Fitting Round Subjects into Round Holes:
The Importance of Eligibility Criteria
Rita Cosgrove, BS, Senior IRB Analyst
Introduction
A study’s eligibility criteria are an essential component of any research protocol. Eligibility
criteria help define the study population, and ensure the safety and the integrity of the data. Well
defined eligibility criteria help make a protocol safe, ethical and scientifically valid.
Eligibility Criteria: What Are They?
Frequently called the “inclusion/exclusion criteria”, eligibility criteria specify
the details which precisely define what makes an individual, sample or dataset
appropriate or not appropriate for participation in a study. These criteria are the
ingredients which, when combined, determine the needed participant, sample, or
dataset for a given protocol. Inclusion and exclusion criteria generally include
age, gender, medical condition, previous treatment history, and other
characteristics unique to the protocol. Inclusion criteria are those factors that must apply to an
individual in order for him or her to participate in the research. Exclusion criteria are those
factors which, if they apply to an individual, would prevent him or her from participating.
Eligibility criteria vary greatly depending on the risks of the study, the study question, and the
type of study (clinical trial versus survey). Participants with specific illnesses or conditions may
be sought for some protocols; healthy participants for others; and in some studies, both groups
may be required.
Safety
When investigators design a research protocol, they attempt to define all subjects to whom the
study question may be applicable. Then, they identify those factors that might present too great a
risk for subjects to participate. Individuals might be excluded for a variety of safety reasons,
including actual or potential medical and psychosocial conditions. Others may be excluded
because their inability to understand the research or the consent process, and/or their inability to
comply with the research requirements, would put them at risk. It is a mistake to assume
eligibility criteria are arbitrarily used to reject or exclude people from participating in the
research. The opposite is actually true: The criteria are used to identify appropriate participants.
When the IRB reviews the research protocol, the eligibility criteria are carefully scrutinized. The
IRB is required to make certain determinations during protocol review, including a determination
that “Risks to subjects are minimized: (i) By using procedures which are consistent with sound
research design and which do not unnecessarily expose subjects to risk.” [45CFR 46.111 (a)
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(1)]. The IRB may determine that the best way to minimize risks would be to exclude certain
populations who would be at increased risk. Examples of exclusions to minimize risk might be:
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Excluding subjects who might be too young to understand the risks associated with the
collection of confidential data
Excluding subjects from behavioral studies whose psychological condition (e.g. high risk
of suicidality) might be too risky for participation in the research
Excluding subjects from testing using functional MRI if they have metal implants or
claustophobia
IRB approval of a protocol includes approval of the inclusion and exclusion criteria as they are
written. These eligibility criteria are NOT guidelines, but instead are requirements that must be
followed to help ensure the safety of the subjects. Enrolling subjects who do NOT meet the
eligibility criteria, even if only by a small margin, potentially puts subjects at risk and is a
violation of federal research regulations [45 CFR 46.103 (b) (4) (iii)], and institutional policy and
procedures.
During IRB audits, investigators are frequently cited for violating eligibility
criteria. They often tell the auditor that they decided to enroll a subject because
he or she “almost fit” the criteria or because the criteria in question did not
affect the subject’s risk. While this may be true, failure to comply with the
eligibility criteria precisely as described in the IRB approved protocol is a serious protocol
deviation that could directly impact the subject’s safety. Consider, for example, if a subject was
enrolled in a study using MRI even though she had a metal implant and/or serious
claustrophobia. This could result in serious physical injury to the subject and/or mental
trauma/anguish.
Scientific Validity of the Study
Poorly designed, vague, incomplete, or inaccurate eligibility criteria hamper efforts to enroll
appropriate subjects in sufficient numbers to answer the study question. Many studies are
jeopardized because of problems with recruitment and enrollment. The better defined the
eligibility criteria, with less room for interpretation and confusion by those doing the
recruitment, the better the chances of enrolling an adequate number of appropriate subjects.
When developing eligibility criteria, investigators should be careful not to so narrowly define the
subject population that it is impossible to find enough individuals to meet the sample size
requirements. If the study question cannot be answered because of under enrollment, then
subjects have been put at risk needlessly for research that cannot yield generalizable knowledge.
While the design of the eligibility criteria is critical to the validity of the data, so, too, is the
proper utilization of these criteria to the study outcome. From the start of the study and
throughout its course, it is the investigators’ responsibility to ensure that all subjects meet and
continue to meet all eligibility criteria. As noted in Dr. Colton’s Clinical Research Times June
2007 feature article, “A Statistician Reflects on Fraud in Clinical Research”, a common
fraudulent activity in clinical trials is to “include subjects who would otherwise be excluded.”
