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Ep. 14 Jeff Baker and Competitive Advantages in FDA Discussions
75 Plays5 months ago
Jeff Baker, biotech veteran and former FDA Deputy Director, describes how the ability to tell a story is a competitive advantage, even in discussions with the FDA. We also dive deep into the COVID response and advanced manufacturing
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Transcript
Introduction to Spark Time
00:00:00
Speaker
Hi, everyone, and welcome to Spark Time. I'm Dani Stoltzfus. And I'm Will Riddle. Of Mighty Spark Communications. Our mission is to use scientific innovation to drive transformative change.
Inspiring Transformative Change
00:00:11
Speaker
We believe that compelling storytelling is the most effective tool we have in our arsenal to motivate and inspire audiences to invest themselves in audacious goals. We are scientists by training, storytellers by experience, and entrepreneurs by nature. Let's get started.
Evolution of Biotech and FDA
00:00:28
Speaker
Today we're excited to share our conversation with Dr. Jeff Baker. We started with his history at the FDA. Biotech was such a different world in the 1980s. The agency was in a renaissance period, only just grappling with biologics and recombinant products at the time.
00:00:45
Speaker
Yeah, so we hear so much from the private sector side of biotech as well as the public side. And it was really noteworthy to hear Jeff's perspectives on interactions with the FDA from before he joined and after he joined. So Jeff is such a compelling storyteller.
00:01:01
Speaker
Yeah, he totally is. And he spoke quite a lot about how he thinks about end Indian mind thinking as being essential. He doesn't just mean setting milestones and achieving them, but instead thinking about the patient and really working backwards from that point.
00:01:17
Speaker
Right. One of the most interesting pieces of advice from Jeff was how to have a great
Building Trust with the FDA
00:01:24
Speaker
conversation with the FDA. yeah It's probably not a surprise to the listeners of this podcast to hear that it's based on building trust with the people on the other end of the table.
00:01:34
Speaker
Yes, very true. and I also really enjoy getting to hear some of the inside scoop around the COVID response, Project Warp Speed, for example, but also how all of the biotech community collaborated to squash what seemed like an impossible problem into a ah solvable timeframe.
00:01:51
Speaker
Yeah, that was really cool to hear Jeff's recounting of of that time. We also talk about advanced manufacturing and why Jeff thinks we're still stuck in
Advanced Manufacturing Challenges
00:02:01
Speaker
the past. He spent his career thinking about these ideas and problems. For example, why are we still making vaccines and eggs? And as a virologist, I could speak to why it works, but it's also quite rate limiting and surprising to think how little innovation has take root at scale. Anyway, let's get into our conversation.
00:02:20
Speaker
Today, we're joined by Dr. Jeff Baker. He is a biochemist by training, and he spent over 20 years in the pharmaceutical industry, leading development and manufacture of first-in-class biological products, having twice received the Willy Research Laboratory President's Award. He served as Deputy Director, Office of Biotechnology Products at the US FDA for 10 years, receiving six awards or citations for renewing and rebalancing OBP review, inspection, and research programs,
00:02:47
Speaker
And in 2018, received an FDA Honors Award for contributions to modernizing the US s
COVID-19 Collaboration Challenges
00:02:52
Speaker
regulatory system for biotechnology products through sustained creative leadership and collaboration. He was FDA liaison to Manufacturing USA and to the Advanced Manufacturing National Program Office and participated in interagency responses to the COVID pandemic. He retired from the FDA in 2021, but remains active in the biotech community as a senior fellow for NIMBL, senior strategic advisor for the Center for Biomedical Innovation at MIT, a participant in multiple NASEM study groups, and a university lecturer.
00:03:24
Speaker
Dr. Baker, of course, is joining us today to discuss his opinions and not the position of the FDA. Jeff, it's really wonderful to have you
Interdisciplinary Insights in Biotech
00:03:32
Speaker
on the podcast. Thanks for joining us. How are you doing today? I am great in the ways that matter and happy to visit with you. Awesome.
00:03:40
Speaker
and Wow, that was seriously um an impressive bio. And so I didn't even know where to begin. So I'm going to go back all the way to the beginning and rewind to 1988, Jeff. Can you tell us what it was like to work in biotech at that time? Because I'm imagining a scenario that was a little wild western in nature and not a lot of rules to go by.
00:04:00
Speaker
Well, it was very different. I think, come first of all, I was educated by professors to be a professor. And remember, this is all pre-email and pre-internet and all this. And I get a phone call one day from Eli Lilly and company ah that they were putting together a team that they thought
Innovative Recruiting Practices at Eli Lilly
00:04:19
Speaker
they could make therapeutics using recombinant DNA technology. And of course, recombinant insulin had been out there, and and that Lilly wanted to expand their portfolio, and they were putting together a team and wanted to talk to me about this. And I, of course, said, oh, oh no, no, no, no. I'm a real scientist. as i I roll my eyes, you know but but I really don't want to work for a company. you know No, no, no. I'm a molecular cell physiologist. They said, well, just come out and talk with us.
