FDA issues guidance for Impact of Certain Provisions of the Revised Common Rule on FDA-Regulated Clinical Investigations

FDA announced the availability of a new guidance entitled “Impact of Certain Provisions of the Revised Common Rule on FDA-Regulated Clinical Investigations.” This guidance clarifies that certain provisions of the 2018 Requirements related to informed consent are not inconsistent with FDA’s current policies and guidances.  The guidance also reminds stakeholders that FDA’s current regulations for expedited review and continuing review must be followed for FDA-regulated studies.

The revisions to the Department of Health and Human Services’ (HHS’) Federal Policy for Protection of Human Research Subjects (45 CFR 46, Subpart A; “the Common Rule” or “2018 Requirements”) have created certain differences between FDA’s human subject regulations and HHS’ human subject regulations.  While FDA intends to undertake rulemaking to harmonize, to the extent practicable and consistent with other statutory provisions, its regulations with the 2018 Requirements consistent with Section 3023 of the 21st Century Cures Act, we recognize the potential for confusion in the interim for sponsors, investigators, and IRBs who are involved in both HHS-regulated research and FDA-regulated clinical investigations. This guidance is intended to clarify the impact of certain provisions of the 2018 Requirements on FDA-regulated clinical investigations.

The guidance is available to download on FDA’s website

FDA Issues Final Rule on Clinical Investigator Disqualification

The U.S. Food and Drug Administration (FDA) announced an amendment that will expand the scope of clinical investigator disqualification.  Under this new regulation, if the FDA Commissioner determines that a clinical investigator is ineligible to receive one kind of test article (drugs, devices or new animal drugs), the investigator will also be ineligible to conduct any clinical investigation that supports an application for a research or marketing permit for other kinds of products regulated by FDA.  This final rule is intended to help ensure adequate protection of research subjects and the quality and integrity of data submitted to FDA.  This rule will become effective May 30, 2012.


The final rule is available using the following web link: 

Conducting Effective Clinical Investigator Audits

The 

audit of clinical investigator sites is often related to monitoring activities.

Like the monitor, an auditor ensures that reported trial data are accurate and complete, and that the trial is conducted in compliance with Standard Operating Procedures (SOPs), Good Clinical Practice (GCP) and applicable regulatory requirements.

These activities help to ensure that the rights and well-being of subjects are protected, viable product candidates reach the public with fewer obstacles, and potential risk or liability to the Company is reduced: i.e., protect the patient, protect the product, protect the Company.

Although both the auditor and monitor share these directives, the auditor differs from the monitor in the scope and performance of their work.  Whereas an individual monitor may be concerned primarily with overseeing the progress of a clinical trial at a particular investigator site(s), an auditor is guided by the importance of the trial in submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s) with a particular trial or clinical program.  The scope of an audit also includes an assessment of monitoring activities as they relate to the conduct of the trial.

To perform this function, the auditor must be independent of the monitoring and QC (Quality Control) functions to reduce any potential bias from experience with a particular study or investigator site and appropriately evaluate the risks inherent to a particular clinical trial relative to concurrent clinical development activities.  It is from this vantage point that clinical investigator sites are selected for audit based on criteria defined in the audit plan for the trial.

Auditors are qualified and selected to conduct investigator site audits based on their training and experience.  An auditor must be proficient in the practice of audit conduct, particular aspects of the trial and interpreting relevant information to identify compliance trends.  Preparation for a clinical investigator audit typically includes a review of the Investigator’s Brochure, Protocol and amendments, Informed Consent Forms, CRF’s (Case Report Forms), CRF completion guidelines, monitoring reports, SAE (Serious Adverse Event) reports, site correspondence and other relevant documentation in the Trial Master File.  The audit should be scheduled such that the Principal Investigator (PI), Site Coordinator(s) and other key staff will be available during the audit.  The auditor(s) will discuss site performance and any identified issues with the clinical project team prior to visiting the site.

During conduct of an audit, auditors will perform a detailed review of site regulatory files, informed consent forms, study correspondence, investigational product/material accountability records, and selected patient files including a comparison of information recorded on source documents with data recorded on case report forms.  Interviews will be conducted with the Principal Investigator, Study Coordinator and other site staff to discuss trial roles and responsibilities as well as the conduct of study activities, including procedures for gaining informed consent.  An auditor should use appropriate interview techniques to gain additional information to identify potential issues and performance trends as well as the attitudes and behaviors that led to any identified data discrepancies or events observed.  For example, is the Investigator reluctant to admit or correct mistakes?  Is the data recorded deliberately misleading or is it the result of a limited number of staff taking on too large a volume of work?  

These observations may result in the discovery of protocol violations, discrepancies in data or differences between site staff description and performance of trial activities.    It is an essential part of effective audit technique not only to be able to relate individual observations and data points to identify trends and patterns that may seem hidden among individual discrepancies, but to interpret the value and context of these trends relative to the risks to data integrity and compliance for the trial as a whole. 

If illegal or unethical activity is indicated, the auditor should record their observations, safeguard evidence and obtain copies of pertinent records.  A key distinction between demonstrating fraud and misconduct on the part of an investigator is the ability to prove intent.  Records and testimony collected during an audit may prove essential to being able to make this legal distinction.

During the audit exit interview, audit findings are presented and specific questions asked by both the site staff and auditor(s) to ensure accuracy.  There should be no ‘surprise’ audit findings if an auditor has been communicating effectively with site personnel throughout the conduct of the audit.  The auditor should also communicate with investigators and site staff to identify any issues or concerns that may fall within the influence of the Sponsor.

As a representative of the Sponsor, it is important that an auditor carry out their work in a professional manner.  How an auditor conducts her/himself, both on site and in correspondence, could have a potential impact on the liability of the Company.  Inappropriate conduct on the part of the auditor may be subject to actions related to securities laws, antitrust laws, violation of due care, or even aiding and abetting.  In addition to the standards of ensuring confidentiality and avoiding conflicts of interest, an auditor should not make any promises to site personnel on behalf of the Sponsor or tell auditees how to do their work (thereby inheriting partial liability for work conduct).  

Audit reports may be notoriously dry and matter-of-fact, but this approach is both to mitigate legal liability and provide a report of site performance with limited bias.  

It is not enough, however, to just write an audit report and file it away.

Timely follow-up and correction of audit observations will help to keep site operations compliant and data accurate.

Particular site observations may indicate more general actions for the study that can improve the compliance, accuracy, speed and/or costs of conducting the trial.

Conducting effective clinical investigator audits requires auditors to maintain standards of professional conduct and proficiency to provide an independent, unbiased report to management on the conduct of a clinical trial.  Clinical investigator audits, as part of an overall quality oversight program, help to effectively manage the risks to trial subjects, ensure data integrity and limit potential regulatory or legal liability associated with the conduct of clinical trials.