A Look at the FDA's Report on Top Clinical Trial Site Violations

Posted by Paddy Wall on Feb 15, 2021 3:32:45 PM

The following is an excerpt from our eBook ‘How to Improve Site Compliance’. Click here to read the full eBook.


The FDA inspects clinical trial sites and produces warning letters for violations found. The US Food and Drug Administration (FDA) annually reports the top most commonly cited violations in clinical trials through their Bioresearch Monitoring (BIMO) program. Let’s take a look at some of the most common.


Failure to Follow the Investigational Plan

Failure to follow the investigational plan has been consistently the top site violation for several years. The FDA categorizes this by the code 21 CFR 312.60, which includes general responsibilities of safeguarding human health by sponsors and investigators.

  • Maintenance and handling of study site binders: a site binder, a collection of hard copy documents in a physical binder at a busy site with many site staff conducting patient visits, might be difficult to keep updated and easily accessible. Even the protocol can be physically cumbersome – often with 100-200 pages of information for a typical study. Site staff will often create short “cheat sheets” to help them through patient visits. This strategy results in documents that the sponsor has not approved and does not control. Even if these cheat sheets are a true reflection of the protocol, there is no guarantee that if a protocol is updated mid-study that the cheat sheet will get a similar update.
  • Protocol updates are often sent by email or regular mail and sites may not receive them for any number of reasons. This can lead to many issues – for example, if a site does not receive an update the staff may continue to conduct patient visits using the outdated protocol.
  • Failure to maintain case history records is categorized by the FDA as code 21 CFR 312.62. An example of this violation might be a subject record missing data like weight, blood sugar levels, or other information relevant to the study. With the sheer amount of patient data that needs to be collected for a typical trial, one can see how sites might be at risk for this violation.

A possible solution to help avoid these top violations? Provide your sites with a central study hub and sponsor-controlled cheat sheets. These can provide a one-stop shop for clinical sites, along with an associated audit trail in case of inspection. They can go a long way toward helping sites stay on the investigational plan.


Inadequate Drug Distribution Records

Inadequate drug distribution records comprise 6% of protocol violations and can affect nearly every aspect of a clinical trial. The FDA categorizes this failure as 21 CFR 312.62, the same as case history records, relating to the record-keeping of the use and distribution of a drug used in a trial. Violations in this category also include deficiency or neglect in the records for receipts, preparation, use, and nature of the investigational drug.


Informed Consent Issues

Informed consent violations can be mitigated and prevented with a full understanding of informed consent requirements. To begin with, informed consent is not a form; it is a process with the key word being ‘informed.’ It’s about a set of activities, including various forms of patient education, to ensure that a participant understands the requirements of the study.

Informed consent incorporates the following key information elements:

  • A statement that the project is for research purposes and that participation is voluntary
  • A summary of research purpose, procedures, and duration
  • A list of any potential risks or discomforts
  • Reasonable expected benefits
  • Alternative course(s) of treatment, if applicable

Best practice templates can be found on the National Center for Complementary and Integrative Health (NCCIH) Clinical Research Toolbox. On this site, you can also find guidance on version control – because informed consent must conform to version control standards – as is the case for all essential study documents.


Other Top Violations

Other top site violations reported by the FDA are General responsibilities of sponsors and Insufficient IRB meeting minutes, both of which are general categories that deal with sponsor and investigator accountability on a clinical trial.

Protocol violations and deviations defined

Now let’s look at violations that are specific to the study protocol, as these also affect site compliance.

Protocol violations are any changes made to the protocol of a research study that have not received prior approval by the IRB. Examples may include:

  • Inadequate informed consent
  • Study inclusion/exclusion criteria not met
  • Unreported adverse events
  • Investigative drug issues, such as use of prohibited medication
  • Missing tests or mishandled samples
  • Study personnel intentionally deviated from study protocol, Good Clinical Practice (GCP), or regulations
  • Repeated non-compliance issues by study participant including missed visits

Protocol violations are categorized as Major (reportable) or Minor (not reportable). The criteria for Major violations are:

  1. The violation has harmed, or posed a significant or substantive risk of harm, to the research participant.
  2. The violation resulted in a change to the participant’s clinical or emotional condition or status.
  3. The violation has damaged the scientific completeness or soundness of the data collected for the study.
  4. The violation is evidence of willful or knowing misconduct on the part of the investigator(s).
  5. The violation involves serious or continuing non-compliance with federal, state, or local regulations.

Minor violations, or deviations, are any unapproved changes in the research study design and/or procedures that are within the investigator’s control and not in accordance with the approved protocol that do not have a major impact on either the participant’s rights, safety, or well-being, or the completeness, accuracy, and reliability of the study data. An example of a deviation may be that the study participant did not return for a scheduled study visit or a participant refused a blood draw.

Although deviations are a non-reportable offense, they are still defined as unplanned changes to protocol:

  • They are less serious non-compliance instances that don’t necessarily make a patient ineligible.
  • They occur when, without significant consequences, the activities during a study diverge from the IRB-approved protocol, e.g., missing a visit window because the subject is traveling.
  • They are not considered to be as serious as a protocol violation.

The above is an excerpt from our eBook ‘How to Improve Site Compliance’. Click here to read the full eBook.

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Topics: patient engagement, Clinical trial process, Clinical trial protocols, Inspection

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