00:04:49
Speaker
And that's something right off the bat that's very different, that at the time, and and I don't want to be melodramatic about it, but there was a little bit of, you know, a tone, a flavor of selling out to go work for a company, you know, and it's it was just ah ah a different vibe, as they would say today. And also, you didn't get a degree in biotechnology.
00:05:13
Speaker
ah that were not biochemical engineers and things. ah So what Lilly was doing, a gentleman named Dave Denon was leading the charge, ah was recruiting molecular life scientists from all over the United States who worked in very diverse fields that had a history of problem solving.
00:05:35
Speaker
and took this recruiting approach that if we throw them all together and give them these tough challenges, the good things will come from it. So right off the bat, comparing contrast now with must-have-thus-and-such-degree-in-five-years experience or whatever, because but nobody had that experience.
00:05:54
Speaker
And sos so it was a very exciting time ah intellectually. And during the recruiting process, I was very direct with Dr. Denon. I said, look, yeah I don't want to blow smoke at you. I don't know anything about this kind of stuff. And he laughed and said, well, that that's OK, because the stuff we want you to do hasn't been done yet.
00:06:15
Speaker
And which is another fabulous retreating approach, you know? And so so those were things that were very different and and and we were moving forward. It was ah very much focused ah on interdisciplinary, synthetic thinking.
00:06:33
Speaker
Today, I think you're rewarded ah very well by society for being being a specialist. I think you reward extremely well for being an extraordinary specialist for all you anti-CD11, BFI prime promoter region people out there. You know, but but ah this was more, we're looking for generalists, we're looking for an interdisciplinary thinkers who can wear an engineering hat, a biochemist hat, a development science hat, who can wear a business hat, who can wear a regulatory hat, because really the regulatory framework was was being written on the fly.
00:07:11
Speaker
and we were all sorting it out together. So I don't know that I would describe it as the Wild West. I would describe it as a very exciting Renaissance period ah that ah was indeed very different in a lot of ways.
00:07:25
Speaker
Well, to me, that sounds amazing. I love the sound of getting to wear 15 different hats and truly being an interdisciplinary scientist. And I've spent most of my career trying to achieve that, so I would have loved the 80s, I think, for that reason. Yeah, so thanks for that, Geoff. Definitely. So Geoff, you might be one of the few people out there who have worked on both sides of the
Communication Mindset Shift with FDA
00:07:45
Speaker
fence. So as a drug developer at Willy and Metamune, but also as a leader at CDER at the FDA. so How did your mindset on communication change from when you were the one seeking approval to when you were giving approval in in the ways that you contributed to that? So it said in a different way, if I were filing an IND today, what is the most important advice you would give me? um Well, and that a number of things were similar and a number of number of things were different. In that specific arena, I did have a shift in thinking.
00:08:16
Speaker
ah When I was in industry, I very much had a perspective of, um gosh, you know, really don't don't tell FDA anything because only two things can happen. Nothing and something bad. Answer all of the questions completely and honestly and play your cards close to your chest. Also, when I was in industry, and an enormous amount of um energy was invested in messaging and wordsmithing and things like this. And I was quite proud of that at the time. you know Look how clever and look how strategic we're being ah with with our communications and all.
00:08:56
Speaker
Now, when I got on the agency side, you know often we inherit the sense of our former selves. And I suddenly realized that whereas I thought I had been fencing with the FDA, I had been fencing with my own shadow. And frankly, ah in in general, you know your your average, your your typical reviewer, your typical ah regulatory person, they want to see you succeed.
00:09:24
Speaker
they They want to see you bring a new medicine, you know, to ah help healthcare care people. ah They want to go home and have satisfaction that they've helped in that mission.
00:09:36
Speaker
and a lot of the gamesmanship and communication stuff that I was a part of. I mean, let there be no mistake that that all the the messaging really, I think, frequently got in the way of ah mutual goals, you know. ah And I really, at FDA, I i suddenly became aware of of a couple of things. One was that the the filters that industry puts in place for for very important risk management ah reasons sometimes are very contrary to having the outcomes that they want to have.
00:10:15
Speaker
you know and secondly and This is probably aligned with your podcast. the The ability to tell a good story is a competitive advantage. and And I had a lot of meetings with a lot of different sponsors, a lot of different companies bringing things forward.
00:10:32
Speaker
you know, and a group that could come in and clearly and succinctly talk about what they had going on, keep it science centered, keep it patient centered. Boy, that was a great meeting. the The meeting where afterwards you walked away and went, wow, what was that all about? Because they have beautifully crafted slides, but what What were we talking about, Eamon? That's not a good meeting, you know? um So so i I would say particularly for folks who are in on aggressive ah development timelines, ah things like this, and I'm speaking from mostly from the CM and&C side,
00:11:14
Speaker
um the the the The folks who come in and say, just tell us what to do, and we'll do whatever you say, and we're ready to go, they don't have as good a set of outcomes as folks who come in and say, first of all, here's what we're doing. Here's why. You know, we think we're fine. There's a couple of things we have some questions about, but we're working on them. Hey, do you think we've missed anything?
