Robert Packard, President at Medical Device Academy, Inc

Jesus Moreno (00:02.012)
Welcome back to Global Trials Accelerators, the podcast where we dismantle the barriers to clinical innovation. I am your host, Jesus Moreno. And today we're diving deep into the prelude and aftermath of clinical trials. In the medical device world, the valley of death isn't just about failing a study. It's often failing the regulatory strategy before the study even begins. Joining us today is Rob Packard.

a regulator consultant with over 30 years of experience in the medical device, pharmaceutical and biotechnological industry. A chemical engineer by training Rob has several, excuse me. A chemical engineer by training Rob has served as a CEO of a laparoscopic imaging company.

and spent three years as a lead auditor for one of the world's largest notified bodies. He is the specialist startups call when they are dealing with high risk implant drug devices or a complex 510 case of mission. Rob, it's an honor to have you with us. Welcome to the show.

Robert Packard (01:18.658)
Thank you very much.

Jesus Moreno (01:21.778)
Rob, your career covers every side of the medical device industry. You've had the technical foundation of a chemical engineer, the experience of a CSUN CEO, and the critical eye of a lead auditor. How has evaluating nearly a thousand companies transformed the way you approach the

regulatory preparation process.

Robert Packard (01:55.892)
most of the, companies that I've audited over the years, it was for either a supplier audit for another medical device company, or it was for a certification process. when I was working full time as a, as a, notified body auditor, I would have to make the decision on whether they met the requirements for.

ISO certification for 1345. So when I would visit these companies, was very, it was very targeted on, this meet the requirements for certification? But as a consultant, my, my role is evolved into much more of a practical approach. So as a consultant, when a company asked me to help them or audit them,

it's you've seen all these companies, where do we fit in the spectrum? Are we doing less than most companies? Are we doing more than most companies or right in the middle? And what advice do you have for us that would be practical? Because just doing paperwork for paperwork sake isn't really helpful to the companies. So

as a person that's been an entrepreneur and run my own company in the medical device field, I can not only benchmark what they're doing, say, this is where you are in the spectrum. You're doing less than most companies, you're doing more than most companies, or you're doing just about the average. But I can also say, if it were my company, this is how I would do things.

And these are the things that really add value and help you get to market and help you be successful. And these are the things that are really making your paperwork look nice, but they're not helping the patient. They're not helping the doctor or nurse that's using the product. And they're not something that the regulator is going to really focus on. It's just paperwork. So identifying the difference is really helpful for

Jesus Moreno (04:00.241)
you

Jesus Moreno (04:11.664)
Mm-hmm.

Robert Packard (04:14.399)
some companies. I know that, for example, when the FDA announced that they were going to be switching over to the QMSR instead of the QSR, a lot of consultants said, you've got to do a process FMEA for every single process you have. It doesn't even say you have to do a process FMEA, let alone do one for every single process you have. What the FDA does

is when they come into a company for an inspection, now they're asking, can I see your process FMEA for this product that I'm going to be inspecting? And they look on that process FMEA for what the most high risk items are in the manufacturing process, and they focus on those. So it's only a tool that helps them identify what's important. And they're only looking at it

for the production of a product, not every single product you have and not every single process you have. Like, how do I create a label and how do I apply the label and how do I pack things in a box? Those aren't the high risk processes that they're looking for. There's some other process that is high risk that they want to focus on. So I think part of...

my job as a consultant is just to help them identify what's important, both from the entrepreneur standpoint of running your business, but also from the regulator standpoint, what is the regulator going to look at and scrutinize most? And I think other people get too focused on the paperwork in what it says on page 42 of this standard instead of,

worrying about what's really important, what will be a safety issue, what will be a performance issue, what will make your business run well and what the regulators feel is the thing that they need to spend their time on.

Jesus Moreno (06:24.026)
So it's more about the spirit of the standard than the standard itself or following it to the letter.

Robert Packard (06:30.785)
Yeah, the intent rather than the letter. Yeah, and and I guess some people call that more of a liberal approach rather than a very conservative approach. And I think that would describe me in just about everything. I'm very much about trying to do things that are practical and you can, you what's...

