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FDA Office of Regulatory Affairs - A Historical Look and Evolving for the Future

Joel Martinez
Tech analyzing sample - ISPE Pharmaceutical Engineering

In 2018, after 35 years, I retired from the U.S. Food & Drug Administration having spent a career as an FDA Investigator, beginning in the Orlando District Office, with stops in the Los Angeles District Office, and finally retiring from the Dallas District Office.

There have been many changes at FDA since my beginning, but one thing that has remained constant is industry confusion, in some cases, as to the internal organization of FDA and its review processes related to investigational drug submissions.

When a sponsor submits an IND (Investigational New Drug) application, an official filing with the agency, the IND is routed to a review division within CDER that has the expertise and category oversight of the investigational drug.

During the clinical study phase, all communication between the sponsor and the Agency is with that review division. When the sponsor eventually submits a NDA (New Drug Application) it does so to the same review division, however, at that point CDER’s, Office of Investigations (OSI), joins the review process in a larger capacity. OSI acts as the liaison between the medical reviewers of the review division and ORA (Office of Regulatory Affairs) FDA Investigators, with ORA being the field component of the FDA.

It is ORA that is responsible for the conduct of all inspections, investigations, and sample collections. OSI along with CDER’s review division select which clinical investigators will be audited and once the clinical investigators have been identified, OSI issues BioResearch Monitoring (BIMO) assignments to the field (ORA). The BIMO assignments are locationally driven, with the FDA Investigator located near the clinical investigator site. During the FDA inspection OSI staff are the primary contact to the FDA Investigator providing direction and expertise as necessary.

Upon completion of the FDA inspection, preparation of the Establishment Inspection Report (EIR) ensues followed by a supervisory endorsement of the EIR which is then forwarded to OSI for their review. OSI is responsible for final classification of the EIR, i.e. No Actions Indicated (NAI), Voluntary Actions Indicated (VAI) or Other Actions Indicted (OAI) and communication inspectional findings to the review division. Collectively, OSI and the review division make the decision on whether to accept the clinical data in support of the NDA. If a decision is made not to accept the clinical data from that one clinical investigator, the review division will communicate this decision to the Sponsor. OSI is then responsible for any post-inspection correspondence with the clinical investigator.

As you can imagine, training of the FDA investigators is paramount to a safe and effective program. Back in 1983 the training concept was one of the pyramid principle to be applied to new hires. As a new hire one was given exposure to every program area under FDA’s responsibility. The rationale was, for example, a new hire would be trained in food inspections because that is where one really develops their basic knowledge and practice of evidence development.

In addition, new hires were also trained in biologics (from Blood Banks to Plasmapheresis Centers), Drugs (from active pharmaceutical ingredients to final dosage manufacturers), medical devices (refurbishers to Class III medical device manufacturers) and veterinary medicine (from tissue residues to medicated feeds). The pyramid effect gave the field FDA Investigator basic knowledge of all program areas, as the FDA Investigator was considered the Eyes and Ears of the agency and a foundational knowledge across all program areas was thought to be advantageous. As the FDA Investigator progressed in their personal career and up the pyramid, they could then specialize in one or two program areas of their choosing.

Today’s new hires are immediately forwarded to their specialty program.

This change is in part due to the ORA (Office of Regulatory Affairs) realignment that occurred about 3 years ago. In the Drugs and BioResearch Monitoring (BIMO) area of FDA, this means that new hires are placed into one of two divisions focusing on the United States. Team One has coverage area in the eastern U.S. and Team Two, which covers the western U.S. All FDA BIMO Investigators are ORA certified.

Good Clinical Practices (GCP) inspections have also evolved to having the FDA Investigator ensure 100% data integrity through review of source documents with a comparison of BIMO assignment data listings as well as determine full compliance of the clinical investigator with the study protocol and applicable regulations

As FDA processes, staffing and training continue to evolve the Agency is continually seeking to strengthen efficiencies without losing sight of the urgent need to ensure integrity and safety of the products under its assessment and purview. A basic background in the Agency’s structure and submission review processes helps sponsors to understand the processes, with which department they will be communicating with at each time, as well as the training of those with whom they are working to facilitate approvals.