Clinical trials enable researchers to uncover which medical approaches are safe and effective for their patients, helping individuals make more informed choices regarding their health.
BA/BE studies are part of pharmacokinetic (PK) research, which examines how drugs enter, travel through, and leave the body. As an integral component of drug development, these studies must be carefully planned out.
What is a Bioavailability/Bioequivalence (BA/BE) Study?
Bioavailability/Bioequivalence (BA/BE) tests are one of the cornerstones of drug development. They determine how much medication reaches bloodstream and becomes effective; in addition to being part of generic approval processes. Each regulatory agency has their own set of requirements when conducting BE/BA testing; however, there are a few basic standards which must be fulfilled to guarantee successful testing results.
Be studies typically involve healthy adult volunteers or patients receiving two products at once under controlled conditions: either the test product and its reference product are administered simultaneously under standardized conditions and then their rate and extent of absorption into systemic circulation and availability at their site of action are compared. A drug can be considered bioequivalent if its 90% confidence intervals for geometric mean ratios Cmax:AUC0-t between test and reference products fall within an acceptable range between 80-125%.
BE testing may be less stringent for drugs with broad therapeutic windows, such as digoxin or phenytoin, when their therapeutic index is sufficiently narrow; in these instances, the FDA has implemented an alternative procedure known as scaled average bioequivalence. This approach assumes that within-subject variability associated with the pharmacokinetic response exceeds between-subject variability as well as careful dose titration and patient monitoring of the therapeutic index of the drug in question.
Note that relative BA studies are more prevalent than BE studies and frequently form the basis of BE testing, due to being extrapolable directly onto pediatric populations without needing for additional clinical bridging studies.
Furthermore, relative BA/BE studies can provide invaluable data during the development and formulation of pediatric products, informing their instructions for use and making formulation decisions easier. Unfortunately, though they offer many advantages, relative BA/relative BE studies may still reveal differences in PK properties between test and reference products even when no significant bioequivalence criteria have been fulfilled.
What are the Benefits of a BA/BE Study?
Drug manufacturers rely on BA/BE studies to make better decisions regarding drug preparation and delivery in tablet, capsule, liquid, or injectable forms. They may modify dosage or shape of medications in order to address issues like adverse reactions risk or make them easier for patients to take. Furthermore, BA/BE studies provide invaluable data regarding new formulation performance compared to its reference product in terms of bioavailability and therapeutic equivalence (i.e. no significant variation between rates and extents of drug absorption).
Additionally, results of clinical testing can help ensure that the combined effects of individual actives within an FDC match those seen from its mono products – an essential requirement for approval of such compounds. This is especially beneficial where there may be poor PK DDI between individual actives.
However, achieving BE for FDCs can be more complex than for individual mono-products due to their complex pharmacokinetic profiles, which tend to be more complicated than those of mono-products. Furthermore, it may be hard to ascertain which individual APIs contribute most towards overall efficacy because many APIs feature nonlinear PK parameters that complicate this task.
One factor thwarting BE for FDCs is their higher chance of failure when compared with mono-product studies; this is likely caused by random chance in PK evaluations of FDCs versus mono-products because there are more samples and longer sampling intervals involved.
An BE study designed to compare a newly formulated drug against its reference product typically involves administering both products to healthy volunteers or patients and monitoring its concentration in their blood during this study.
Clinical researchers understand the importance of recruiting participants from all backgrounds for research studies. By recruiting diverse participants, scientists can develop medicines and treatments likely to work for as wide a population as possible. Once potential volunteers understand what will be asked of them in terms of participation in studies they can make an informed decision – a process known as informed consent.
How Can I Participate in a BA/BE Study?
Manufacturers wishing to demonstrate bioequivalence between generic medications and their Reference Listed Drug (RLDs) must conduct bioavailability and bioequivalence studies on generic products in order to demonstrate they meet efficacy and safety requirements, similar to RLDs. Such evaluations assess absorption rates of active ingredients, helping ensure equivalent effectiveness and safety profiles between generic versions and RLDs.
Bioavailability and bioequivalence of drugs can be evaluated through various methodologies, including in vivo testing, in vitro testing and clinical trials. In vivo testing involves administering the medication to healthy volunteers or patients and monitoring blood concentration of active ingredients over time; while in vitro testing measures bioavailability using dissolution tests. Finally, clinical trials evaluate safety and effectiveness by looking for adverse reactions, dosage adjustments and how well the drug works in different patient populations.
While BA/BE studies can be completed internally, many manufacturers prefer outsourcing them to contract research organizations (CROs) instead. CROs offer cost-effective services such as designing the study, conducting analysis and writing reports; plus they can save both time and money by managing administrative duties involved with BA/BE studies so the company can focus on its core business activities instead.
Numerous comments expressed concerns that the final rule could allow generic manufacturers to exploit failed BE studies to disparage competitors and undermine consumer trust in the drug industry. Some of these concerns included the possibility that manufacturers might release such studies under Freedom of Information Act requests or share failures to unfairly compete.
However, FDA does not believe that its new requirement to submit all BE studies conducted on a given formulation will cause undue burden or delay to ANDA applicants or review. They believe most (if not all) applicants will comply with it and submit all BE studies of which they are aware. Furthermore, its inspection resources are limited so they do not expect to inspect every site where BE studies were conducted.
How Can I Get Help with a BA/BE Study?
For your BA/BE study to be successful, it requires the expertise of a contract research organization (CRO). A CRO can assist with every aspect of a study’s design and conduct; such as bioanalytical analyses, study design, clinical monitoring data management as well as pharmacokinetic analyses as well as medical writing services and regulatory support services.
CROs can assist companies not only with developing new drugs but also existing therapies. For instance, companies may use BE studies to verify whether new delivery methods or dosage of existing medications are safe and effective without needing full clinical trials – saving both time and money in doing so.
Finding a reputable CRO when conducting a BA/BE study is crucial, as its quality can have an enormous impact on the success of your product. Look for one with experience in your therapeutic area as well as scientific and medical experts available to manage the project and have the appropriate equipment and facilities in place to carry out this analysis.
An effective BA/BE trial requires recruiting many healthy volunteers who do not receive any direct benefit from taking part. Therefore, it’s imperative that you select a CRO with experience recruiting and overseeing these participants for clinical trials.
Ba/Be studies in clinical research are an integral component of developing generic versions of innovative drug products, helping patients lower costs for pharmaceuticals while creating more cost-effective alternatives when patents expire. Unfortunately, many pharmaceutical companies lack the internal capacity or expertise required to conduct BE studies themselves – in these instances partnering with an experienced CRO like Raptim can save both time and costs associated with conducting these critical studies themselves. Our team is well versed in conducting multiple types of BE/BE evaluations including pharmacokinetic and toxicological testing on novel formulations.