Conducting Clinical Trials in Canada Inspections of Clinical Investigators

Clinical Investigator Inspections

Mike M. Rashti President, BIMO Auditor and Trainer, LLC

Abstract: This article provides an overview of the U.S. Food and Drug Administration’s (FDA’s) foreign inspection program and the Bioresearch Monitoring Program as it is applied to inspections in Canada. How to prepare for an inspection and differences between inspections of clinical research sites in the United States and Canada are discussed. Protocol violations observed at Canadian sites that have been documented by FDA Form 483s (Inspectional Findings) and Warning Letters are noted in this article.

Introduction

At the end of an FDA inspection, clinical research sites want a handshake from the FDA investigator, not an FDA Form 483: Inspectional Observations. This article highlights a number of considerations that will help to prepare for an FDA inspection.

FDA BIMO Program

The FDA BIMO Program conducts inspections of clinical investigators, sponsors, contract research organizations (CROs), institutional review boards (IRBs), and non-clinical laboratories. FDA investigators conduct inspections of firms (the general term used by the FDA for all organizations) involved with FDA-regulated products. After the center creates the assignments, field staff from the Office of Regulatory Affairs conducts the inspections. FDA investigators use the Code of Federal Regulations and the compliance program guidance manual to guide their inspections. The centers classify the inspection results as NAI (no action indicated), VAI (voluntary action indicated), or OAI (official action indicated). The FDA investigator corresponds only with the center that made the assignment.

How Canadian Sites Should Prepare for FDA Inspections

Table 1 highlights how Canadian clinical research sites should prepare for an FDA inspection. For research purposes, the author believes that all clinical research sites should be prepared as if every day is an FDA inspection day. If everything is up to date and there are no issues at the site, the inspection will be easy. Therefore, the clinical investigator, the clinical research coordinator, and the entire staff must know the FDA regulations (CFR 312 for drugs and CFR 812 for devices) and the protocol, and they must have adequate communication with the sponsor/CRO and the research ethics board (REB) in Canada. 

Clinical research site personnel should be trained through the investigators’ meeting, the clinical research coordinators’ meeting, and the site initiation visit. The clinical investigator should attend and participate in the investigators’ meeting. This is the time to raise any issues with the protocol, such as any inclusion/exclusion criteria that will make recruitment difficult. Sometimes, a separate meeting is held for the clinical research coordinators.

During the site initiation visit, the clinical research monitor usually provides the initial training for the clinical investigator and the clinical research coordinator. Training should continue throughout the study. If the clinical research site personnel need re-training, the monitor’s reports should indicate this finding. Only a few of the monitoring reports that the author has reviewed noted that a site needed training or re-training. The clinical research site personnel should know the relevant FDA regulations and the requirements of the REB, and they should have documents ready and staff available for an FDA inspection. Relevant FDA regulations include:

  • 21 CFR 50 (informed consent regulations)
  • 21 CFR 56 (IRB regulations)
  • 21 CFR 312 (Regulatory responsibilities of clinical investigators for drug studies)
  • 21 CFR 812 (Regulatory responsibilities of clinical investigators for device studies)

Documents that should be ready for inspection include the regulatory binders, the original source documents, correspondence, and case report forms (CRFs), some of which may be computer-based. Inspections in the United States can take as long as necessary; however, the FDA requires foreign inspections to be conducted within five working days. The clinical investigator, the sub-investigators, and the clinical research coordinator should be available during the inspection. The first thing that the FDA investigator does during an inspection is interview the site staff to determine whether the clinical investigator really signed the FDA Form 1572 and supervised the clinical trial.

Differences between Inspections in the United States and Canada

There are differences between inspections in the United States and Canada (Table 2). In the United States, the FDA investigator calls the clinical research site to arrange the inspection. In Canada, the FDA’s Division of Field Investigations arranges the date/time of the inspection and handles travel for the FDA investigator. Foreign inspections are usually done during the week from Monday through Friday.

