FDA Inspections Need Not Be Stressfful: A Q&A With Dr. Harvey Arbit

Posted by Complion on Aug 2, 2016 2:07:55 PM

The following is based on a transcript of the Question and Answer portion of “FDA Inspections Need Not Be Stressful,” a Complion webcast featuring Dr. Harvey Arbit, PharmD, MBA, RAC, CCRP. Dr. Arbit is the president of Arbit Consulting, and is an adjunct professor at the University of Minnesota College of Pharmacy.


I work in medical device research. The FDA mandates that we implement 21 CFR 820.30 design controls, which we have done. How do I prevent scope creep from design controls becoming a full blown quality system with elements such as MRBs, dot control, cape, supplier audits and perhaps 50+ SOPs and forms to oversee; perhaps less than 20 total devices.

Dr. Arbit:

I believe the gist of the question is: if you’re a small company and you’re manufacturing devices, how compliant must you be with the QSR, which is the quality regulations?

You need to be compliant with all of them. The FDA really doesn’t care whether you have one device or a million devices. Each one must be in compliance 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.


Will a 483 always be given at the end of an inspection?

Dr. Arbit:

The answer is no. There used to be little joke that went around that the FDA never leaves an inspection without leaving a 483. That’s not true. I have been involved in a number of inspections where the FDA has left without presenting a 483. There may have been some minor violations, which didn’t require any further action of the FDA’s part. Again, if you’re following your protocol, you’re following your SOPs, you’re following the laws and the regulations, you have nothing to worry about and the FDA probably will not leave a 483 and you will be in just fine shape.


Why does the FDAs have to post the warnings online publicly? Can’t they just assign the P.I.?

Dr. Arbit:

I think your question, if I can interpret is, why does the FDA have to identify the individual who is the recipient of the warning letter?

I think that is part of that whole process. It’s almost like paying for your crime. People are going to know who it is that is doing what kind of research. For example, if I were a pharmaceutical company and I’m looking for an investigator to study one of my drugs under an IND, one of the things that I’m 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 don’t 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 is actually in better shape than before. They’ve learned from it. They’ve made corrections. They’ve cleaned things up, and things go forward in a much better fashion.


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’re going to obviously introduce themselves, they’re probably going to ask for the P.I. on the study, and they’re 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. Don’t give them any other information because at this point 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.


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:

That’s probably question for another topic, but let me see if I can address it quickly. 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 -- in other words, 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, which is, in other words, the rest of the universe, 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, which is 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’s 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.


How weighted are follow-up letters in reference to FDA inspection?

Dr. Arbit:

If I may, you’re asking if you respond to the 483, how much weight is given to that? A lot, if you can get it there before that whole package goes down to Washington because you may have made some corrections. Again, the FDA is looking for voluntary compliance and if you can voluntarily make all these corrections to the FDA’s satisfaction, you’re 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. 


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’ve had that happen and had to explain to the FDA that it’s our policy that the institution holds the IND but it’s investigator initiated. Therefore, the institution is treating it as a sponsor investigator IND. 

But, yes, 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.


Does the FDA have specific audit tools or worksheets that they use for review? Are these sheets available to sites?

Dr. Arbit:

As mentioned in my presentation, the FDA provides instruction manuals for investigators that walk you through what they do, how they do it, and why they do it.



Editor’s Note: Links to these resources are available in the Complion feature webinar and feature article "FDA Inspections Need Not Be Stressful."

Topics: Insider

A Learning Experience

Posted by Complion on May 11, 2016 12:38:47 PM
It’s good when you can learn from your mistakes. It’s even better when you can learn from someone else’s mistakes.

Jill Heinz, owner and site manager of Treasure Valley Clinical research in Boise, ID, admits to a few missteps in the early stages of her implementation of Complion’s eRegBinder solution. At the time, enthusiasm for the new system and eagerness to start using it got best of her. Jill and her team dove in without much of a plan. It wasn’t long before they realized that the process they had in place was not working.

Jill and team went back to square one to begin a more deliberate transformation. They developed a new workflow for organizing and managing regulatory information, one that would take advantage of eRegBinder’s features. That new strategy paid off, and early wins helped to overcome staff reluctance to embrace the new system. Once word spread among staff members and stakeholders about the capabilities and benefits of the new system, the initial value only increased.