00:11:43
Speaker
That's a good meeting. It's just open on his forthright. And how can we bring these medicines to patients? Right. Everyone wants to hear a plan, right? and And know that the intentions behind it are aligned with your own. I think that makes a lot of sense. Sure. There's a there's an FDA guidance on expedited programs. And if you look at the section on CM and&C, ah particularly on breakthrough development, um there's there's some very carefully worded paragraphs there that we worked very hard on.
00:12:15
Speaker
that basically say at at at the time of getting this this this status, this expedited status, it does not say the cake has to be fully baked. o What it does say is you need to come in with a plan to provide a reasonable level of assurance that you can provide product of an adequate quality and an adequate supply to meet the needs of the patients. And, you know,
00:12:46
Speaker
Come again and saying, well, we're working on it. we're We're looking for a contractor. Well, we're negotiating that. That's not a plan. That may be a status report. you know But that that's that's not a plan. And so the ability to to clearly communicate, be an end in mind thinker, and crisply articulate your plans is is a real advantage to a company coming in.
00:13:13
Speaker
I really love that advice. Having lived through the CMC experience on the development side, I can tell you that those guidelines are very confusing, and so I love the idea of, well, just come in and tell us your plan, because that is um that's advice I can understand, and I really appreciate you sharing that perspective, Geoff.
00:13:34
Speaker
and Well, good science should carry the day. yes yeah Good science and sound engineering practice should carry the day. And remember, guidance is not regulation. yeah Guidance is guidance. it's it's It's the current best thinking and perhaps recommended practice.
00:13:50
Speaker
oh But come in and articulate good, patient-centered, risk-based science. And we'll move forward more quickly. We'll move forward with, I'm being very transparent here, we'll move forward with less gamesmanship. And just get to where we all need to be.
00:14:07
Speaker
yeah yeah and I want to come back to that concept of patient-focused science for a second because we often hear people talk about the drug development process as being too slow and too costly, and the FDA of often gets blamed for that problem. so First of all, do you think the process could or should be cheaper and faster?
00:14:33
Speaker
And second, do you think we should be approving more drugs per year to increase patient access? And what would the logistics of that look like? Well, I think that my first reaction is I don't buy into those as the critical metrics. how Those are business metrics.
00:14:50
Speaker
You know, I think that the ah mission of the agency and the review process is to assure that a drug is safe, that a drug reproducibly meets label claim, and let there be no mistake. The company comes in and and should be able to articulate their label claim. You know, what's this stuff going to do, right?
00:15:08
Speaker
yeah you know, yeah ah that reproducibly meets subtle claim. And then thirdly, that you can make it the same way over and over and over. And that's not a matter of ritual. It's because the data which assures safety and efficacy typically comes from lots one, two, three, whatever. But you want to apply it to lot 18, 29, and 142. So having that process be reproducible and in control allows all of those data, which assure safety and efficacy,
00:15:38
Speaker
to be scientifically sound in their application. So when we talk about things being too expensive, taking too long, whatever, coming into the regulatory agency, first of all, ah it you're making your case. It's an exercise in technical advocacy. This is safe. Here's all my data. This meets label claim. Here's all my data. I can make it reproducibly. And here's all my data.
00:16:07
Speaker
What can draw out that process is hedging, minimalist approaches, things like that. um Another thing that can draw out the process is very clear open communication between the sponsor and the company. ah We love to talk to scientists, engineers. And hey, I have a question. I noticed that you have this measurement here. What's up with that?
00:16:36
Speaker
you know. um Frequently though, we have to go through the the high priesthood of vice presidents and QA, regulatory affairs and all this before you can actually ah talk to to to the to the contributors. ah That can slow things down. So for me, ah it's it's making a sound technical assurance of safety, efficacy, and reproducibility. The timeline is in largest part for the review timelines in the United States are determined by the user fee acts, and they're negotiated, and those timelines are met with with great discipline and diligence, similarly for the expedited review programs.
Drug Development Efficiency Debate
00:17:25
Speaker
So when people say, oh, it takes too long, oh, it's too expensive, well, you know,
00:17:32
Speaker
We want everybody to see the circus. It's a great circus. I want everybody to see the circus. In order to see the circus, you have to have a ticket. And the ticket is we know what we're doing. The ticket is it's safe. It works. We can make it reproducibly. That's the ticket.
00:17:49
Speaker
you know And if the investment is in what is the critical information that I need, that can involve speed to market, not having extraneous stuff. People that say, I don't have time to figure out what's important, what's not. I'll just send FDA yeah everything. Well, that's a choice. you know And there are there are outcomes that come with that.
00:18:12
Speaker
the company that says, oh, I only want these, I don't want these seven measurements. I want three measurements because then I have half the chance of failing. Well, first of all, what does that tell me about your reproducibility? colonism But second of all, what? know And and this this draws things out and whatever. So there's just no substitute for knowing what's important, what's not important.
