates a clinical
investigation” (21 CFR 312). A sponsor develops a research plan for the clinical
investigation, which is then evaluated by the FDA. A sponsor can be a drug company,
cooperative group, or even an individual physician.
After careful review of the IND application, the FDA will allow human studies to
proceed if it determines that the risk of exposure to the drug is reasonable.
This determination is based upon:
Data from prior animal or human testing

Methods of manufacturing
Plans for testing and reporting significant toxicities
A well-developed clinical research plan that minimizes risks to the subjects
For research subject to 21 CFR 312, a sponsor cannot begin a clinical investigation
until the IND is granted by the FDA and the IRB approves the study.
Investigational Use of a Marketed Drug

Researchers may want to use an approved product in the context of clinical studies.
When the principal intent of the product’s investigational use is to develop
information about safety or efficacy, an IND may be required.
However, as noted in the regulations at 312.2(b) the clinical investigation of a

marketed drug does not require an IND if all of the following conditions are met:
The data will not be used to support a new indication, new labeling, or significant
change in advertising.
The research does not involve change to the route of administration or dosage
level, subject population usage, or other factors that significantly increases the
drug product’s risks of harm (or decreases the acceptability of the risks).
The research is conducted in compliance with IRB review in 21 CFR 56 and informed
consent requirements in 21 CFR 50 (Protection of Human Subjects 2024).
The research is conducted in compliance with requirements for promotion and sale at
21 CFR 312.7.
Exemption from IND submission requirements does not mean exemption from IRB review
and approval or from the requirement to obtain subjects’ informed consent.
The FDA should be consulted if there are any changes to the research that may
affect the IND exemption status. For example, the study is modified after initial
approval to change the dosage level of the product which may increase the potential
risk of harm to subjects.
Form FDA 1572

Researchers may not participate in an investigation subject to IND regulations
until they sign and submit to the sponsor the “Statement of the Investigator, Form
FDA 1572.”
Form FDA 1572 is the agreement between the researcher and the sponsor assuring
compliance with FDA regulations (FDA 2010). The Form FDA 1572 is also the document
that notifies the FDA of relevant changes in researchers conducting clinical trials
under the IND.
Form FDA 1572 Requirements (FDA 2010)
Researchers participating in drug and biologic studies subject to the IND

regulations must sign Form FDA 1572.
Form FDA 1572 outlines the commitments that must be made by the researcher(s)
regarding the conduct of the study.
Form FDA 1572 must list education, training, and experience of researcher that
qualify the researcher to conduct the study.
Form FDA 1572 must list the research sites (names and addresses) and clinical
laboratories to be used in the study.
Form FDA 1572 must list subinvestigators.
Form FDA 1572 must list the IRB of record for that study site.
Form FDA 1572 must include protocol information.
Note: Form FDA 1572 is only used in clinical investigations of drugs and biologics,
not devices.
"Off Label" Use of Drugs, Devices, and Biologics

Good medical practice and the patient’s best interests require that physicians use
legally available drugs, biologics, and devices according to their best knowledge
and judgment. If physicians use products for an indication not listed in the
approved labeling, they have the responsibility to be well informed and to base the
proposed use on scientific rationale and medical evidence.
Use of a marketed product in this manner, when the intent is the practice of
medicine, does not require the submission of an IND per 21 CFR 312.2(d) or IDE per
21 CFR 812.2. However, an individual organization may under its authority require
oversight for this practice (such as review by a medical practice or pharmaceutics
and therapeutics committee).
Devices
In research with devices, it is important to know what is considered a medical
device and when medical device research may be exempt from FDA regulations.
The Definition of a Medical Device

A medical device is any healthcare product that does not achieve its primary
intended purpose by a chemical interaction or by being metabolized.
Medical device examples include:
Surgical lasers
Sutures
Pacemakers
Diagnostic aids such as reagents and test kits for in vitro diagnosis
The Medical Device Amendments of 1976
The Medical Device Amendments of 1976 and the Safe Medical Devices Act of 1990
provide the regulatory framework for medical device development, testing, approval,
and marketing.
Manufacturers who wish to market a new medical device may need to submit a
premarket notification to the FDA.
Some medical devices are exempt from the premarket approval process.
If the device is not exempt, the FDA at 21 CFR 807.81(a)(1) (Establishment