Jill shared details of her organization’s implementation experience during a recent Complion webinar, motivated by the hope that she could help others to avoid her mistakes. A detailed overview of her experience is now available from Complion, including recommendations for specific steps you can take to help to insure a smooth transformation from paper-based management of regulatory information to the speed and efficiency of eRegBinder.

Thanks to Jill’s openness and generosity you can learn from her mistakes. Don’t let that opportunity go to waste.

Click here to download your copy of “eRegulatory Experiences from a Site Without Binders.”

eRegulatory Experiences from a Site Without Binders

Posted by Complion on Apr 13, 2016 12:43:47 PM

Questions and Answers

The following is based on a transcript of the question and answer segment in the Complion webcast eRegulatory Experiences from a Site Without Binders, presented on January 27, 2016. The webcast featured Complion CEO and founder Rick Arlow and special guest Jill Heinz, a 14-year research industry veteran and the owner and the site manager of Treasure Valley Clinical Research.

The questions were posed by members of the audience.

Question: Does the FDA approve of sites going paperless?
Rick: Yes, and the regulations are in place. Sponsors have already done it as well, and they came up with those regulations for Part 11 back in 1997 to help expand utilization. But you have to be able to show that you meet all of the requirements.
Question:  Jill, how long ago did you test the waters for the research site?
Jill: We started in the summer of 2015. Since then we've started a couple new studies, and I have to say it gets easier and easier each time. So, the industry is coming around.

A year ago it was still pretty new. It was new to me. But now, each time I approach a study sponsor about it, its easier and easier and they are all for it.
Question: Does an eBinder need to be 21 CFR 11 compliant?
Rick: Yes! If you're not keeping any paper backup and the eBinder is your sole record, it must be compliant. If you are using a hybrid system where you may be keeping things on a shared drive or other system, but your physical, authoritative, auditable copy is that paper binder, then the shared drive does not need to be Part 11 compliant. That's because it's not the single source of the truth.

If you are not going to maintain any paper or any wet-ink signatures, and it's within a system, that system must be compliant. It's not just the software, but you need to have those processes and that documented validation process in place.
Question: Do you keep the original documents in a binder?
Jill: At my site, no, because a lot of the original documents never actually made it to paper form. Because you can eSign within this, you dont need that ever to be printed out. So there is no original wet signature. Even for the documents that have a wet signature, once they're uploaded into the system, we don't keep them in binders.

Several study sponsors have requested that we send the originals anyway, because they want the originals at their site, and what is in our paper binders are the copies anyway. So we absolutely do not keep two binders anymore. That just doesn't even make sense anymore.
Question: What percentage of missed information do you encounter usually?
Jill: I hope we don't have any missed information. I think our binders are 100% accurate. If it's missed, it's not necessarily the eBinder. It's probably human error. But no, I haven't seen any missed information.
Rick: As a best practice, solutions should have the ability to provide reminders or have you easily report or search through the information to see what's there and what's missing.
Question: What did you use to save all of your regulatory binders if you did not use a server? Do you use an external drive?
Jill: For our paper binders, which are six inches thick, we were archiving them on paper. We didn't scan ours in. In the past we archived them the old-fashioned way. We'd  take them out of the actual binders and then put them in the big old paper boxes and send them off to our archive facility.

Again, we're only about a year into this -- we haven't archived any of our eRegBinders yet. But, it's my understanding that there's a couple different options, and Rick can maybe discuss it more since I haven't actually archived an eBinder. If we want, we can print it at any time, and you can archive it in the old-fashioned paper way, print it off and archive it that way. You can continue keeping it on the system or you can put it into an external hard-drive or jump drive.

