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How the FDA Conducts a Clinical Trial Inspection: An Interview With Former FDA Inspector Patrick Stone

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Clinical studies have become increasingly virtual because of COVID-19. How has this affected the way the FDA inspects clinical trials? Join Darshan Kulkarni as he talks with former FDA auditor Patrick Stone about his experience investigating sites and sponsors. Plus, we’ll discuss why virtual monitoring may be more cost-effective than other options.

Darshan: Hey everyone. Welcome to another episode of DarshanTalks. We have Patrick Stone with us as always. He is our favorite ex-FDA auditor, who is always kind, always comes online and talks to us about his experiences at FDA investigating and auditing multiple sites, multiple sponsors and not multiple manufacturers.

Narrator: This is the DarshanTalks Podcast. Regulatory guy, irregular podcast. With host Darshan Kulkarni. You can find the show on Twitter @darshantalks or the show's website at

Darshan: Welcome Patrick, tell us more about yourself before we jump in.

Patrick: Sure. I was with FDM for 13 years. For the past nine years, almost 10 now, I've been assisting with the manufacturing of drugs, but lately I've been assisting more with the clinical research side, the good clinical practice side. And there's been a lot of new orphan drugs and fast track drug sponsors that have needed assistance. So that's typically where I'm at right now, assisting sponsors make their way to market, if everything looks safe and effective.

Darshan: Okay. We're talking about sponsors coming to market. We're talking about what steps they take. Here's my first question, Patrick, in these times of COVID, have things slowed down in sponsors bringing products to market?

Patrick: I think they have accelerated from my perspective, because what I'm seeing is more sponsors are coming to consultants like myself, to get things done in a different way. We can do more virtually, we're finding out for the past seven months, than we could traveling around chasing compliance per se. In my guesstimation, I would say there's more because there's two factors involved in that. One is, the FDA is a lot more collaborative these days, and they're providing a little more assistance and consulting in a certain way, not pure consulting, but they're not telling sponsors, "Look, you figure it out. We'll talk to you later," that's not their approach anymore.

Darshan: Okay.

Patrick: Their approach is, "Let's work on this. Let's see if we can get this done compliant," and they're in a little more collaborative vein per se. You see a lot more sponsors or a lot more organizations that are bringing products to market that, per se, would have taken a little longer or would have needed more money now because of the fast track and the abridging per se, we're not shortening things, but we're somewhat abridging them from an FDA review standpoint. It would make sense that you would see a flood of products trying to emerge in that type of setting.

Darshan: Before we talk about the quote unquote, abridging process, again, speaking as someone who follows the industry, who follows clinical research, do you think this is a result of the new FDA commissioner, or do you think this is just the direction the industry was headed and the FDA is finally accepting it?

Patrick: The commissioner has some parts to do with that. They're part of a cabinet and the cabinet direction stipulate some of this, but I think what we're seeing more of is the actual centers are opening up their avenues and they're really the ones that drive this, CDRE, CBRE, they're the driving forces for whether a product makes it or not, not necessarily the commissioner, the commissioner just gives them kind of a direction, but I think what we've seen in the last three to four years with the right to try, and would say even six to seven years ago, a little further than that, it seemed like the administrations are wanting the long process of approval to be abridged, to be shortened in the way that is safe and that we still follow the quality by design specifications that are laid out and in the 21 CFR.

Darshan: Quick question. And again, I have to admit, I haven't looked into this recently, but QBD, quality by design, I've always thought of it more as a manufacturing process connection. I know that there was a discussion about doing it in clinical research. Did the guidance on that come out and did I just miss it?

Patrick: No, it's always been a full system approach, right? The quality system is embedded into the quality by design paradigm.

Darshan: Right.

Patrick: And the quality by design paradigm is ICH. It's the improvement or the harmonization of all of our regulatory bodies that are involved ICH to streamline every aspect, okay, not just the manufacturing, but in a parallel sense, the road to market as well. It does all fit together, it all fits together because now, think of even three years ago, would you have seen a quality agreement between a CRO and a sponsor based on GCP?

Darshan: No, that's the funny thing, I'm starting to see them, yeah.

Patrick: It's mandatory now. It's not, you shouldn't just start seeing them. ICH requires it and does-

Darshan: Really? I haven't seen enough to [inaudible 00:06:43], good to know.

Patrick: Yeah. E6(R3), well really R2-R3 because we're already in the R3 paradigm because it's been provided, the guidance is out. There's a very strict part in there that specifically says quality agreements are necessary for GCP and we want to see them. And they're also described as you would see a GMP quality agreement where there are penalties or not per se penalties, but if let's say the CRO gets it wrong, well now, at their own costs, they have to either figure out root cause or remediate, which typically wasn't something that the big box heroes would agree to and now they have to.

Darshan: I have to admit, we started this conversation with me thinking about doing a full blown conversation around virtualization. I really want to talk about that, but you've raised so many other questions and we'll talk about those hopefully if we've got a chance, otherwise, we'll push it to the next podcast.

Patrick: We'll weave them in because it's part of our current operating set up. We have no choice.

Darshan: Right.

