The FDA’s 2004 guidance document on the handling and retention of testing samples for bioavailability and bioequivalence studies has a broad scope. The recommendations in this document apply to:

•       Contract Research Organizations (CROs)
•       Drug Manufacturers and/or Their Sponsors
•       Site Management Organizations (SMOs)
•       Clinical Investigators
•       Independent Third Parties with reference to the Handling of Reserve Samples from relevant bioavailability of drugs studies

The purpose of this document is to clarify the responsibilities of each of the agencies/individuals mentioned above with reference to maintaining the Final Rule of 1993 on the retention of testing samples.

The Document Proposes Corrective Measures

The FDA’s Division of Scientific Investigations (DSI) and field investigators from the Office of the Regulatory Affairs conduct inspection visits to the sites where drug manufacturers and/or their sponsors conduct bioavailability and bioequivalence studies.

Some lapses discovered during such inspections:

•       Testing sites do not have reserve samples.
•       Testing sites often return the reserve samples to the drug manufacturers and/or their sponsors. That violates the regulations specified in 21 CFR 320.38 and 320.63.
•       Sometimes drug manufacturers and/or their sponsors, or SMOs, or contract packaging facilities determine the study test article and the reference standard for each subject. Testing facilities cannot then randomly select any sample from the supply of reserve samples.
•       Another of DSI’s findings is that such deviations from regulatory compliance happen more often with bioequivalence studies involving pharmacodynamic endpoints. Such studies are usually blinded studies conducted by contracted parties at multiple sites.
•       Some clinical investigators mistakenly believe that they do not need to retain reserve samples as they are not CROs.

This guidance document seeks to clarify responsibilities to ensure that such regulatory noncompliance does not happen.

The Proposed Corrective Measures

•       Reserve samples should always be preserved at testing facilities.
•       Drug manufacturers and/or their sponsors must supply the test material and the reference standard in a manner that allows the testing facility to randomly select one test material and one reference standard and preserve the rest as reserve samples.
•       The FDA stresses that it is incorrect to supply study medications in unit-dose packaging while the reserve samples get supplied in bulk containers.
•       In the case of a blinded study, the drug manufacturer/sponsor should also supply a sealed code for blinded studies, which should remain at the testing facilities. This is necessary for the FDA to break the code if necessary.
•       In the case of receiving multiple shipments of the same test material and the same reference standard for multiple studies, the testing facility should retain one reserve sample of the test article and one of the reference standard from each shipment.
•       The quantity of the test material and the reference standard preserved as reserve samples should be enough for the testing facility to be able to conduct all the bioavailability studies and all the bioequivalence studies five times.
•       Whichever type of testing facility be used for a bioavailability study and a bioequivalence study for a generic or a new drug application, the reserve samples must always remain at the testing facility.
•       If a drug manufacturer/sponsor recruits an SMO for contracting clinical investigators to conduct multiple bioavailability studies and bioequivalence studies for the same test material, the same recommendations apply to the SMO.
•       The recommendations about the reserve samples apply to in vitro BE studies also.
•       For inhalant products, five times the testing quantity and five times the reference standard do not need to be maintained. It is sufficient to maintain 50 units of each as reserve samples.

Final Note

Though an FDA guidance document is not legally binding, this one is an exception. The proposed measures here are to ensure regulatory compliance. The weight of this document is greater than other similar documents, therefore.

The FDA has emphasized this in a 2016 notification.