Guidance on Presenting Changes of Protocol to IRB

Version Date: November 29, 2011

Effectively communicate to the IRB what will be changed, why the changes are being proposed, how the revisions alter the IRB-approved protocol, and the impact of the changes on the risk/benefit ratio of the study will reduce modification requests from the IRB and shorten IRB review time.  This document was prepared to help study teams present clear and complete descriptions of changes of protocol.

Change Form vs. Modified IRB Application
In ARROW study teams must complete 2 steps when preparing a change of protocol.
Step 1: The first step in completing the change form, which is where study teams identify and describe the proposed changes.  Do NOT upload any revised study team documents (e.g., consent document, protocol) to the change form.  For guidance on completing the change form, please see the "How to Describe Changes" section below.

Step 2:  The second step is revising the modified application.  The modified application is a copy of the currently approved IRB application for a study.  The modified application must be revised to reflect the proposed changes described in the change form, including uploading any documents that are being revised as part of the change of protocol.  These changes need to be reflected in the IRB application because this document is used by the IRB to track changes to the study over time.  It is important for study teams to consider all the areas of the application that may be affected by a specific change.  For example, a change in sample size affects the Subject Population pages of the application and requires updates to the protocol document and consent forms; if the increase in sample size includes a new subject group it will also affect the Research Design sections of the application and protocol, and may affect recruitment procedures and recruitment materials.  Neglecting to consider the "ripple effect" of a revision makes IRB pre-review more time-consuming.

For additional guidance on this 2 step process, please see How to Complete Changes of Protocol .

Providing Documents with Changes Tracked/Highlighted
In order for an IRB to assess updates to previously documents, study teams must upload copies of any study documents to which changes are being made.  For example, if a formal protocol is associated with the study and is being updated, the revised version of this document must be upload into ARROW.  The changes made to documents must be highlighted or tracked so that the IRB can easily compare the previous version of a study document with the revised version.  The tracked changes function in Microsoft Word is the preferred way of highlighting revisions to documents.  All revised documents should be uploaded using the Upload Revisions button in the modified application. 

How to Describe Changes
The change form asks study teams to provide a description of each change, a rationale for the proposed changes, and describe what effect, if any, each change will have on the risk/benefit ratio of the study.  Specific guidance regarding how to address each of these sections as follows.

A detailed account of the changes is critical. Reliance on a study sponsor’s description of the proposed revisions is not recommended because they often do not provide the specificity the IRB needs to assess the changes. It is also not helpful just to provide a list of changes even if reference is made to a specific section of the protocol that is revised. The HS-IRBs office recommends that study teams organize the proposed changes by category and describe all changes relating to that overall type of revisions. Study teams also are encouraged to provide a brief description of what was previously approved by the IRB and how the changes alter what the IRB approved. For example, revisions related to recruitment could be described together and labeled “CHANGE IN RECRUITMENT METHODS.” The description of changes should include what was previously approved by the IRB and how the changes alter what the IRB approved. If the number of subjects will be increased, specify how many subjects were previously approved by the IRB, how many more will be enrolled as a result of this change, and the statistical justification for this change in subject number. Or, if additional monitoring will be added, describe the monitoring in place before and whether the change will alter the timing, length or number of study visits (e.g., “Previously subjects had ECGs every six months; two additional ECGs are being added, one to visit 4 and one to visit 8 to monitor for possible cardiac toxicities…” See the appendices for specific example of how to present changes. 

The rationale for each of the change(s).

It is essential to explain why changes are being made.  In some cases, there is an overall rationale for the changes (e.g., recruitment has been slow and the sample size, eligibility criteria, and recruitment methods are being revised in an effort to increase the accrual rate and enable the study to be completed in a reasonable time period). In other cases, each specific revision is being made for a different reason that should be described.
When reviewing a change of protocol, the IRB needs to assess whether the risk/benefit ratio of the study remains acceptable. Study teams need to explain how the proposed changes affect risk/benefit and why the potential benefits of the revised study continue to outweigh the potential risks to subjects. Changes may pose new or increased risks to subjects (either as the result of a new risk or exacerbating a risk already present), have no effect on risks to subjects, or decrease risks to subjects. If new or increased risks are identified, describe whether the benefits to subjects offset these risks. In the case of therapeutic research, it may be that new risks are identified but given the nature of the subjects’ disease and their limited treatment options the potential subjects may still be expected to directly benefit from the protocol treatment. In the case of non-therapeutic research, any significant increase in risks needs to be well-addressed especially to demonstrate that the societal benefits of the research are critical. 

This section should also address any changes in design or sample size that would affect whether the study’s objectives can still be met. If substantive changes in study design are being made, please provide a new statistical justification, describe how data collected before this change will be incorporated into analyses, and address why the study should continue.
If a study team does not think that the changes have an impact on the study’s risk/benefit ratio, the study team needs to explain why. For example, if the consent form is being revised to update risk information but the risks are commensurate with those previously known for the research study, the new information may not have any effect on the overall risks to subjects. Another example might be that a study team is adding a new survey and the instrument is similar in scope and type of questions to what the IRB previously approved.
If this changes involves new information that should be disseminated to subjects, describe this is this section, including how the information will be provided to subjects (e.g., via telephone, letter or consent form addendum) and the timeframe within which the information will be disseminated to subjects (e.g., they will be informed with 1 month or by their next study visit, whichever comes first).  New information that could affect subjects' willingness to participate in a study or information that describes new risks that are life-threatening or result in permanent disability should be provided to subjects promptly.  Copies of revised consent and assent forms and/or addenda to the consent form should be uploaded in the IRB application, with the changes highlighted or tracked, as described above.
Need for Re-consenting of Previously or Currently Enrolled Subjects
If it is not expected that subjects will be re-consented, explain why the change does not represent new information that would affect subjects' willingness to participate in the study of significant new risk information.  If all the subjects have completed study treatment, only information about late effects (e.g., increased rate of cancer) would be expected to be provided to subjects.
The change form requests a description of what changes are being made to study documents. Please describe and reference the specific documents that have been updated and the types of revisions made.