Registration 2014) determines whether the device is substantially equivalent to
similar devices marketed before the 1976 amendment. These devices are often
referred to as 510(k) devices and require a summary to be submitted to the FDA to
determine substantial equivalence (21 CFR 807.92).
If the new medical device is not substantially equivalent, the company may need to
demonstrate safety and efficacy in a premarket approval application, which could
include clinical trials.
Investigational Device Exemption (IDE)

An investigational device is a medical device that is undergoing clinical trials to
evaluate safety and effectiveness. The IDE regulations at 21 CFR 812 specify how to
conduct these clinical trials.
The regulations require that devices be classified as significant risk (SR) or non-
significant risk (NSR) devices.
The sponsor often first makes this classification, but the IRB must agree with the
determination.
The risk determination should be based on the proposed use of the device and not on
the device alone.
For example, daily wear contact lenses are considered non-significant risk devices
in normal daily use. If subjects are required to wear the contact lenses for
sleeping overnight for a study, then the contact lenses would be considered a
significant risk device because the potential risk of harm (such as eye injuries)
increased.
Significant Risk (SR) Devices

As noted in the regulations (21 CFR 812.3), an SR device is one that:
Is intended to be implanted into a human;

Is used in supporting or sustaining human life;
Is of substantial importance in diagnosing, curing, mitigating, or treating
disease, or otherwise prevents impairment of human health; or
Otherwise presents serious risk to health, safety, and welfare of a subject.
For use of a significant risk device in research, the sponsor must submit an IDE
application to the FDA per 21 CFR 812.20. There is no specific form for this
purpose, but the regulations list elements required in the application.
The trial cannot begin until the FDA grants an IDE and the IRB grants approval for
the study. By definition, a study with a significant risk device poses more than
minimal risk to the human subjects and requires convened IRB review.
Non-Significant Risk (NSR) Devices

An NSR device, by default, does not meet the criteria of significant risk. It is
considered to have an approved IDE application (that is, no application is filed
with the FDA). NSR devices are studied without FDA oversight if the sponsor
complies with certain FDA requirements such as monitoring, record keeping, and
properly labeling the investigational device.
The IRB must agree that the study meets the criteria for non-significant risk. The
clinical trial of an NSR device requires IRB approval, informed consent, and proper
study monitoring and it must meet all other regulatory compliance requirements.
However, an NSR device study does not require approval by the FDA and only must
follow the abbreviated requirements at 21 CFR 812.2(b) (FDA 2006).
Examples of NSR devices include:
Conventional hospital catheters

Dental filling materials
Menstrual pads or tampons
Transcutaneous electric nerve stimulation (TENS) devices
Informed Consent
Informed consent is the voluntary agreement of subjects to participate in the
research. Regulations contain requirements for what must be included in the
informed consent process and documentation.
Elements of Informed Consent

Elements of informed consent, as required by the FDA, are found in the regulations
at 21 CFR 50.25 and are similar to U.S. Health and Human Services (HHS) regulation
at 45 CFR 46.116 (Protection of Human Subjects 2018).
The HHS regulation was revised in 2018 and has some additional requirements that
are not included in the FDA regulation. For example, at t 46.116(b)(5) there are
specific requirements for the format of the presentation of information during the
consent process, specifically that “key information” be presented first. Also, that
information be presented in a way that facilitates subjects’ understanding of the
reasons to participate or not. Further, 46.116(b)(9) requires additional statements
about if identifiable private information or identifiable biospecimens will be used
in future research. The FDA regulations do not have these requirements.
The FDA does require the following statements in the informed consent form:
Statement that the subject’s records may possibly be inspected by the FDA.
Statement that the clinical trial will be listed in a registry. Per 21 CFR 50, the
required language is, "A description of this clinical trial will be available on
http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not
include information that can identify you. At most, the Web site will include a
summary of the results. You can search this Web site at any time."
Exceptions from Informed Consent
The FDA at 21 CFR 50.23 and 50.24 provides exceptions to the requirement for
informed consent under certain circumstances.
For emergency circumstances requiring an exception from informed consent, the FDA
distinguishes between the unplanned emergency use of a test article for one
individual (21 CFR 50.23) and planned emergency research (21 CFR 50.24).
21 CFR 50.23 Exception from General Requirements