What good is it if you can only do it once? Is this something I can do every day? If you don't like your broccoli, then why are you going on a broccoli diet? You're not going to be able to sustain it. So if your business is not going to be able to do all that paperwork every single day, then why are you trying to do it once for the

Jesus Moreno (07:02.289)
Mm-hmm.

Jesus Moreno (07:17.253)
Yes.

Robert Packard (07:28.513)
the inspector or auditor that's coming. Design a system in a process that you can do every day and do it well. And so the practical approach is what I try to emphasize and I try to keep it simple. I hear a lot of people say, what we really like is you take these really complex standards and you make it easy to understand and you make it simple.

that I'm actually quite proud of. Because it takes me a long time and a lot of repetition of reading it and seeing it done by a lot of companies and actually doing it myself before I can explain it in simple terms.

Jesus Moreno (08:14.13)
And you've mentioned that you love the training aspect of your work. And for listeners, let's give them a little bit of context in regards to ISO 13485 and 14975. If I may summarize them quickly, you can tell me if we're close to the practical definition of them. I see 13485 as it governing

Robert Packard (08:18.54)
I do.

Jesus Moreno (08:43.794)
the company's quality system and the 14971 covering the device risk management. And to a layman, that sounds like dry compliance hurdles, but they are the bedrock of commercial survival. Would you agree with that statement?

Robert Packard (09:09.197)
It should be some companies we would, we use the term that the company is just providing lip service. They're just going through the motions and they're not really embracing it. So when we see a company that is taking it seriously, 1345 is how they run their business. They want to make a quality product. They want to follow those

Jesus Moreno (09:34.706)
Mm-hmm

Robert Packard (09:38.734)
regulations and they're doing it not just because the standard says so, but because that's how they really want to run their business. And they believe that it's going to make a better product. So that's 1345. And the basis of it right from the beginning was a very simple model of the process approach. So what is your process? What are the inputs? What are the outputs?

and planning your quality system, executing the plan, then checking it, which involves auditing and measuring things. And then when you find things that aren't perfect and nothing ever is, you come up with a way to improve it and start the cycle over again. So they call it a plan, do check cycle or PDCA. And so don't worry about trying to make it perfect the first try.

try to instead build a process that can improve and evolve and become better over time. On the risk management side, that's a little different because it has two parts. One is process risks. So if I'm training somebody, how do I make sure that I'm taking a risk-based approach? And then we have

Jesus Moreno (10:47.598)
Why do you

okay.

Robert Packard (11:08.109)
product risk that's very different. Product risk would be, it going to harm a patient or is it going to harm a user?

Jesus Moreno (11:21.33)
Why do you think so many startups have a blind spot here? Is it a symptom of the founders prioritizing the engineering aspect of the prototype over the engineering of the business?

Robert Packard (11:36.936)
I think, most CEOs, are interested in running the business and, not interested in filling out the paperwork. and they see that the paperwork is being something that is a necessary evil.

They don't see how it can really improve their business. I think it's just they're not waiting. They're not patient enough to wait to see the benefit. We just had a CEO that we were helping train him on how to adopt 1345. And he wanted to jump right into his clinical study.

He's like, I have the doctors lined up. I have the product. I want to go. I want to go. want to go. And I kept on saying, wait a second. We don't have this information. We don't have this information. And I was going through the suppliers that he had. And I was like, you haven't defined who the suppliers are going to be. You haven't defined what your specifications are going to be. And he didn't understand why that was important. And I was.

Jesus Moreno (12:59.762)
you

Robert Packard (13:01.951)
And I finally got to the point one day where I, where we had all the suppliers identified. We had all the specifications identified. And he, he looked at how it was that day and he compared it in his mind to what he had six months before. And he's like, it's so much better now. Like before I was.

I didn't have a box to put it in. I didn't have a pouch to sterilize it in. I didn't have a sterilizer identified. I was buying components from multiple suppliers. Now I'm just buying several components from one supplier. He's like, it's so much easier to run it now. He's like, now I only have to order things from three different companies and I'm done. Like, that's it. I only have these

very, so he had a fewer, he had a smaller list of suppliers. He knew exactly what he would order. He knew what size it was. He knew what cost it was. He knew how it was going to be delivered. So everything was clear. And I'm like, that's how it's supposed to be. You spend more time in the beginning, trying to identify exactly who you're buying something from, what you're buying from them and what the specifications are.

