Prospective Protocol Waivers
(07/13/2011)

Question 1:

Occasionally we find that a sponsor will provide a prospective protocol exception/waiver to allow a deviation from a protocol requirement. I have the following questions:

1. Is it acceptable for the sponsor to provide numerous waivers or a blanket waiver across sites to allow for deviations from a protocol requirement until the sponsor obtains an approved amendment to the protocol? Or must the sites comply with the requirement as is until a protocol amendment is approved (assume the changes are not safety related)?

2. Must all protocol waivers that are prospectively approved by the sponsor also be approved by the IRB/EC prior to deviating from the requirement?

3. Are documented blanket exceptions to the protocol permitted? For example, one site cannot comply with a certain protocol requirement/test. Can the sponsor exempt that site from the requirement with a blanket exception for all subjects enrolled at that site?

4. For prospective waivers provided by the sponsor for an investigator to deviate from a protocol requirement:

a. Does the site still need to report this as a deviation?

b. Does the sponsor need to report such prospectively granted deviations to FDA (e.g., in progress reports, PMA)?

For any protocol deviation (major, minor, prospectively granted, deviation without prospective approval), does the sponsor need to report all of them to FDA or only some?

Answer 1:

In your questions, you referenced PMAs so I'll answer in terms of the device regulations.

1.-The expectation is that the protocol is followed until it is amended. Depending on the type of changes being made, prior approval from FDA may or may not be needed. 21 CFR 812.35(a)(3) allows certain changes to be effected with notice to FDA within 5 days of the change being implemented. For protocol changes, this would include those changes that do not affect: (A) The validity of the data or information resulting from the completion of the approved protocol, or the relationship of likely patient risk to benefit relied upon to approve the protocol; (B) The scientific soundness of the investigational plan; or (C) The rights, safety, or welfare of the human subjects involved in the investigation. (See 21 CFR 812.35(a)(3)(ii).) Other changes would require prior FDA approval, in accordance with 21 CFR 812.35(a)(1), unless the change from the investigational plan was needed to protect the life or physical well-being of a subject in an emergency (see 21 CFR 812.35(a)(2)). In such cases, the deviation must be reported to FDA within 5-working days after the sponsor learns of it (see § 812.150(a)(4)).

2.-FDA's regulations for IRBs requires that IRBs follow written procedures that ensure 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. (See 21 CFR 56.108(a)(4).)

3.-In general, allowing such blanket exceptions is likely to compromise the study. If a site is unable to perform required tests, the sponsor should consider replacing that site with one that can perform the required tests. Potentially, data from sites that do not follow the protocol may be considered invalid and may be eliminated from the data analyses.

4a.-I assume you mean the site reporting the deviation to the IRB. FDA's regulations require IRBs to follow written procedures for ensuring prompt reporting to the IRB of changes in research activity (21 CFR 56.108(a)(3)).

4b.-FDA does expect deviations from the protocol to be reported. The IDE regulations require sponsors to submit progress reports to FDA on at least an annual basis (see 21 CFR 812.150(b)(5)). Although the regulations do not identify the specific contents of a progress report, in guidance, FDA has indicated that progress reports include descriptions of any deviations from the protocol (Suggested Format for IDE Progress Report, available at www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm046717.htm#sugforforidepro).

For any protocol deviation (major, minor, prospectively granted, deviation without prospective approval), does the sponsor need to report all of them to FDA or only some?

In general, all deviations should be reported to FDA.

Question 2:

Your answers were disseminated and a couple of additional questions have resulted pertaining to protocol deviations and waivers.

1. Is a sponsor and/or investigator at risk of receiving an inspectional observation (i.e., 483):

a. Where numerous or blanket protocol waivers were granted by the sponsor during a study?

b. Where numerous or blanket waivers were granted by the sponsor during a study but for which a protocol amendment addressing those was later approved?

2. In #2 below, you cited Part 56; however, the reason the question was initially asked is because the regulation is not clear to everyone on that point. Can you tell us if a request to deviate from a protocol requirement (not for purposes of eliminating a hazard to a subject) would require approval from the IRB in addition to the sponsor? Examples might include a deviation from a specific inclusion/exclusion criterion or to perform an alternate test than the one required by protocol.

3. Regarding #4a. below, the question was actually intended to ask about the investigators reporting responsibility overall (e.g., in the Case Report Form and to the IRB). You cited Part 56, but again, the reason the question was asked was because individuals are familiar with what the regulation specifies but are not clear regarding how to interpret it relative to this question. For a deviation that the sponsor prospectively waived, can you please clarify whether a site would need to report this deviation in the CRF and to the IRB?

