Any variation or exception to the inclusion or exclusion criteria is considered a change to the research project (note: project includes not only the protocol but everything else considered by the Board when reviewing the research). Both sets of federal regulations (OHRP and FDA) require that any change in research may not be initiated without prior IRB review and approval.  IRB-01’s Policies and Procedures mirror this requirement by requiring prior approval for any change no matter how minor it is.  In addition IRB-01 further communicates the need for prior approval for all changes in our initial and continuing review approval letters.  Additional supporting information about the federal and IRB requirements are at the end of this message.

WHAT TO DO: 
If a potential subject does not meet all inclusion/exclusion criteria perfectly, you must:

1. Obtain written permission (e-mail or letter) from the sponsor for the exception/variance.  This documentation should provide specific details about the exception such as the specific enrollment criteria values that are not met (i.e. what the protocol requires and the subject’s status/values), explaining/justifying potential risk to this subject, and discussing the potential effect (if any) on the research as a whole.  We also ask that the sponsor discuss whether or not the enrollment criteria should be permanently adapted to match this exception (if the altered values are ok for one subject, why not everyone?).
2. Complete an IRB-01 Project Revision form (http://irb.ufl.edu/docs/frm-rev.doc) requesting that the IRB approve the exception/variance to the previously approved inclusion exclusion criteria.  You must provide specific details on what the criteria are, what the potential subject’s actual values/status are, discuss potential risk to the subject, and discuss the potential effect (if any) on the research as a whole (you may refer to the sponsor’s letter if the information is present there).
3. Submit both of the above to the IRB-01 office and receive IRB approval BEFORE enrolling the potential subject.

When do you need approval for the exception? 
The IRB can work with you to quickly obtain approval, but we must be notified of the urgency.  Please be sure to inform office staff if urgent review is needed.  If the exception is no more than minimal risk then it can be reviewed as soon as possible by an IRB Chair.  If however the exception is greater than minimal risk then it can only be approved by the full Board.

Lastly, UF IRB-01 and WIRB® are not alone in requiring prior IRB approval for single patient enrollment criteria exceptions.  For example, Partners Healthcare System in Boston, the University of Kentucky, and University of Oklahoma all require prior IRB approval for these kinds of exceptions/variances.

Regulatory References:

OHRP - 45 CFR 46.103(b)(4) “…changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval…”

 FDA - 21 CFR 56.108: “…changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval…”

 FDA - 21 CFR 312.60:  “An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations;”

Please note that OHRP and the FDA have both cited investigators specifically for failing to obtain IRB approval for enrollment criteria exceptions.

IRB-01’s initial and continuing review approval letters state:  “The IRB has approved exactly what was submitted.  Any change in the research, no matter how minor, may not be initiated without IRB review and approval, except where necessary to eliminate hazards to human subjects.  If a change is required due to a potential hazard, that change must be promptly reported to the IRB.”

IRB-01’s Policy and Procedure manual states “The IRB must consider and approve all changes to previously approved research, no matter how minor, before they are implemented. Proposed changes may affect, but are not limited to, the protocol, informed consent form, and the Introductory Questionnaire.  Investigators are responsible for reporting proposed changes in research activity to the IRB, and for ensuring that changes in IRB-approved research are not initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject.  If changes to the protocol are implemented for the safety of the subject prior to IRB review and approval, such changes must be reported to the IRB within 5 days, with any supporting documentation necessary for the IRB to make a determination.” 

• More significantly, on page 28 IRB-01’s P &P specifically addresses this exact issue under section Minor Changes in Enrollment Criteria:         
  “An investigator may face a situation where a prospective research subject may not exactly meet the entrance criteria specified in the protocol.  When the sponsor is notified, the sponsor indicates they will accept that subject into the protocol.  However, the IRB considers enrolling a subject that does not meet entrance criteria into a research protocol as a protocol violation.

  The following are steps the investigator must take to avoid being out of compliance with Federal regulations on Human Subjects Research.

  a. Thoroughly review the inclusion and exclusion criteria for your research protocol.  If you feel they are too restrictive, address this with the sponsor or appropriate individual.

  1) If the protocol has already been submitted or approved by the IRB, submit a revision to the IRB.

  2) You must receive approval for this revision prior to enrolling subjects under the new criteria.”

We realize this is more work for all of us, but it is necessary in order to protect potential subjects and research integrity, as well as to comply with federal reguations. 

One thing we recommend to researchers and sponsors is to either (a) provide language in the protocol that allows the sponsor to approve specific exceptions (e.g. Lab “y” value must be > “x”; exception – potential subjects with a value between “x” and “z” may be approved with sponsor approval), and/or (b) have less stringent requirements.   

Please contact our office if you have any questions.  Thank you!

NOTE: this announcement was distributed (1) in the February 2006 edition of the IRB newsletter, and (2) via e-mail to the IRB-01 e-mail list (IRBMAIL-L@lists.ufl.edu) on January 06, 2006. The information was published previously in the IRB-01 Policy and Procedures Manual.