Source: https://www.hhs.gov/ohrp/sachrp-committee/recommendations/2012-march-30-letter-attachment-c/index.html
Timestamp: 2019-04-24 10:38:38+00:00

Document:
A problematic area in human subject protection is the wide divergence among institutions, sponsors, investigators and IRBs regarding the definition of and the procedures for reviewing protocol deviations.
In virtually every research study departures occur from the procedures set forth in the IRB-approved protocol. Various terms are used to describe these departures, including “protocol deviations,” “protocol violations,” “protocol variances,” and “non-compliance.” For the purposes of this recommendation, such departures shall be herein referred to as “protocol deviations.” Protocol deviations occur for a variety of reasons, such as an investigator’s decision to deviate from the protocol, the subject’s lack of adherence to the protocol, or external/environmental factors (e.g., severe weather or holidays) that change the performance of a protocol. Some protocol deviations are anticipated and/or intentional; others are not. Some protocol deviations are known or identified before they occur; others are only discovered to have occurred after the fact. The HHS and FDA regulations and guidance are inconsistent in addressing protocol deviations, and even among the various FDA regulations and guidance documents there are inconsistencies. However, as noted below in its central recommendation, SACHRP believes that FDA and OHRP can provide guidance to clarify their currently existing positions on this issue.
Deviations that occur because an investigator, research staff or other party involved in the conduct of research intentionally decides to deviate from the approved protocol.
Deviations from the protocol that are identified before they occur, but cannot be prevented.
Deviations from the protocol that are discovered after they occur.
Deviations from the protocol performed to eliminate apparent immediate hazards to the subject in compliance with 45 CFR §46.103(b)(4) and 21 CFR §56.108(a)(4).
Changes in research made in compliance with 45 CFR §46.103(b)(4) and 21 CFR §56.108(a)(3) and (a)(4).
Both of these activities are outside of the scope of this recommendation.
Section VI provides SACHRP’s secondary recommendations regarding the three types of deviations.
(4) Deviations from the investigational plan. An investigator shall notify the sponsor and the reviewing IRB (see §56.108(a) (3) and (4)) of any deviation from the investigational plan to protect the life or physical wellbeing of a subject in an emergency. ... Except in such an emergency, prior approval by the sponsor is required for changes in or deviations from a plan, and if these changes or deviations may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects, FDA and IRB [approval] in accordance with §812.35(a) also is required.
Approved by the IRB and FDA (if applicable) before implementation (except when necessary to eliminate apparent immediate hazard(s) to human subjects).
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.
At the current time, much of the regulated community is unaware of these positions. 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 remainder of this letter contains discussion points and references for FDA and OHRP consideration, and minor recommendations on specific points.
Lab criteria: One test is out of range for a benign reason (increased alkaline phosphatase, LDH or SGOT in a runner, or increased bilirubin in a person with Gilbert Syndrome). The investigator decides to enroll the subject despite the out-of-range lab criteria.
Age criteria: The criteria includes an age requirement of 20-60 years of age, but a potential subject turned 61 a week before screening. The investigator decides to enroll the subject despite being outside of the age range.
Payment: The protocol specifies that subjects will be paid twenty dollars per visit. To compensate for higher expenses, the investigator decides to pay certain subjects more than other subjects.
Timing of study visit: At the time of enrollment, the investigator realizes that due to a planned vacation the subject will miss one out of 12 regularly scheduled two-week study visits. The investigator decides to enroll the subject despite this knowledge.
Timing of washout: A planned vacation interferes with a washout period. Shortening the wash-out period from 14 to 12 days will allow the subject to be enrolled. The investigator decides to enroll the subject with a 12-day washout.
Pre-treatment exceeded: Protocol entry criteria specify that only a certain amount of pre-treatment of disease is acceptable. A potential subject has exceeded it to a minimal extent. The investigator enrolls the subject despite knowledge of the extent of the pre-treatment.
Changes to survey instrument: In a behavioral study utilizing a questionnaire, the investigator realizes that two of the questions would work better in reverse order. The investigator re-orders the questions without IRB approval.