In life-threatening conditions involving an individual person a test article may be
used where requirements for an exception from informed consent are met. More
specifically, FDA regulations (21 CFR 50.23) permit exception from informed consent
in life-threatening situations where:
The researcher, with the concurrence of another physician not participating in the
clinical investigation, believes and certifies in writing that the situation for
the human subject is life-threatening and necessitates the use of a test article
(that is, an investigational drug, device, or biologic).
The subject and/or legally authorized representative (LAR) is unable to communicate
consent. More about the definition of LAR.
There is insufficient time to obtain consent.
No alternative exists that will provide an equal or better chance of saving the
subject's life.
The IRB must be notified within a maximum of five days if a test article was used
in an emergency situation for one individual.
21 CFR 50.24 Exception from Informed Consent Requirements for Emergency Research
The FDA permits exception from informed consent requirements for planned emergency
research (21 CFR 50.24). Unlike the exception noted in 21 CFR 50.23, the activities
described in 21 CFR 50.24 are associated with an IRB-approved research study that
involves research in emergencies.
According to the FDA (2013), emergency research studies:
Involve subjects who have a life-threatening medical condition that necessitates

urgent intervention (for which available treatments are unproven or unsatisfactory)
Involve subjects who because of their condition cannot provide informed consent
Have the prospect of direction benefit to the subject
Must involve an investigational product that must be administered before consent
can be obtained (from subject or LAR)
Have no reasonable way to identify prospective individuals likely to become
eligible for participation
Note: Unlike the use of a test article in an emergency situation for one individual
(21 CFR 50.23), IRB prospective review of the full research plan is required for
emergency research (21 CFR 50.24).
FDA Waiver or Alteration of Informed Consent for Clinical Investigations Involving

No More Than Minimal Risk to Human Subjects
Effective January 22, 2024, the FDA regulations allow an exception from the
requirement to obtain informed consent. An IRB can approve a waiver or alteration
of consent for a no more than minimal risk clinical investigation, provided certain
conditions are met (21 CFR 50). Mirroring the HHS regulations, the FDA regulations
state that the IRB must determine and document that:
The clinical investigation involves no more than minimal risk to the subjects;
The clinical investigation could not practicably be carried out without the
requested waiver or alteration;
If the clinical investigation involves using identifiable private information or
identifiable biospecimens, the clinical investigation could not practicably be
carried out without using such information or biospecimens in an identifiable
format;
subjects; and
Whenever appropriate, the subjects or legally authorized representatives will be
provided with additional pertinent information after participation.”
This is an effort to harmonize FDA and HHS regulations for human subjects research
and facilitate minimal risk research. This regulatory update replaces the previous
FDA guidance (2017).When FDA and HHS Regulations Differ
The revised Common Rule (2018 Requirements, with a general compliance date of 21
January 2019) differs from the FDA regulations particularly with the consent
requirements. This means that some studies that are subject to both regulations
must comply with differing regulations simultaneously.
The FDA (2018) issued guidance for sponsors, researchers, and IRBs entitled “Impact
of Certain Provisions of the Revised Common Rule on FDA-Regulated Clinical
Investigations” to try and reduce confusion and burden for research that must
comply with the different sets of regulations.
Basically, the FDA (2018) guidance says that the regulation that offers the greater
protection to human subjects should be followed.
For example, the revised Common Rule has a “key information” requirement for
consent, and the FDA regulations do not. However, this key information requirement
offers additional protections to subjects and it is not in conflict with any FDA
regulations.
However, research that is no longer subject to continuing review under the revised
Common Rule would still require continuing review under FDA regulations pursuant to
21 CFR 56.109(f).
The FDA guidance (2018) further states that they are making efforts to harmonize
the FDA regulations with the Common Rule and future revision to FDA regulations is
forthcoming.
Is verbal consent appropriate?

