Human Research Ethics Committee, Faculty of Health Sciences, University of Cape Town

Protocol Amendments

Standard Operating Procedure

Protocol Amendments

Policy

Amendments to an approved protocol may become necessary as a study proceeds. Amendments may be minor or major. The Human Research Ethics Committee must review and approve all amendments to protocols involving human participants before implementation. All applications for an amendment must include the rationale or justification for the proposed change(s). The justification for an amendment must clarify how it will change the study, how it will affect risks to participants and what safeguards will be introduced to protect participants from additional risks. If the revision requires a change in the informed consent process, a revised consent form must be submitted with the amendment. Terms such as amendments, revisions, addenda, administrative changes, additions and modifications are used interchangeably to describe changes in an approved study.

Purpose

The purpose of this policy is to describe the procedures involved in applying for an amendment to an approved protocol. The policy also provides guidance on how to apply for a study exception (i.e. a temporary change or a change which affects only a few participants).

Definitions

Minor Amendments

A minor amendment is defined as a change that does not materially affect the balance of risks and benefits in a study or does not substantially change the specific aims or design of the study. Examples of minor amendments include:

Administrative or informational amendments:

Changes in research staff.
Changing the study title or telephone numbers.
Addition or removal of qualified investigators, study sites.
Revision of format of consent documents, recruitment materials or questionnaires.
Correction of typographical errors.

Procedural amendments

Drawing slightly different amounts of blood.
Changing frequency at which blood is drawn.
An increase or decrease in proposed number of participants supported by a statistical justification.
Narrowing the range of inclusion criteria.
Broadening the range of exclusion criteria.
Changing the amount of compensation, within reasonable limits.
Revisions to the informed consent documents to improve clarity, to include missing elements or to revise lay language.
Decreasing drug dosage or frequency of administration.
Decrease in number of study visits provided such a decrease does not affect collection of relevant safety-related data.

Major Amendments

Such amendments involve significantly increased risk to participants and often reflect changes in the direction of a study that may substantially change its purpose or goal. Changes that alter the overall purpose or objective of a study may require a new study submission.

Examples of changes that may affect the balance of risks and benefits include:

Adding a new activity that may increase risk to participants.
Changing drugs or medications as well as dosages.
Changing levels of radiation exposure.
Adding a vulnerable population.
Adding or changing invasive procedures.
Adding a research arm to the study.
Substantially extending the duration of exposure to the test material or intervention.

To obtain Human Research Ethics Committee approval for amendments, the principal investigator must submit an amendment application form describing all proposed modifications with a rationale for the changes (fhs006 and a synopsis of proposed changes). This applies to the protocol and the informed consent forms. In addition, all proposed changes must be indexed and highlighted in the revised protocol and consent documents. Major changes must be incorporated in the protocol and a revised protocol submitted. The approval of an amendment does not alter the original approval or expiry dates assigned to the protocol.

Amendments to Retrospective Record Reviews or Repositories/Databases

In the case of minor amendments to, for example, approved retrospective record reviews or repositories/ databases, the principal investigator can submit a covering letter describing the planned changes. It is not necessary to complete an amendment form. Examples of minor amendments might include:

Minor wording changes in the study’s title
Minor adjustments in participant numbers
Minor adjustments in the duration of the study

Amendments to Study Staff

The principal investigator must notify and obtain approval from the Human Research Ethics Committee for any staff changes by completing a study staff amendment form (fhs007). This includes the addition of students who are joining an active study for degree purposes.

Guidelines for Describing Potential Changes and Preparing a Synopsis

A concise description of potential changes is essential and the Human Research Ethics Committee no longer accepts any research amendments that do not include a local PI-constructed synopsis describing planned changes. The Committee cannot rely on a study sponsor’s description of the proposed revisions as it seldom provides adequate contextual detail to assess the changes. The degree of detail in the synopsis will depend on the nature and complexity of the proposed amendment. Researchers need to include enough information for Committee members to assess the amendment independently of any other protocol documentation. Any change in the risk-benefit ratio of the study must be defended. It is important to explain why changes are being made. For instance, there may be an overarching rationale for the changes (recruitment has been slow and the sample size, eligibility criteria and recruitment methods are being revised to increase the accrual rate and enable the study to be completed in a reasonable time frame); or each specific revision may be made for a different reason that needs clarification.