00:18:41
Speaker
being focused, being on task. And again, I'm going to go back to being patient centered. We have so much room to grow with regards to risk based patient centered specifications. You know, are these specs relevant to the clinical outcomes? If the answer is you don't know, okay, well, now you have two choices. You go do the work. Oh, that takes too long. It's too expensive. Or you start crafting a lot of other arguments and taking a lot of other approaches. um I know this is a really long answer, but but I think one of the great successes of of the US regulatory program for the last many years is the biosimilars program. And the reason I say that is is that the standard was not identity. The standard was that the that the drug had to be highly similar
00:19:37
Speaker
with no clinically relevant differences. And that that standard has spilled into a lot of things. Is this variability clinical clinically relevant? Is this measurement clinically relevant? Is this range clinically relevant? And FDA is very open to arguments that are scientifically based that come in and said, we have XYZ variability, but you know what? That's really not clinically relevant. And here's why.
00:20:07
Speaker
Or similarly, we think this is really important, and here are our ranges, and this this is based on assuring a clinically relevant outcome, and here's why. I like that a lot, and I think that's good policy. I think it's good for the public health, and I think it requires focus. ah It also requires an investment in understanding, and it requires end-in-mind thinking rather than milestone-based thinking.
00:20:39
Speaker
So many good takeaways there, Jeff. i And i I love that you bring it back to the thinking about the patients and being patient-centered and you know the biosimilar is a very good example of that.
00:20:54
Speaker
Definitely. And maybe maybe on the topic of biosimilars and and CMC, as we've been discussing, Jeff, I'm a little curious about advanced manufacturing. You've spent a lot of time thinking about this in the past. And and I know you have some thoughts about advanced manufacturing and and how we incorporate more advanced manufacturing techniques into drug development and um drug drug product manufacturing. so But I'm curious, what are the incentives that are going to drive advanced manufacturing? oh That's a good question.
00:21:30
Speaker
um i think that ah ah First of all, let's start with the term manufacturing. yeah When I talk about manufacturing, I'm talking about commercial manufacturing. You take in raw materials, you add value to them, you sell something that has more value. That's what I mean by manufacturing. yeah yeah yeah right and um And I think that one of the things that's changed in the biotech space
00:22:00
Speaker
is that ah you you asked me about about the earlier days of biotech. One of the things that's changed is, in my opinion, or whatever. um Earlier in the game, manufacturing was viewed as a value center.
Manufacturing as a Value Center
00:22:11
Speaker
And the reason was that that biotech manufacturing was new. It was thought that it might be risky. We're figuring out how to do it. And so a differentiator between companies that were successful and perhaps less successful was their ability to actually commercialize their manufacturing. And that manufacturing was a value center and investors looked at, are they really going to be able to bring this baby home?
00:22:38
Speaker
and tank And so one of the consequences of that is you had end in mind thinking. You viewed ah manufacturing science as ah more of a capital investment than an expense. yeah and And you recover value from the capital investments area under the curve over time, as opposed to it to a shorter shorter horizon.
00:22:59
Speaker
um And I think that that one of the things that happened as we moved through the 21st century is that we quit seeing manufacturing as a value center and again seeing it as a cost center. and And what do you do with value? Hey, you optimize it.
00:23:15
Speaker
What do you do at cost? You minimize it. And you start seeing more and more contract manufacturing. You start seeing more and more, boy, can I make this? Or like how can I trim corners on this? ah You see ah enhancement of of ah ah cookie cutter approaches that may be sub-optimally efficient.
00:23:38
Speaker
but ah don't don't require a lot of the technical and intellectual capital that true manufacturing sciences ah support does. So where I'm going with all this is ah when we talk about advanced manufacturing, it starts with, do you see this as being a value center or a cost center? And I think one of the things that's happening today is that advanced manufacturing, and in my opinion, rarely happens in a commercial environment. That if if Scotty on Star Trek beamed us up from from where we are and dropped us into a monoclonal antibody facility, it's it's very unlikely you would know if it was the year 2024, if it was the year 2015. I guess you could look at well people wearing shoulder pads or something. yeah yeah yeah but
00:24:34
Speaker
but but But, you know, ah the the actual manufacturing technology is has has not advanced. And that's crazy. When you look at what's happened with the molecular life sciences and the analytical sciences and big data and all the stuff that we can do is in silico modeling the and the the innovation machine, I think, is healthy and is churning along and somewhere that the clutch that connects it to commercial manufacturing has gotten broken. And that innovation is not burning and churning in the commercial manufacturing area. So one root cause, um I think you asked about drivers. I think the driver for advanced manufacturing is value. Look at your manufacturing as value, efficiency, reproducibility, minimizing surprises,
00:25:28
Speaker
fungibility and flexibility, mobility, all that is derived from advanced manufacturing. If your metrics are cost, so value is multivariate and complex, risk-based.