According to 21 CFR 56.109(c)(1) (Institutional Review Boards 2018), the FDA allows
the IRB to waive the requirement for the subject (or the subject’s LAR) to sign the
consent if two conditions are met:
The study includes no more than minimal risk of harm to the subject
The research involves no procedures requiring written documentation of consent
outside the context of participation in a research study
With a waiver of written documentation of consent, the consent of the subject or
the subject's LAR is still required. The subject or LAR could provide their consent
verbally. The IRB may require the researcher to provide the subject with written
materials about the research per 21 CFR 56.109.
Emergency Use of an Investigational Biologic, Drug, or Device

Researchers and IRBs may be confronted with the need to use an unapproved
investigational drug or device on a human subject in an emergency situation. In
these circumstances, review by a convened IRB may not be feasible because of the
problem’s emergent nature. When this happens, attention must be given to the
IND/IDE requirements, informed consent, and IRB procedures.
FDA regulations cover both unplanned and planned emergency use:

Regulations at 21 CFR 50.23 cover unplanned emergency use
Regulations at 21 CFR 50.24 cover planned emergency research
Note: Individual patient access in an emergency is also known as “emergency
expanded access use,” “emergency access,” or “individual patient access in an
emergency.” This is a category of the FDA’s expanded access program.
The Definition of Emergency Use

Emergency use is the use of an investigational drug or device with a human subject
in a life-threatening situation, or in which no standard acceptable treatment is
available and there is not sufficient time to obtain IRB approval.
Life-threatening means that the likelihood of death is high unless an intervention

interrupts the process. It also applies to a condition that is immediately and
severely debilitating and that causes irreversible morbidity (such as, blindness or
paralysis) per 21 CFR 56.102(d).
IND/IDE Requirements for Emergency Use

If an individual subject does not meet the criteria for an existing research plan,
or an approved research plan does not exist, the usual procedure is for the
physician to contact the manufacturer and determine if the drug can be made
available for an "emergency use" under the company's IND.
If there is no IND, the FDA per 21 CFR 312.36 may authorize the manufacturer to
allow the drug to be used in advance of an IND submission.
In addition, if the company agrees to provide the product, the physician can
contact FDA, explain the situation, and obtain an emergency IND to permit the
drug’s shipment.
If there is no IDE, the physician may use the device and notify FDA of its use
after the fact. The physician should obtain both an independent assessment from
another physician and informed consent from the subject, before emergency use of
the device occurs.
IRB Review Requirements for Emergency Use

In an emergency use situation, the FDA at 21 CFR 56.104(c) permits an exemption
from prior review and approval by an IRB.
For emergency use of devices, concurrence of the IRB chair is required before the
use takes place.
However, individual organizations may have a variety of policies to handle this

situation. For example, the researcher may be required to notify the IRB office
when emergency use is being considered.
HHS regulations do not prohibit a researcher from using any investigational or

approved drug or device in an emergency situation for the subject’s clinical care,
but they do not consider information collected to be research data.
FDA does consider this to be a research use and wants the data reported to them.
IRB review and approval is required in all circumstances if the researcher wishes
to use the data for research purposes.
After an Investigational Drug or Device has Been Used in an Emergency

Subsequent use of the investigational product at the organization should have
prospective IRB review and approval. If the IRB was not notified before the
investigational drug or device was used in an emergency situation, the IRB should
be notified per organizational policy or within five working days (21 CFR 50). The
FDA and sponsor should be notified as necessary.
Responsibilities of Different Parties in Research

All parties involved in research have responsibilities.
Sponsor Responsibilities
A sponsor may be an individual, a private company, or other organization that is
responsible for the initiation and conduct of a study involving a drug, device, or
biologic.
Researchers who design and conduct their own studies assume this responsibility in
addition to their role as researcher. Often these are called "investigator-
initiated" studies.
Selecting clinical researchers qualified by training and experience.