Jesus Moreno (14:09.81)
you

Robert Packard (14:28.447)
so you don't have to think too hard later, you just repeat. It's sort of like a carpenter, they have a saying, measure twice and cut once. It's so much more difficult when you don't measure. Like, well, it's not quite level, it's not quite straight, it's too short, it's too long. That's what happens when you don't measure. So I was trying to get him to do the measure stuff, like, how long does this need to be?

what material does it need to be made out of? we actually end up, I kept on saying like, he had a little clamp that he put on the product. He had a piece of wire and then he put a clamp on it to hold it in place. I was like, well, what does the clamp need to be made out of? And how strong does it need to be made? And does it need to be plated or not plated? And he got so frustrated. He's like, you know, I don't even need a clamp. I can just twist it around the...

this and it will be fine. And I'm like, so eliminate the clamp. And he's like, I can do that. And like, it's your design. If it will hold without the clamp, then eliminate the clamp. That's an improvement. One less thing to worry about. So he eliminated that. every little tiny things like that, the more we talked about it and the more we tried to refine it, the simpler it became.

and the easier it became to build. And he saw his cost of making the product actually reduce. Over time, it went down, down, down. So he started out, oh, it's going to cost me $10 to make this. And now it's down to $5. And then it's down to $2. It became less expensive to build. He had better suppliers that could deliver exactly when he wanted it, exactly where he wanted it, and the packaging he wanted.

It was just a better solution in the end, but it was because the detail that we put into the planning and refining it. And he didn't want to do that in the beginning. He thought it was a total waste of time. It was just wasting his money. I said, now that we have everything exactly the way you want it, we don't have to discuss this unless we have a problem in the future. So now you can go ahead and you can order pallets if you want to of this.

Robert Packard (16:57.569)
We don't have to be careful. We can be aggressive and buy a lot of product and build a lot of product because we know we're not gonna make a change now. And so it was all, it all became this light bulb that went off in his head. Like it really was worth it to do all that work. Thank you for making me do it. He actually did thank you for forcing him to go through those steps.

And it was painful for him and it was probably even more painful for myself because I knew where it was necessary, but I was struggling to get him to see the value. And then when he finally got there, he acknowledged, like, this was really worth it. And he was very proud of what we we've had in the end. And we had we even had a little bit of luck.

Some people don't know a lot of details about sterilizers, but we were gamma sterilizing this product and you have to put it in a big metal carrier and it just so happened that exactly the quantity of boxes that fit in the the carrier was exactly what would fit on a pallet and There wasn't any extra room. It just it was like it was they built the sterilization facility for our product and I was like

Jesus Moreno (18:17.266)
Mm-hmm.

Robert Packard (18:18.219)
That's not what happened. You know it isn't. What happened is we went and got the measurements and we designed the box to fit it. So we designed it to fit perfectly. It looks, after the fact, like it was luck, but it wasn't. We actually planned it that way. He's like, I didn't know you could do that. I'm like, well, most people don't. They don't measure and they cut and then they wonder why it doesn't fit right.

So that was the advantage of taking their time to come up with the right specification for what size box to use. And we didn't use an expensive vendor. We just went to Uline and picked the Uline box, but we picked the right box that fit perfectly.

Jesus Moreno (18:48.624)
Mm-hmm.

Jesus Moreno (19:11.62)
Now shifting gears and putting on the lens of the lens of a entrepreneur that's, you know, fighting that burn rate. How do you optimize this transition process between having an idea, having, trying to move fast, trying to hit those milestones quickly.

but taking the time to strategize and assign for success. What are some of those traps, hidden traps that you look for when you work with an early company to settle the systems up?