In the United States, the FDA investigator presents his/her credentials and issues FDA Form 482, Notice of Inspection. In Canada, the FDA investigator only presents credentials.

In the United States, the inspection can take up to five weeks or as long as is needed. In Canada, the FDA investigator has a week to complete an inspection and, if necessary, issue an FDA Form 483.

FDA Form 1572 for Canadian Sites

FDA Form 1572 (Statement of Investigator) is a contract between the FDA and the clinical investigator. It states that the clinical investigator will:

  • Conduct the study according to the protocol
  • Personally conduct/supervise the study
  • Ensure proper consent and IRB review
  • Report adverse experiences
  • Read/understand the investigator’s brochure
  • Ensure associates know their obligations
  • Maintain adequate and accurate records
  • Ensure that the IRB complies with CFR 50 and 56 and does initial and continuing review
  • Promptly report to the IRB all changes in research activity

Under 21 CFR 312.120, the FDA will accept a well-designed and well-conducted foreign clinical study not conducted under an Investigational New Drug (IND) application as support for a marketing approval if the following conditions are met:

  • The study was conducted in accordance with good clinical practice (GCP). For the purposes of this section, GCP is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that ensures that the data and reported results are credible and accurate and that the rights, safety, and well-being of trial subjects is protected.
  • The FDA is able to validate the data from the study through an on-site inspection if the agency deems it necessary.
  • Supporting information is provided, including: Clinical investigator qualifications, description of the research facility, detailed summary of the protocol, and results of the study.

If the above criteria are met, Canadian clinical research sites may choose to not submit anFDA Form 1572.

FDA Legal Authority/Jurisdiction in Canada

Table 3 provides an overview of FDA legal authority in Canada. If an FDA investigator visits a clinical research site in Canada for an FDA inspection, he/she should have access to all of the clinical study records including the originals of the:

  • Source documents
  • Informed consent forms
  • REB approvals and correspondence
  • Investigational product records.

The FDA investigator also needs copies of everything that he/she collects from the clinical research site, which are called “exhibits.” Attachments are the FDA forms, and the exhibits are the records collected by the FDA investigator. Exhibits could include training records and serious adverse event reports.

The FDA also has the legal authority to issue Form FDA 483 and warning letters. About one-third of clinical research sites will not receive Form FDA 483 because there are no inspectional observations. About 40% of sites receive a Form FDA 483 with a few observations. A Form FDA 483 could result in a warning letter. Form FDA 483s are not public; however, warning letters are posted on the FDA’s website.

Other possible consequences of an inspection include debarment/disqualification of the investigator, invalidation of the study, delayed New Drug Application (NDA) approval, or disapproval of the study. The more prepared that the clinical research site is for an inspection and the more knowledgeable staff members are about the study, the better the inspection will go and the sooner the NDA will be approved.

If the FDA investigator performs an inspection and finds no problem, the inspection will be classified as NAI (No Action Indicated). If there are some problems, the inspection will be classified as VAI (Voluntary Action Indicated), where some voluntary corrections are necessary. OAI (Official Action Indicated) means that the FDA investigator found serious non-compliance requiring regulatory or administrative action.

If an inspection is classified OAI, the clinical research site will receive a warning letter within about a month of the conclusion of the inspection. A warning letter will be publicly available. The last paragraph of the warning letter states:

“Within fifteen (15) working days of your receipt of this letter, you should notify this office in writing of the actions you have taken or will be taking to prevent similar violations in the future. Failure to adequately and promptly explain the violations noted above may result in regulatory action without further notice.”

Experience in Conducting Inspections in Canada

An inspection in Canada is always pre-announced, which provides clinical research sites with time to prepare. The duration of an inspection is usually five working days; however, it can take less time. The study monitor (the sponsor’s representative) is usually present during inspections in Canada. In the United States, the monitor is not usually present during inspections.

In the author’s experience, clinical research sites in Canada are generally very friendly, even after receiving a FDA Form 483.