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Finally, in the data analysis phase, well defined and implemented eligibility criteria are essential
to the relevance of the results and to answering the study question.
Ethical Concerns about Generalizability
In an effort to protect the most vulnerable individuals, some groups--such as children or pregnant
women--used to be commonly excluded from participation in research. At times, researchers
have continued to exclude these groups from research that posed no additional harm to them,
almost as a matter of habit.
Federal regulations [45 CFR 46.111 (a) (3)] require equitable selection of research subjects. In
each IRB protocol, the investigators are asked to define the subject population, including
whether subjects will belong to one or more vulnerable populations. If any vulnerable groups
that would be affected by the research results are excluded, the IRB determines whether that
exclusion is justified. The intent is not to over-protect vulnerable populations, but to ensure as
much as possible that the research findings can be generalized to all appropriate individuals
outside the study populations. “Routine exclusion of certain populations based on sex, race, or
age results in a disparity of information about treatment options for the excluded groups and
equal distribution of the risks and benefits of research” (Amdur and Bankert. Institutional Review
Board Management and Function. Jones and Bartlett Publishers. Page 158; 2002.).
Exceptions to the Eligibility Criteria
There may be times when an investigator wishes to enroll a subject who does
not precisely fit the eligibility criteria. This could happen because the subject is
slightly outside the age range, the lab values are slightly out of range, etc. As
Dr. Colton notes, “Sometimes the inclusion of patients who should be excluded
from the trial can have a noble motive. A clinical investigator may feel that it is
in his/her patient’s best interest in regard to medical care to be included in the trial, rather than to
exclude that patient because of an exclusion criterion in the protocol that the investigator knows
has little or no clinical meaning for the patient’s prognosis.” (CR Times, June 2007). No matter
how strongly the PI feels, the PI must obtain IRB approval for the change in eligibility criteria,
even for just one subject.
The PI could submit an amendment to the IRB to modify the enrollment criteria. After the
amendment is approved, the subject can be enrolled. The amendment process is also used if the
investigators, at some point during the study, determine that the eligibility criteria need to be
modified to add additional protections to subjects, or could safely be broadened to improve
recruitment.
The amendment option may not work for all cases. The PI may not wish to amend the protocol
for all subjects but may want to just make an exception for a single subject. In such cases the
investigator can submit to the IRB a request for a protocol exception. The protocol exception
must contain the following information:
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The specific inclusion/exclusion criteria to which the exception applies
The PI’s justification as to why the exception will not impact the safety of the subject
Whether the exemption impacts the scientific validity of the data/data analysis plan
Whether the exception requires modification to the consent form/process
Verification from the sponsor (if there is one) that the exception is acceptable
All protocol exceptions MUST be prospective; they cannot be approved after the subject has
been enrolled. Most sponsored protocols have a predetermined process for protocol exceptions.
These must be followed; however, approval by the sponsor to make an exception to the
eligibility criteria is NOT sufficient. IRB approval is REQUIRED. The IRB office has an
administrative process to review protocol exceptions but, while some may be approved by
expedited process, those that represent a potential change in risk must be approved by the full
IRB panel.
If an eligibility criteria violation is retrospectively discovered during the course of a study, the
Principal Investigator must submit a protocol deviation report to the IRB as soon as the
discovery is made. Eligibility criteria violations, if determined to be major protocol deviations,
may need to be reported by the IRB to OHRP (and to the FDA if applicable).
Tips for Staying Compliant
Investigators are encouraged to be creative in their methods for ensuring that subjects meet the
study’s eligibility criteria. The most important factor in ensuring compliance is intensive training
of ALL study staff. Each member of the study staff must understand the importance of eligibility
criteria and the role it plays in maintaining the safety of the study. (Have them read this article!)
Then, the study staff must completely understand the details of each study specific inclusion and
exclusion criteria. They must know how to determine whether subjects meet the criteria. Study
staff must also understand the exception and deviation process, and know to notify the Principal
Investigator if they find that a subject has been enrolled who is not eligible or is no longer
eligible.
Many investigators carry small cards that clearly describe the eligibility criteria for studies.
These cards are easily referenced each time the screening or consent process is conducted. It is a
good practice for investigators to incorporate an eligibility checklist into each subject’s study
record so that study staff can document on one form how each of the inclusion and exclusion
criteria have been met.
Conclusions
Eligibility criteria are an important part of the IRB approved protocol. They are not mere
guidelines but requirements that investigators must adhere to throughout the research study.
Exceptions cannot be made, even with the sponsor’s approval, unless the exceptions are also
approved by the IRB.
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