Robert Packard (19:59.918)
A lot of the companies, they worry about the things that they don't understand that are at the end. And they don't know what's important and is a critical path item right now. So for example,

When you're designing a medical device, if you can build your device, you can make a whole bunch of samples, but if you make them out of materials that are not biocompatible, you're gonna have to start the whole thing over again, because you're gonna have to change all your materials to a new material that's biocompatible. So very early on, I'll emphasize, we need to select the right materials and make sure they're biocompatible before we go any further.

And they want to jump to doing some expensive tests at the end, like a clinical study. But no, no, no, you got to step back and make sure you're making it out of the right material, or we'll have to repeat the whole entire clinical study over again, because you changed the material. So we need to spend time on this critical path item now. Once they pass that, there's another critical path that comes right after it. And there's always another critical path item.

Jesus Moreno (21:09.234)
you

Robert Packard (21:27.885)
because I've been through the process hundreds of times, I know what the critical path items always are. But all they see is a thousand details and they don't know which ones are the important ones. And so part of it's just pointing out, you first have to select the right materials and verify they're biocompatible. If you have an electric medical device, they're like, well, I need to get a quote for electrical safety testing and send it off to the lab. I'm like, time out.

Before you do that, you have to do a risk analysis. Like why? Because if I send the unit to the electrical safety lab without a risk management file, they won't be able to complete the process. The first two weeks is testing. The remaining six weeks is filling up the paperwork and the report. If you don't give them the risk management file, they can't fill out the paperwork and the report at the end.

so they can't give you a certificate saying it's safe. They have hundreds of pages they have to review to make sure it's safe, and if you're not giving them the paperwork, they can't finish the job. So start with the paperwork first, because that's gonna take you longer than the testing. The testing, all I need is a handful of units in two weeks. The paperwork, it's gonna take me six weeks to...

to fill out the paperwork, but it's gonna take me six months to make the paperwork. So they have this gigantic risk management file they have to create, and it is gigantic. If I printed it all out, it would be thousands of pages. But they don't understand that a lot of the delay in electrical safety has nothing to do with safety testing. It has to do with verification that all the risks that are required in the standard have been addressed.

Jesus Moreno (23:11.802)
you

Robert Packard (23:23.615)
in the paperwork. And so the labs that do the best job are the ones that really understand the standard and know how to go through those files. And my favorite example to them is you're going to get a checklist that's 80 pages long asking you where all the things can be found in your documentation. If your documentation is 10 pages long, but the checklist is 80 pages, you're probably missing some things. But if you have thousand pages,

And you have an 80 page checklist, probably somewhere in those thousand pages, each of the things in the checklist. So they, they start to like, well maybe I do need to worry about that paperwork because if I need to create a thousand pages, it could take me a long time. So that's usually one of those critical task items that they don't want to worry about because it's not fun. It's not exciting. It's they don't see any value in it, but they won't get their electrical safety certificate without it.

So that's something I focus on. But there's this little steps like that along the way. like, you're worrying about the fun, exciting stuff at the end. And you need to do this stuff at the beginning or you won't get there.

Jesus Moreno (24:46.244)
It is quite an involved process, it? But for the CEOs and entrepreneurs that might have jumped the gun and have already started their clinical trial, can you walk us through how they could potentially realign themselves with

Robert Packard (24:50.284)
It is.

Jesus Moreno (25:15.73)
missing, having missed some of those critical steps, is there a way to recuperate or to take that raw messy data that came out of that maybe unsuccessful clinical trial and make it valuable for their regulatory process? Or do they need to scrap the whole thing and start all over?

is there a strategy they could use to potentially realign the results rather than having to start all over.

Robert Packard (25:58.142)
normally I try to prevent that messy situation right from the start. they, they will come up with a protocol. Let's say it's, 50 pages and they'll want to take that protocol and they'll want to send it to an IRB and get approval so they can do their study. And I say timeout, let's make sure that the FDA says.

that we're collecting the right information so we can get approval. And they're like, no, they'll just make us do more. And I'm like, not necessarily. It could be as simple as you're measuring heart rate, but I want you to also make this other measurement that's maybe blood pressure. And you can't.

