Bioequivalence (BE) studies play an integral part in drug development and reduce costs, but sometimes the trials fail for various reasons.
Traditional power calculations for BE trials rely on fixed values of the expected log(T/R) ratio th. We propose an assurance concept utilizing the standard deviation of the distribution of potential values to quantify uncertainty.
Background
Establishing the bioavailability (BA) of a drug product is an integral component of drug development and should inform dosage adjustments, reformulations and regulatory decisions. BA/BE studies are also integral parts of FDA evaluation of INDs, NDAs, and supplements to ascertain whether new products are safe and effective for their intended indications.
BA/BE studies are required of all orally administered drugs and may be conducted either under fasting or fed conditions. These studies measure the rate and extent of drug absorption from the GI tract to the bloodstream, providing insight into how much medication reaches systemic circulation.
Recently, there has been significant dialogue about the purpose and methods for BA/BE testing and which methods should be used to differentiate pharmacokinetic profiles appropriately. There are two fundamental perspectives regarding this matter; 1) using BE investigations as surrogates for clinical trials that assess therapeutic equivalence; and 2) BE investigations must provide methods and conditions which reliably detect differences in formulation performance.
Public comments on whether or not to continue relying on individual criterion testing of BE/BEE fell into four general categories. They included justification for individual criteria (absence of evidence that subject-formulation interactions are clinically significant); burden associated with replicate study designs (recruitment costs, institutional review board restrictions and capacity issues; increased monitoring for adverse events; delays; increased monitoring for drug exposure etc); justification for an individual criterion and drug exposure considerations).
(3) concerns over the accuracy of reference-scaling BE criteria for highly variable drugs; and (4) various issues (aggregate vs. disaggregate BE criterion, discontinuity and mean/variance trade-off). Based on these comments received, the FDA has decided to utilize replicate study designs for all orally administered modified-release drugs; with the exception to products that demonstrate low within-subject variability with a wide therapeutic window.
Food Effect and Feed BE studies should test the maximum strength of any drug product that is intended to be commercialized; however, clinical safety considerations may prevent its use, necessitating testing at lower strengths instead.
Methods
A BA/BE study is a clinical trial designed to test the rate and extent of drug absorption. This can be accomplished in various ways, but typically involves administering medication to healthy volunteers or patients and monitoring how much of it enters their blood over time – this results in a plasma concentration-time curve that provides information on drug exposure rates; this information can then be used in clinical safety and efficacy trials as well as to create dosage instructions.
BA/BE studies are an integral part of drug development. They allow researchers to detect any issues that could cause adverse reactions or hinder its performance and address them accordingly, for instance, reformulated medications might need to reduce side effect risks or make taking it simpler; this practice is prevalent throughout the pharmaceutical industry and many medications change this process.
There has been much discussion and disagreement regarding how best to conduct BA/BE studies, with differing viewpoints regarding subject selection and pharmacokinetic measures. Some regulatory bodies prefer single drug administration because this provides maximum sensitivity for comparing pharmacokinetic profiles while other recommendations advocate conducting studies under steady-state conditions that more closely reflect clinical settings.
FDA’s recent guidance details various approaches that can be taken to establish or measure BA for orally administered drugs. These approaches include:
Replicate BE studies, in which both drugs are given to multiple groups of subjects and an average BE is calculated, is preferred by some regulators but can be difficult to implement due to cost and burden considerations of replicate study designs. Therefore, the advisory committee suggested an individual BE criterion be made available for sponsors that allow market access in compelling circumstances.
The guidance further advises sponsors that BE measures be log-transformed for ease of analysis using standard statistical techniques. A common or natural log may be selected; it’s up to each sponsor to decide on an acceptable log value. It should also be remembered that performing additional tests to gauge whether BE results are normal can introduce bias into estimates and estimates should not be done without proper consideration and risk being incorrect.
Results
BA/BE studies provide essential information about the absorption of drugs. With this knowledge comes decisions regarding dosage changes, reformulations and regulatory approval decisions; furthermore, the results from these studies can also aid patient outcomes by assuring they receive their necessary dose of medication. Furthermore, these studies can identify any interactions or potential adverse reactions that might impact treatment – leading manufacturers to revamp the formulation of said drug to lower risks while increasing efficacy.
An BE study is a randomized and controlled trial wherein a generic drug is compared with its reference product in an attempt to demonstrate bioequivalence. Volunteers receive one or more doses of each of both products with an interval between doses for washout. Blood samples are taken at various intervals during which their pharmacokinetic parameters (PKs) are assessed in order to measure the bioequivalence of each. Eventually, BE study results determine if generics can truly compete against reference products regarding efficacy and bioequivalence.
Measures used to assess PK parameters during BE clinical trials can vary widely, but some basic guidelines must be observed to ensure accurate and reliable data. First, BE measures must be consistently log-transformed; sponsors should select either natural log or common log transformation as stated in their clinical study protocol. Furthermore, statistical analyses on original data should be avoided with appropriate justification provided.
As part of their evaluation of BE, sponsors should make sure that both products undergo similar dosage and administration methods during clinical trials to establish BE. In particular, sponsors should ensure that any controlled-release formulations undergo identical release rates between test and reference products.
Since 2000, regulatory authorities and scientific communities have made impressive strides toward standardizing approaches to BE assessment. This standardization has led to rapid generic drug development as well as better access to affordable healthcare for many patients. Furthermore, efforts are ongoing to develop more efficient and scientifically sound BE assessment methods for challenging special dosage forms.
Conclusions
BA/BE studies in clinical trials are an integral part of drug development, providing invaluable data that inform dosage adjustments and reformulation decisions. They can also be used to compare generic medicines against their original brand-name equivalents in terms of safety and efficacy.
To determine bioavailability and bioequivalence, a drug must first be given to healthy volunteers or patients, and its concentration measured over time; these results will then be compared with that of its reference drug at that same point and time point under similar conditions.
FDA guidance suggests that BE measures be log-transformed before statistical analysis to ensure consistent analysis. Either a common or natural log should be chosen, which must remain constant across the study.
Sponsors do not need to test for normality after log transformation but this decision must be documented in their clinical trial protocol and statistical analysis plan (SAP). For highly variable experimental drugs with within-subject variability exceeding 30%, replicate cross-over design trials may be utilized to satisfy regulatory requirements.