In these situations, the investigator or another party decides to deviate from the protocol. Sometimes these intentional protocol deviations are a one-time event. Other times they lead to the implementation of a permanent change to the protocol or other research documents. These intentional protocol deviations may or may not adversely affect the safety, rights and welfare of the research subject, and they may or may not adversely affect the scientific validity of the research.
The second topic of focus for this recommendation is deviations from the protocol that an investigator, research staff and/or other party involved in the conduct of the research are able to identify before they occur, but cannot prevent from occurring. An example is a research subject who is on a business trip and calls the investigator to announce that she is stuck in a snow storm and cannot be at a study visit scheduled for the next day. The investigator knows in advance that the deviation will occur, but it is not under the investigator’s control, and it is not the investigator’s intent to deviate from the protocol. (See point V.5 below).
The third topic of focus for this recommendation is deviations from the protocol that occur because an investigator, research staff and/or other party involved in the conduct of the research deviate from the protocol unintentionally, and such deviations are not identified until after they occur. Examples include an investigator’s accidental failure to perform a protocol-required physical, a subject’s failure to self-administer or incorrectly administer the test agent, or a coordinator’s accidental failure to perform a protocol-required blood test on subjects. These deviations from the protocol were not planned nor intended. These types of deviations must be analyzed upon discovery such that a determination may be made as to the root cause of the deviation, and whether or not such a deviation(s) constitutes an unanticipated problem involving risks to subjects or others and/or constitutes serious or continuing non-compliance.
The three protocol deviations described in Sections II-IV that are the focus of this recommendation need to be contrasted from deviations to eliminate apparent immediate hazards and from IRB-approved changes in research. Both of these activities are already addressed in the regulations and IRBs are required to have written procedures addressing these activities.
Deviations from the protocol performed to eliminate apparent immediate hazards to the subject in compliance with 45 CFR §46.103(b)(4) and 21 CFR §56.108(a)(4): These differ from the protocol deviations as described in the examples above in that these types of deviations are performed in reaction to a perceived hazard, such as the occurrence of an unexpected serious adverse event. They are intentional, but they are done to prevent harm to subjects in a time-sensitive situation, as specifically allowed by the regulations. Thus, they are distinct from the intentional deviations that are the focus of this recommendation.
IRB approved changes in research under 45 CFR §46.103(b)(4) and 21 CFR §56.108(a)(3) and (a)(4): In addition, the protocol deviations that are the focus of this recommendation also need to be contrasted from IRB-approved changes in research. If an intentional protocol deviation is implemented with appropriate review and approval by an IRB and, when applicable, by the sponsor, then it is a change in research as allowed under the regulations at 45 CFR §46.103(b)(4) and 21 CFR §56.108(a)(3) and (a)(4) rather than a protocol deviation. If it is implemented without such review and approval, then it is an intentional protocol deviation.
The guidance should reinforce the responsibility of investigators and research staff to follow the written protocol as provided by the sponsor and approved by the IRB. Strict adherence to the protocol is more likely to protect human subjects and preserve the integrity of the data and research.
The guidance should encourage sponsors and investigators to develop protocols that include flexibility in research methods where possible without adversely affecting subject safety or science. Flexibility that is built into the protocol will reduce the number of changes that have to be reviewed by the IRB and should reduce the number of incidents of deviations and non-compliance by investigators.
The guidance should also address one-time intentional protocol deviations that are not intended as a permanent change to the protocol. The guidance should state that these deviations are changes to the research that require IRB review and approval, and when applicable approval by the sponsor, before the investigator may implement them. These deviations will commonly qualify for expedited review by the IRB. This is SACHRP’s central recommendation, as noted above.
The guidance should explicitly distinguish the three types of protocol deviations described in Sections II-IV above. The guidance should also distinguish the three types of deviations from deviations to eliminate apparent immediate hazards and from IRB-approved changes in research.
The guidance should specifically address administrative procedures and regulatory status of deviations from the protocol that are discovered after they occur. The guidance should also contrast those procedures and regulatory status from the procedures and regulatory status for intentional protocol deviations. For research under FDA regulations, the sponsor should also evaluate these protocol deviations as part of its monitoring duties and take any necessary actions. The agencies should consider whether the guidance should take an approach similar to that in the FDA guidance “Adverse Event Reporting to IRBs” and the OHRP guidance “Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events.” It will be particularly important for the agencies to balance the burden on investigators and IRBs versus the protection of subject safety and scientific integrity when considering this issue.
