Protocol Deviations That Affect Safety or Rights

Part of Human Subjects Protection for Clinical Research Staff: Risks, Adverse Events and Unanticipated Problems.

About 4 minutes. Free, in your language, no account needed.

Why this matters

Protocols are written so that a study protects participants and produces reliable results. Sometimes the plan and reality part ways: a visit happens outside the window, a test is missed, a form is signed late. Some of these slips are small. Others touch participants' safety or rights, and those are the ones this lesson is about.

ICH E6(R3) is the international baseline in this course. The US federal regulations (45 CFR 46, 21 CFR 56) are taught as the detailed worked example, and passages that name them are US law. Outside the United States, follow your national law and ethics committee requirements. State or local rules may add requirements, and your IRB's procedures set reporting details.

The basic rule on changes

No deviations from or changes to the protocol should be started without prior documented IRB/IEC approval of an amendment. The exceptions are changes needed to eliminate immediate hazards, or, as regulation permits, changes to logistical or administrative aspects only (ICH E6(R3) section 1.4.7).

US rules say the same thing differently. Investigators must conduct the research according to the terms of the IRB's approval until proposed changes are reviewed and approved, except to eliminate apparent immediate hazards (45 CFR 46.108(a)(3)(iii); 21 CFR 56.108(a)(4)).

What the investigator does about deviations

ICH E6(R3) section 2.5.3 to 2.5.5 says the investigator should:

• document all protocol deviations;
• review them, and for those deemed important, explain the deviation and put measures in place to prevent it happening again;
• deviate only where necessary to eliminate an immediate hazard, and inform the sponsor promptly when that happens;
• report the immediate hazard, the change and any proposed amendment to the IRB/IEC.

Two points matter for your daily work. First, all deviations are documented, not just the serious ones. Second, the investigator, not the coordinator, decides which are important. Your job is to catch them and bring them forward.

What goes to the IRB

ICH E6(R3) says the investigator or institution should promptly report to the IRB/IEC (sections 1.4.8 and 2.4.6):

• deviations made to eliminate immediate hazards;
• changes that increase risk to participants or significantly affect the conduct of the trial;
• suspected unexpected serious adverse reactions (SUSARs), per applicable requirements;
• new information that may adversely affect safety or conduct.

This list is about specific categories, not about every deviation. Whether a given deviation goes to the IRB depends on its nature, the protocol, and your IRB's procedures. Ask rather than guess.

Rights-affecting errors

Some errors cut to participants' rights. ICH E6(R3) names two kinds: enrolling a participant before IRB/IEC approval of the consent materials, and starting study procedures before the consent form is signed and dated (sections 1.4.6, 2.8.1(a), 2.8.7). These are not paperwork slips. A person who has not agreed has been treated as if they had.

In practice

A coordinator realizes during a visit that a participant had a study blood draw at the previous visit before the consent form was dated. The signature was there, but the date line was blank. She stops, tells the investigator, and documents what happened and what she found. The investigator reviews it as a potentially important deviation, decides what to explain and change so it does not recur, and checks the IRB's procedures for what to report. The coordinator does not backdate the form or fix the line quietly.

What this looks like when it goes wrong

A participant misses a visit window by a day because of a snowstorm. The coordinator notes it and moves on. At another visit, a research assistant starts the screening procedures while the participant is still reading the consent form, "to save time." Nobody records it as a deviation because nothing physical went wrong. Later a monitor compares the time stamps and sees the procedures began before the signature. This is a rights-affecting error, and the site has no documentation, no assessment and no prevention plan.

Key takeaways

• Do not start protocol deviations or changes without documented IRB/IEC approval of an amendment, except to eliminate immediate hazards or for logistical or administrative aspects only.
• The investigator documents all deviations, reviews them, and explains and prevents recurrence of important ones.
• Specific categories go promptly to the IRB, such as deviations to eliminate immediate hazards, changes that increase risk, SUSARs and new safety information.
• Enrolling before IRB approval of consent materials, and starting procedures before the consent form is signed and dated, are rights-affecting errors.
• When in doubt, document it and tell the investigator. Never alter a record to hide a slip.