4. This last question is not about protocol waivers but rather deviations of a particular nature. If a subject is enrolled into a study prior to having protocol-required documentation confirming eligibility, is this still considered a deviation if the documentation is obtained at a later point in time? Or is it acceptable to retract the deviation since the appropriate documentation was later obtained (e.g., ECG obtained from the referring doctor or from another dept) showing the subject was eligible upon entry? (I agree the subject should be appropriately qualified with all supporting documentation upon enrollment; however, these instances occur and the sponsor is left with determining how to deal with it)

Answer 2:

1.-Yes, sponsors and/or investigators may be at risk of receiving an inspectional observation in the situations you describe.

The Compliance Program Guidance Manual for FDA Staff (CPGM) discusses protocol deviations. I'm providing excerpts with information pertinent to your questions. Concerning Bioresearch Monitoring of Clinical Investigators, available at www.fda.gov/downloads/ICECI/EnforcementActions/BioresearchMonitoring/UCM133773.pdf, the CPGM includes the following guidance for inspections of investigators in relation to adherence to the protocol (See Part III, section D.3.):

Verify that the clinical investigator followed the study protocol approved by the IRB. The investigator is responsible for ensuring that an investigation is conducted according to the investigational plan. (21 CFR 312.60; 812.100) Review any changes to and deviations from the protocol.

Protocol changes/amendments. During the course of a study, a protocol may be formally changed by the sponsor. Such a change is usually prospectively planned and implemented in a systematic fashion through a protocol amendment. Protocol amendments must be reviewed and approved by the IRB, prior to implementation, and submitted to FDA.

Protocol deviations. A protocol deviation/violation is generally an unplanned excursion from the protocol that is not implemented or intended as a systematic change. A protocol deviation could be a limited prospective exception to the protocol (e.g. agreement between sponsor and investigator to enroll a single subject who does not meet all inclusion/exclusion criteria). 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. Protocol deviation is also used to refer to any other, unplanned, instance(s) of protocol noncompliance. For 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, would be considered protocol deviations. Determine whether changes to the protocol were:

i. Documented by an amendment, dated, and maintained with the protocol; ii. Reported to the sponsor (when initiated by the clinical investigator); and iii. Approved by the IRB and FDA (if applicable) before implementation (except when necessary to eliminate apparent immediate hazard(s) to human subjects).

For device studies: determine whether deviations to the protocol were:

i. Documented, showing dates of and reason for each deviation;

ii. Documented, with prior approval from the sponsor for deviations from the investigational plan, except if emergency use (see iv). iii. Documented, with prior approval from the reviewing IRB and FDA for deviations from the investigational plan that may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects, except if an emergency (see iv). iv. If emergency use, documented notification of the sponsor and the reviewing IRB of any deviation from the investigational plan to protect the life or physical well being of a subject. In addition, determine that this notice was given within 5 working days after the emergency occurred. (21 CFR 812.150(a)(4))

Collect correspondence or other documentation that supports adverse inspectional observations.

Concerning Bioresearch Monitoring of Sponsors, Contract Research Organizations and Monitors, available at www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/ucm133777.htm, the CPGM provides the following guidance in relation to protocol deviations (See Part III, Section E, Selection and Monitoring of Clinical Investigators):

4. Determine how the sponsor/CRO handles serious deviations from the approved investigational plan (which includes the study protocol) or FDA regulations.

5. Determine if the sponsor/CRO/monitor identified any clinical investigators who did not comply with the investigational plan or FDA regulations. If so, did the sponsor/CRO secure prompt compliance? (When there is a CRO, determine who has the responsibility to follow up on noncompliance and secure investigator compliance, the sponsor or the CRO.) When instances of continued clinical investigator noncompliance are identified, obtain evidence of prompt correction or termination of the investigators participation in the study.

Additionally, the table in Part V that provides potential citations and examples, an example of a failure to adequately monitor the study is provided for "The sponsor, monitor, or CRO instructed one or more sites to violate the protocol or instituted ad hoc protocol changes without IRB approval or notifying FDA." (See Part V, page 6 of 7.)

2.-As indicated in the excerpts from the CPGM provided above (where it is stated "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"), the expectation is that IRB approval would be obtained for protocol deviations.

3.-Deviations from the protocol that have prior approval should be documented. Information recorded on the case report form should accurately reflect the conduct of the study. So, a deviation from the protocol should be reflected on the case report form.

If prior approval was obtained from the IRB, I don't believe additional reporting at the time of the deviation is needed, however, I believe the deviation should be included in the progress report to the IRB. Including information about all deviations that have occurred in the progress report will help ensure that the IRB has complete information about the progress of the study for their continuing review. Please note, however, that the IRB's procedures need to be followed and each IRB may have specific procedures for how to report deviations, whether the deviation was previously approved or not. The IRB's procedures need to be followed.

4.-I believe this would depend on the specific wording in the protocol. If the protocol specifies that the documentation must be obtained (on file?) prior to enrolling the subject, then this could be considered a deviation even if the documentation is obtained later. If the protocol does not specify when the documentation must be obtained, then as long as the documentation is available at the time of an inspection, I don't believe it would be considered a protocol deviation.


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