The guidance should state that IRBs need written policies and procedures addressing the three types of protocol deviations described in Sections II through IV above. The guidance should highlight any areas where IRBs may exert flexibility in defining and determining which changes must be reported to them. For purposes of clarity, the guidance should also explicitly distinguish the two types of protocol deviations outlined in Section V above.
SACHRP recognizes that many institutions and IRBs currently do not have policies and procedures in place for reporting and/or handling the three types of protocol deviations described above. The issuance of guidance that only addresses points #3 - #9 above is likely to significantly increase the burden on IRBs. Thus, it is important that there is appropriate emphasis placed on points #1 and #2 above, both in guidance for IRBs, education for investigators, and through dissemination of best practices. For example, it would be extremely helpful to the research community for FDA and OHRP to each identify and publish, in a consistent manner, examples of how to incorporate flexibility into protocols, education programs that help increase compliance of investigators, and models IRBs can use to manage protocol deviations.
The HHS and FDA regulations are inconsistent in addressing protocol deviations. Even among the various FDA regulations there are inconsistencies. FDA regulations and ICH-GCP requirements are inconsistent. These inconsistencies leave IRBs, sponsors, and investigators with no clear direction on how to handle protocol deviations. The HHS regulations only use the term “changes in a research activity,” and state that the only changes that do not need prior IRB review are those that are “necessary to eliminate apparent immediate hazards to the subject.” The term “deviation” does not appear in the HHS regulations. OHRP has not issued any written guidance on protocol deviations or on the definition of a change in research. However, OHRP’s stated position is that any deviation from a protocol is a change in research that needs prior IRB review and approval.
The FDA regulations and ICH guidance both use the term “deviation” in addition to “changes in a research activity” in various sections. However, the use is not consistent among the three sets of FDA regulations (21 CFR §56, §312, and §812); nor is it consistent between the FDA regulations and the ICH guidelines. The FDA regulations pertaining to IRBs are similar to the HHS regulations pertaining to IRBs, in that, they only address “changes in research activity.” However, the ICH-GCP, adopted by FDA as guidance, uses the term “deviations,” and requires that IRB procedures specify “that no deviations from, or changes of, the protocol should be initiated without prior written IRB/IEC approval/favorable opinion of an appropriate amendment, except when necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change of monitor(s), telephone number(s)).” Unfortunately, the guidance only provides examples of minor changes that do not need prior IRB review. It does not provide examples of minor deviations that do not need prior IRB review.
The FDA regulations pertaining to investigational drugs (21 CFR §312) are similar to the FDA regulations pertaining to IRBs, in that, the regulations themselves only use the term “changes in research,” but do not use the term “deviation.” However, as with the FDA ICH-GCP, the guidance for investigators does use the term “deviations” in a similar fashion to the ICH guidance for IRBs. The ICH states, “The investigator should not implement any deviation from, or changes of, the protocol without agreement by the sponsor and prior review and documented approval/favorable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change of monitor(s), change of telephone number(s)).” As with the ICH IRB guidance, examples of minor changes to the protocol that do not need prior IRB review are provided, but examples of minor deviations that do not need prior IRB review are not provided.
Finally, the FDA ICH guidance has a section addressing the monitoring responsibilities, which is not internally consistent in regards to deviations. In §5.18.4, among the monitor’s responsibilities is “Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations.” However, §5.18.6 states that monitors should report significant deviations in monitoring reports: “Reports should include a summary of what the monitor reviewed and the monitor's statements concerning the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken, and/or actions recommended to secure compliance.” Minor deviations are not addressed and “significant” is not defined.
§46.103 Assuring compliance with this policy—research conducted or supported by any Federal Department or Agency.
(iii) 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.
OHRP has not issued written guidance on protocol deviations. However, OHRP’s unwritten position is that all planned protocol deviations are changes in research that need prior IRB review and approval before implementation.
(4) for ensuring that 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 where necessary to eliminate apparent immediate hazards to the human subjects.
