“Quality is a journey, not a destination.” That’s the message imparted by the U.S. Food and Drug Administration’s (FDA’s) David Burrow during his ACRP 2018 meeting session on “CDER BIMO: Compliance and Enforcement: What You Need to Know.” Burrow, PharmD, JD, is director of the Office of Scientific Investigations at the Center for Drug Evaluation and Research (CDER).
Always a popular and informative speaker, Burrow spoke to another standing room only audience. “Quality is about maintaining a network of commitments” with the entire spectrum of clinical trial professionals, he said. Taking it a step further, Burrow told attendees “this is not about fooling the FDA.” Executed properly, “protocol is the blueprint for quality,” he said.
Burrow used interesting statistics to provide some insight into FDA enforcement priorities. For example:
- Nearly 75% of clinical investigator inspections are associated with New Drug Applications (NDAs) or Biologic License Applications (BLAs).
- Some 30% of clinical investigator inspections follow a complaint.
- At 80% of all cases, protocol deficiencies are the most common issue cited by FDA from inspections. Adequate record-keeping comes in at 40%, with drug accountability and consent issues tied at 10%.
FDA inspectors have a specific focus when they come to take a look around to check up on an institution’s compliance programs, including:
- Verify the primary efficacy and safety data.
- Source of subjects; did they exist? “This is listed for a reason,” Burrow said. Fabricating the existence of subjects does happen from time to time.
- Did the subjects meet the inclusion/exclusion criteria?
- Was investigational review board (IRB) review obtained? Ditto for consent?
- Adherence to protocol?
- Verify primary efficacy measure.
- Adverse events?
- Safety data (e.g., labs and EKGs).
- Drug accountability? Blinding of data?
Turning to FDA Form 483s (observations from inspections), Burrow acknowledged it’s not mandatory to respond if you receive one. That said, opting not to do so means you forfeit a chance “put yourself in the best possible light.”
“A complete and timely response demonstrates your acknowledgement and understanding of the observations to the FDA,” he said. It also demonstrates a commitment to correcting the observations, and can help establish credibility with the agency.
Burrow offered an interesting way to look at the issue. “You can take a selfie and see that you have four double chins, or you can have a professional photographer” take the shot of you and come out with a vastly superior result, he said. “It’s the same person, there’s nothing dishonest, but think of the different image you present.”
For Burrow, deciding to respond is smart decision number one. Smart decision number two is to take the time to craft a thorough and intelligent response. He offered some tips:
- Include a commitment from senior leadership. Burrow has received letters that weren’t even signed by the principal investigator or other relevant personnel addressed in the original 483.
- Address each observation separately.
- Note whether you agree or disagree. “The inspector was at your site for a week,” Burrow said. They may have missed something, or you found documents after they left. If the FDA has it wrong, show them why.
- Provide both corrective and preventive actions.
- Provide both completed and planned actions.
- Provide timelines for completion.
- Provide a method of verification or monitoring the effectiveness of the actions.
- Submit documentation (e.g. training and standard operating procedures).
- Submit the response within 15 working days. This last one is very important, Burrow said. By failing to do so, you risk the FDA not weighing it as heavily in its follow-up reports.
Burrow left attendees with some final words of wisdom. “Compliance is about what you need to do. Enforcement is about what happens when you don’t,” he said.
Author: Michael Causey