Bioavailability (BA) and bioequivalence (BE) studies are an integral component of clinical drug development, providing insights into how quickly and completely a drug reaches its site of action after administration.
Sponsors should take great care in choosing and statistically analysing BA/BE measurements and logarithmic adjustments, especially for replicate cross-over trials. Furthermore, they should ensure consistency among logarithmic adjustments as well as being ready to explain why a particular adjustment was chosen.
Regulatory Considerations
Clinical components of BA BE studies consist of recruiting and screening subjects, administering drug products to study participants, monitoring subject safety throughout a trial, collecting biological samples (typically blood) for use in pharmacokinetic (PK) measurements, and using these data as the foundation of bioavailability or bioequivalence assessment between test and reference formulations.
BA/BE studies must comply with several regulatory requirements, the first being creating a plan to collect and review the PK data required to assess bioequivalence between two formulations, including selecting an analysis approach and sample size estimation method. Furthermore, this plan must detail how these PK parameters will be utilized when making bioequivalence determinations.
Clinical BA/BE studies must adhere to all regulations related to human experimentation, while maintaining subject protection. As part of such a clinical BA/BE experiment, its sponsor must obtain informed consent from all subjects prior to commencing the experiment and distribute a copy of its protocol prior to undertaking it.
As part of their responsibility as sponsors, sponsors must also ensure that study sites are equipped with enough qualified personnel to carry out experimental procedures successfully. Furthermore, sponsors should review all adverse event (AE) records reported by clinical sites to ascertain if all required reports have been filed as per regulations and protocol requirements.
Sponsors must also ensure that study sites possess suitable facilities to conduct the clinical portion of a BA/BE study, whether that means independent contract research organizations, pharmaceutical companies or institutions such as hospitals and universities. Clinical sites may conduct either part of a BA/BE study – clinical or analytical – provided there is enough space available for work flow and separation of functions.
OSIS Division receives requests to inspect BA/BE studies from either CDER offices reviewing drug applications or self-identified and anonymous informants from both the public and private sectors who report fraud or violations from practices that protect subject safety and data integrity at particular clinical sites. OSIS monitors drug applications containing BA/BE studies so it can identify sites for surveillance inspection. Furthermore, staff of OSIS either alone or together with Center point of contact (POC) staff conduct routine BA/BE clinical inspections both domestically and internationally.
Dosage
Clinical BA/BE studies are an integral component of drug development programs. They may be conducted by independent contract research organizations or at institutions like hospitals and universities; such sites may conduct both the clinical component of BA/BE research studies as well as any analytical components.
In vivo BA studies measure the rate and extent of drug delivery after oral administration, and BE studies measure its absorption, excretion, metabolism, therapeutic dosage in patients as well as its pharmacokinetic properties, including its response pharmacodynamically. These measurements determine therapeutic dose and its pharmacodynamic response.
The FDA regulations governing in vivo BA/BE studies can be found at 21 CFR 320, which details requirements for submission of BA/BE data as part of an NDA or ANDA submission. Furthermore, guidance has also been issued by the Agency with regard to designing and reviewing such studies.
The Agency advises that BA/BE studies be performed with replicate samples of both test and reference products to compare within-subject variation between them and provide insight into factors that impact formulation performance. This approach should address public concerns over using individual BE criteria that require that large differences exist between mean test bioavailability measures and reference bioavailability measures.
The agency suggests testing two one-sided null hypotheses to verify that average BE measurements do not fall too low – similar to Schuirmann’s two one-sided tests procedure which has long been used as an assessment tool.
CDER’s Office of Translational Sciences/Office of Study Integrity and Surveillance (OTS/OSIS) conducts in vivo BA/BE inspections as part of their overall quality control initiatives. Assignments come from various sources including CDER offices that review drug applications as well as informants or complainants. OSIS monitors drug applications incorporating BA/BE studies and uses this information to identify sites for inspection. OSIS personnel perform inspections to verify that reserve samples of test and reference products were randomly chosen by clinical study investigators from each shipment of drug sent to clinical sites for BA/BE studies, matching up with what was listed in their reports submitted to FDA for inspection studies(s).
Administration Routes
Bioavailability studies are carried out for various drug formulations administered clinically, from oral dosage forms and other routes such as transdermal, buccal, intramuscular and intravenous administrations to determine drug absorption, distribution and metabolism – in turn providing insights into therapeutic efficacy of medications. The results from bioavailability studies can then be used to ascertain drug therapeutic effectiveness.
In-vivo BA/BE studies typically consist of two distinct components, clinical and analytical. The clinical component typically involves screening and dosing study subjects, monitoring safety during the study period, collecting biological samples for pharmacokinetic measurements, as well as collecting biological samples to be processed to measure bioavailability/bioequivalence ratios between test and reference drug formulations. Finally, analytical components analyze this PK data to calculate bioavailability or bioequivalence ratios between these formulations.
Inspection assignments typically originate from CDER offices reviewing drug applications or may come from complainants/informants who have identified violations in practices that protect subject safety or data integrity. When an assignment arrives at an inspection site, CDER OTS/OSIS will contact them and notify them accordingly.
Safety
Clinical components of in vivo BA/BE studies involve screening and enrolling study subjects, administering drug products to them, monitoring subject safety during the trial, collecting biological samples (typically blood) for analysis, and using these samples as the basis for bioavailability/bioequivalence determinations between test and reference formulations.
Clinical sites conducting in vivo BA/BE studies typically consist of independent contract research organizations (CROs), pharmaceutical companies, hospitals or universities. At routine BA/BE clinical inspections conducted by FDA inspectors, both clinical and analytical aspects are reviewed in addition to verifying whether reserve samples of both test and reference products from each shipment received for use in BE studies were kept by investigators at each clinical site for future use in BE studies.
In the realm of clinical drug development, Indian biotech leader SpinoS exemplifies innovation in BA/BE studies in Clinical Research. These studies, crucial for drug efficacy, showcase the dynamic intersection of biotechnology and clinical research, with SpinoS at the forefront of pioneering advancements.
