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“Minor Change” What Exactly Does That Mean?

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1 “Minor Change” What Exactly Does That Mean?
Presentation to SACHRP by Gary L. Chadwick, PharmD, MPH, CIP Professor and Associate Provost University of Rochester March 4, 2009

2 45 CFR 110 § Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. (a) [list of categories] (b) An IRB may use the expedited review procedure to review either or both of the following: (1) some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk, (2) minor changes in previously approved research during the period (of one year or less) for which approval is authorized. (Emphasis added)

3 21 CFR 110 § Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. (a) [list of categories] (b) An IRB may use the expedited review procedure to review either or both of the following: (1) some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk, (2) minor changes in previously approved research during the period (of 1 year or less) for which approval is authorized. … (Emphasis added)

4 HHS (OHRP) v. FDA (HHS) The regulations are identical, it is the official interpretations and guidance that vary somewhat. This may cause some procedural inconsistencies between IRBs depending on which guidance they are following, and from that, how the IRB defines a “minor change.”

5 Definition FDA says IRBs should decide case-by-case, and that the regulations should not define minor change (by list or examples). Ref: Comment # 82 in the 1981 Preamble OHRP implies the same, but adds that the local definition (types of changes [list?]) should be written in IRB policies. Ref: Guidance on the use of Expedited Review Procedures (2003) “The scope of investigations regulated by FDA is so broad that FDA does not believe that it is feasible for the agency to list all of the different changes that might be considered to be minor. The agency advises that it considers that changes that result in increased risk to human subjects are not minor. However, FDA is unable to generalize about whether changes that apparently do not entail increased risk are minor. For example, the agency recognizes that a substantial increase in the number of human subjects above that originally approved by the IRB might be considered to be a minor change in some clinical studies but a major change in others. Therefore, FDA believes that it is up to the IRB to determine on a case-by-case basis whether a proposed change in a protocol is minor.”

6 Federal Guidance “The [FDA] advises that it considers that “changes that result in increased risk to human subjects are not minor.” Ref: Comment # 82 in the 1981 Preamble OHRP states “any change that would materially affect the assessment of risks and benefits should not be considered minor.” Ref: 1993 IRB guidebook, chapter 2. (Emphasis added)

7 What is “Risk?” Both FDA and OHRP emphasize “risk” in the determination of minor change, but is it “no” increase or “no significant” increase? is it the risks themselves or the “assessment” of risk/benefit? Are the FDA and OHRP saying the same thing, but using different words? is the risk determined by any one subject or by the pool of subjects in the study?

8 Calls to Define The definition itself is not recognized as a problem area for IRBs; most define “minor change” something akin to: “any change that does not change risk, or if it does, it lowers the risk.” (Note: generally, risk-benefit assessment, is not specifically included. Is that an omission, or a “but of course it is included?” SACHRP Subpart A committee no floor is a problem, i.e., any change must go through IRB review (e.g., when the 716 area code changed to 585, literally hundreds of ICDs had to be revised by expedited review.)

9 1974 v. 1981 Regulations One Choice versus Three
Convened meeting = default procedure Expedited review is an optional procedure Exemptions (“101b carve-outs”) added Minor change (§ 110) does not allow a less than expedited review i.e., some type of “non-IRB” or “administrative” review akin to exempt. This “requirement” can be a major burden with no addition to human subject protection.

10 ICH: a “Third Choice for Changes?”
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 to trial subjects, or when the change involves only logistical or administrative aspects of the trial (e.g., change of monitor, change of telephone number). (Emphasis added)

11 ICH as FDA Guidance ICH requirements don’t always track with FDA regulations (multi-national agreement). However, the ICH is official FDA Guidance, so are administrative changes OK? with FDA if not OHRP? only for drugs, not devices?

12 OHRP Memo to CTEP (9/29/2008) “regarding the implementation of changes to protocols and informed consent documents for NCI/CTEP-sponsored clinical trials … in which new or modified risk information is considered to represent no more than a minor alteration in the overall risk-benefit relationship for subjects.” (Note the emphasis on changes to the risk-benefit assessment, not on the risk in and of itself.)

13 CTEP-generated Suspensions
“when CTEP identifies or learns about new or modified risk information that necessitates changes to the description of the reasonably foreseeable risks or discomforts during the obtaining of informed consent … new subjects cannot be enrolled until revised informed consent documents, and any proposed changes to the protocol, have been reviewed and approved by the IRB.” “These regulatory requirements provide two important protections for human subjects. First, the IRBs can determine whether or not the requirements of HHS regulations at 45 CFR are still met in light of the new risk information. In particular, the IRB must determine whether or not risks to subjects are minimized and whether or not risks to subjects are reasonable in relation to anticipated benefits (45 CFR (a)(1) and (2)). The second protection is for the IRB to review the way in which the information is provided to prospective subjects to ensure that it is in language understandable to the subject and that it accurately presents the new risk information.” (Emphasis added)

14 Determining Minor Change
“IRBs have significant latitude in setting the parameters for what changes to research are considered minor. Determining whether or not a particular change to a research protocol or informed consent document is minor should take into consideration the nature of the previously approved research and the content of the previously approved protocol and informed consent documents.” (Emphasis added)