00:25:45
Speaker
Cost is discrete, fits nicely on Excel spreadsheet where your cells turn red, green, and yellow. And it's arithmetic. you know yeah And so if if you're doing cost, no, you're not going to do advanced manufacturing. What what what I do works just fine. I don't want to incur that risk. I don't want to incur the switch over time. I don't want to do this. I don't want to do that. When we talk about ROI, return on investment, that's that's just those are just cost metrics.
00:26:14
Speaker
you know Here's why I think my return is going to be, but now I'm going to adjust that value based on risk factors. Let's go to the dry board and make a list of all the things that could go wrong. And you're going to end up saying, I don't know, let's make vaccines and eggs.
00:26:28
Speaker
oh is your meat yeah You're going to end up ah but doing things the way we've done them for 20 years. So I'm respectful that people want to minimize risk. I'm respectful. They won't go with what's tried and true.
00:26:45
Speaker
But we have ourselves in a bit of a pickle now yeah because the commercial manufacturing infrastructure, and I include the talent base, really is divergent from the innovation infrastructure and the talent base and all the tools that are being used and the and the the worldview.
00:27:08
Speaker
And i you know I hope this makes sense to your or your listeners, but I go back, I'm always asking myself, how can this be? Why is this? And I think one, there are probably many, but I think one root cause is that we see manufacturing as unfortunately necessary overhead. And then manage it that way. As opposed to say, manufacturing is the last step in that value realization that stands between my great idea and the patient.
00:27:38
Speaker
that's i mean That's where the rubber hits the road. yeah you know and And we're not there in our thinking. Fascinating. Absolutely fascinating.
00:27:50
Speaker
Yeah, and it's a perfect segue into what I want to talk about next, which is what happens when you have a worldwide pandemic and you just aren't ready for all of that advanced manufacturing all in one go. And I want to talk a little bit about COVID now. And previously,
00:28:08
Speaker
We interviewed Melissa Moore, the CSO Emeritus of Moderna, and she spoke very candidly about it what it was like inside Moderna during that time and how they how they had to scramble really to get what they did done in such a short amount of time.
00:28:23
Speaker
And we know that you went back to the agency during the COVID pandemic and we know you can't share everything, but we would love to hear some of what you can share around the challenges that you face during that time. For example, how do you even begin to think about distributing millions of vaccines across the country? Well, that's a That's a very large book that is yet to be written. questions And when those books come out, there are going to be dozens of them from dozens of people sitting in dozens of different seats in the bleachers. yes None of whom are liars. All of them are describing the game that they witnessed. yeah
00:29:03
Speaker
um i I think to describe the context, first of all, you need to understand that that no one at FDA is sitting around with nothing to do, ever. And go walk in and sit down at your desk and say, gosh, you know. And so from a capacity management perspective,
00:29:25
Speaker
the The governmental system is set up not to optimize capacity management, but to to maximize that throughput. you know Second of all, ah anybody who does capacity management engineering or process design knows you have rate of input, rate of exit. And these are all control points. At at FDA, there is no control. You you take whatever comes.
00:29:52
Speaker
you know You can't say, oh, I'm sorry, the bowl is full. No. You you you take whatever comes, and then everybody wants an exit rate as quickly as possible. So of course, there's the story around the vaccines. And the the people in CBER who who just worked extraordinarily hard partnered with ah developers all over the world in very open, very forthright, very honest conversations.
00:30:21
Speaker
with with fabulously successful and aggressive ah development programs, to where if you go back and you look at non-adopters, people that didn't want to take the vaccine, one of their arguments was they couldn't possibly have developed it this quickly. You know, it can't be safe. They couldn't have developed it this quickly, which is kind of a crazy argument, okay? And then within the US, we had Project Warp Speed,
00:30:48
Speaker
where there are dozens and dozens of stories. but But the central strategic thought was, you know, we're going to assume that somebody's going to come up with a life-saving vaccine that's safe and efficacious.
00:31:02
Speaker
um We're not going to worry about that. We're not going to worry about when it comes up, how are we going to make millions of doses and distribute them and get them into people's arms?
00:31:14
Speaker
And there are a lot of different ways to do that. And there was enormous collaboration across different parts of the government. ah that The US military was hugely, just just a fabulous partner. If you think about it, ah they are experts at logistics. I need a fuel pump from an F-14 and some remote geographic location. you know There's a fuel pump there, right? Right, right, right. They're really good at that kind of stuff.
00:31:39
Speaker
Um, a lot of dedicated people really, really worked on, on moving these things forward from the manufacturing side. And, and obviously a lot of it, I can't, can't go into detail, but I can tell you that there were a lot of companies that stepped up and said, we have capacity. What can we do to help? And that was really cool. That was really cool. This idea of we're, we're not competitors now. We're all in this, all in this together.
