What has allowed the government to — for once — move at the speed of industry to help curb the pandemic? And will the FDA be able to maintain this pace once the pandemic winds down?
We caught up a long-time regulatory expert to find out.
Transcript
Meagan Parrish: It isn't just the pharma industry that has broken into a fast-paced sprint during this pandemic. The FDA has also had to strap on its running shoes and race to keep up because any stumble could risk delaying innovation and ultimately approvals for needed vaccines and therapeutics. So, what has allowed the government to, for once, move at the speed of the industry? And will the FDA be able to maintain this pace once the pandemic winds down?
I'm Meagan Parrish, and you're listening to Off Script, pharma manufacturing's podcast that runs beyond the pages of our magazine to discuss the issues that matter to pharma most. Today, we're taking a deep dive into what changes the FDA instituted in 2020 to expedite coronavirus-related clinical trials and approvals, including the use of master protocols and rolling regulatory reviews. We're also looking at what changes might stick around for the long run and which ones could get nixed as the industry settles back into the status quo. What should pharma companies do to stay on top of what's happening at the FDA, and how might a new commissioner under the Biden administration impact these issues? To help us get a better understanding of this shifting regulatory environment, I'm joined today by Ronan Brown, the senior vice president and head of IQVIA Integrated Global Compliance, where he helps pharma companies find high-tech solutions to manage compliance issues. Ronan, thanks so much for joining me.
Ronan Brown: Thank you very much for having me. It's a pleasure to be here.
Meagan: Absolutely. So, I wanted to start by just thinking back to the beginning of 2020, when these very aggressive timelines were proposed for getting a vaccine developed and for getting one approved by the FDA. And I'm wondering now, if you're surprised by the success the industry has had in meeting those timelines because there was definitely a lot of skepticism at the beginning that the industry was going to be able to pull it off.
Ronan: You know, it's an amazing achievement. If you reflect back on it, I think the fastest vaccine ever developed took four years, and generally, you're talking about a time frame of 10 years to get to the market. To do it in 10 months, which I think is the time frame that we had for the first EUA approval, is outstanding. And, you know, it's taken a lot of bodies to come together to be able to achieve that. I think it's a true reflection on how our industry can move things when they really, really need to.
Meagan: Right. And, of course, you know, the industry has gotten a lot of help on the regulatory side with improving efficiencies in order to sort of pave the way to these vaccines being developed and approved in these really fast timelines. So, I was wondering if you could tell me about some of the increased regulatory efficiencies you've seen during the pandemic and how they've aided the faster development of these COVID-19 therapeutics and vaccines?
Ronan: Well, I would probably put it into three buckets. One is the regulatory agencies in terms of some of their openness to discussions with companies developing these treatments and vaccines and how they've changed some of their processes. The second and this is probably more at a granular level, in terms of sites and investigators is local regulatory changes that have accelerated startup of clinical trials. And then the third bucket would be around how regulatory authorities have absorbed the data, have changed how they are going to review data to issue EUAs, and do rolling reviews of the data that's being generated. Those three things together have hugely contributed to it. And there are some examples in terms of the C-TAP initiative, reducing expedited pre-IND reviews down to seven to 10 days from 60 days previously. And in Europe, I think it was 70 days down to less than 20 days. And that allowed developers to get in front of the agencies, talk through their development plans, the needs for data, how they were designing studies and get really key input very, very quickly.
Meagan: Right. Of the three buckets that you named, were there any in particular that you think sort of had the biggest impact on the development process?
Ronan: Yes. I think regulatory startup times for studies have been a bane in the life of developers for years and average times to set up studies ranged up to one year, and we've seen timelines come down and approvals given within 24 hours. And I mean, it's just mind-boggling that it's taken this to really drive some of those changes. And there's ways that they've been done and I can go into a couple of examples, but that probably on its own has had the biggest impact because most of the companies had to do two to three studies in the space of 10 months when they wouldn't even got the first study up and running.