Examples for the presentation of a change of protocol

Example #1
Description of Changes Section
Change in experimental gas dosing: We propose to broaden the options for use of a third dose of an experimental contrast gas for MRI imaging (Visit 2 and 9).

Change in study visits: We wish expand visit window for resolution visits to accommodate the occasional subjects who do not resolve their cold symptoms within 6 weeks of the acute infection they undergo for this protocol.

Rationale Section
Rationale for change in experimental gas dosing:  The technology and hardware used to acquire the MR images is relatively new, and there have been instances when unanticipated failures have led to lost data.  When this happens, the researchers would like the option to use a third dose of the experimental contrast gas rather than repeat a scan.  The faster imaging will allow a shorter breath hold time and has been previously tested on normal volunteers.  It is necessary to validate the newer technique in patients with lung disease so that it can be compared to existing imaging sequences.  The use of the third dose of the experimental contrast gas will extend the total exam time by 10 minutes (see revised consent form) to allow for additional preparation time of the gas and scanning.
Rationale for change in study visits:  There are individuals who do not resolve their cold symptoms within 6 weeks of an acute respiratory infection.  We would like to obtain resolution assessments at a time when cold symptoms have resolved so that these assessments can be used as a baseline for the acute cold assessments.

Effect of Risk/Benefit Ratio Section
Effect of change in experimental gas dosing on risk/benefit ratio:

The proposed change should have no effect on the risk/benefit ratio.  Previous protocols at this site (IRB number 2010-XXX, 2011-XXX) and at other sites have used three doses of the experimental contrast gas in smoking and non-smoking subjects, and in patients with a wide range of diseases, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis without serious adverse events and no respiratory-related adverse events.  The risk due to the use of the experimental gas already exists in the current protocol and is addressed by continuous monitoring of ECGs and blood oxygen saturation.  There is no increased risk to subjects associated with the additional inhalation of the gas assuming adequate recovery of between breath holds; the current 5-10 minute gap between scans to prepare each dose of the gas should provide adequate recovery time.  We have scanned more than 60 subjects for this present protocol with no respiratory-related adverse events.  The procedure description has been modified in the protocol to include the option third dose of the gas.

Effect of risk/benefit ratio: No effect expected to risks to subjects. The change may increase scheduling inconvenience. The protocol and consent form have been revised to include the potential need to delay the resolution study visit.

Revised Document Section
The following documents have been revised to reflect these changes and uploaded in the initial review application: the study protocol (to reflect the additional dose of experimental contrast gas and change in window for resolution visits), Main Study Consent Form for Healthy Volunteers, (to reflect the addition of the dose of the experimental contrast gas and potential need to delay the resolution study visit) and letter to potential subjects (to reflect the addition of the dose of the experimental contrast gas).

Example #2
Description of Changes Section
Change to survey instrument:  We would like to ask participants what they believe the directions for each inhaler is during the final interview. It will be phrased as "What are the directions for ____ inhaler" and will be asked for each inhaler. We will be looking for number of puffs taken and number of times daily taken.

Addition of a new study site: Because recruitment is occurring at a lower rate than expected, we are proposing to expand recruitment of subjects to include patients at UW Health Clinic West. The same subject identification and consent procedures will be followed as previously described, but additional study team members are being added who will obtain informed consent and perform study procedures at that clinic. A separate personnel change form will be submitted to add the new personnel. A letter of support for this study from the clinic manager has been uploaded in the IRB application and the protocol has been updated to reflect the new site.

Addition of a new federal grant: The PI received funding from NIH for this study, which is being added to this protocol. This study was previously unfunded.

Rationale Section
Rationale for change to survey instrument: Recently, while reviewing data from the counseling session there were quite a few participants who were unable to report correct inhaler directions. We spent some time educating on inhaler directions and would like to see if there is a difference in understanding of inhaler directions between the two groups

Rationale for new study site:  Opening recruitment at UW Health Clinic West should increase the chances of meeting our original recruitment goals. We expect to be able to recruit 10-15 subjects from this site.

Rationale for adding the new federal grant:  Aim 1 of the federal grant describes the activities that will occur in this pilot study. Aims 2 and 3 will be submitted as a separate IRB protocol.

Effect on Risk/Benefit Ratio Section
Effect of change to survey instrument on risk/benefit ratio: The addition of inhaler directions should not change the risk/benefit ratio. If a participant does not want to answer the question for any reason they can choose not to answer. Additionally, if a participant does report incorrect inhaler directions, the interviewer can review correct inhaler directions with the participant and they may begin to use their inhalers correctly

Effect of new study site on risk/benefit ratio: The addition of the study site should not affect the risk/benefit ratio as the same privacy and confidentiality protections described for the original subject population remain in place and the new location’s facilities are commensurate with the clinic the IRB already approved.

Revised Document Section
The following documents have been revised to reflect these changes and uploaded in the initial review form: the study protocol (revised to add the new sites and clarify recruitment procedures followed at each site), main survey instrument (to reflect the change in question about inhaler directions described in this change), and several recruitment materials - subject brochure, letter to subjects, study flyer, newspaper advertisement – (to reflect the additional recruitment sites). In addition to the revised document, a copy of the federal grant that now supports this study has been uploaded in the initial review form.