00:32:05
Speaker
um I think another set of things that happened that might everybody might not have seen, because you don't you don't see the problems that don't happen. Does that make any sense? Yeah. But enormous work went into stabilizing the drug supply. And there's an appropriate focus on the extraordinary efforts and successes of developing the industry in the vaccine. Very appropriate. But also, all over the world, supply chains were compromised.
00:32:34
Speaker
all over the world, um ah things were a snarl. And really, if you think back on it, ah there Were there shortages? Absolutely. But you didn't have a lot of people going to their local pharmacist and not getting their meds. You didn't have a lot of people that that that were not able to get the critical things yeah that they needed. um ah Kelly Rogers, who's the biotech program manager at NIST, had a great quote where she said, gosh, who knew that the world ran on pipette man tips?
00:33:07
Speaker
you know know ah you know Yes, and we learned all over about disposable bags and PPE and things like this. And there was enormous amount of work resolving all those very, very complex, sophisticated supply chains that um I also want to say that was a big, big part of it. And a lot of times when it doesn't fail, you don't see it. And that's good, right?
00:33:33
Speaker
But boy, there's a lot of work behind that. So lots of stories, many, many other people are going to be telling them. you know, ah but it was a lot of people working really, really hard. And another thing I'll throw out to you is that at the end, let me tell you what, we we can talk a lot about what happened. Let me tell you what didn't happen. That's easier, right? yeah What didn't happen was, right. Good job, you guys. Take a few months off and recover. but and And then we'll all get back together and figure out where we were and kind of pick up the pieces.
00:34:10
Speaker
right No. and And we talk about speed to market reviews and things. The reviews continued. You know, there were a lot of challenges with inspections. the the yeah the The reviews continued, oversight continued, shortage management continued, criminal investigation into things like awful things like counterfeiting or people who were exploiting the situation continued.
Pandemic Workload Impact on FDA
00:34:32
Speaker
All that stuff just went on. And that's one of the reasons that in many ways it was such a body blow to the workforce at places such as the FDA yeah is that not only was there the extraordinary commitment, which
00:34:44
Speaker
the entire biotech enterprise had to resolving the pandemic dilemma, ah but there was no recovery. like Right. Good job, you guys. yeah take take Take a couple of free months. Go reintroduce yourself to your kids and but well we'll see you in April. Yeah, no, that that that that didn't happen.
00:35:06
Speaker
yeah
00:35:11
Speaker
yeah Really heroic, really cool to hear. And you know in communications, we totally understand that. If you know something didn't go wrong, it's hard to say that, well, it looks like it went right. People don't tend to to see that argument as well. So totally hear that in ah in a different vein. Well, but but I think before we step away from the topic of the pandemic, that this this is a great story because I think the biotech community as a whole in a very organic way, rose up on its hind legs and did advanced problem solving. Frequently in the total absence of centralized leadership, ah certainly frequently or the the the informal networks were fully, fully leveraged, fully, fully developed, and the biotech community as a whole should take some pride in that. that but it's ah It's a look at what we did moment.
00:36:06
Speaker
You know, ah no, everybody's names will not be in the footnotes, you know. Yeah. But ah it was really for one of a better term, an organic uprising of the biotech community. And we science the heck out of a problem to global benefit. Yes. Yes. Thank you for highlighting that because it's absolutely true. I love that. All right. So.
00:36:32
Speaker
Now that we've talked about this huge success, I want to talk about some bottlenecks. so One topic we haven't spent much time talking about on the podcast is what happens when a biologic nears commercialization. so Given your experience both at NIST and at Nimble, can you talk to us about the bottlenecks that the biopharmaceutical industry faces and what preclinical and early clinical stage companies should be thinking about now when it comes to manufacturing? Well, first of all, when you talk about bottlenecks, it's bottleneck to an outcome. And I think that there has to be an honest
00:37:14
Speaker
introspective ah conversation with oneself within one's company about what is success was our successful outcome.
Defining Success in Biopharma
00:37:23
Speaker
Now, when I was in the game, successful outcome was three years on the market hitting all of our commercial goals. Okay, that's success. Let's work backwards from it.
00:37:38
Speaker
and figure out what's what are bottlenecks, what's critical path, what is, what isn't, what do we need, what do we not need to differ from failure modes analysis. Now, on the other hand, i'm I'm getting ready to show my age. I talk about the right hand side of the acetate. People don't even use overheads anymore. yeah The right hand side of your timeline,
00:37:58
Speaker
is not, ah say, three years meeting commercial manufacturing goals. If the right-hand side of your timeline is submission, if the right-hand side of your timeline is derisk this thing enough to get purchased by somebody else, if the right-hand side of your timeline is the next infusion of funds from whatever source, okay that's a different game. And you're managing different risks, and it has different consequences.
00:38:26
Speaker
isnt Manufacturing is capital intensive. And so it's a strategic choice. Do you want to kick that decision down the road and kick those w risks down the road and say, ah, we'll worry about that later? Or do you want to say, gosh, this is where my big pain points are. Here's where my critical failures are. The last thing I want to do is be in a situation where I have something that's safe and efficacious and meets patient needs. And now I have to wait two or three years to make it. I mean, that's the last thing I want.
