This CP provides procedures for FDA investigators conducting domestic or international inspections of clinical components of in vivo bioavailability (BA) and bioequivalence (BE) studies conducted at clinical sites that recruit subjects, administer drug products to them, and collect biological samples for PK measurements.
Pharmacokinetic properties measured during BE and BA studies must comply with certain FDA requirements, which can be found in 21 CFR 320.
What is Bioavailability?
Bioavailability refers to the fraction of an administered drug that reaches systemic circulation after administration, providing a quantitative measure of drug absorption which can be measured through clinical trials of BA and BE studies and reported as the area under the concentration-time curve (AUC).
Age, gender, weight, disease state, diet, other medications, and nutritional status all play a part in how quickly and completely drugs are absorbed by patients. A properly conducted BA or BE study allows researchers to ensure these factors do not skew results toward subject variability; rather they should only reflect differences among drug products themselves.
Additionally, the chemical properties of a drug product can significantly impact its bioavailability. Some drugs may not dissolve well or absorb efficiently in the digestive tract due to high pKa values or hydrophobicity/polarity characteristics or low first-pass effect; such effects can often be mitigated through formulation changes like enteric coating or extended-release formulations – helping increase bioavailability for better absorption by patients.
Once a drug enters the bloodstream, its metabolism and excretion are subject to pharmacokinetic processes such as metabolism and excretion. These processes may reduce or prolong plasma drug concentration by forming drug complexes with protein molecules or chemical reactions such as gastric acid hydrolysis or digestion enzyme hydrolysis (eg, tetracycline and polyvalent metal ions); binding with other drugs in the intestinal tract (eg, cholestyramine); or binding to mucus membranes of the digestive tract (digoxin to cholestyramine).
The bioavailability of drugs is determined in part by their volume of distribution (Vd). A drug with a larger Vd can spread more widely throughout the body and reach organs where its therapeutic effects may have an impact.
BA and BE studies are performed to assess the degree of bioavailability and rate of absorption when comparing one pharmaceutical product with another that is similar in terms of dosing route, concentration-time profile, and clinical use. Bioequivalence determination occurs when AUCs of generic and reference products can essentially superimpose.
Giving nurses a deeper knowledge of BA/BE testing principles can facilitate safer and more effective medication administration. By including this knowledge in their training, nurses will feel more at ease interpreting the results of patient BA/BE studies to ensure that any prescribed doses are safe and efficacious.
How is Bioavailability Measured?
Bioavailability studies allow researchers to measure the rate and extent of drug absorption through oral routes, which allows them to compare various formulations of drugs, to determine whether they possess equivalent efficacy as their reference product. Results of bioavailability studies can also assist doctors and pharmacists when prescribing medications; for instance, physicians may wish to prescribe an antibiotic that quickly reaches its intended site of infection to prevent resistance formation while providing full therapeutic benefit.
An absorption rate for any drug can be measured by measuring its blood concentration at various time points following administration. Peak time refers to when plasma drug concentration reaches its maximum point – this indicates the rate of absorption; the area under the concentration-time curve (AUC) shows how much of that drug reaches systemic circulation over time and also provides insight into the rate of absorption.
PK analyses not only measure the speed and extent of drug absorption, but they can also reveal how a substance is distributed, metabolized, and excreted from the body. Bioavailability/bioequivalence studies are performed to assess the properties of both new and generic medications.
The design of clinical trials plays an essential role in establishing the parameters used to measure drug bioavailability. For example, trials that feature high intrasubject variability for any given parameter may necessitate multiple replicates and cross-over designs to ensure accurate comparisons.
Raptim’s specialized veterinary laboratory can conduct bioequivalence (BE) and BA/BE studies that comply with GLP and VICH-GCP guidelines for companion animals, providing pharmaceutical companies with essential trials when developing animal-derived medicines and vaccines for human use.