Meagan: Right. Yeah. If you have a couple of examples you could share that'd be great.
Ronan: Yeah. I mean, so for those who are less familiar with the clinical trial process, certainly in the U.S., many institutions demand local IRB approval versus central IRB approval. Local IRBs can take four to five months to review protocols and approve them. And overnight, institutions gave up on their IRB requirements because it was just simply impossible to meet the timelines. There was still a central IRB and that then allowed us to initiate and bring up many more sites much, much quicker than you would have done in the past. You know, and then simple things that electronic contract signatures were not allowed previously, and just that alone shaved many days off the time frames in terms of regulatory approvals. So, you know, there were some really tactical things at a local level that have changed and hopefully for the better. We're seeing institutions realize that it doesn't have to take five to six months to set up a study anymore. We can do it in much, much shorter time frames and still maintain the patient safety.
Meagan: Right. And so, now, of course, everyone is wondering which one of these changes might stick around for the long run because it seems like from my perspective, and correct me if I'm wrong, but just like you said, we're finding out that patient safety can still be preserved while making these changes. I haven't heard necessarily of any adverse consequences for these timelines. So, assuming that we discover that indeed, everything went pretty well at this pace, which efficiencies do you think the industry is really going to push to keep?
Ronan: So, it's interesting because I think at a government regulatory level, it has been resource-intensive to the extent that they removed pre-specified timelines to review documents. You didn't have to submit all the documents in the same format or very strict format. They allowed some flexibility in kinds of the non-clinical data that they were looking at. But the challenge has been that it has required us, or regulators, to really focus all of their resources to review these and so you have seen some slippage in reviews in other areas of non-pandemic-related therapies. So, whether they can maintain that over the longer term, I think is going to be tricky. What I think we will see is the clinical trial regulatory startup initiatives continue. And I know, as an example, if you go outside of the U.S., Brazil, which used to be one of the longest startup times because of the regulatory requirements has gone from over 250 days to 70 days. In fact, I was just asking a Brazilian colleague, would that be maintained post-pandemic? And there's actually legislation going through the Brazilian government at the moment to try and effect that permanently.
Meagan: I see. Are you aware of any sort of official push to keep any of these efficiencies that we've had in the U.S. at the moment?
Ronan: Not...I mean, I think at a local level, they are down to the institutions and we are certainly seeing institutions realize the benefits of starting studies quicker, and they can then do more studies. So, we are hopeful that that will continue, and it's less dependent on the FDA's requirements and more the local regulatory requirements. So, we do anticipate that there's going to be an adoption of some of this, and it may not be quite to the same extent of reliant on a central IRB as an example, there may be some kind of hybrid approach with less information required locally, but I think we will definitely see some of these things stick.
Meagan: I see. If you were a pharma company, which one of these changes would you want to stick the most? Would it be the clinical trials startup?
Ronan: Well, I think you would want a combination of them because what has the biggest effect on you running the study will be how fast you can get it up and running and start accumulating data. At the same time, getting that input early in terms of what you're trying to do has obviously been key. And then on the back of that, submitting the data on a rolling basis. I mean, so I wouldn't pick any one from a pharmaceutical company perspective because they've all contributed. And you've seen the use of EUAs as a way of getting treatments out very, very quickly. Once the data has been accumulated, it doesn't negate the need to do the full submission. And I think one of the things that's interesting between March and December, there were 350 EUAs issued by the FDA for both treatments, diagnostics and devices whereas there were only 23 between 2013 and 2019. So, a huge step up in that. But they still have to go through the full application afterwards.
Meagan: Right. So, do you think that the industry could kind of target these EUA approvals to get their products on the market more quickly going forward? Or do you think it would not work for a non-pandemic setting?
