Clinical research employs people to test medications, devices, diagnostic products and treatment regimens on themselves. Clinical research doesn’t always benefit its participants directly but instead provides useful knowledge that benefits society as a whole.
BA/BE studies can help generic drugmakers establish therapeutic equivalence with brand medicines at a reduced cost, by eliminating costly clinical trials. Spinos performs BE clinical trials according to FDA guidelines, guaranteeing consistent logarithmic adjustments while streamlining regulatory submissions by using log-transformed BE measures for regulatory submissions.
Regulatory Requirements
BA/BE studies (also referred to as bioavailability and bioequivalence studies) measure how quickly drugs enter the bloodstream after administration and determine their bioavailability and bioequivalence, playing an integral part in approving generic drugs and helping ensure patients can access safe, effective medicines at lower prices.
Before generic drugs can be approved by regulatory agencies such as FDA, BE studies must first undergo approval by FDA. BE studies are designed to compare generic versions with their reference products through randomised, controlled trials in which each participant receives both test drug and reference product and their bloodstream concentration is tracked over time to establish statistical equivalency between them.
As part of an ANDA or ANDA amendment/supplement submission, applicants submit results of BE studies as part of an ANDA or ANDA amendment/supplement application. One of the most frequently asked questions regarding BE studies concerns when an applicant needs to conduct additional BE studies for either new products or changes to existing ones; FDA’s final rule offers clearer guidance than prior regulations on this point, mandating that BE studies be conducted using identical drug product formulation (referred to as “sDPF” in industry jargon) submitted with their ANDA or ANDA amendment/supplement application submission application submission submission application or amendment/supplement applications submitted for approval in their ANDA application or amendment/supplement submission application or amendment/supplement submission.
Some commenters have voiced concerns that the definition of “same drug product formulation” is too expansive and may lead to an increase in BE studies being submitted for review by FDA’s Division of Bioequivalence. FDA carefully designed this rule’s requirements in order to balance their need for additional BE data with their desire for an efficient ANDA review process; additional staff are being hired so we believe these new requirements will enable us to fulfill our obligations of assuring adequate BE information from ANDA applicants.
Study Design
Bioequivalence (BE) studies compare the rate and extent of absorption between two drugs/formulations to determine their therapeutic efficacy, an essential step in the approval of both new drug products as well as generic versions of existing medications. Furthermore, BE studies can help designers of drug formulations reduce risks associated with adverse reactions while increasing ease-of-use for patients.
To ensure an accurate evaluation of BE, it is crucial that BE studies use an appropriate design. Most typically, BE studies employ randomized double-blind placebo controlled designs which ensure all participants receive identical doses of the test and reference product and is free from biases. Furthermore, wash out periods must also be included into this design to ensure plasma concentration drops below the limit of quantification before continuing treatment periods.
BE studies typically involve healthy volunteers, although they can also be conducted in other patient populations such as children or the elderly. The results from such trials can then be used to develop pediatric formulations or extrapolate BE findings from adult clinical studies to the pediatric population.
However, it’s important to keep in mind that differences in drug absorption may be caused by factors other than formulation. BE results could prove misleading without taking these risk factors into account; such as age-related changes to how the body processes drugs or different methods for administering medication.
As suspensions can have a dramatic impact on drug absorption rates, using one instead of its parenteral equivalent could alter relative BE results between pediatric formulation and parenteral equivalent products even though both contain the same active ingredients. Therefore, sponsors should understand any risks involved with applying BE or relative BE results from adults to pediatric populations before undertaking BE/relative BE clinical studies.
Study Methods
Bioequivalence (BE) refers to the degree to which a drug is absorbed into the body and reaches its intended site of action. It can be determined by comparing absorption rates of test products versus reference products under similar experimental conditions within an appropriately designed clinical study.
To conduct a BE study, samples of the drug must first be given to healthy volunteers or patients and their bloodstream concentration monitored over time. With either single ascending dose or multiple ascending dose clinical trial designs available, results can then be used to ascertain if two products are bioequivalent.
BE studies should ideally involve healthy volunteers whose disease process should remain stable throughout the duration of the study, although safety considerations may necessitate testing on patients whom the drug is intended for instead of healthy subjects. When this occurs, single dose pharmacokinetic (PK) BA/BE studies may be more suitable than multiple-dose (multiple-dose).
Results of BE studies are typically reported in Module 2.7.1 of a clinical study report, though regulatory agencies such as Food and Drug Administration (FDA), European Medicines Agency (EMA), Therapeutic Products Directorate (TPD), or Therapeutic Products Directorate in Canada may provide guidelines or templates on how to format this information, such as PK data or BE results.
Pilot BE studies are often undertaken by sponsors in order to help them determine the optimal approaches and areas for further investigation regarding BE evaluation. Although these trials tend to be smaller in scale than pivotal BE studies, they can still be susceptible to variations and sensitive to variance – in order to help minimise this, some investigators utilise population-based approaches when analysing BE data.
No matter the method chosen for a BE study, all research should take place under fasting conditions unless a patient experiences intolerance of fasting. In such instances, FDA guidance documents on food effect BE studies (SUPAC-MR) may be useful; use in tandem with the ICH E3 guidelines to ensure all necessary information is included.
Results
Bioavailability (BA) and bioequivalence (BE) of drugs are essential elements in gauging their efficacy for patients, and its results help determine effectiveness and performance in terms of patient wellness.
Studies involving BA BE studies in clinical trials involve giving the drug to healthy volunteers or patients and measuring how fast the active ingredients enters the bloodstream over time – the results help doctors decide the appropriate dosage to prescribe for different medical conditions.
BE/BA trials must be performed under various conditions in order to produce data that are both accurate and representative of real world use. They should take place both fasting and feeding conditions so as to take into account any effects caused by diet on absorption; multiple batches should also be tested in order to detect any differences in quality; any differences must be addressed prior to conducting another BE/BA clinical trial.
For a BE/BA study to be successful, test and reference drugs must possess similar pharmacokinetic (PK) parameters. These PK parameters include Cmax (maximum dose reaching bloodstream), Tmax (time it takes to reach this point), AUC and area under curve (AUC). Furthermore, BE/BE studies should involve large numbers of participants for proper results to become statistically significant.
Depending upon the nature of a BE/BA clinical trial, multiple parallel or repeated-dose studies may be required. Participants in these trials should include males and females of various ages and races as well as regular washout periods between administrations of each dose. To ensure accuracy of results from BE/BA trials, each subject’s PK parameters should be measured at multiple time points and administrations.
FDA guidance recommends log-transforming BE/BE measures prior to statistical analysis so they can easily be compared with normalized PK measurements from parallel trials. If a Sponsor uses another approach for log-transforming their data, they should justify their approach within their clinical study protocol and statistical analysis plan.
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