AAM, BMS ask FDA to acknowledge role of third parties in BA/BE studies

Stakeholders want the US Food and Drug Administration (FDA) to acknowledge that testing sites used for bioavailability (BA) and bioequivalence (BE) studies are often operated and audited by third parties who should also bare responsibility for compliance and maintaining the facilities.

In April, FDA proposed a draft guidance on ensuring data integrity in BA/BE studies that was open for public comment until 3 June. Broadly, stakeholders asked the agency to provide clarity on several key areas in the guidance.

The Association for Accessible Medicines (AAM) noted that sponsors, also referred to as applicants, are not always the ones who conduct BA/BE studies, and the guidance should also consider when a contracting site is tasked with conducting such studies on their behalf. The group said that while the sponsor is responsible for the integrity of the study data in the premarket application, they may not have granular knowledge of the study that the testing site has.

"It may not make sense for the applicant to have a detailed site-specific data integrity quality management system (QMS) in place that may be duplicative of the testing site’s data integrity QMS, and it may not be technically possible for the applicant to integrate its QMS with the QMS of the testing site," said AAM.

AAM also noted that auditing testing sites shouldn’t only be the responsibility of sponsors since third parties are often contracted to oversee such sites.

“Contracting third-party auditors can free up applicant personnel to conduct quality assurance activities and can bolster the independence of the audit,” the group argued. “We recommend FDA clarify in the Draft Guidance’s discussion of monitoring plans that although applicants can conduct the audit themselves, they may instead contract for a qualified third party to conduct the audit.”

Bristol Myers Squibb (BMS) also commented and said that as it is currently written, the guidance seems to require a formal auditor to conduct such audits. The drugmaker said such audits are often conducted by a Clinical Research Associate (CRA) and asked FDA to clarify the issue.

AAM also recommended that FDA reword the guidance to reflect that the responsibility for maintaining a good QMS, which includes proper study conduct protocols, should apply to the sponsor when they conduct all or parts of the BA/BE studies themselves. It also asked the agency to clarify that QMS expectations may vary based on the type of testing site.

The guidance states that the reporting structure of the testing site should be open and transparent for personnel at all levels to ensure there is good communication about errors and failures that could affect data integrity. AAM, however, said that FDA's proposal is overly vague and it's more important to include language that testing sites have clear communication, an internal reporting structure and escalation procedures.

"Having such reporting and escalation systems in place can help ensure that any potential study data integrity issues are brought to the attention of the most appropriate personnel, recorded appropriately, and addressed in a way that is efficient, effective, and complies with applicable requirements (including any applicable requirements in the study protocol (e.g., study controls, such as those related to blinding), and requirements related to protection of protected health information and personally identifiable
information)," said the group.

AAM also had recommendations for elements that should be considered when implementing a QMS for a testing site that is tasked with gathering BA/BE study data. One of the recommendations is to allow sites four weeks instead of FDA’s recommended two weeks to archive their data after a study has been completed to make it less burdensome for the site administrators.

"In many instances it could be very challenging from an operational perspective to archive all study data within two weeks, particularly for multi-site studies," said the group. "Patient-based BA/BE studies, for example, are often executed at more than ten different investigator sites, making it particularly difficult to collect, organize, and archive all the data within two weeks. Rushing the process may also be more likely to cause rather than prevent mistakes that might impact data integrity."

BMS further asked FDA for clarity on issues such as whether audits and their findings are considered forms of communication by FDA. It noted that in the guidance it states that audit outcomes such as noncompliance and data irregularities should be communicated to testing site management and personnel.

"While it is understood that any communications regarding study decisions should be maintained in order to reconstruct the study, in the case of an audit by the applicant or third party, those should be maintained separately and not considered as communications," said BMS.

The drugmaker also asked for more clarity about FDA's expectations for the contents of monitoring plans, and monitoring bioanalytical methods.

Guidance comments

AAM, BMS ask FDA to acknowledge role of third parties in BA/BE studies

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