The amendment synopsis must:

Be written in simple, non-technical and jargon-free language which is readily understood by Committee members who include non-scientists, non-experts in the PI’s field and who represent the community. Acronyms must be spelt-out when used for the first time.
Specify how the amendment will advance health and scientific knowledge in this population.
Succinctly identify the amendment’s purpose and objectives in the context of currently available and relevant knowledge.
Provide a brief overview of inclusion and exclusion criteria, if applicable.
Describe, if applicable, how participants will be recruited if different from the previously approved protocol. Specifically, address how, when, where and by whom participants will be identified and approached.
Indicate whether any changes in design or sample size might affect a study’s likelihood of achieving its objectives. If substantive changes in study design are intended, please provide a new statistical justification, and describe how data collected before this amendment will be incorporated into analyses.
Describe the probability and severity of foreseeable harms (physical, psychological, social, and economic) that might occur in the amended protocol.
Describe any changes in site-specific measures to protect participants’ privacy and the confidentiality of the collected data.
Explain how risks will be minimised and how safety will be protected.
Describe expected benefits to individual participants and potential societal benefits within the local setting.
Indicate whether post-trial treatment access will be affected by the amendment.
Explain any changes to how, when, where and by whom consent and assent will be obtained.
Clarify special protections for vulnerable participants such as children, cognitively-impaired, terminally or critically ill.
Provide information on availability of compensation for research-related costs (e.g., travel) and inconvenience.
Provide information on the on-going availability of insurance for research-related injuries.
Where appropriate, briefly describe any changes to existing measures and protections for collection, storage and exchange of biological specimens.
Identify and justify any aspects of the amendment that could reasonably be considered morally controversial.
Please make sure that all amendments are highlighted with coloured track changes.
Please provide updated informed consent and assent documents with track changes if applicable.

Amendments Requiring Full Committee Review

If the Chairperson or Committee determines that an amendment requires review at a full committee meeting then, at least 7 to10 days before the convened meeting, all members should receive and review an electronic synopsis of the proposed amendment and revised informed consent documentation (if applicable), and at least one member must receive the complete protocol.

The following materials are sent to the main reviewer. Amendments requiring full committee review will be assigned to a primary reviewer and will be placed on the agenda of the next scheduled meeting. For reviews of amendments requiring full committee approval the following materials are sent to the main reviewer:

Summary of proposed changes containing the relevant information required to determine whether the proposed changes increase the risks to human participants.
New or revised study instruments that include but are not limited to:

New and/or revised informed consent and assent documents.
Data collection instruments.
Revised protocol.
Revised investigator’s brochure, if applicable.

The complete Human Research Ethics Committee protocol file is available to all members prior to the scheduled meeting.

As part of the review, a decision will be made as to whether previously enrolled participants should be given information about the amendment when such information may impact their willingness to take part in the research. A written report of the final decision will be sent to the investigator, including a signed original copy of the amendment form (fhs006).

Unless proposed changes will significantly increase risk to participants or others, the Chair or designee will review amendments using an expedited procedure.

Guidelines for Reviewing Amendments

Identify which part of the protocol is being reviewed:

Administrative details (e.g. study personnel, phone or fax numbers).
Inclusion or exclusion criteria.
Methods or procedures (e.g. adding a new questionnaire, increasing numbers of blood draws, adding extra visits).
Treatment parameters.
Stopping rules.
Consent documents.
Recruitments procedures (e.g. advertisements, posters, incentive gifts).

Does the amendment increase risk for currently enrolled participants?
Does the amendment increase risk for future participants?
Should currently enrolled participants be re-consented?
Is the amendment justified?

The Human Research Ethics Committee must review and approve all amendments to protocols involving human participants prior to implementation. The only exception is a protocol deviation that may be necessary to eliminate apparent immediate hazards to research participants. In this case, the principal investigator must notify the Chair in writing of such changes within seven calendar days of their occurrence. The Chair or a designee will review these changes as events that may represent unanticipated problems involving risks to participants or others and determine whether the change was consistent with ensuring participants’ continued welfare.

Study Exceptions

Occasionally investigators want to make a temporary change or a change which affects only one or a few participants. These temporary or limited changes are defined as ‘study exceptions’. Examples of study exceptions include:

Enrolment of a participant who does not meet the eligibility criteria, for instance a participant whose age slightly exceeds the age inclusion criterion.
Changing the dose of a study medication when justified.
Changing a visit date.
Adding an extra visit or omitting a visit.

All study exceptions must receive Human Research Ethics Committee approval prior to initiation and must be listed in the subsequent progress report. Submission and review of study exceptions must follow the policies defined for submission and review of amendments. The review must also determine whether the exception can affect participants’ well-being, adversely or favourably, especially where an investigator repeatedly requests eligibility exceptions in the same study.

The following information should be included in a request for a study exception:

Protocol title and investigator’s name.
The rationale for the exception – why is it the best choice for the participant.
How the exception differs from the approved protocol.
Whether the trial sponsor, if any, supports the exception.
Whether data collected as a result of the exception will be analysed differently from the other data.
Whether the exception changes the balance of risks and benefits.
Whether an amendment to the study will follow.
The only exception to this policy is when the eligibility exception is necessary to eliminate apparent immediate hazards to the participant. If an eligibility deviation has occurred without prior Human Research Ethics Committee approval, the deviation must be reported as a protocol deviation or violation. The Committee cannot retrospectively approve the eligibility exception request and therefore must review the exception as a protocol deviation, following steps described in the policy on ‘Protocol Deviations’.

Last Revised January 20131