after you've completed the study, can't go back and measure what their blood pressure was six months ago. It's too late. I don't know what it was. I didn't measure it. I don't have the data. And the says repeat your study. So I try to convince them, let's spend a little bit of time now. And it's usually 75 days because that's how long the FDA will take to review your data and have a meeting with you. said, let's take 75 days.

and let's send that protocol to the FDA and get their feedback on it now so we don't have to redo your entire study. Because I don't want you to spend a million dollars on a clinical study and then have to repeat it and spend another million. I want you to just spend that million dollars once. And one of the other things that I point out is there are certain things in your clinical study

Jesus Moreno (27:29.455)
And this would

Robert Packard (27:49.006)
protocol that are really important and certain things that are not really important. So one of the things is the inclusion and exclusion criteria. A lot of companies want to design a study where they only look at the best possible patients. So I want somebody that's non-smoker, ideal weight, ideal age, you know, nothing is wrong with them. Like, so my study will go perfectly. Well, that's great. But then

The FDA will say, you don't have any older patients, you don't have any younger patients, you don't have any fat patients, you don't have any patients with this wrong. So you can't treat any of those patients that you didn't test. You're gonna have to put all kinds of limitations in your indications and warnings and precautions because you didn't look at those other populations. And so you should really design inclusion exclusion criteria as broadly as you can so you learn

where there are problems and where there are no problems. So if you think your device will work for tall and short people, then evaluate tall and short people. Don't just look at the person that's 5'8 and 140 pounds. You've got to look at all the people, the people that are giant like me and the people that are little tiny people like my sister. So inclusion exclusion is one of the...

things that I have them focus on and try to write it as broadly as they can because that's the population they want to treat when they have the product on the market. The second thing I try to get them to focus on is what is your one primary endpoint? I see most entrepreneurs, they're not clinical experts, so they hire an academic. They hire somebody at a university. Oftentimes the product was spun out of a university, so they go back to the university and

They asked somebody at the university, how do I design a clinical study? Well, the person at the university is an academic and they're writing things for publications. They have no idea what will be interesting for their publication until after they've done the study. So they want to have it as broad as possible. The FDA wants the exact opposite. They want you to have one indication and that's the one primary endpoint that you're measuring and you must pass.

Robert Packard (30:15.027)
If I'm trying to make a product to, let's say it's an implant and I'm trying to make sure that it lasts for a certain length of time and it heals in a certain length of time, there's so many different things I could look at, but what is the one thing the FDA cares about most that I want as my primary endpoint? And that's gonna be directly related to that device and the acceptance criteria for the study.

that a lot of times it's you have three or four or five different things that you have as endpoints, but you've got to sit down with the FDA in the pre-sub and say, well, which one of these should be our primary endpoint and which one should be our secondary? And the FDA says, well, if you want this indication, this needs to be your primary endpoint. If you want a different indication, it would be a different primary endpoint.

And in the last meeting I had with the FDA where we reviewed a clinical study protocol, the FDA said you actually have two different choices. You do not have to include both. Only one of them needs to be primary. So you decide as a company whether you want it to be this criteria or that criteria, but you don't have to do both. And they're like, oh, that saves us so much money. Like exactly the reason why we have the meeting with the FDA because they, they saw that we were trying to do both.

And we only needed to have one. And they said, you only need one primary endpoint. You don't need two. So pick the one that's easiest. And that was almost word for word with the, they were like, pick one. They actually basically he's like, we got to make sure that's in the meeting minutes because that saves us a lot of money. I'm like, that's why she said it. And so then they said, you can have as many secondary endpoints as you want, but you don't have to pass them all.

You can only make claims and have indication for the things that you passed, but because they're secondary endpoints and not the primary, it's not a make or break whether you're going to, you're not going to get cleared because you missed a secondary endpoint. You just won't be able to say you can meet that criteria if you don't have the data. So that really helps them to understand you only need one primary endpoint and be very selective about it. And when you submit your protocol to the FDA, ask a question about

Robert Packard (32:39.501)
Is this the right primary endpoint or would one of these other secondary endpoints be more appropriate? And the third thing that I try to get them to focus on is the sample size. And I know every company in the world wants to hear their sample size is one or two. Like, the magic number three, we're going to do three patients. And that's it for a whole study. Almost everybody doing a clinical study knows that three is not enough. But.

