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Bioequivalence Inspection


November 2017

Bioequivalence Inspection

Nothing makes your morning coffee turn colder faster than when you’re informed the FDA is at the door for a “for-cause” inspection. Invariably, this type of inspection is a self-inflicted wound caused by scientific misconduct, human subject testing violations, or compromised bioequivalence data related to bridging studies for a change in formulation or manufacturing process or a submission of an ANDA for generic products.

For-Cause Inspections in Bioequivalence (BE) Studies

Demonstrating bioequivalence in a trial is crucial to the approval of certain drugs. The studies conducted to establish this bioequivalence are submitted by a drug’s sponsor to the FDA’s Center for Drug Evaluation and Research, or CDER. The standard by which BE is measured is its pharmacokinetic similarity to the reference-listed drug (RLD). Bioequivalence is the absence of a significant difference in the rate and extent to which a compound is available at the site of drug action when administered at the same dose under similar conditions in an appropriately designed study.

Bioequivalence data are assessed in various ways, such as pharmacokinetic study design, bioanalytical methodology, clinical study reports, statistical analysis, and in vitro dissolution testing. The FDA reviews these data, noting any and all deficiencies. If the FDA finds evidence of deficiencies within these areas of the study, a for-cause inspection may be issued. Particularly, the OSI’s investigation seeks to ensure that a sponsor’s trial is compliant with Title 21 of the Code of Federal Regulations.

Specific Reasons the FDA Conducts a For-Cause Investigation

According to findings in an article published by The American Association of Pharmaceutical Scientists (AAPS), the FDA may request a for-cause inspection for myriad reasons. The most common among them being:

Integrity and Validity of Submitted Data

The most commonly reported reason for a for-cause investigation starts with the actual data submitted in the study. There are a number of factors that can contribute to a study being flagged, including data biases, conflicting information about the trial from other FDA sources, any deviations from expected protocols, lack of method validation, and any information deemed conflicting or missing.

According to the aforementioned findings. bBetween 2003 and 2011, 55 of 91 for-cause BE inspection requests were the result of the study’s data. The fact that so many bioequivalence studies are flagged for their initial data underlines the importance of its accuracy.

Too Many Re-Analyzed Samples

The second most-common reason for a for-cause study stems from the integrity of the analyzed samples. If, for example, the FDA discovers an inappropriately high amount of sample analysis repeated throughout the initial trial, they will inevitably require additional documentation justifying the high number of repeat sample analysis. As FDA data on the number of for-cause studies resulting from these incidences suggests, this required documentation is seldom included. While only 7% of analyzed studies failed to provide the required documentation for their large number samples, it is important to remember that this is something the FDA scrutinizes.

Previous Inspections of Test Site

If the test site listed on a sponsor’s bioequivalence study has a history of negative findings or previous for-cause investigations, chances are that the FDA will pay closer attention to a sponsor’s study.

This reason underscores the importance of a reputable and proven clinical CRO to manage the study site. The FDA understands that clinical CROs and locations with a clean record are more likely to continue this trend in future bioequivalence studies. Furthermore, the sponsor of a clinical trial must ensure that the CRO follows standard operating procedures for clinical trials and the guidelines established for current Good Clinical Practices in such documents as “Integrated Addendum To Ich E6(R1): Guideline For Good Clinical Practice E6 (R2).

Missing or Inaccurate Documentation

In tandem with the quality of submitted data and documentation, any missing data or documentation is clear indicator to the FDA that further inspection may be required. Furthermore, any documentation the FDA suspects to be inaccurate in any way may also lead to a for-cause inspection.

It is rather self-explanatory, but if the FDA has reason to believe that a sponsor’s submitted bioequivalence study is anything less than forthright, it calls the entire trial’s integrity into question. Quality assurance is important at every stage of a clinical trial, but any documentation reviewed by the FDA needs special attention.

Issues with the Study’s Overall Design or Conduct

The final reason the FDA may decide to conduct a for-cause investigation of a bioequivalence study is perhaps the most open-ended. This issue calls into question the very manner in which a study is approached and conducted. Examples of this may include the number of control test subjects in a sponsor’s study or even the overall efficacy of a sponsor’s quality assurance program.

Reduce the Risk of a For-Cause Investigation with InClinica

With decades of combined experience with bioequivalence studies, the InClinica team understands the important facets and reasons that might lead to a for-cause investigation by any regulatory authority. More important, InClinica’s quality assurance team works tirelessly to ensure that every aspect of a sponsor’s drug study is FDA-compliant and eligible to proceed to future phases of testing.

Learn more about the InClinica Difference or contact us to start your drug’s bioequivalence study the right way.