Informing and qualifying researchers by obtaining their commitment to supervise the
study, follow the research plan, and obtain consent.
Monitoring the study’s conduct by auditing documentation and conducting site
visits.
Completing regulatory filings related to the IND or IDE, adverse events, amendments
or revisions, progress reports, withdrawal of IRB approval, and final reports.
Controlling the distribution, tracking, and dispensation of the regulated products.
Researcher Responsibilities
FDA regulations at 21 CFR 312 and 21 CFR 812 outline investigator responsibilities.
Ultimately, investigators are responsible for the conduct of the investigation, as
well as:
Ensuring IRB approval for the study is obtained before any subjects are enrolled.
Ensuring that informed consent is obtained in accordance with FDA regulations.
Ensuring that the investigation is conducted according to the investigational plan
and applicable regulations.
Administering the drug or using the device only in subjects under the researcher's
supervision or under the supervision of a recognized sub-researcher.
Maintaining adequate records of the dispensation of the drug or device.
Returning unused materials at the end of trial.
Preparing and maintaining adequate case histories and signed informed consent
documents.
Maintaining correspondence with the IRB and the sponsor to make sure that both have
reviewed research plan amendments, recruitment materials, and Investigator’s
Brochures.
Retaining records in accordance with regulations.
Providing progress, safety, final, and financial disclosure reports.
Notifying the sponsor if IRB approval is withdrawn.
Complying with International Council for Harmonisation (ICH) guidelines, if
applicable.
Inspections and Audits
The FDA’s Bioresearch Monitoring Program conducts "not for cause" and "for cause"
inspections of IRBs, clinical researchers, and sponsors.
The purpose of this monitoring is to ensure the quality and integrity of data
submitted to FDA for regulatory decisions and to protect human subjects.
The FDA may conduct on-site reviews of IRBs, research sites, pharmacies, and
manufacturing sites. The FDA may also inspect, review, and copy records associated
with the research.
21 CFR 11 – Electronic Records; Electronic Signatures
The regulation 21 CFR 11 (Electronic Records; Electronic Signatures 2018) is often

referred to as Part 11. It is intended to enable the use of electronic documents in
the regulatory process for drugs and devices.
Part 11 specifies processes that must be in place assuring that electronic

documents and signatures are equivalent to paper documents and handwritten
signatures.
For electronic systems to comply with Part 11, a number of requirements must be
met.
For example:
Computer systems utilizing electronic records and signatures must ensure accuracy,
reliability, and consistent performance. Standard operating procedures (SOPs),
audits, testing, and training are required.
Computer systems must use and maintain secure, computer-generated, time-stamped
audit trails independently recording the date and time of entries and actions that
create, modify, or delete electronic records.
Computer systems must use system checks ensuring that only those individuals
authorized to use the system are allowed access to the system (and access only
those parts of the system they have authorization to use), alter records, and
perform operations.
Procedures must be established to ensure that records are retained for a duration
of time, in an appropriate format, and to meet FDA requirements at a minimum.
In 2003, the FDA clarified the application of Part 11 and limited the scope of its
enforcement. Under this narrower interpretation, the FDA (2003) generally would not
consider Part 11 to apply when computer systems are used to generate paper
printouts of electronic records, and those paper records meet all the FDA
requirements.
The FDA (2003) plans to publish a revised rule updating and clarifying the Part 11
requirements and the FDA's scope of enforcement. Until then, researchers and IRBs
should check with their information technology support personnel (and as
appropriate, sponsors) to ensure that either Part 11 compliance is maintained or
that Part 11 does not apply.
Case StudyFDA-Regulated Research
Summary
It is important for researchers and IRBs to understand and appreciate the FDA
regulations so that they may fulfill their regulatory roles and responsibilities.
There are many resources available (for example, guidance documents from the FDA)
that could assist in interpreting and understanding the regulations.
References
Electronic Records; Electronic Signatures, 21 CFR § 11 (2018).
Establishment Registration and Device Listing for Manufacturers and Initial

Importers of Devices, 21 CFR § 807 (2018).
Institutional Review Boards, 21 CFR § 56 (2018).
Investigational Device Exemptions, 21 CFR § 812 (2018).
Investigational New Drug Application, 21 CFR § 312 (2018).