They don't know how much is enough and it's almost like we have these conversations like how much can I get away with? How little can it be and the FDA will say yes, and that's not how it works. You have to hire a biostatistician and you have to show that statistically you that your product will do what it you're saying it will do compared to a control group. So

If you're saying this is going to make somebody heal faster, you have your control, you have your experimental, and you have to show statistically that it's going to heal better. The bigger the benefit your product provides, the fewer patients you need to prove that. So if you look at my sister and me, she's 5'1", and I'm 6'6". You don't need a statistical sampling to know that I'm taller than my sister.

One is enough. can see, yep, he's a lot taller. But if we were twins and we were both the same height, you would have to take lots of measurements to make sure which one's actually taller by a millimeter. so when you're trying to show a product that's barely better than another product is good enough to get cleared by the FDA or approved by the FDA,

you have to do a lot larger patient population. So sometimes the secret to having a smaller clinical study is to make a better product or pick an endpoint that your product is better for and have that thing that you are trying to say your product does have that be a secondary endpoint. Have the thing that your product does best have that as your primary endpoint and measure that because that'll keep your

Robert Packard (35:01.931)
your size of your clinical study down. And the companies, don't want to hire a biostatistician. And when they, when they come up with, when they talk with the biostatistician, the biostatistician says, well, how much better is your product than the competitor? Like, well, we don't know. Like, well, you need to know, you need to have at least an educated guess, or I can't do any calculations. I can't even estimate.

So that's the purpose of the feasibility studies that we do. People are like, well, why can't I just jump into the end study? Because you need to do a small population of patients to figure out how much better your product is so you can design the pivotal study that you're going to submit. And 10 might be enough.

But you might have to do a little bit more. You might have to do 20 patients in a feasibility study to prove that this product is this much better than something else, your control group, so that the biostatistician can calculate it properly. And I see a lot of companies saying, no, no, no, I just want to jump into the final study. I want instant gratification. I want to get my study done and I want to get clearance. If you do that now, we might be picking the wrong endpoint because we don't have enough data yet.

We might be measuring it the wrong way. We might be picking the wrong control group, and you're going to end up with a really big study because you didn't, you weren't patient. Take a little bit of time, measure a slightly larger population, maybe 20 patients instead of 10. Make sure you know what is the best primary endpoint and how to measure it so you can easily show this product, this new product is so much better than the old.

And that way you can have a much smaller sample size for your study. And we just had a client recently, they started out with six patients and they were like, okay, we're ready to do our clinical study. and the CRO that was managing the study said, hang on a second. Like, I know it may sound like we just want more of your money, but you don't have enough data yet to figure out what your sample size is going to be for the pivotal study. I think we need a little bit more data.

Robert Packard (37:26.015)
a pilot study in between our six person feasibility and our final pivotal study to make sure that we know all the clinical endpoints that we want to measure and we know what the sample sizes are going to be and we don't have any adverse events that we didn't know about. So they designed a little bit bigger study, they're doing some more patients and that will make so much difference in the end because now we'll know exactly how that

clinical study is likely to go because we have a little bit more data. But if we did it, if we designed the entire study off of six patients, it's a poor design. The only way it's going to go well is if we got lucky. And luck is not a good strategy.

Jesus Moreno (38:11.896)
Absolutely not. And you've mentioned that engaging early and often with FDA is critical for the process to be successful. But for a cash strapped startup, is US first still the gold standard or are you seeing more side doors success with multiple countries or fragmented approach to keep that burn rate low?

Robert Packard (38:42.253)
So in terms of regulatory approval, the FDA has certain advantages. Number one, the 510K process is a lot faster than a CE marketing strategy. The FDA doesn't require that you get ISO certified. They require that you're compliant with ISO 1345, but they don't require that you're certified to it. So you don't have to to certificate. Some of those savings are substantial.

Getting MDSAP certified for Canada would be $25,000- $30,000. It's $0 for the FDA because they don't require a certificate at all. Submitting a 510k is $6,517 or $571. It's like $6,500 right now for a small business. But that won't even get me my application fee for some of the notified bodies.