I haven't had to do that. I'm hesitant to recommend that last one. Again, if I did, if I got to the point of wanting to archive it in the form of a jump drive or external hard drive, I would do it in multiple locations. So that if there was a natural disaster of some sort, I have it on more than one system. If our system crashes, then there goes my RegBinder. So, I would put it on something external.
Rick: Yes, that's a very good point. We typically see that the majority of sites that are using this platform are archiving electronically throughout that period of time. If you are going to pull that down and store it either on paper or electronically, the big thing to think about is changes in technology. For instance, my computer now doesn't have a CD drive. And who knows how long USB will be around? You need to think about security and accessibility in the long term, 10 or 15 years down the road.
Question: You mentioned that need to validate software. What software are you referring to?
Rick: If you are using any software to store information electronically, and the information stored in that software is the sole source of that information -- you're not keeping a paper backup -- then that software must be validated following the best practices I described in the presentation.
Question: With the technology becoming more accepted, is any effort being made nationally for a standard or a nomenclature between sponsors, CROs, IRBs, and sites, as we share similar documents?
Jill: I have talked with study sponsors about that. I originally asked Rick, "Why aren't you going to the study sponsors? This seems like it would be better rolled out there. I've since talked with a number of study sponsors, and, obviously, they have all their internal electronic regulatory binders. They all keep it electronic within their systems.

But, because the Code of Federal Regulations is pretty clear that its the sites responsibility, it's hard for sponsors to dictate which eRegBinder you have to use at your site. Every sponsor I've talked with said, "We like the idea of eRegBinders, but it's not our responsibility, and so we don't want to get into that.

Rick, you might have a better answer. But that's just been the response I get from sponsors.
Rick: Yes, I think that's very accurate. On the sponsor side it's called a trial master file, whereas sites are typically referring to this as a regulatory binder. As Jill mentioned, in GCP and FDA, there are different requirements for the site as well as the sponsor. They have, within the last decade, primarily transitioned over to maintaining this information in a more electronic fashion.

From that standpoint, though, the site is responsible for maintaining their own records and validating their own system. Although they may be providing a portal to facilitate providing and receiving information, typically the site still maintains the paper binder and may be scanning it into those portals. Various sponsors have gotten together through the DIA and developed an eTMF reference model. OASIS, the independent group, has also developed a standard nomenclature for sponsor records.

But no standard nomenclature currently exists for research sites. So while many sites, whether they're on paper or using an electronic binder, may be developing their own standards, I believe there's a lot of opportunity and value for sites and other stakeholders to come to identify what that standard would be. It would be valuable for the research sites, because everyone could then follow that same structure.

It would be valuable for the sponsors, as well, so that they know how it's mapping from the site files into their own electronic files. So, that's something I am very passionate and interested in. We'd love to connect with others, and I think that will be happening over the next several years.
Question: Jill, do you do cooperative group studies at the site? If so, how does this go over with them?
Jill: We don't. Having done cancer research years ago, I do understand the format of a cooperative group. But we don't do those studies. I don't have any experience with that with eRegBinder. I have a lot of networks and various study sites across the country that I'm associated with. I go to the conferences and I talk with people, and I talk with various study sites across the country. And I feel like it's moving in this direction, that people are ready to move forward with this.

I feel that this is going to be inevitable, and not just in our industry. We'll all be using less paper. Things are getting more electronic. We like being able to do things from our phones, from anywhere. We can do it from the coffee shop. We can do it from the clinic. We see doctors walking around with their iPads instead of actual charts these days.

So it feels like it's inevitable. I talk to everybody in my networks and my groups, and this is met with very favorably: "Boy, I really hope this catches on so that it makes it easier for us to get access to documents." Because right now, you have to go into the office and make sure. You have to scan that document in and fax it off, and it's just too time consuming.
Rick: On an anecdotal personal level, we are seeing more cancer centers and other oncology organizations that are moving into this model. Obviously, it's very different if they're doing investigator-initiated trials, if they are managing sponsored studies or cooperative-group studies. But the consistent theme that I've heard has been that having a single, centralized place to keep all this information across those various trials has definitely been very, very valuable.
Question: How does the sponsor respond? Can the cost of an eRegBinder be reimbursed by study sponsors?
Jill:  I was surprised I didn't get that question first, because that was one of my concerns. Obviously, these systems cost our site money; we have to pay for it. We've got to house it on a server somewhere and all that good stuff. I'm a small site with a small budget, and I was hesitant at first. I have never actually got it approved as a line item, though I predict that day is coming.

  We've done a couple contracts now since starting this, and I usually put it in the startup fees and can get it put in as additional funds when I describe what it is and how it's going to save the company money. The people on the other end don't have that ability to put that line item in. We all can put in a pharmacy line, that's pretty standard. A lot of times I get, "Well, I can't put it as a line item, but can we put some padding over here for it? Okay, yeah, sure, however you want me to get paid for it.

