Regulatory Focus™ > News Articles > 2020 > 1 > FDA, MHRA Officials Stress the Criticality of Data Integrity in Clinical Trials

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Posted 23 January 2020 | By Zachary Brennan 

FDA, MHRA Officials Stress the Criticality of Data Integrity in Clinical Trials

3031 As clinical trial methodologies and new technologies are deployed, data integrity and the safety of clinical trial participants remain at the forefront of regulatory oversight, officials from the US Food and Drug Administration (FDA) and the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) wrote in an article published this week in Clinical Pharmacology & Therapeutics.

International regulatory collaboration on good clinical practice (GCP) has become critical for adequate oversight and the assessment of data integrity because of the increasing numbers of clinical trial sites per study, their locations outside the regulatory agencies’ regions, the limited resources of such regulatory agencies and the accelerated timelines by which regulators have to review  marketing applications.

Back in October 2018, FDA and MHRA held their first joint GCP workshop to discuss these fundamentals, with the authors noting: “From these discussions, the importance of data integrity in clinical trials cannot be overstated.”

Data integrity has been an issue for even some of the largest biopharma companies, like Novartis, and has been the topic of recent guidance from the World Health Organization. Concerns about data integrity are also frequently mentioned in FDA warning letters (like this one, or this one).

Concerns with audit trails, blinding and data management were discussed in the recent article, in addition to sponsor oversight of electronic systems and electronic health records used at sites, electronic source data, protocol deviations and management of these deviations, and novel clinical trial designs and the challenges in ensuring the quality and reliability of study data. FDA and MHRA will hold another joint GCP workshop this year to further discuss these issues.

As an example of deficiencies with audit trails, the regulators explained how a clinical investigator inspection for a pivotal, randomized, double-blind, pharmacokinetic (PK) study, showed that the regulator’s review of the data listings in the clinical study report, as compared to source data, revealed that several study subjects appeared to have received opposite treatments (i.e., active drug instead of placebo), mixed treatments (i.e., active drug and placebo), or opposite dietary conditions (i.e., dosing under fed conditions instead of fasted conditions or vice versa) during the study.

“The agency consequently had significant concerns about the reliability of study data and communicated these concerns to the applicant,” the FDA and MHRA officials wrote, although review of the audit trails later verified that the correct treatment allocation and dosing under the correct dietary conditions occurred during the study.

In terms of blinding, the authors used the example of inspectors identifying a poorly designed interactive response technology (IRT) reporting system that resulted in unblinding.

“The IRT produced blinded and unblinded reports, and while access controls for the two reports were assigned and restricted to either blinded or unblinded study personnel, as appropriate, both reports contained IMP [investigational medicinal product] lot numbers which could be used to unblind the treatment assignment. A review of the system access logs also revealed that blinded study personnel had been able to access and view unblinded IRT reports,” the article says.

Inspectors have also regularly observed inappropriate unblinding due to inadequate data management, the authors further explain.
And although international collaboration is key to ensuring the safety of clinical trials, the authors also explain some of the differences among regulators.

“For example, a key difference is that EMA inspections are focused on GCP systems and processes in clinical trials and also grade each finding and cite ICH E6 (R2) on GCP noncompliance. FDA inspections, on the other hand, take an outcome-focused approach, focusing on data line listings to verify data provided in marketing applications and cite 21 Code of Federal Regulations (CFR). Additionally, FDA has a unique group of GCP and Bioavailability/Bioequivalence (BA/BE) reviewers who perform data reliability assessment based on inspectional findings from registration trials and convey the relevant findings to the assessors or reviewers in review divisions.”



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