SUBJECT:  Changing Study Protocol 

All amendments or revisions, major and minor, must be submitted to the HRAC for approval. The determination as to whether an amendment is major or minor is made by the HRAC Chair, and is determined by the degree of risk involved in the change (45CFR46.110; 21CFR56.110).

The request for approval of an amendment must be made in a letter signed by the Principal Investigator, describing the changes and indicating the reason for the change, the investigator’s opinion as to what the impact of the change will be on the study and on the subjects in the study and whether or not changes are needed to the consent form.

If a sponsor or a granting agency has requested the amendment, a copy of the communications from the sponsor, as well as a copy of the amendment and/or the amended protocol should also be included.

Drug Trials:  Clinical investigators are responsible for protecting the rights, safety and welfare of human subjects in the studies they conduct (21CFR § 312.60, 21 CFR Parts 50 and 56). An investigator must notify the HRAC of changes in the research activity or unanticipated problems involving risks to human subjects or others, and must not make any changes in the protocol without HRAC and sponsor approval, unless necessary to eliminate apparent immediate hazards to human subjects (21 CFR § 312.66).   Clinical investigators are also responsible for following the signed investigator statement (Form FDA-1572) (21 CFR § 312.60). The investigator’s signed statement includes a commitment to: (1) follow the study protocol, and to make changes only after notifying the sponsor, unless necessary to protect the safety, rights, or welfare of the subjects; (2) personally conduct or supervise the research; and (3) inform sub- investigators and others assisting in the conduct of the investigation of their obligations in meeting these commitments (21 CFR § 312.53(c)). Clinical investigators are also responsible for following the investigational plan (21CFR § 312.60).

A major amendment is one that affects the subject’s risk/benefit ratio, changes treatment modalities or adds a new population. Major amendments require the same type of review as new protocols. The investigator’s department before being submitted to the HRAC must approve them. The Primary Review Committee and the Full Board review major amendments and written HRAC approval before they may be implemented.  Examples of major protocol deviations include:

Deviations from the eligibility criteria that affect patient safety

1. Deviations (omission or delay) of safety monitoring procedures
2. Deviations in the administration of study products
3. Deviations in obtaining informed consent

A minor amendment would involve only logistical or administrative changes. These amendments can be granted expedited review, but they also require written HRAC approval before they may be implemented.

The only type of amendment that does not require written HRAC approval before it may be implemented is a change that is necessary for the safety of a subject. In this event, the protocol change may be implemented immediately, and the HRAC notified after the fact. The HRAC will then review the amendment and determine if, in its opinion, the amendment was necessary. The HRAC will then notify the investigator of its approval or disapproval.

The HRAC will notify the investigator of its approval, disapproval or request for additional information about the amendment in a timely fashion. Except in the case of amendments that are necessary for the safety of a subject, amended protocols may not be implemented until written approval is received from the HRAC.

Revisions to the consent form are treated as amendments to the protocol. The request must be made in a letter from the Principal Investigator, and must include the reason for the request. If the study sponsor or granting agency has requested the revision, a copy of the communication from the sponsor should be attached.  Two copies of the revised consent form must be attached: one with highlighting, to indicate where changes have been made, and one clean copy that can be stamped once it receives HRAC approval.

Recruitment materials, such as flyers, advertisements and TV and radio scripts that were not submitted with the original protocol are considered to be modifications to the protocol, and must be submitted for HRAC approval. These will usually receive an expedited review and approval. Flyers that will be posted at CPMC must have the HRAC number on them, and must show the HRAC stamp of approval.  There are several restrictions on the wording of advertisements and flyers.

1.    They must clearly state that individuals are being asked to participate in research.

2.    They may not promise "free treatment," unless all subjects will receive treatment of known effectiveness at some point during the study.

3.    They may not promise that subjects will be cured of any condition.

4.    They may state that subjects will be paid, but should not emphasize payment.

Revisions to FDA Form 1572.  Section 4.5 of the Good Clinical Practice guidelines states that the trial should be conducted in compliance with the approved protocol. The investigator should not deviate from the protocol in any manner without the agreement of the sponsor and the prior review and documented approval of the HRAC. The only exception is when the change or deviation from the protocol is necessary "to eliminate an immediate hazard(s) to trial subjects." If such an event occurs, the investigator should submit as soon as possible a written justification for the implemented deviation or change to the HRAC (along with a proposed protocol amendment, if appropriate), the sponsor and, if required, the FDA.