00:38:58
Speaker
right? and yeah and And do that kind of end in mind thinking. So you asked about bottlenecks and pinch points, but it goes back to what's your what's your output? You know, what's what's your end game? So it starts there.
00:39:10
Speaker
Now, the second thing with bottlenecks and pinch points, and and i i I encourage people who have an interest, there's there's a fabulous book by Hoppen Spearman. It's classic. It's not a breakthrough. It's called Factory Physics. It talks about these things. but You cannot eliminate bottlenecks. That's just silly. There's always going to be someplace that's a bottleneck. What you want to do is make sure you manage bottlenecks so they're in the most value adding,
00:39:40
Speaker
or the least risky place that they can be. I want to have my bottleneck where it has the least impact on the overall project, the least impact on the overall project, and the least impact on my resource burn. But of course there are going to be bottlenecks because something's always going to be slower than another thing. right right so So accepting that just at the front and saying, now, I want to manage to an outcome,
00:40:07
Speaker
is a big, big, big step forward. I'm a big fan of of of end in mind thinking. I'm a big fan of risk-based approaches. And I'm a big fan of approaching project management as a science. And anybody who's using mean time, well, I can tell you, if you have a a spreadsheet or a Gantt chart or something where you say my average time is X, ah without even seeing your report, I can tell you there's 100% likelihood that that number's wrong.
00:40:36
Speaker
okay right we all so We're fully willing to accept error bars in our assays. All timelines have error bars. And managing the knock-on effect of those multivariate impacts on the timeline is just science. It's just engineering like any other. That's the science of project management.
00:40:59
Speaker
And project management should not be something that's done on a side or that's a career development opportunity for ah for an employee or something. It can be a critical make or break um ah you know ah success element yeah you know to what you're doing and and moving these things forward. Now, and the last things I carry on about this for a while is there are certain things that are non-compressible timelines.
00:41:27
Speaker
They need to look at what's compressible and what isn't compressible. If I throw a whole bunch of money in, a whole bunch of people at this, will it go any faster? If the answer is no, 18 months stability takes 18 months. It's like a rule.
00:41:40
Speaker
right ah If you're working in 10 or 20,000 liter tanks, it takes X amount of time to fill them and Y amount of time to drain them, it's a rule. okay Understand what's a non-compressible timeline. On the other hand, if if I can apply my innovation to the same innovation that I applied coming up with nanoprobes for pH to say, gosh, how can I crush the turnaround time on this assay?
00:42:10
Speaker
you know, then that's a compressible timeline. And the easiest way to take something off the timeline is not to do it at all. and And those are classic lean elements. And lean is only successful if, in fact, you know what's critical and what's not critical. Otherwise, you're going to be carving out by accident critical elements. yeah But ah the the easiest way to knock something out, not to do it at all, is to say, you know what?
00:42:41
Speaker
um charged, monoclonal antibody charge distribution, sialic acid content for my particular product made this way is simply not clinically relevant. And here's why.
00:42:54
Speaker
And people go, oh my gosh, oh my gosh, you have to do charge distribution of sialic acid content. And if nothing else, it lets you use words like di- and triantinary sialic acid content, which makes you look erudite and smart in front of other people. you know but But the thing is, is it clinically relevant or not clinically relevant? And and if it's not clinically relevant, don't do it.
00:43:14
Speaker
yeah There, I just helped your timeline, you know? but But this goes back to risk management, risk aversion, and also an investment in understanding. Understanding and knowledge management are different from assessment and data analysis. One is measurement and arithmetic. The other is a grasp of risk, possibility, opportunity, what's a big deal and what's a little deal.
00:43:44
Speaker
you know And those are success elements too. And this goes back to workforce development and recognizing that intellectual capital is indeed a critical asset, not just unfortunately necessary overhead.
00:44:00
Speaker
Yes, definitely. And I think that the one thing I'm going to take away from this meeting above all else is end in mind thinking. I love that expression. So thank you for sharing that with us, Jeff. It's it's a great way to to think about the world.
00:44:16
Speaker
So, in kind of coming to, you know, the end of our time together today, I want to talk about your decades of experience across multiple facets of drug development. You no doubt have seen everything there is to see. Both good and bad. No, no. Let's push on. Yes. And we like to ask all of our guests, what key pieces of advice would they give to an early stage company? So for example, what is your message for those who are approaching the FDA for the first time or beginning to think about manufacturing at scale?
00:44:54
Speaker
I think that that those are a little different because um you ask about key message for for for product and process development and then a key message for moving into manufacturing and approaching the agency. I think that one thing that's critically important through product and process development is what is my product?
Understanding Product Attributes
00:45:17
Speaker
ah her What's my product? What is the unmet need?