Ronan: Certainly, I don't think it will. It was really done out of necessity to accelerate, but I think some of the things around rolling reviews and looking at the data could possibly be looked at as a way forward because, compiling everything and crossing all your I's and dotting your T's before you have to submit, adds six months to the end of any cycle, and then there's the review after that. So, that's a challenge, but if you can submit on an ongoing basis [and] have it reviewed on an ongoing basis, you can certainly bring the timeline down.
Meagan: Yeah. I was wondering about the rolling reviews. Was this not happening at all before the pandemic?
Ronan: It was not as far as I'm aware. It was always, you know, here's the submission format, pull everything together in terms of your regulatory documentation and then submit it all at once. This was now very much as you get data, you can submit it. And obviously, the requirements for an EUA are very different to a full approval.
Meagan: I see. And you talked about how intensive this has been for the FDA and their workload. I mean, do you think that the FDA would have to kind of have some sort of radical reorganization in order to keep these kinds of changes with more staff and more changes to processes?
Ronan: I think any regulatory agency that has been swarmed with applications to run studies to address the current pandemic will certainly need to take a view of what is sustainable in the longer term from a resource perspective. We know most of them are resource-constrained. And so, that's why I said at the beginning, certainly we will see some elements of this go back because they're unsustainable with the number of people and the resources that are required to review and look at the data and provide the feedback. I mean, just getting together the advisory boards for the vaccines before the holidays, they happened in record time. And that was because everyone dropped what they were doing to make sure we could push this through.
Meagan: Yeah. So, in other words, pharma companies shouldn't get too excited about some of these expedited processes?
Ronan: I think to some extent, whether there will be a review of what is required from a pre-IND and I mean, certainly in Europe, just removing pre-specified dates for submission allows you to submit as soon as you've got it versus wait until next month when the next review, when the submission date comes in. I mean, that certainly, you could see that being something that would be taken forward. But yeah, I think resources will be required and I guess that means greater financial resources for the different regulators.
Meagan: Right. So, we talked about some of the changes that might stick around for the long term. What about the ones that you think are more likely to go back to the status quo?
Ronan: That's a tricky question. Because I think, I mean, one thing we did not touch on, how studies are being conducted and the regulatory changes that are being pushed through around those. And I think we are going to see those accelerate and become broader base. And by that, I mean the guidance that was issued around decentralized studies, and I think we're going to see more and more of that across all different therapeutic areas moving forward. Things that will go back very quickly to how things were done in the past, I think on the backend we're probably going to certainly see less use of EUAs and back to the more traditional review of data. But hopefully, that won't be as impactful in terms of the time frame as running studies in this kind of environment using a more decentralized approach.
Meagan: And there's definitely been a lot of chatter among industry analysts about these changes that occurred during the pandemic. I'm wondering and I should say I'm sensing that there's definitely a lot of interest in the industry, of course, in terms of keeping some of these efficiencies, have you sensed any willingness on the part of regulators to push for these changes to become permanent?
Ronan: Oh, absolutely. I mean, the guidance around decentralized studies, these have been absolutely critical in terms of running, you know, being able to recruit and continue clinical research in the current environment, and that we definitely see that as an area that will continue and grow. Prior to March last year, there was some adoption of more decentralized approach to studies using direct-to-patient nurse and televisits to be able to limit the burden on patients, but with the access to sites being limited, people not being able to travel but still having to continue to run your study, this whole use of technology in decentralized studies is accelerated. And so, I think that's here to stay.
Meagan: So, Stephen Hahn, the most recent FDA commissioner, just recently sent out his goodbye tweet, I think a couple of days ago, and we're waiting to find out, of course, who the new head of the FDA is going to be. Do you think that these kinds of questions about whether or not the agency pushes to keep these efficiencies could come down to who is chosen to run the agency?
Ronan: We do. And you know, I think...and their openness to innovation, absolutely is going to be a key driver to their willingness to adopt. But we are seeing it across the industry, that Janet Woodcock, I think she's acting at the moment, is certainly very open to innovative approaches. So, we hope that this is here to stay.