BA/BE studies can assist researchers in identifying potential issues with new drugs, including interactions between medications and safety concerns. Once completed, these studies can then be used to modify an existing formulation to enhance efficacy or administration and potentially decrease risks related to adverse reactions while increasing effectiveness and speeding the path toward the market.
What is Bioequivalence?
Bioequivalence between drug products refers to their similar in vivo bioavailability; that is, reaching therapeutic levels in similar amounts within the body. This measure typically uses geometric mean ratio (GMR) data with a 90% confidence interval derived from log-transformed log data for comparisons between them; however, the term can also refer to how fast or slow each product absorbs into your body or whether its peak blood levels reach quickly or slowly; or whether or not its elimination rate occurs quickly or slowly.
The FDA defines bioequivalence as “the extent to which a new pharmaceutical resembles an existing drug product in terms of absorption, distribution, metabolism, elimination, and clinical effect.” The FDA states that this does not imply that two drugs have equal efficacy or safety or that they can be interchanged.
Furthermore, bioequivalence requirements vary among dosage forms; thus ensuring there are sufficient bioequivalence assessments conducted for every dosage form.
Assuming a generic drug has the same bioavailability as its brand-name equivalent for tablets and capsules, usually only individual or population studies may be needed to establish its bioavailability. When dealing with other formulations such as time-release preparations, enteric-coated pills, or intramuscular injections it may require further investigations.
Bioequivalence studies should ideally involve volunteers of both genders aged 18 years or over who volunteer to take part, to ensure results that apply to the general population.
When selecting volunteers for participation, other factors such as stress, blood loss, and chronic disease state effects as well as medications or special diets might influence within-subject variability and lead to non-comparable results that need to be considered in selecting volunteers for participation in bioequivalence studies.
The United States uses average bioequivalence as the criteria for new formulations or additional strengths of approved drugs, and manufacturers must prove them before filing an ANDA with the FDA. In New Zealand, Medsafe must approve new forms of existing brand name drugs – this can include modified forms like stronger tablets with different flavors/coloring or new dosage formats like intramuscular injections.
How is Bioequivalence Measured?
To gain an understanding of how bioequivalence is measured, we must first investigate PK (pharmacokinetics), which explores how drugs enter, move through, change in their body, and eventually exit our bodies – these processes typically being separated into absorption, distribution, and metabolism categories.
An important aspect of PK is establishing the rate at which drugs enter and are absorbed into the body, with parameters like AUC (area under concentration-time curve) and Cmax being useful indicators of this process.
To achieve these measurements, clinical trials are carried out under controlled circumstances in a clinical environment. Study designs may include the single ascending dose (SAD), multiple ascending doses (MAD), drug-drug interaction studies, or random assignment to one of two groups and administration of either new drug vs old drug as a comparison tool between the performance of new vs placebo/control drugs.
Regulatory expectations have become more relaxed when it comes to BA/BE studies for drugs with high within-subject variability and wide therapeutic windows (Class D, highly variable drugs). When testing drugs that meet this profile, scaled average bioequivalence studies may be performed, which measure any significant difference in the rate or extent to which the drug becomes available at its target site after administration at similar molar dose levels and conditions.
BE/BA studies can be used to guide dosage adjustments, reformulations, and regulatory approval decisions – ultimately impacting product quality and efficacy approval by the FDA.
BE/BA studies can also assist when switching over from a marketed drug to generic alternatives; BE/BA will ensure the generic is safe and effective at treating the same disease, while for orally administered drugs the BE/BA studies determine their rate and extent of absorption into the bloodstream as well as duration.
BA BE studies require investigators to select individuals who are representative of the general population in terms of age, sex, and race. Furthermore, BE/BE measures must be logarithmically transformed before statistical analysis; sponsors are advised to select an adjustment that meets this criterion, and this should be stated explicitly within both clinical trial protocols and statistical analysis plans (SAPs). Raptim has established a contract research organization that conducts BE/BA studies compliant with GLP and VICH-GCP regulations.