So the cost of doing C marking is zeros more for the application. It's still the same testing. I still have to do the same biocompatibility, the same electrical safety, the same performance testing, but the route to regulatory approval is different for the quality system and it's different for the application. It's a 510K versus

a technical file review. In terms of a clinical study, it's a completely different answer. The FDA has a guidance document that says that they will accept outside the US study data. So we get all these companies that ask the dumbest question that I can possibly think of. like, will you accept outside the US data? Well, yes, that's why the guidance says that it

We accept outside the US data. That's why we have the guidance to tell you what you need to do to have it be accepted. What a dumb question. They don't say the what is the dumb question, but they do. They make sure I've actually had several meetings with the FDA and clinical study questions where the FDA is actually put the link for the guidance in the chat and said, yeah, make sure you can open up the guidance and read it. But they caution all these companies.

Robert Packard (41:08.989)
it's harder to meet the requirements for an outside the US study than it is to meet the requirements for an inside the US study. Yes, it is harder, but it's not impossible. And it doesn't mean you have to study more patients. That's what costs a lot of more money. So if I have to do a lot more patients, has to, it's going to cost me more money. But there are very subtle things that could cost

more money and put limitations that you hadn't anticipated. For example, if I have to measure, if I have to do some sort of analytical test, a blood chemistry, measuring, let's say I'm looking for a cancer marker and I'm doing a cancer study and I'm measuring for this one analyte, I have to use the same

lab chemistry test in the US that I use in the other countries. It has to be available and approved in the US. So I can't take a cheaper test that's available in, let's say, Mexico or Canada or Brazil or Italy. I can't take a cheaper test that's available in those countries. I have to use the same test that I would use in the US.

that's approved in the U.S. So I have to make sure upfront that either I send that test to that country and set them up to do it, or I find a lab in that country that can do those tests with the same equipment and the same test method. And so that little nuance of you have to make sure you're doing the test all the same are important and change where you might select to do your study because, they don't have that equipment at that hospital.

I'll have to find another hospital that does. So, you know, this hospital has a three Tesla machine and this hospital only has a 1.5 Tesla machine. I have to do my imaging on a three Tesla so we can't use the hospital as the 1.5. It could be something simple like that. But those little details are all the things that the FDA will check. Like, well, this data does not equal that data, even though your

Robert Packard (43:34.03)
protocol was the same, your comparison testing for the control group and the analytical data that you gathered is not done on the same test method using the same equipment. So therefore I can't compare these two. It's like the difference between stepping on an uncalibrated scale versus a calibrated scale. The calibrated scale, have confidence that that's how much it weighs, but the uncalibrated scale, it might be accurate, it might not be. I have no idea.

I have to check and the FDA isn't going to check. They're just say they're not the same, not going to accept this data. So that I find that is one of the big differences between doing an outside the US study and an inside the US study. It's not that the FDA won't let you do it. It's the companies don't take the time to make sure that all the things that they're gathering data on the height, the weight, the blood pressure.

all the lab chemistry that they're gathering, all the imaging data they're gathering is the same in whatever country that is, is in the US. Most of them only understand at the level of, use the same protocol in both countries. Or even worse, well, they were similar protocols. Similar isn't the same. The FDA wants the same protocol. So you need to go through the process of asking the FDA for feedback on your protocol that you're going to use

in Mexico if you want to include the Mexico data in your US submission. So, and once you get the FDA's feedback and they like it, you have to use that same protocol everywhere. And those little details, just the companies don't want to take the time. They're like, I don't want to have another meeting. I don't want to wait another 75 days. like, but you would rather waste a million dollars on your clinical study and have to repeat it later. Well, no.

So this is how we have to do it. We have to go through another 75 days and fine tune the protocol and make sure the FDA agrees on it. And when you go select your clinical sites, you have to do a due diligence. You have to do a site selection. You have to do a site initiation. You have to do site training. You have to do monitoring of the sites. And that's why the FDA says be careful.

Robert Packard (45:58.7)
You have to meet all the requirements in this guidance. Because if you don't, they won't be able to accept your data.