Patrick: If we want to get the work done, we have to do it virtually. We'll weave them in the discussion for sure.

Darshan: Exactly right. Let's actually start by talking about this push towards the combination of virtualization of studies, the decentralized studies and has COVID... Everyone talks about this right now. I just read an article saying that investors are putting in some serious money behind decentralized studies. If that's true, how does auditing a decentralized study differ from what you did say, a year ago?

Patrick: Well, first of all, what I see is the price for operating has gone down from my perspective and from my client's perspective, because in the past, let's say that we had a multinational trial. And we always do this risk based approach to what sites will be chosen and it's usually the sites that have the most subjects or the sites that have the most SAEs or the most deviations protocol. Deviations is another risk ranking factor. And then they would send me off to France or to South America or to Michigan, wherever.

Darshan: That's horrible.

Patrick: And now what we're seeing is they're asking me to do this virtually because some of these countries won't even let someone from US in and we're getting them done quicker with the same amount of compliance review. Some of my sponsor clients were very apprehensive six months ago about being virtual in a QA audit. Now, we've seen the virtualization and monitoring because FDA has been talking about that for the last 10 years, the decentralization models and the models of you don't have to go to the site for every monitoring visit. You can do certain things virtually. And we would say that you can get a lot more done that way. And that was the guidance that they'd put out. We've seen it from a QC perspective, but now they're needing to do this from a QA perspective, which is a lot different.

Darshan: Let's start from the beginning. Let's say you were still at the FDA and COVID has hit, and you have a potential sponsor you want to audit, talk to me about how you choose your sponsor. Talk to me about how you'd walk through an audit.

Patrick: Well, if we're talking about an FDA audit, those always come from the review division. I would be getting an inspection from them, like an assignment, and they would have a sponsor, let's just say ABC. Let's say this is tied to a market application. Typically, three to four clinic sites get audited first. They send me to those clinic sites first, and then after the, we call it ammunition is gathered or the deviations or the gaps, however you want to call them, after those have been gathered from those clinics site audits, and those audits are centered around safety, they're centered around data validation, data integrity, and they're centered around IP accountability, obviously protocol adherence is in there, and that comes through reviewing the records, but the most important aspects are obviously safety and data validation.

Once those are done and the review division has their cycles between that, then they come up with a long list of items to cover for the inspector during the audit. And those laundry list of items in many cases are what makes or breaks the application itself, whether the sponsor's inspection ready, but as far as preparing for these audits, it's very different to prepare for a clinic site audit, which is pretty much cut and dry and there's a playbook. And that playbook is a compliance program guide 7348.811, I believe. And it gives you every question, every area of coverage and this is where you find some of the quality by design aspects in those compliance program guide. And then for the sponsor audit, it's completely different because first-

Darshan: Patrick, I'm going to stop you for a second.

Patrick: Go ahead.

Darshan: You just currently finished a site audit, you found some discrepancies, and now are you directly going to jump to the sponsor? Are you part of an SMO and audited the SMO itself? Or are you going to jump to the CRO? What is that process, if you will?

Patrick: Right. After you gather the site-specific gaps and information, then you can work on what SMOs per se, what vendors or the sponsor themselves. Typically, the FDA doesn't chase the application. They also do not chase the manufacturing. They're going to expect the sponsor to have all that information at the headquarters there and be able to speak to the oversight and the issues involved with any deviations or what we would call 483 Observations listed from those site audits. The sponsors should have all vendors, subcontractors, SMOs information, so that they can [inaudible 00:14:34] whether it's a QC person or a QA person from the quality unit, speaking to those aspects, if I find a direct observation relating to an SMO, then I will want to see the plans in place, the SOPs for oversight in place and the certificates of review or audits. And that's how I would follow that thread or that aspect. It all gets done at the sponsor.

Darshan: I just want to make sure I understood you correctly. What you would typically do is you would start from the site, collect data, based on the data, that data will tell you whether you need to go to the SMO level or jump to the sponsor. Once you get to the sponsor, you'll look backwards again, look at the sponsor themselves, evaluate what they have with the CRO and or the SMO and go from there. So you're coming in both directions. Did I understand that correctly?

Patrick: No, that's correct. That's absolutely correct. And there's a lot to be gleaned at the site that QA has to be aware of. You're not just looking at, did the principal investigator follow the protocol, you're looking at how the monitoring went, how the training of the site went, you're comparing the TMF data or documents for essential documents with what's at the site. There's a lot that you can tell, whether the system is in control and functioning as it should or whether it's broken down somewhere.

Darshan: You're talking about whether the system's broken down somewhere, and you're talking about the overall general process. Let me ask you a couple of things that have been in the news and how you would end up chasing those, or if you even chase those. The first one would be the right to try. You find out from the grapevine, or you find out somehow that this sponsor has had some potential subjects who have invoked the right to try. Do you go and audit that? Or how does that play itself out?

