The following is based on a question and answer session Complion held with Dr. Harvey Arbit, PharmD, MBA, RAC, CCRP. Dr. Arbit is the president of Arbit Consulting, and an adjunct professor at the University of Minnesota College of Pharmacy.
Question: The FDA mandates that 21 CFR 820.30 design controls are implemented. How is “scope creep” prevented from design controls becoming a full-blown quality system with elements such as MRBs, DOT control, supplier audits and perhaps 50+ SOPs and forms to oversee; perhaps less than 20 total devices?
Dr. Arbit: You need to be compliant with all of them. The FDA really does not care whether you have one device or a million devices. Each must be compliant with good manufacturing practice. In fact, the Food, Drug, and Cosmetic Act says that if your product is not manufactured under a good manufacturing practice, it is adulterated.
Question: Will a 483 always be given at the end of an inspection?
Dr. Arbit: The answer is no. There may have been some minor violations, which did not require any further action of the FDA’s part. If you are following your protocol, you are following your SOPs, you are following the laws and the regulations, the FDA probably will not leave a 483.
Question: Why does the FDAs have to post the warnings online publicly? Can’t they just assign the P.I.?
Dr. Arbit: I think that is part of that whole process. It’s almost like paying for your crime. If I were a pharmaceutical company and I am looking for an investigator to study one of my drugs under an IND, one of the things that I am going to be looking for is that investigator’s previous compliance record. Has that investigator ever gotten a warning letter? Yes, you can ask the investigator, but the investigator could say ‘no’ and if the names of those investigators on the warning letters have been purged then you do not know who got it. So, therefore, you can’t really perform due diligence.
The same thing with investigators being disqualified. There’s a disqualification list and it names all of those investigators who have been disqualified. And again, you could ask an investigator if he/she has been disqualified, but they could say ‘no’. Then you do a search and you find out that in fact they have been.
There is a real need to identify these people. It’s not there to embarrass them. In fact, oftentimes an investigator who gets a warning letter learns from it. They’ve made corrections. They’ve cleaned things up, and things go forward in a much better fashion.
Question: When you receive a telephone call from the FDA for an inspection, what might you ask them to verify their true representation?
Dr. Arbit: You’re thinking “is this a prank phone call?” Well, I guess we can’t even rely on Caller ID to ensure we know who we’re talking to. They’re not going to be asking for any specific information. They are going to obviously introduce themselves; they are probably going to ask for the P.I. on the study, and they are going to know the name of the study. They’re going to tell you specifically why they’re calling and why they want to come in for an inspection.
You set up a date and time. Do not give them any other information — they have not issued a 482 and, therefore, the inspection has not started. Basically, all you’re doing now is confirming a meeting date for the FDA to come in and start their inspection.
Question: Can you provide an example of SR, NSR assignment that might appear in the IRB minutes for a medical device study submitted for review?
Dr. Arbit: Device studies are different from drug studies in that some studies are considered non-significant risk and others are considered significant risk. If it is a significant risk study — if the device is one that is an implant, or it sustains life or has some other similar purpose — the FDA may say that this a significant risk study. In that case you would need to file — and I stress that word file — an IDE with the FDA and follow all of the IDE regulations in 812. If, on the other hand, the investigational device is not a significant risk, then an IDE application is not submitted to the FDA, but the regulations state that an IDE is considered to be in effect.
You then have to comply with the abbreviated IDE requirements — 812.2b — which basically says you’re going to keep records, you’re going to monitor, you’re going to get an informed consent, you’re going to have IRB approval, you’re going to label the devices. It’s really all the same requirements as full submitted IDE except the IDE doesn’t go to the FDA. Instead the IRB serves as the surrogate overseer.
If you conduct your study as non-significant risk, that is what the IRB has to put in their records. If you were to present your protocol to the IRB and say, “this protocol is non-significant risk,” and the FDA disagrees with you, then you may have to get the FDA involved to determine who’s right because the FDA may not approve your protocol until it is determined to be significant risk or non-significant risk. But it is a requirement for IRBs to review that significant risk/non-significant risk determination and document in their minutes as to what their response was.
Question: How weighted are follow-up letters in reference to FDA inspection?
Dr. Arbit: A lot, if you can get it there before that whole package goes down to Washington because you may have made some corrections. The FDA is looking for voluntary compliance, and if you can voluntarily make all these corrections to the FDA’s satisfaction, you are better off. If the FDA still issues the warning letter, your response to that warning letter is very important. If they don’t believe that you’re sincere in your response or they don’t think that you are really making changes, or you haven’t put procedures in place to prevent those same incidences from happening in the future, they may come out and do another inspection.
Your response is extremely important. Not only making the response, but being sincere and honest, showing integrity to make these corrections and to become compliant. Not just, “sorry we goofed up”. Your response should convey that you will look at these things more closely in the future and provide assurance that all of your people are complying with the FDA regulations.
Question: When an academic institution is the holder of an IND, the institution is the sponsor, correct? If so, can the FDA audit the institution?
Dr. Arbit: Correct! In some academic institutions, the University of Minnesota, for example, their policy is that if you’re going to be an investigator and it’s investigator initiated, and you need to file an IND, you will be the sponsor. There are some institutions where the institution’s policy requires the institution to always be the sponsor. Either way is fine.
The FDA looks at sponsor investigator studies slightly differently than when the sponsor and the investigator are not the same. I have had that happen and had to explain to the FDA that it is our policy that the institution holds the IND, but its investigator initiated. Therefore, the institution is treating it as a sponsor investigator IND.
They can go in and they can now go to whoever is that individual who is representing the institution as the sponsor. They’re going to go in and they’re going to want to look at sponsor documentation. Because there can be similarities in sponsor obligations and the investigator requirements, just as there can be differences. You want to be sure that if your institution is the sponsor, there is somebody who is complying with sponsor obligations.
Question: Does the FDA have specific audit tools or worksheets that they use for review? Are these sheets available to sites?
Dr. Arbit: The FDA provides instruction manuals for investigators that walk you through what they do, how they do it, and why they do it.
For more about FDA inspections, be sure to download the feature article, “FDA Inspections Need Not Be Stressful.“