Meagan: Okay, great. So, you think that Janet Woodcock is someone who would support these kinds of changes?
Ronan: She definitely does, but she's only the acting commissioner at the moment.
Meagan: Yeah. We'll see. I'm wondering, did any of these changes impact pharma companies developing drugs not related to COVID? You talked about how there are potentially some negative consequences for companies, but do companies developing other therapeutics and drugs during the pandemic experience get to experience any of these increased efficiencies in 2020?
Ronan: You know, actually, I think there are some anecdotal commentary around, you know, certain dates being missed because resources have been redirected to focusing on COVID-related studies. So, I think probably more of that versus application of this to non-pandemic-related therapies.
Meagan: Okay. And so, now looking at the regulatory landscape for 2021, and there being some uncertainty about what exactly it could look like, especially as the pandemic winds down, what do you think that pharma companies should do to prepare for this shifting regulatory environment?
Ronan: Well, I think there's two elements here. One is the need to stay up to speed with the regulations. I mean, they have evolved so quickly and at such volume across the world that having really good regulatory information is absolutely critical. I mean, I think the FDA issued 72 COVID-specific guidances from March to the end of the year. So, keeping up to speed with what is required, what can be done has been a burden in the past, and in this environment is even more critical because things are changing on a weekly basis. So, I think companies are looking at how they're collecting regulatory intelligence, how they're using it, and how can you dovetail that with the operational aspects have been starting up studies and making sure you tick all the boxes. You know, and especially when you think about what are the safety requirements post-marketing once you've developed and when you've taken 10 months to develop a drug versus 10 years. And I think those are the really key elements that they're going to see...you're going to see a lot of focus. I think the second element has been around...and it's really down to the kind of more remote working and how that has impacted a company's ability to meet some of these timelines. When a lot of the safety reporting in the industry is conducted out of India and people could not get into their offices, and there's much more of an office-based culture there, suddenly you are left with these big hurdles in terms of how do you keep processing safety reports to regulate your timelines. And so, we have certainly seen a lot of emphasis and much more interest around cloud computing and how do you build your regulatory intelligence across the cloud.
Meagan: Right. And you mentioned some of the technologies that have been used during this sort of remote working environment that everyone's experiencing. Can you tell me about some of the technologies that pharma companies could maybe or should maybe consider adopting in this new regulatory environment to help with compliance?
Ronan: Yeah, I mean, I think we had seen a change or certainly a greater interest in pharmaceutical companies to embrace a more integrated regulatory information management system, whether that comes from pulling regulatory intelligence data, through to compiling it, and publishing it. And so, we will see a greater adoption of that kind of technology and breaking down some of the silos between functions within the company, like the regulatory group and the safety team, which have traditionally operated fairly isolated and exchanged data in a very old-fashioned way, through SharePoint sites and emails. And so, we are now starting to see much more interest in terms of end-to-end regulatory information management systems.
Meagan: Okay, great. Now, was there anything else really important about the regulatory changes we experienced in 2020 that we haven't talked about yet?
Ronan: No, I think we've covered most of the elements. I mean, it has been a huge achievement to drive some of these development activities in the time frame we've seen. And that really has been a lot of leadership by the agencies in terms of providing guidance, being open to change which...you know, and more flexible than they have ever been. And maybe one thing that we didn't see as much in the past, but certainly because of the global nature of the pandemic, you've seen a greater collaboration across agencies in terms of alignment of what they're requesting and how they're doing things and what they're reviewing and sharing information. And we think that will be certainly something that will continue.
Meagan: Great. Well, it'll definitely be interesting to see how things play out at the FDA in the coming years and this year, in particular.
Well, Ronan, thank you so much for taking the time to chat with me today and break all this down.
Ronan: And yeah, it was great being here. And thank you for taking the time.
Meagan: Yeah, absolutely. You've been listening to "Off-Script: A Pharma Manufacturing Podcast." Stay informed, everyone, and stay well.
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