The other thing is, because it does save me room, I won't have to archive. These studies aren't going to take up nearly as much room archiving. So my archiving fee that I can always get approved goes towards that.

I feel like I've got it covered for every study, creatively. If you do contracts, the thing with any budget is being creative. I don't feel like I've ever lost money on it.

Well, I shouldn't say that. That first binder, when I jumped in and did it incorrectly, a lot of staff time was used. So, that's my goal for this webinar: hopefully, nobody makes that mistake, because that did cost me time, and time means money, because I pay my staff.

That would be my only issue, when we were implementing and going about that implementation incorrectly. It took more time and, therefore, money. After this, every binder now is the same. Every onboarding's the same. It's pretty standard, and I never feel like I don't get my money out of it.
Question: What do you do when a sponsor wants you to use their eBinder software?
Jill: I've never actually had that. Like Rick mentioned, they have their trial master file, but the regulations don't allow me to actually use that as my record as well. The sponsor is tasked with keeping their own records, and I'm tasked at my site to have my own. I can't rely on the study sponsors. If I did, I would be really nervous about doing that. I don't think the FDA would think that's great at all, from my point of view.

You need your own binders. You need your own regulatory documents housed. If a study sponsor came to me and said, "We want you to use this binder," I guess I would go through all the things to make sure it's 21 CFR compliant. To make sure they're going to archive and that I own that information, not them. That's the other key -- it's my responsibility to have that access to that information. So, I don't want them being in charge of it. If they shut it down, where does my information go?

I would be nervous if a study sponsor came to me and said, "You must use this as your RegBinder. Or even having them tell me about that source. Source is always my responsibility. If you want to provide it and I like it and it meets our specifications, great, I'll use it. But nine times out of ten I say,  "No, we have our own source documents. We will design them the way we want, so that we know that at our site, it meets our standards." So, I would handle it that same way. I hope that answered the question.
Question: How do you get around the sponsor who has a delegation log with no wet-ink signatures?
Jill: We have what we call a dynamic document folder, an electronic binder in which we keep 90% of our documents. But, for example, product accountability logs that you're probably in every single day, and changing every day, we actually keep in a very small, half-inch binder, along with screening and enrollment logs. Because, again, you're adding names to that, hopefully, daily or weekly.

So, these dynamic documents are the ones that are changing. Now, when you come to the delegation logs, you can electronically sign those. You don't change those very often. Rick can correct me if I'm wrong, but I believe you could actually keep those electronically in the binder and still make changes to the signatures, where a PI could sign off if a staff member left.

We keep our delegation log in that dynamic binder, at this point. The plan is that when we archive the study, and everything's fine -- all the drug accountability logs are final and signed off and all the drugs are returned, when enrollment's done -- we will upload those documents to the system and then archive it with the system. But right now, because we make so many changes to it, I will say there are two or three documents that we do keep out. The delegation log is one of them.

Again, I think the eRegBinder system has a way of dealing with it. But we chose not to use that capability. Rick, you might want to address how other sites might do it because you've seen more.
Rick: Some sites are doing as Jill is doing. Others use different methods. The one thing you should think about there, as well, is that if you are going to be scanning such documents into the system, something that was formerly on paper, you do need to think about how you're creating a certified copy. There's no magic or complexity there.

As an example, you might want to establish a best practice around reviewing a specific number of pages to make sure that everything was scanned correctly. If you're going to get rid of the original, keeping the scanned document as your sole copy, you want to make sure that the scanned copy has all aspects of the original, and that a page wasn't lost or that a signature wasn't lost. There are different ways to accommodate dynamic logs and forms in an electronic system. Having dynamic logs and forms, there's different ways to accommodate for those in an electronic system. We've seen sites that have done that electronically. It depends on what works best for your team.

For some examples, like a temperature log on a freezer, if it's literally posted on your freezer and someone goes there and checks it and writes it down on paper, it probably makes sense to still keep that in paper. But we've seen sites that have done that electronically as well. It really just depends on your needs.

The most important thing, as Jill mentioned, is identifying the workflow. How are you creating a standard? Whether you're using an electronic system or using a paper-based system, look for opportunities for improvement to help save time and ensure compliance.

Topics: eRegulatory

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