00:45:21
Speaker
What are the critical quality attributes? What is going to make it successful or not successful? What am I going to sell? What's my product? And doesn't that sound, golly gosh, that sounds so basic. But I'm consistently surprised that people that say, oh, well, we have this platform. And oh, well, we have this technology. And oh, well, we can do this, that, and everything. I go, boy, fabulous. High fives. What's your product? I mean, a good idea is something that we want more than our money.
00:45:51
Speaker
A product is something the other guy wants more than his money. you know so So what's your product? And so now what's going to make that product successful? If you're fabulously successful, what's that going to look like and and walk it back? And so now that sets you up for looking at manufacturing and site sourcing. What do I need? What do I not need?
00:46:15
Speaker
um do Do I view manufacturing as a critical capability? um um i Certainly, had my views on it. you know ah when when i When I go to the agency, now what you're going to do is, again, this is an exercise in technical advocacy. Job one is you want to talk to the FDA, and when you're done, you want FDA kind of going, well, okay, those guys know what they're doing.
00:46:41
Speaker
You can agree or disagree on specs and things, right? But job one is you want to go, those guys know what they're doing. OK, you walk in. Hey, we know our product. We know our process. We know our customer base. Here's the data we have.
00:46:58
Speaker
We have a very high level of assurance that this is safe, that this is going to work, that we can make it reproducibly. You know, guys, there are some things we haven't worked out yet. We're still working on A. We're still working on B. C is an 18-month study. you know It's underway. we'll We'll give you the data when we have it, but we're optimistic. We're we're struggling with how to do alpha, beta, gamma, but <unk>re we're working on it. That's open, honest, forthright talk about where you are and where you're going.
00:47:26
Speaker
And that's going to get you so much farther than saying we look forward to fully leveraging our cross-functioning line, but nevertheless, individually accountable matrix environment to the benefit of the public health and the patient, as well as stockholders. I mean, far better. Far better to come in and say, this is my product. this This is what it's going to do. This is how it's going to work. And guess what? I know how to make it. Here's my data.
00:47:55
Speaker
and And if you don't know, don't pass go. Do not collect $200. Go figure it out. ye you know but But here's my story. I'm ready to go. I'm ready for prime time because, there is ah again, there's a predisposition. We all want to see those products hit the market and get out there.
00:48:20
Speaker
But ah you guys like stories. We don't have time for this one. Go Wikipedia or something. Go look up the Kefaufer Harris Amendment. And this was a pivot point like in the history of the world or yeah know or so or something, but where where it said the burden is on the company to make the case that their product is safe, efficacious, and reproducible.
Proving Safety and Efficacy
00:48:44
Speaker
The burden is not on the government to set the standard. Now, I like that because science moves fast. Innovation moves fast. Government moves slow.
00:48:57
Speaker
culture The expertise, the best and brightest minds in the world are are out there in the industry doing what they do so well. Let's let them do it. Go wild. you know Go do it. And then come in and make your case to the regulatory bodies. you know We know what we're doing. Here's the science. Here's the engineering. And and and let's move things forward.
00:49:23
Speaker
Jeff, what a great cap to the conversation. I want to say thank you so much for sharing all of your perspectives. I mean, it's just been incredible. So thank you for being on the podcast. Yeah. Thanks, Jeff.
00:49:35
Speaker
Well, of course, I really loved hearing that Jeff thinks the ability to tell a compelling story is a competitive advantage, even in the highly regulated discussions that take place within the FDA. Being able to succinctly say who you are, what you do, and why is an invaluable tool. That's the whole ethos of this podcast.
00:49:57
Speaker
Yeah. It's, of course, no surprise to our listeners that the FDA wants a plan. But I think hearing Jeff's perspective on what constitutes a plan is insightful. Less of the operational aspects and more of what you intend to do and why you intend to do so, which, of course, is just good communication in any situation.
00:50:18
Speaker
Yeah, I agree with that. And I also want to discuss Jeff's advice around talking to the FDA. I really liked how he framed it, that you should be letting them know what you're doing, give them a plan, and then asking for clarification. Our listeners are probably thinking, well, that's certainly an oversimplification of those discussions.
00:50:38
Speaker
And whilst that might be true, I think the concept of pairing that with the end-in-mind thinking of that this needs to be safe, it needs to meet the label requirements and be reproducible over time for the patient, I think we get a really good framework of how and why those discussions should take place.
00:50:57
Speaker
Yeah, completely agree. There are plenty of caveats, but if we start with the patients and end with the patients, we'll be aligned with the agency. I also agree with Jeff's points, which stem from the Kefour-Harris Amendment in response to the outcome of using thalidomide, that government moves quite slowly in comparison to innovation. Therefore, the burden of proof that a drug is safe, efficacious, and can be made reproducibly is on ah the innovator rather than the government.
00:51:27
Speaker
Well, I really enjoyed this discussion and I think it shows that even in regulated discussions with the FDA, that telling a compelling story that clearly articulates our plan, what we intend to do and why, is always a competitive advantage. So join us next time as we continue this journey to power scientific innovation with storytelling to drive transformative change and solve our most demanding challenges.