Differences between Health Canada and FDA Findings

There are some differences between Health Canada and FDA GCP findings (Table 3). In the United States, the most common deficiencies are:

  • Protocol deviations
  • Recordkeeping
  • IRB communications
  • Informed consent (e.g., the wrong date)
  • Lack of drug accountability (receipt, use, and return or destruction)
  • Adverse events.

In Canada, the most common deficiencies are:

  • Protocol deviations
  • Lack of qualification, training, and education of site personnel
  • Informed consent
  • Incomplete records
  • Lack of drug accountability
  • Medical care and decision issues
  • Labeling.

Examples of other findings in Canada that are not typically seen in the United States include:

“There was no written procedure available that outlined how informed consent was to be obtained from subjects considered for enrollment in clinical trials at the site.”

“There was no system in place to ensure that the laboratory equipment and refrigerators used to store blood samples would be subject to routine maintenance calibration.”

The following examples are from FDA Form 483s issued in Canada:

Example #1: “Source documents did not identify the individuals who collected them.”

Example #2: “Changes and cross-outs in the source documents were not identified to show who made the corrections.”

Example #3: “Changes to the case report forms (CRFs) were not documented to show who discovered the mistakes, such as the clinical research coordinator or the study monitor.” 

Example #4: “There were discrepancies between the CRFs and data listings (e.g., laboratory values and AEs).”                                                                     

The following examples are from FDA Form 483s issued in the United States:

Example #1: “Three of the subjects who entered into the study were ineligible due to their exclusion criteria.”

Example #2: “SAEs for 5 subjects were not reported to the sponsor or the IRB in a timely manner.” 

Example #3: “Protocol amendment # 2 was not submitted to the IRB for approval.”

Example #4: “There is no documentation of the return of the study drug to the sponsor.” 

The majority of FDA Form 483s issued for drug studies fall under 21 CFR 312.60. FDA Form 483s issued in both Canada and the United States have found:

“You failed to conduct the clinical investigations according to the investigational plans: 21 CFR 312.60.”

Conclusion

In the author’s view, site staff should try to ensure that during the inspection, the FDA investigator is comfortable and feels welcome. For example, a heated meeting room could be provided during the winter months and an air-conditioned meeting room could be provided during the summer months. The clinical investigator should visit with the FDA investigator each day during an inspection to determine whether the FDA investigator needed any additional assistance. This would demonstrate interest in the inspection. The clinical investigator and other study staff members should not argue with the FDA investigator. Staff members should document everything that takes place during an inspection including maintaining a telephone call log. Site staff should use “notes to the file” to explain mistakes or findings; however, those notes to file should not be excessive.


Table 1: Preparation of Canadian Sites for an FDA Inspection

  • Always be ready for an inspection
  • Training:
    • Investigators’ meeting
    • Clinical research coordinators’ meeting
    • Site initiation visit
    • Monitoring visits 
  • Knowledge:
    •  FDA regulations:
      •  21 CFR 50, 56, 312, and 812
    •  REB requirements
  •  Documents and staff: 
    • Regulatory binders
    • Source documents
    • CRFs
    • Staff available to assist the FDA investigator

Table 2: Inspection Differences between the United States and Canada

  • United States:
    • The FDA investigator arranges the inspection
    • The FDA investigator presents credentials and issues FDA Form 482 – Notice of Inspection
    • The inspection can take up to 5 weeks or as necessary
  • Canada:
    • Division of Field Investigations arranges the date/time of the inspection
    • FDA investigator presents credentials
    • The inspection is usually completed within five working days

Table 3: FDA Legal Authority in Canada

  • Inspections:
    • Access all of the clinical study records, including:
      • Source documents
      • Informed consent forms
      • REB submission, approval, and correspondence
      • Investigational product records
    • The FDA investigator may ask for copies of exhibits
  • Actions:
    • FDA investigator may issue Form FDA 483
    • FDA may follow up with
      • Warning letter
      • Debarment/Disqualification of investigator
      • Invalidation of the study
      • Delayed NDA approval or disapproval of the study

Leave a Reply

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.