Patrick: Typically, unless those subjects show up on a MedWatch or some sort of adverse event that maybe is unexpected or is a death, especially if there's a trending, but if there isn't trending and these subjects are taking this product on a right to try basis, it somewhat falls in line with the compassionate use that we used to have, as the go-to or the emergency use. The right to try has just expanded on those two avenues of allowing subjects to take a product when they are... The right to try is not one of these where you have to be in late stage or in an almost death stage to do the trying, which is what compassionate and emergency use was. Now we've expanded that. We don't have enough inspectors to cover that type of paradigm where you would be looking at that. Though again, it's always risk-based. The decision-making will be on a risk-based approach and only those right to try projects that have the serious consequences or critical outcomes, then for sure they will be looked at by FDA.

Darshan: You mentioned the word critical outcome, again, I'm not sure I know the answer to this question, but I believe the president used a product, it was Regeneron wasn't it?

Patrick: Yes.

Darshan: And I believe it was thought to be an under compassionate use. My question for you is obviously the President of the United States is as critical as it gets, so from that perspective, would you, when I say you, obviously we're talking about the FDA, would they go and audit Regeneron to make sure that their process is as clean as it can be? Would that typically happen upfront? Or this is an emergency situation, you backtrack? How would this have played itself out, do you think?

Patrick: Well, for sure, it would be an after the fact of review and unless the commissioner or some surrogate of the commissioner got involved, it really wouldn't be looked at per se, unless something bad happened to the president. Because we see an effectiveness, he's able to operate, there's no intubation, there's no criticality to the case, I think that it would be looked at, at a later date. And obviously what the FDA is looking for is more how many, so if we're talking about onesies, twosies, which we're not talking about in this case, because the president probably isn't the only one getting that medication on that right to try use. If enough individuals warranted that, so statistically significant amount, because that's where it always comes in. If it's significant, the FDA gets interested otherwise, they leave it until it's actually marketed, applied for marketing.

Darshan: That takes me to finishing out the concept around compliance and the two other issues, well, let's start with... I'm trying to decide, I'm trying to choose to, I'm trying to be specific on which questions I ask you, but are you aware that the FDA just put out a new proposed guidance around intended use?

Patrick: I hadn't seen that. Are we talking like a couple of months or just like recent weeks?

Darshan: Like in the last few days.

Patrick: Oh, okay. Yes.

Darshan: I'm happy to send you a copy.

Patrick: Yeah. I would definitely like to see that because I have three sponsors that I'm working with right now, and those are some of the issues.

Darshan: Okay. I'll make sure I send that to you. But the reason I was asking that question is, do you look at potential clinical trial, patient recruitment ads to evaluate things like intended use, based on the ads themselves and the types of claims that are being made, or is that outside the scope of what you would be doing in an audit?

Patrick: No, that is well within the scope. I look at all IRB reviews and approvals, and I match those reviews and approvals with the way that recruitment was done. And what we're finding is that for the most part, the clinic sites or the principal investigators are using those approved materials. Now, what we sometimes see though, is that the principal investigator or a sub investigator do somewhat of an ambulance chasing where they know subjects are coming in to clinics and they pop up on their bedside and this is subjects that they aren't familiar with, or that are not in their clinic. And they ask them about the trials, that's where we see some of the issues when you get that type of chasing of the subjects in their weakest moment or in a hospital bed per se.

But yeah, no, for the most part, the IRB is very strict on this. The monitors are looking at it, so it wouldn't be just something that me as a QA or me as an FDA inspector would be focusing on, it should be what the monitor is looking at and working on with the sites and ensuring that their recruitment is within the approved process and that it's transparent to everyone involved.

Darshan: It's funny you mentioned transparency because that was going to be my next question, which was, as I'm sure you know the put out a guidance basically saying that, "We want to make sure that as part of our transparency initiative, you register on Is that something you tend to look at it when you audit? Again, obviously the monitors should be doing that and the site itself should be doing that depending on the type of study it is, or the sponsors should be doing that. But again, do you actually go back and look just to make sure?

Patrick: Right. Yeah. That's one of the first things I do is a search on the title, the number and the specifics that are provided in because what I find is a lot of times that's not correct, or they don't match.

Darshan: Yep.

Patrick: So that is something we look for, something I specifically look, I would say hopefully the good auditors will be looking for that, and it's on my template. It's on my check sheet. I have a checklist for everything I do, that checklist is based on FDA current practices. And for sure, I did that as a FDA auditor and I still do that as a contractor.

Darshan: And you put that into a 483, if they are not compliant.

Patrick: Oh yeah. If that doesn't match up, for sure, because then we have change control issues or essential document mismanagement. There's all sorts of observations that cascade because of that one item.

Darshan: Right. Obviously, Patrick, you've done this a bunch of different times. If people want to contact you and need your help, how do they find you?

Patrick: Sure. You can come to my website, You can find me on LinkedIn, I'm definitely there as well. But for sure those are the best ways to contact me right now. And I thank all of your listeners for their time and wish them all patients safety endeavors.

Darshan: Awesome. Thank you again for jumping on again, Patrick.

Patrick: I appreciate your time as always. Thank you.

Narrator: This is the DarshanTalks Podcast. Regulatory guy, irregular podcast. With host Darshan Kulkarni. You can find the show on Twitter @darshantalks or the show's website at

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