FDA’s final rule clearly indicated its intent not to restrict BE studies to data related to only one drug product formulation; pilot studies that generate BE data will also be considered BE studies for review purposes.
One comment suggested that an expansive interpretation of the same drug product formulation requirement will lead ANDA applicants to make SUPAC level 3 changes such as altering manufacturing sites to avoid submitting failing BE studies.
Bioavailability (BA) and bioequivalence (BE) of drugs is determined by measuring their concentration once they reach their site of action, typically through oral medication entering systemic circulation via gastrointestinal tract and reaching target organ or tissue for therapeutic effect. To ensure reliable and cost-effective BA/BE studies are carried out it is vitally important that researchers are familiar with various experimental designs, approaches, and design elements used for conducting these tests.
BA/BE testing is an essential component of drug development, serving as the main way to evaluate formulation changes and lot-to-lot consistency among generic products. Furthermore, it serves to demonstrate therapeutic equivalence between generic versions of innovator products and their generic equivalents.
BA BE studies in clinical trials assess pharmacokinetic (PK) parameters like area under the curve (AUC), peak concentration time and time to maximum concentration. To ensure valid results, it is crucial that randomised, cross-over designs with adequate washout periods allow for measurements on each drug in each treatment group prior to administering another one; washout periods must last at least 5 half-lives after administration of each drug in each group.
Healthy volunteers are typically preferred over patients in BE/BA clinical trials as they are easier to recruit and typically more amenable to extensive pharmacokinetic sampling schedules. Furthermore, healthy subjects tend to be less likely to possess inter- or intra-subject factors which could hinder absorption or disposition of the drug compound.
An effective pilot bioanalytical study can be an excellent way to gauge the feasibility and reliability of BE/BA studies, serving as an ideal prelude for more rigorous clinical trials by verifying analytical methodology is sound and precise. A pilot bioanalytical study should adhere to ICH E3 guidelines and include all sections required by full clinical trial reports.
FDA guidance documents outline several in vivo methods that may be employed to assess or establish BA/BE of drug products, including single and multiple ascending dose clinical trials, food effect studies, and any other approved in vivo methods. In vivo BA BE clinical trials are often included as part of an investigational new drug application (IND) or abbreviated new drug application (ANDA) submitted under 505(j).
Bioavailability (BA) and bioequivalence (BE) measure how quickly and to what degree a drug becomes available at its site of action, in humans. Both measures must be measured through appropriately designed clinical trials that utilize statistically valid tests with sufficient samples sizes to produce reliable results. To measure or establish BE accurately, sponsors must select tests with adequate sample sizes that yield accurate results.
Food-effect and fed BE studies should ideally involve healthy volunteers 18 years or older capable of giving informed consent and fully understanding the nature and risks associated with the study. If safety issues prohibit enrollment of healthy subjects, however, these studies may also involve patients.
When conducting both fasting and fed bioequivalence evaluation studies, the same lot and strength of drug product should be used in each. Ideally, testing at its maximum strength would be ideal; if clinical safety concerns prohibit this option then BE determination for lower strengths can be performed using dissolution profile comparisons instead.
FDA’s proposal addresses the delicate balance between needing additional BE information and not overburdening the ANDA review process with unnecessary burdens. According to their proposal, FDA believes that additional passing BE studies on developmental formulations of a developmental formulation, even when performed using different testing batches, can provide valuable insight into whether the final generic product meets bioequivalence standards set by reference listed drug(s).
FDA’s rule mandates that ANDA applicants submit data from all BE studies they conduct on the same drug product formulation submitted for approval, or else risk undermining its overall goal by creating an overly burdensome regulatory process which discourages applicants from filing ANDAs; this is especially pertinent to ANDAs that have already passed one BE study; currently, ANDA applicants who conduct multiple BE studies using one final formulation are often not reporting all their BE results to FDA, leaving many unaware of these additional BE studies’ existence.
Regulatory authorities around the world are constantly searching for ways to lower drug costs for their citizens, and one effective strategy is bioequivalence (BE) studies. BE studies play an integral part of generic drug development processes and their results help determine whether an approved generic product should be approved for marketing.
An BE study is used to compare the bioavailability of two drug products with similar active ingredients. There are various methodologies for conducting BE studies, and several factors must be taken into account in order for the study to succeed.
These factors include drug formulation, the duration between doses, potency, and pharmacokinetic properties that play an integral part of BE studies.
Regulatory agencies provide guidelines and templates for bioanalytical evaluation (BE) reports. A BE report’s structure is similar to that of clinical study reports, including sections for PK analysis, BE data collection, adverse events reporting and bioanalytical methods. FDA, EMA and TPD all publish guides that outline how to create BE modules 2.7.1.
The final rule will produce economic benefits for individuals and society as a whole by requiring all BE studies submitted to FDA are accurate and complete, which will reduce product discontinuation due to unfavourable BE determinations while simultaneously increasing ANDA review process quality by permitting FDA to more carefully consider BE information submitted by applicants.
ANDA applicants should thoroughly comprehend the impact of the final BE rule, reviewing draft guidance and working closely with their CROs to implement an appropriate BE protocol. ANDA applicants should ensure their CRO is aware of their obligation to submit both passing and failing BE studies for submission of data.
Additionally, the final rule requires ANDA applicants to submit results of all BE studies conducted or obtained during their annual reporting period in order to prevent product withdrawals and adverse health impacts arising from failed BE determinations. This provision will help protect consumers against product withdrawals caused by failed BE determinations.
The final rule ensures that FDA has access to all BE data generated by manufacturers, enabling the agency to make an informed decision as to whether a generic drug is bioequivalent to its brand-name equivalent. This benefit will reduce product discontinuation risks, eliminate adverse health impacts from lack of access, and increase economic benefits through greater availability of cheaper medications.
Not only will this rule ensure BE studies are conducted and submitted according to good clinical practices, it will also increase data quality and ensure consistent interpretation by the agency of BE results. In doing so, this final rule can help prevent incorrect BE determinations that could potentially delay approval of generic drugs or lead to the rejection of legitimate ANDAs.
Applicant should be mindful that the new requirement to submit all BE data generated by an ANDA applicant will result in an increase in the number of BE studies required for submission, particularly for small entities. Based on an estimated cost per BE study for small entities, it is anticipated that under the final rule 177 ANDAs (622 original ANDAs plus any amendments or supplements) will need to conduct an additional 51 BE studies annually.
This increase represents a 10-percent rise in the annual submission requirements for BE studies by ANDA applicants; since most BE studies conducted by ANDA applicants yield passing results, this change should have minimal ramifications on ANDA approval rates.
FDA indicated in its preamble to the proposed rule that BE data generated with non-identical formulations to that of the marketed product could be important and should be submitted. Such BE results could suggest that there may be significant discrepancies between their bioequivalence because their rates of absorption differ (68 FR 61640 at 61641).
When ANDA applicants submit bioequivalence (BE) data to us for ANDA review, including BE results generated through studies with formulations different than that approved for market approval, we must obtain all available BE studies so we may use them to prove bioequivalence between their marketed ANDA generic and its reference listed drug (RLD).