Designing Fit-for-Purpose GCP SOPs: Are SOPs Required by Regulation?

In our last blog post, we imagined designing SOPs for GCP activities that fit a clinical study team’s needs and objectives. Today we’re going to look at the first step in that process.  From a regulatory perspective, are we required to have Standard Operating Procedures (SOPs)?

21 CFR Parts 50, 54, 312, and 314 do not require standard operating procedures for clinical trial activities. Part 50 references “informed consent procedures” throughout, but these are clearly study-specific procedures.

21 CFR Part 11 does require “procedures and controls designed to ensure the authenticity, integrity, and…confidentiality of electronic records.”  Nothing in Part 11 requires these procedures to be “standard,” or applicable across systems.  In theory, they could be system-specific, although if a sponsor or CRO has more than one system, it makes sense that they would be standard.

The EU Clinical Trials Directive references informed consent “procedures” (again, implying that they are study-specific)

Its replacement, the EU Clinical Trials Regulation, references procedures to be described in the protocol (informed consent, unblinding, source data identification, handling missing data, subject withdrawal, accountability, monitoring, adverse event collection, eligibility).  No references imply the existence of standard (non-protocol-specific) procedures.

Both the Directive and Regulation reference ICH GCP E6 R2 which include the following references to Standard Operating Procedures:

• 1.55 SOPs are included in the Definitions section where they are defined as “detailed, written instructions to achieve uniformity of the performance of a specific function.”
• 1.38 Monitoring involves reviewing trial conduct activities against SOPs (not specified)
• 1.6 Audits are conducted against SOPs (not specified)
• 5.5.3 SOPs must be maintained for system setup, installation, use, validation, system security, change control, data backup, recovery, contingency planning, and decommissioning of electronic trial data handling and remote electronic trial data systems
• 5.8.2 The sponsor’s “policies and procedures” should address the “costs of treatment of trial subjects in the event of trial-related injuries in accordance with applicable regulatory requirements.”  Presumably this “procedure” could be study-specific, but typically “policies” are understood to be broad.
• 5.18.5 and 7: Site monitors should follow the “sponsor’s established written SOPs”as well as study-specific monitoring procedures. I
• 5.19.3  Auditing, “if or when performed,” should comply with the sponsor’s auditing procedures
• 7.1 Investigator’s Brochures should be reviewed at least annually and revised in compliance with the “sponsor’s written procedures,” which are presumably standard procedures as it would not make sense to have a product- or study-specific procedure for an IB.

Other “procedures” referenced in GCP could be considered standard OR study-specific, e.g.,

• 2.13 Systems with procedures that assure the quality of every aspect of the trial
• 3.1.2 and 4.4.1 Subject recruitment procedures
• 4.2.6 Procedures to ensure the integrity of the trial-related duties and functions performed and any data generated (in reference to responsibilities subcontracted by the investigator to another party)
• 4.7, 6.4.8 Randomization procedures
• 4.8.10, 6.4.2 Trial procedures
• 4.9.3 Written procedures to assure that changes or corrections in CRFs made by sponsor’s designated representatives
• 5.0 Procedures for data collection and processing
• 5.6.3 Procedures for data recording/reporting
• 5.13.2 IP reconstitution procedures
• 5.14.3 Procedures for handing IP
• 6.4.7 IP accountability procedures
• 6.5.3 Subject withdrawal procedures
• 6.6.3 Procedures for monitoring subject compliance
• 6.8.3 Procedures for eliciting adverse event reports

To recap, requirements for standard procedures are as follows:

• If you are running a study in the US, you are required to have system-specific or standard procedures to describe controls for regulated systems.
• If you are running a study in the EU, or if you are running a study in the US and required to demonstrate compliance with GCP per your SOPs, you are required to have standard procedures for updating an investigator’s brochure, conducting site monitoring, auditing (“if” you audit), use of electronic data capture systems, and compensating subjects for injury. Other written procedures are required, but may be study-specific.

Interesting, isn’t it?

Of course, even if you’re not required by law to have SOPs, you still might want them.  In the next set of blog posts we’ll look at criteria for articulating our goals for SOPs and SOP approaches that fit with different goals.