With 483s from a key set of human clinical study inspections, we used the Redica Systems Expert Model for GCP to show how many inspector observations involving “Responsibilities of the Investigator” fit into several useful subcategories that provide actionable insight for your operations.

“Responsibilities of the investigator” was the largest major category of observations in 483s issued to clinical investigators (CIs) of human clinical studies over the past 20 years.

The second most common type of observation in this key dataset involved “data integrity,” a subject covered in the previous article in this series, “Data Integrity and Your Clinical Investigator: What the Data Shows.”

Redica Systems Senior GMP Quality Expert Jerry Chapman presented our breakdown of “Responsibilities of the Investigator” observations in his April 6 presentation, “Evaluating Clinical Study Deficiencies Found During Inspection Using AI,” at the 2022 Society of Quality Assurance Annual Meeting. The third article in this series will address the results of applying our GCP Expert Model to Warning Letters, and how that result differed from our findings in 483s.

[Related: For more on identifying trends in FDA GCP inspections, download a recording of a webinar featuring Redica Systems Senior GMP Quality Expert Jerry Chapman.]

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Why Did We Choose this Dataset?

We gave this dataset priority because it is fairly representative. According to FDA deficiency statistics, inspections of CIs from 2016-2021 account for about 75% of BIMO inspections. Including inspections of institutional review boards (IRBs) in that total accounts for about 87%. This is why we focused our first GCP expert models on these two areas. The remainder of BIMO inspections were concentrated on sponsors/contract research organizations (CROs)/sponsor investigators. (Note: Our analysis omits GLP, BA/BE, PADE, and REMS inspections.)

GCP Inspection Landscape

Focusing on inspections of CIs, far more of these BIMO inspections (in data covering 2017-2021) resulted in 483s than in Warning Letters; about one-third resulted in 483s, with Warning Letters at fewer than one in 100. And it should also come as no surprise that the No. 1 observation in 483s overall— beyond just CI inspections—is always 21 CFR 312.60, “protocol compliance.”

Our GCP Expert Model supplies the detail behind that broad “protocol compliance” category, showing which aspects of protocol compliance deserve your focused attention because they are often found deficient.

What is truly important is the content of the observations, not the number of observations—though industry lore often gets it backward

How Redica Systems Extracts Crucial Detail

With more than 50,000 unique 483s, 483 Responses, and Establishment Inspection Reports (EIRs), and more, Redica Systems has more publicly available enforcement documents than any other non-governmental entity. Our GXP subject-matter experts, such as Jerry Chapman, build proprietary expert models for each GXP area with the help of dozens of data scientists and engineers. With these GXP Expert Models, a computer algorithm analyzes documents as a human expert would.

To do this, we use optical character recognition to make every document—PDFs included—text-searchable, and we carefully proofread them all. Finally, we parse the text based on logical document sections—each section serves specific functions and features specific language and other properties. Along with properly directing the algorithm’s search, this careful parsing is crucial for avoiding misleading results. Only then are the documents available for analysis.

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“Responsibilities of the Investigator” in Our 483 Dataset

Our dataset includes more than 1,200 483s issued to CIs over the past 20 years, which amounts to about 6,700 pages and 2.7 million words.

As we turn our model to this dataset, what do we see?

Our Expert Model for GCP found that nearly 1,000 of these 483s had issues that could be broadly categorized as “responsibilities of the investigator.” It is the largest category by far.

FDA 483 analysis
“Responsibilities of the Investigator” was the largest major category of observation, followed by “Data Integrity” and “Informed Consent.”

Breaking Down “Responsibilities of the Investigator”

We classified observations involving “responsibilities of the investigator” into several major subcategories, then used our GCP Expert Model to see how many of each—and what share of each—existed in a 20-year set of CI 483s. As shown in the figure below, our model categorized 483s into six neat categories of observations, with the three largest categories accounting for nearly 90% of the total:

Responsibilities of the Clinical Investigator
  • General Responsibilities Under §312.60 — Conducted according to investigational plan, otherwise known as protocol compliance
  • General Responsibilities Under §312.60— Three small subcategories not overlapping with protocol compliance
  • Assurance of IRB Review
  • Investigator Record-keeping and Record Retention — Case histories
  • Investigator Record-keeping and Record Retention — Disposition of drug during study
  • Investigator Record-keeping and Record Retention — Miscellaneous
  • Investigator Reports — Financial Disclosure Reports

A Further Breakdown of Protocol Compliance Observations

It is probably no surprise that protocol compliance, otherwise known as “conducted according to investigational plan,” is at the top—it is nearly always the number one observation in 483s.

Would it not be helpful to know the specific protocol violations noted under §312.60?

But what is behind those protocol compliance observations? The Redica Systems Expert Model for GCP breaks it down into six valuable subcategories of §312.60 citations based on our model:

  • Dosing Issue — Incorrect dose or administration
  • Inclusion/exclusion Criteria — Not including or excluding subjects according to pre-determined criteria
  • PI Personal Attention — Problems related to oversight of the principal investigator
  • Lab Issue — Failure to conduct labs on time or to read labs at the right time
  • Assessment Issue — Inappropriately conducted assessments of different types
  • Adverse Event Reporting
FDA 483 Analysis Not According to Plan
Actual, useful subcategories of §312.60 observations showing where you can focus your attention at your own site.

The largest subcategory within protocol compliance observations concerns subject inclusion/exclusion criteria, followed by four other categories in roughly equivalent shares: aspects of dosing, adverse event reporting, lab issues, and assessment issues.

However, these are the general areas where we recommend focussing your attention in operations. These are the areas where the FDA is finding the most issues on inspection—they are the best places to make sure that your site does not have gaps.

But this is not the only way that Redica Systems can help.

How Redica Systems Can Help You

Our models show what the FDA is looking for, and the deficiencies it finds — not just at a high level of detail, but at an actionable level of detail.

And our clients can go beyond seeing observations at a macro level. They can trace them back to specific Warning Letters and specific 483s, giving them a great deal of utility when it comes to due diligence. For example, this utility includes gaining insight into their own operational deficiencies and those of company partners and contract organizations.

Here is how Redica Systems Expert Models for GXP can help you:

  • Vendor Quality — Intelligence to identify and control risk with your critical GLP, GCP, GDP, and GMP vendors

Study startup and ongoing vendor monitoring that draws from full regulatory histories on GLP and GCP vendors.

Strategic inspection preparation based on current inspection findings at your sites and others. Find trends in the data to identify where to focus your attention.

Tactical inspection preparation using complete FDA investigator profiles. What do they tend to look for? What do they tend to find?

Did you miss Part I? Read it here. Part III of this article series provides further insights and conclusions from Jerry Chapman’s SQA presentation.

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