15 Sponsor v. IRB Determinations
“When CTEP determines that the proposed changes are minor, these changes may be reviewed by the IRB under an expedited review procedure if the IRB chairperson (or another experienced IRB member designated to conduct expedited review by the chairperson) concurs with CTEP’s assessment. If the IRB chairperson (or designee) does not concur with CTEP’s assessment that the changes are minor, the changes must then be reviewed at a convened meeting of the IRB.” “Having carefully reviewed several of the most recently issued CTEP Action Letters, we note that the changes typically proposed in such letters are intended to inform investigators, IRBs, and subjects about the previously unrecognized risks and to implement procedures that will decrease those risks (e.g., by revising the inclusion or exclusion criteria or by implementing additional safety monitoring procedures).”

16 Minor Change – Discussion Points
When is a change “minor” or “not minor” where is the line (value added) between expedited and convened review? What about “administrative” changes? If the determination of “minor change” is tied to risk assessment, can an administrative change (e.g., adding a comma), which has no affect on risk, be considered not encompassed by §110? Should a sentence be added to the end of 46/56§110(b) that mirrors the ICH exception?

17 Case Scenario 1 In an IND pediatric cancer clinical trial, the DMC (DSMB) discovers that all children over 15 die (none under 15), the sponsor sends out a revised protocol changing: eligibility criteria from 8-17 to 8-14, and adding “increased risk of death, if over 15” The risk for those over 15 is “GTMR,” but the eligibility change mitigates that risk. Is this a minor change for expedited review?

18 Case Scenario 2 In a survey study of criminal behaviors, the PI finds she needs to link to a database and needs to record names. She sends the IRB a revised protocol changing: the data collection tool to add “full name” adding Certificate of Confidentiality (CoC) The risk for the subjects now is “GTMR,” but the CoC mitigates that risk. is this minor change with expedited review? does the whole study need convened review?

19 Cases / Examples Consent form “typo” corrections (misspelling “,” “.”)
Consent form wording changes “nausea” changed to “nausea or upset stomach” “blistering” changed to “Stevens-Johnson syndrome” Adding the word “approximately” to table of lab tests schedule. (e.g., instead of “on the 7th day” to “approximately on the 7th day”) PI leaves institution and a new PI takes over. variant of above: study personnel change (study coordinator / nurse / technician / recruiter, etc.)

20 More Cases / Examples Old data collection sheets replaced with new ones. This change is noted in a revised protocol. simple reordering/formatting additional data points Change in the Investigator’s Brochure (with no change in protocol or consent) to add a report of a possible link to cancer (i.e., not proven) does “possible” mean convened or expedited? In an approved pediatric study, changing a 10ml blood draw to two 20ml draws (still in 50ml limit)

21 Still More Cases / Examples
Changes to subject “n” (e.g., doubling 10 to 20) serial additions (e.g., lasik 10 to 12 to 15 to 20) Changes to eligibility criteria, which affects the size of the study enrollment if increasing enrollment is it convened meeting only if decreasing enrollment is it eligible for expedited Changes in recruitment materials not specifically included in the regulations both OHRP and FDA suggest review ( ( Recruiting Study Subjects FDA requires that an Institutional Review Board (IRB) review and have authority to approve, require modifications in, or disapprove all research activities covered by the IRB regulations [21 CFR (a)]. An IRB is required to ensure that appropriate safeguards exist to protect the rights and welfare of research subjects [21 CFR (a) and ]. In fulfilling these responsibilities, an IRB is expected to review all the research documents and activities that bear directly on the rights and welfare of the subjects of proposed research. The protocol, the consent document and, for studies conducted under the Investigational New Drug (IND) regulations, the investigator's brochure are examples of documents that the IRB should review. The IRB should also review the methods and material that investigators propose to use to recruit subjects. (2) Research Review Materials (a) Initial Review Materials. HHS regulations at 45 CFR set forth the criteria that must be satisfied in order for the IRB to approve research. These criteria include, among other things, determinations by the IRB regarding risks, potential benefits, informed consent, and safeguards for human subjects. In conducting the initial review of proposed research, IRBs must obtain information in sufficient detail to make the determinations required under HHS regulations at 45 CFR  Materials should include the full protocol, a proposed informed consent document, any relevant grant application(s), the investigator's brochure (if one exists), and any recruitment materials, including advertisements intended to be seen or heard by potential subjects.

22 Strategies to Comply with Both Sets of Regulations - 1
Joint OHRP/FDA guidance should clarify that, when making a “minor change” determination, the IRB should consider both the affects of proposed change on risks and benefits as well as the changes proposed to mitigate risk and improve benefit. The risk/benefit analysis of the change drives the determination of “minor change.” (Use examples, not lists.)

23 Strategies to Comply with Both Sets of Regulations - 2
IRBs should review their local definition of “minor change” to ensure that the concept of risk/benefit analysis is considered, and not have the sole determinate condition be the risk of a modified procedure or finding. IRBs should consider the risk-mitigating effects in assessing the overall change. i.e., the “package,” not any specific / separate risk must be considered.

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