Jesus Moreno (46:08.55)
Thank you for that, Rob. That's very insightful and paints the complete picture of how important it is to go through those tedious yet important steps. And speaking directly to investors and C-suite executives listening, it is easy to assume that passing a regulatory audit means a company is ready for the global stage.

Compliance on paper does not always equate to scalability for a business. So what is the quiet red flag you're looking for in a quality management system that tells you that a startup is built to pass a test today, but it's fundamentally equipped to scale globally?

Robert Packard (47:07.765)
Okay. So global has two things that they have to worry about. One is the marketing channels and distribution channels. And that's a little bit outside of our scope here, but if a company doesn't have it translated in those languages and doesn't have the regulatory approval in all those countries and doesn't have a distribution and sales partner in those countries, they're not going to sell anything there.

So that's necessary. But the red flag that I often see has to do with a process we call design transfer. Most people understand that I have to do all the design verification testing, like electrical safety and biocompatibility in clinical studies. What they forget is that all you did is did the testing on a handful of units.

Now you have to make thousands or tens of thousands or hundreds of thousands of units and you have to make them all the same. So do you have a procedure on how to make them? Do you have a procedure to how to inspect them? Do you have automated equipment or are you doing everything by hand? If you have automated equipment, have you validated the equipment to make sure it will consistently make good product? So all the design transfer things that we normally have in a design transfer checklist,

Those have to be done. And oftentimes I'll say, so have you had design transfer yet? And they'll say yes. And then when I find out like, well, we approved our drawings. Well, that's great. You approved your drawings and now you can order more of that product that you have a drawing for. But have you got work instructions on how to build those components into a finished device? Do you have inspection methods? Do you have people trained?

So all the things that are in a design transfer list, those tend to be the things that hold the company back from commercialization. They have a 510k, they have C marking, they have Canadian approval, they have Brazilian and visa approval, but they don't have the design transfer piece done yet. And even if they do have some of those design transfer things done, it's often at

Robert Packard (49:33.964)
very small pilot scale only. So, you know, that's great that you have a mold that can make 10,000 parts, but your first order is 100,000. So that tool is going to break and you're going to need to get a new one. So where's your plan for that and how are you going to validate it? So we, that's what I look at. And I think most quality and regulatory people,

Certainly the regulatory people, don't have a real strong operations background. I've actually been an operations manager in multiple companies, having the whole entire facility under my responsibility. So you get to learn what it takes to run a facility. And that's what I did in the pharmaceutical industry and biotech. I actually ran facilities, actually built some of them. So when you run a facility and you build a facility, kind of learn that...

what it takes to go from making one to making thousands. And I think that's that practical know-how of what it takes to scale up and commercialize is what saves some of those companies. Like, OK, I know you want to make one of these and sterilize it, but let's figure out how big the chamber is that we're going to put the boxes into and let's design the box that fits in them. And so that

Understanding how a sterilizer works and what factors are important helped me design their packaging. Most people design packaging so it fits the product. I designed the package that fits the equipment that sterilizes it. And that's a different approach that most people don't take. They hire a packaging engineer to design something around their product. And I want to tweak the packaging in the product.

in very subtle ways so it fits manufacturability. And that design for manufacturability costs you the same amount of work whether you do it at the end or do it at the beginning, but all the product that you made before you did that design for manufacturability gets thrown out. It's just prototypes that you can't sell. So if you want to throw out a lot of product to the design for manufacturability at the end,

Robert Packard (51:54.399)
If you want to throw out very little product, do it early.

Jesus Moreno (51:58.802)
Mm-hmm.

Rob, this has been an incredible masterclass from the prelude to the aftermath of clinical trials and even global scalability. You've reminded us that the clinical trial is only as strong as the regulatory foundation. If you're a founder looking to bridge the gap between animal models and human success, Rob's insights are the blueprint.

Thank you so much for sharing your insights and your time with us. And to our listeners, thank you for joining us. And don't forget to get your regulatory strategies right the first time. Until next time, keep accelerating.

Robert Packard (52:44.877)
Thank you.