Irb Education for August 2012
IRB EDUCATION FOR AUGUST 2012
Educator’s Notes
The apparent reason protocol deviations/violations are not discussed in the IRB Handbook stems from the lack of consistency in terminology, regulations, and guidance in regard to this subject. However, in virtually all research studies, departures from procedures set forth in the IRB-approved protocol occur. Various terms are used to describe these departures, e. g., “deviations,” “violations,” “variances,” “non-compliance;” and these departures may occur for a variety of reasons:
§ An investigator’s decision to deviate from the protocol
§ The subject’s lack of adherence to the protocol
§ External or environmental factors (ex. severe weather or holidays)
Some protocol deviations are anticipated and/or intentional; others are not. Some are known or identified before they occur; others are discovered to have occurred after the fact.
Inconsistencies in Definitions, Regulations, and Guidances
The NIH Regulatory Process Workgroup offered the following definitions of “protocol deviation” and “protocol violation,” as stated in a document dated 11/18/2005:
Protocol Deviation – any change, divergence, or departure from the study design or procedures of a research project that is under the investigator’s control and that has not been approved by the IRB.
Protocol Violation – a deviation from the IRB-approved protocol that may affect the subject’s rights, safety, or well-being and/or the completeness, accuracy, and reliability of the study data.
However, these definitions do not address a variety of departures from protocol that are beyond the control of the investigator and/or that do not affect the safety of the subject or the integrity of the study data.
FDA Center for Device and Radiologic Health (CDRH)
FDA device regulations explicitly address protocol deviations.
§ 21 CFR 812.35(a) – Except in emergencies, the sponsor must receive prior approval of a change in the investigational plan from the FDA (via a supplemental application)and the IRB
§ 21 CFR 812.150(4) and 21 CFR 56.108(a)(3)(4) - requires that investigators notify the sponsor and the reviewing IRB in regard to deviations from the investigational plan to protect the life or physical wellbeing of a subject in any emergency.
FDA Center for Drug Evaluation and Research (CDER)
FDA drug regulations do not explicitly address protocol deviations. However, the issue is directly addressed in chapter 48 of the FDA “Compliance Program Guidance Manual” (see web-link in Reference section of this document, page 4).
§ A protocol deviation/violation is generally an unplanned excursion from the protocol that is not implemented or intended as a systematic change. (Example – Agreement between sponsor and investigator to enroll a single subject who does not meet all inclusion/exclusion criteria.)
§ “Protocol deviation” is also used to refer to any other unplanned instance(s) of protocol noncompliance. (Example – Situations in which the investigator failed to perform tests or examinations as required by the protocol or failures on the part of study subjects to complete scheduled visits as required by the protocol.)
§ Like protocol amendments, deviations initiated by the clinical investigator must be reviewed and approved by the IRB and the sponsor prior to implementation, unless the change is necessary to eliminate apparent immediate hazards to the human subjects (21 CFR 312.66) or to protect the life or physical well-being of the subject (21 CFR.812.35(a)(2), and generally communicated to FDA.
Office for Human Research Protections (OHRP)
OHRP has not issued written guidance on protocol deviations. However, OHRP’s unwritten position is that all intentional protocol deviations are changes in research that need prior IRB review and approval before implementation.
Secretary’s Advisory Committee on Human Research Protections (SACHRP)
SACHRP addressed these regulatory inconsistencies at a meeting in March, 2009 and made some recommendations, as outlined in the following information extracted from their report.
Commentary:
The HHS and FDA regulations are inconsistent in addressing protocol deviations, and there are also inconsistencies among the various regulations and guidances that exist. However, the FDA and OHRP have each indicated in various formats that intentional protocol deviations are changes in research that need prior IRB review and approval. At the current time, much of the regulated community is unaware of these positions.
The SACHRP recommendation specifically addresses three (3) types of deviations:
§ Those that occur because an investigator, research staff, or other party involved in the conduct of research intentionally decides to deviate from the approved protocol.
§ Those that are identified before they occur, but cannot be prevented.
§ Those that are discovered after they occur.
Intentional Protocol Deviations
§ Examples include:
ü The investigator decides to enroll a subject who does not meet inclusion criteria because one lab test is slightly out of range.
