Q&A: FDA Updates: BIMO – What Sponsors Need to Know

Advarra experts Joan Versaggi and Leslie Paul answer questions from the first in the webinar series – FDA Updates: BIMO – What Sponsors Need to Know.

Q: How are inspections assigned domestically in the United States (US) versus outside the US?

A: The BIMO CPGM (Bioresearch Monitoring Compliance Program Guidance Manual) addresses in Part III (Inspectional), section V (International Data) what a Food and Drug Administration (FDA) investigator looks at during an inspection. Section B. 2. notes the Centers (e.g., CDER, CBER) issue sponsor inspection assignments. Domestic inspection assignments are issued through the ORA OBIMO headquarters to the appropriate ORA BIMO division. Foreign inspection assignments are issued to ORA OBIMO headquarters

Q: What are remote “assessments” and how do they differ from the “regular” inspection (i.e. no 482, no 483 etc.)?

A: This webinar covered the changes to the BIMO CPGM 7348.810 (Sponsors and CROs) and how the FDA conducts “regular” inspections. For details regarding the conduct of remote interactive evaluations of BIMO facilities, see FDA’s Guidance for Industry Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency.

Q: Where is the complete response letter in the chain of events?

A: After the FDA conducts their review of the sponsor-provided information, a complete response letter is issued indicating they will not approve the application at that time. This is outlined in 21 CFR 314.110.

Q: Can you give an example of a sponsor-investigator?

A: A sponsor-investigator is an individual who initiates as well as conducts the clinical investigation. A sponsor-investigator must comply with regulatory requirements applicable to both sponsors and clinical investigators.

Q: How transparent should a sponsor be with the FDA investigator during a pre-approval inspection (PAI) when there were issues in unblinding (e.g., mistake at sponsor)? Should the sponsor inform the FDA up front during the inspection? Or just be prepared to talk about it *if* the FDA investigator finds it?

A: Our advice is to be transparent with any quality issues, such as unintentional unblinding. While sponsors should have reported this in the clinical study report, they should be forthcoming with a serious issue and provide an explanation as to what happened, why it happened, and what was done or what controls are now in place to ensure the non-compliance does not occur in the future.

Q: Given that many sponsors are now working remotely due to COVID-19, can we expect that FDA would reach out in advance to schedule inspections, versus coming to a sponsor location unannounced?

A: Inspections under this program are generally pre-announced, unless otherwise instructed in the inspection assignment and at the discretion of the ORA BIMO division. Pre-announcements are generally no less than five calendar days in advance of the inspection.

Q: Can you please comment on FDA collecting more and more data on USB drives? Sponsors have started putting standard operating procedures (SOPs) in place restricting USB drive use due to security issues.

A: It’s best practice to have written procedures governing how electronic data is provided to a regulatory authority if they request it during an inspection. Chapter 5 of the Investigations Operation Manual (IOM) section 5.3.8.3.1 – Electronic Records, provides specific instructions to the FDA Investigators on the collection of electronic records. The IOM states in part, – If there are no mechanisms available for a firm to securely transmit the data electronically to the investigator, the data may be provided to FDA on a CD, DVD or a USB…The information obtained from the firm is commercial confidential information (CCI) and as such must be protected to the greatest extent possible. It is the responsibility of the investigator to make sure the physical data source remains secure. Likewise, data obtained from extra-governmental sources may contain viruses or malware that may be included with the information provided to the investigator either on purpose or accidentally. The transfer of electronic data must be evaluated along with concerns related to safeguarding the security of both FDA and firm information.

Q: What is the expectation of evidence for a sponsor to show oversight for a vendor’s subcontracted services as required by ICH E6 R2?

A: New Section F – Outsourced Services specifically states the following:

Review and evaluate the sponsor’s oversight of outsourced services as appropriate and as defined in contracts, written processes and procedures, and SOPs. Focus on the outsourced services playing a significant role in the clinical trial (e.g., management of primary efficacy endpoint or safety data) and/or were involved in any significant FDA regulation deviations. Determine if the sponsor has processes and procedures (e.g., SOPs, plans, or other work instructions) for selection of outsourced services and activities, and determine what criteria were used to select the CRO (and as applicable, other individuals or organizations providing outsourced services) and whether they meet those criteria.

Q: What documents are available to inspectors prior to the BIMO audit visit?

A: Centers will provide background materials when they issue sponsor inspection assignments, such as:

• Study protocol
• Case report forms (CRFs)
• Data line listings
• Complaint summary
• Any additional information

Q: In providing the list of SOPs, should we provide only current SOPs or all versions in effect during study conduct?

A: The FDA investigator should receive SOPs in place during the conduct of the clinical trial(s). If you have updated SOPs addressing any deficiencies in the SOPs in place at the time of the study conduct, they can demonstrate the sponsor’s improvements.

Q: What’s the thought/guidance for providing a BIMO reviewer’s guide in a marketing authorization application (MAA)? Is it a best practice as it’s optional?

A: I have never provided this with an application, I suppose there may be a good reason to provide one. For example, if the drug has gone through several owners and the sponsor wishes to clearly outline who was responsible for what, when? Further I found the Bioresearch Monitoring Technical Conformance Guide, which is referenced by the Draft Guidance Document: Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions.

To learn more about recent BIMO changes, watch the on-demand webinar FDA Update: BIMO – What Sponsors Need to Know.

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