U.S. Food and Drug Administration (FDA). 2003. “Guidance for Industry – Part 11,
Electronic Records; Electronic Signatures – Scope and Application.” Accessed March
2, 2016.
U.S. Food and Drug Administration (FDA). 2006. “Information Sheet Guidance for
IRBs, Clinical Investigators, and Sponsors: Significant Risk and Nonsignificant
Risk Medical Device Studies.” January.
U.S. Food and Drug Administration (FDA). 2010. “Information Sheet Guidance for
Sponsors, Clinical Investigators, and IRBs: Frequently Asked Questions – Statement
of Investigator (Form FDA 1572).” May.
U.S. Food and Drug Administration (FDA). 2013. “Guidance for Institutional Review
Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent
Requirements for Emergency Research.” April.
U.S. Food and Drug Administration (FDA). 2017. “IRB Waiver or Alteration of
Informed Consent for Clinical Investigations Involving No More Than Minimal Risk to
Human Subjects.” July.
U.S. Food and Drug Administration (FDA). 2018. “Impact of Certain Provisions of the
Revised Common Rule on FDA-Regulated Clinical Investigations.” Accessed November 8,
2018.
U.S. Food and Drug Administration (FDA). 2023. "Institutional Review Board Waiver
or Alteration of Informed Consent for Minimal Risk Clinical Investigations."
Federal Register 88(244):88228-49.
U.S. Food and Drug Administration (FDA). 2012. “Questions and Answers on Informed
Consent Elements, 21 CFR 50.25(c).” February.
U.S. Food and Drug Administration (FDA). 2015. “U.S. Food and Drug Administration
(FDA). 2018. “IDE Guidance.” Last updated September 25.
U.S. Food and Drug Administration (FDA). 2023. "Informed Consent: Guidance for
IRBs, Clinical Investigators, and Sponsors." August.
www.fda.gov/media/88915/download. Accessed August 22, 2023.
Original Release: April 2004
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CITI Program

My Courses My Records My CE/CMEs Support

Each person conducting scientific research based on records should:

Before collecting information from records for research purposes, a researcher

The Institutional Review Board/Independent Ethics Committee (IRB/IEC) at his/her

By the end of this module, you should be able to:

Discuss the risks associated with conducting records-based research.

Confidentiality pertains to the actual handling of the personal information once it

Records-based research must balance the possible benefits of answering important

There is an ethical and regulatory responsibility to minimize research risks to

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

Whenever possible, and to the greatest extent possible, only de-identified or

Specifically, the research data in question must constitute identifiable, sensitive

Through which an individual is identified; or

If a study is funded by the NIH, the issuance of a CoC is automatic. If a study is

For more information, visit the NIH’s “Certificates of Confidentiality (CoC)”

What Type of Review is Required for Records-Based Research?

Obtains information or biospecimens through intervention or interaction with the

To determine if the proposed records-based project meets the regulatory definition

Scholarly or journalistic activities

Is the research eligible for exemption from the federal regulations?

Records-based research may be exempt if any of the following apply:

When Health Information is Involved: Health Insurance Portability and

When records-based research requires access to individually identifiable

Protection of Human Subjects, 45 CFR § 46 (2018).

Original Release: December 2010

This module has a quiz.

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

Your Answer All of the above

Your Answer A breach of confidentiality

These regulations were developed as a result of the exploitation of prisoners to

By the end of this module, you should be able to:

Describe the regulatory definition of a prisoner.

"A Prisoner means any individual involuntarily confined or detained in a penal

This may be interpreted as:

Minimal risk is also defined differently for prisoners and non-prisoners.

Prisoner Minimal Risk is defined in 45 CFR 46.303(d) as follows: Minimal risk is

What kinds of research with prisoners are allowed?

Consultation by Secretary of HHS, OHRP Notifications, and Waivers

In addition to the aforementioned categories, there is also the HHS Secretarial

Additionally, at least one member of the IRB must be a prisoner, or a prisoner

The study information is presented in language that is understandable to the

What if an already enrolled subject becomes a prisoner?

Can exempt research include prisoners?

This also allows subjects to continue participating in exempt research if they

Case StudyResearch Involving Prisoners

Office for Human Research Protections (OHRP). 2003. “Prisoner Involvement in

Protection of Human Subjects, 45 CFR § 46 (2018).

Wiegand, Timothy J. 2007. “Captive subjects: Pharmaceutical testing and prisoners.”

Original Release: August 2009

This module has a quiz.

Additionally, National Institutes of Health (NIH) guidelines as well as U.S. Food

By the end of this module, you should be able to:

Early Medical Experiments

Early American pediatrician Benjamin Waterhouse tested an initial shipment of

National Research Act (1974)

The National Commission's report on research involving children was published in

National Commission Report and Federal Regulations

Review a summary of National Commission's Analysis of Problematic Issues Involving

Regulations and Guidance

Assent and Permission in the Federal Regulations and Guidance

Waiver or alteration of consent or assent is also allowed, as per the requirements

Categories of Allowable Research

Research Involving No Greater Than Minimal Risk