ü The investigator decides to increase the payment to a subject who has greater than usual travel expense to be compliant with the schedule for follow-up visits.
ü The investigator enrolls a subject despite the fact that the subject has stated he will definitely not be able to come for one of the regularly scheduled follow-up visits.
ü The investigator realizes that two questions on a survey instrument will work better in reverse order and decides to re-order them without IRB approval.
§ Comments: Sometimes these types of protocol deviations are a one-time event; other times they lead to the implementation of a permanent change in the protocol or other research documents. These deviations may or may not affect the safety, rights, and welfare of the research subject, and they may or may not adversely affect the scientific validity of the research.
Protocol Deviations That Are Identified Before They Occur, But Cannot Be Prevented
§ Example:
ü Research subject on business trip calls investigator to report that he is stuck in snowstorm and cannot be present for study visit scheduled the next day.
§ Comments: The investigator has been notified that the deviation will occur, but it is not under her control and was not her intent to deviate from the protocol.
Protocol Deviations That Are Discovered After They Occur
§ Examples:
ü Investigator unintentionally fails to perform a protocol-required physical assessment.
ü Research subject failed to correctly administer the test agent.
ü Study coordinator accidentally failed to perform a protocol-required blood test on a subject.
§ Comments: These deviations were not planned nor intended. An analysis should be performed to discover the root cause of a deviation and determine whether or not the deviation constitutes an unanticipated problem involving risks to subjects or others and/or constitutes serious or continuing noncompliance.
SACHRP Recommendations to HHS and FDA
SACHRP’s central recommendation is that FDA and OHRP issue either joint guidance, or if that is not feasible, separate consistent guidance clearly outlining these positions. The guidance should ensure the adequate protection of subject safety and integrity of the study while taking into account the burden on investigators and IRBs. SACHRP makes ten (10) specific recommendations for content and language to be used in the development of guidance that address the inconsistencies in existing regulations and guidance and the three types of deviations that were previously addressed. (Please refer to the PDF of this report to read the specific recommendations.)
Appendix III to SACHRP’s recommendation document contains more information about the regulations, including those from the International Conference on Harmonisation (ICH) in their E6 Good Clinical Practice guidance (see pp. 14-15 of that document). The ICH guidance contains more specificity and also liberalizes the review process for changes to logistical and administrative aspects of the clinical trial.
The Bottom Line for IRBs in Regard to Changes in Approved Research Protocols
The basic regulatory language that supports all IRB decisions in regard to review of protocol deviations is as follows:
45 CFR 46.103(b)(4)(iii) and 21 CFR 56.108(a)(3)(4) – The IRB will follow written procedures for ensuring prompt reporting to the IRB of proposed* changes in a research activity, and for ensuring that such changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject.
(*This word is not in FDA regulations.)
Depending upon the type of change in the protocol that occurred because of the deviation/violation, the submission by the investigator to the IRB needs to be reviewed according to the regulatory criteria for expedited or full board review.
FOR YOUR REFERENCE AS DESIRED
SACHRP – Secretary’s Advisory Committee on Human Research Protections
www.hhs.gov/ohrp/sachrp/mtgings/mtg03-09/present/deviations_examples_from_protocols.doc - 3k
(includes Appendixes that are not included in minutes – below)
http://www.dhhs.gov/ohrp/sachrp/mtgings/2012%20Feb%20Mtg/protocoldeviations.pdf
(See pp. 51-57 for applicable content.)
NIH – National Institutes of Health
from the Regulatory Process Workgroup
http://www.genome.gov/Pages/Research/Intramural/IRB/Deviation_Violation_examples8-07.pdf
FDA – Food and Drug Administration
Compliance Program Guidance Manual, Program 7348.811
Chapter 48 – Bioresearch Monitoring, Clinical Investigators and Sponsor-Investigators, December 8, 2008. (Reference pp. 15-16)
http://www.fda.gov/downloads/ICECI/EnforcementActions/BioresearchMonitoring/ucm133773.pdf
International Conference on Harmonisation
Guidance for Industry
E6: Good Clinical Practice – Consolidated Guidance
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073122.pdf
(See pp. 12 and 20 for applicable guidances.)
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