Feature Article

Fitting Round Subjects into Round Holes
The Importance of Eligibility Criteria
November 2010 Issue

Rita Cosgrove, BS
BU/BMC Senior IRB Analyst
Author has nothing to disclose with regards to commercial support.

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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) (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:

  • Excluding subjects with anemia and neutropenia from a trial that involves a drug known to cause a drop in red and/or white blood cell counts
  • Excluding subjects on medication for high blood pressure from studies that use drugs known to drop blood pressure
  • Excluding subjects with signs/symptoms of infection

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 procedure [BUMC IRB Policies 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 with the exclusion criteria listed in the bullets above and was administered a study drug, even though her oral temperature was 99.9 F. In itself, this low grade temperature is not of grave concern; but if the subject ends up with a serious reaction it would not be known whether the reaction was caused by the underlying condition, the study agent, or both. A study agent administered to a subject with an underlying infection could result in serious illness or even death of the subject. In this example, the subject was potentially put at serious risk of harm for a seemingly minor variation in eligibility.

 

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.” 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 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, via INSPIR, a protocol exception. The protocol exception must contain the following information:

  • 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 that the exception is accepted

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 fast track 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, must 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.

 

Conclusion

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.

*Authors note: To some of you the topic of this month’s CR Times feature article may have a familiar ring.  That is because this article was originally published in the CR Times in September 2007.  Since ensuring subject eligibility continues to be a challenge for many investigators and the enrollment of ineligible subjects continues to be one of the most common protocol deviations seen by the IRB we have decided to bring back this “classic” CR Times article. We hope that those who were not here in Sept. 2007 will be informed by this article and those who read it back in 2007 will take this opportunity to refresh their knowledge of this important topic.  We did, however, changed the quiz questions from those published in 2007.

Quiz

This Quiz applies to the recertification period from July 1, 2009 to June 30, 2011.

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