1 © Huron Consulting Group Inc. All rights reserved. Huron is a management consulting firm and not...

1 © Huron Consulting Group Inc. All rights reserved. Huron is a management consulting firm and not a CPA firm, and does not provide attest services, audits, or

other engagements in accordance with the AICPA’s Statements on Auditing Standards.

One Time Planned Variations versus Protocol Changes

Jeffrey A. Cooper, MD, MMM

One Time Planned Variations versus Protocol Changes Jeffrey A. Cooper, MD, MMM

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DHHS Regulations

§46.103 Assuring compliance with this policy—research conducted or supported by any Federal Department or Agency.(b) … Assurances applicable to federally supported or conducted

research shall at a minimum include:(4) Written procedures which the IRB will follow

...(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 in not in FDA regulations.

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FDA Regulations

§56.108 IRB functions and operations. In order to fulfill the requirements of these regulations, each IRB shall:(a) Follow written procedures:

...(3) for ensuring prompt reporting to the IRB of changes in

research activity; ...(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.

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FDA Regulations

§312.53 Selecting investigators and monitors.(c) Obtaining information from the investigator. Before permitting

an investigator to begin participation in an investigation, the sponsor shall obtain the following:(1) A signed investigator statement (Form FDA-1572)

containing:(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.

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FDA Regulations

§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.

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FDA Regulations

§812.150 Reports.(a) Investigator reports. An investigator shall prepare and submit

the following complete, accurate, and timely reports:...(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.

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Regulations

• The regulations are clear that all changes to research require IRB review and approval prior to implementation except where necessary to eliminate apparent immediate harm.

BUT

What is a change?

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Are these changes?

• Lab criteria:– One test is out of range for a benign reason (increased alkaline phosphatase in a

runner or increased bilirubin in a person with Gilbert Syndrome)

• Age criteria: – Age range is 20-60, but the subject “will be 20 in two months” or “turned 61 last

week.”

• Timing: – A vacation interferes with the protocol For example, vacation interferes with a

washout period, or timing of a therapeutic intervention or a monitoring procedure. Shortening the wash-out period from 14 to 12 days or moving the intervention or monitoring procedure will allow the subject to be enrolled. Judgment made that the subject’s current medications will wash out by 12 days, or that the timing of an intervention or monitoring test is not critical in this subject.

• Drug allergy: – Person is allergic to one of the study meds, but is “such a good candidate in all

other respects” that the subject can be enrolled on a substitute drug or none at all.

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Taxonomy

• IRB jargon includes terms like “deviation,” “violation,” and “exception.” These terms variably include:– Mistakes made in following the protocol– Failures of the subject to comply with procedures– Changes made without prior IRB review and approval– One-time planned alterations

• The usage is not consistent.

• The first three by their nature can be handled with retrospective reporting to the IRB under procedures for non-compliance and unanticipated problems involving risk to subjects or others.

• I will use the term “one-time planned variation,” avoid the usual IRB terms, and limit discussion to this item.

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What do IRBs think FDA and OHRP are saying?

• Nothing in writing.

• FDA – These are not changes, but rather the practical aspects of running a scientific protocol. The regulations do not require prior IRB review, although it is up to local policies and procedures.

• OHRP – These are proposed changes that must be reviewed by the IRB.

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The reality

• IRBs are not sure what the difference is between a change that requires prior IRB review and a one-time planned variation that does not.

• Some IRBs want to restrict the range of one-time planned variation to a protocol, but are under tremendous pressure from sponsors and investigators to not hold up research with IRB review.

• Knowledgeable IRBs believe they are walking a fine line between OHRP, FDA, and sponsors.

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Questions?

• Can a one-time planned variation in a protocol ever not be considered a change to the protocol?

• If so, when?

• If not, when is it a minor change to previously approved research?

• It would be very useful for the research community if FDA and OHRP could issue a joint policy on this issue.

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