According to ICH E6(R2), sections 5.2.1 and 5.5.3.a, respectively, “the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor” and “the sponsor should ensure and document that the electronic data processing system(s) conforms to the sponsors established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e. validation).”

Identifying right CRO is the first step towards increasing chances for a successful BE approval especially in the long term. 

It is advisable that auditor should be independent and well experienced and should be very well aware about process, cultural aspects, quality systems and trained for the given role. Before visiting the CRO, the best practice is to get the comprehensive Quality Questionnaires filled from CRO’s Quality assurance department. Further evaluation of a CRO can be planned based on the responses obtained in the Quality questionnaire. It is important to have a systematic approach, well developed checklists especially where every CRO is USFDA and EMEA approved. Sometime it is also important to know infrastructure, people, regulatory history, financial capabilities and past performance and deliveries and people working with the CRO’s. The checklist can also be based on FDA’s BIMO checklist and should also cover all other aspect of site, including volunteer recruitment process, database, IRB, quality manual, and standard operating procedures, infrastructure etc. Activities and system checks which may be undertaken during an audit and should include: 

Facility Tour: To assess whether there are adequate resources and there are equipment is fit for its intended use and to understand what are the process and if they are matching with SOP to be verified later on. 

System Review: To assess whether SOP has captured all stages of data captured & are verifiable from source data and that written records confirm that the BE study has been conducted appropriately.

Staff interview: To assess whether staff working on the given study are appropriately trained, are clear of their role and are working in line with SOP protocols. Findings and observations from any audit conducted should be documented in a formal audit report. Any deficiencies identified during an audit should be followed up with appropriate corrective and preventative actions.

When bioequivalence study fails to show therapeutic equivalence with the reference drug and become unfit for submission, still such data provides immense valuable insight and clear guidance to decide future course of action when subjected to proper investigation by experts on the formulation under investigation. The investigation should start from formulation strategy and PK comparisons of different parameters and dissolution data for establishing possible IVIVC correlation etc. Few other factors such as study design, sample size, time points, genotypic and phenotypic roles also need to be investigated. Food effect, dietary factors are also critical and should not be missed. A 360-degree approach should be planned with engagement of experts from formulation, biostatistics, clinical and bioanalytical as needed. Problematic areas need to be identified and studied in detail to make conclusions, while auditing and validating the data correctness.

• Based on the detail analysis, one can recommend further actions required, whether it is returning to the formulation development strategy or using different design approach or increasing sample size etc. C-trials has system based investigational approach and stepwise investigation strategy for investigating failed studies which has led to successful solutions and corrective measures to ensure a successful outcome at the end.