(i) Any increase in drug dosage or duration of exposure of individual subjects to the drug beyond that in the current protocol, or any significant increase in the number of subjects under study.
(ii) Any significant change in the design of a protocol (such as the addition or dropping of a control group).
(iii) The addition of a new test or procedure that is intended to improve monitoring for, or reduce the risk of, a side effect or adverse event; or the dropping of a test intended to monitor safety.
(b ) The change has been approved by the IRB with responsibility for review and approval of the study. The sponsor may comply with these two conditions in either order.
(ii) Notwithstanding paragraph (b)(2)(i) of this section, a protocol change intended to eliminate an apparent immediate hazard to subjects may be implemented immediately provided FDA is subsequently notified by protocol amendment and the reviewing IRB is notified in accordance with 56.104(c).
21 CFR §312.53 Selecting investigators and monitors.
(vii) A commitment by the investigator that, ... the investigator will promptly report to the IRB all changes in the research activity ... and will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to the human subjects.
21 CFR §312.66 Assurance of IRB review.
The investigator shall also assure that he or she will promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others, and that he or she will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.
FDA Compliance Program Guidance Manual, Program 7348.811, Chapter 48 – Bioresearch Monitoring, Clinical Investigators and Sponsor-Investigators, December 8, 2008.
21 CFR §812.35 Supplemental applications.
(a)Changes in investigational plan --(1) Changes requiring prior approval. Except as described in paragraphs (a)(2) through (a)(4) of this section, a sponsor must obtain approval of a supplemental application under 812.30(a), and IRB approval when appropriate (see 56.110 and 56.111 of this chapter), prior to implementing a change to an investigational plan.
(2)Changes effected for emergency use. The requirements of paragraph (a)(1) of this section regarding FDA approval of a supplement do not apply in the case of a deviation from the investigational plan to protect the life or physical well-being of a subject in an emergency. Such deviation shall be reported to FDA within 5-working days after the sponsor learns of it (see 812.150(a)(4)).
(3)Changes effected with notice to FDA within 5 days. A sponsor may make certain changes without prior approval of a supplemental application under paragraph (a)(1) of this section if the sponsor determines that these changes meet the criteria described in paragraphs (a)(3)(i) and (a)(3)(ii) of this section, on the basis of credible information defined in paragraph (a)(3)(iii) of this section, and the sponsor provides notice to FDA within 5-working days of making these changes.
(i)Developmental changes. The requirements in paragraph (a)(1) of this section regarding FDA approval of a supplement do not apply to developmental changes in the device (including manufacturing changes) that do not constitute a significant change in design or basic principles of operation and that are made in response to information gathered during the course of an investigation.
(C) The rights, safety, or welfare of the human subjects involved in the investigation.
(4) Deviations from the investigational plan. An investigator shall notify the sponsor and the reviewing IRB (see §56.108(a) (3) and (4)) of any deviation from the investigational plan to protect the life or physical wellbeing of a subject in an emergency. ... Except in such an emergency, prior approval by the sponsor is required for changes in or deviations from a plan, and if these changes or deviations may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects, FDA and IRB in accordance with §812.35(a) also is required.
§1.45 Protocol Amendment: A written description of a change(s) to or formal clarification of a protocol.
§3.3.7 Specifying that no deviations from, or changes of, the protocol should be initiated without prior written IRB/IEC approval/favorable opinion of an appropriate amendment, except when necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change of monitor(s), telephone number(s)) (see section 4.5.2).
§4.5.1 The investigator/institution should conduct the trial in compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies), and which was given approval/favorable opinion by the IRB/IEC. The investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm their agreement.
§4.5.2 The investigator should not implement any deviation from, or changes of, the protocol without agreement by the sponsor and prior review and documented approval/favorable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change of monitor(s), change of telephone number(s)).
§4.5.3 The investigator, or person designated by the investigator, should document and explain any deviation from the approved protocol.
(c) To the regulatory authority(ies).
(q) Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations.
(c) Reports should include a summary of what the monitor reviewed and the monitor's statements concerning the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken, and/or actions recommended to secure compliance.

References: §46
 §56
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 §56
 §812
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 §312
 §812
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 §5
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§46
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 §812
 §56
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