Announcer:
0:00
Welcome to MedEvidence, where we help you navigate the truth behind medical research with unbiased, evidence-proven facts Hosted by cardiologist and top medical researcher, Dr Michael Koren.
Dr. Michael Koren:
0:11
Hello, I'm Dr Michael Koren and I'm really excited about this current edition of MedEvidence. I am the editor of MedEvidence and I have the great opportunity, through this MedEvidence platform, to have really insightful and enlightening discussions with people throughout healthcare, and today we're going to do something a little bit different. Often the discussions are with physicians who are involved in a therapeutic area, or it may be a patient who has been impacted by a clinical trial, or it could be a regulator who's involved in making sure that clinical trials are safe for patients who participate. But today I'm speaking with Norm Goldfarb, and I've known Norm for probably 30 years and Norm is the ultimate behind-the-scenes guy that gets things done in very, very interesting ways and he'll be able to describe them better than I can describe them quite frankly, and we'll get to that in a second. I'm the scenes guy that gets things done in very, very interesting ways and he'll be able to describe them better than I can describe them quite frankly, and we'll get to that in a second.
Dr. Michael Koren:
1:10
But you're kind of like a talent scout, promoter, coach, cheerleader and also somebody that's a great communicator and you've used those skills to help us immeasurably in clinical research and I want people to get to meet you and also to explain how you got interested in clinical research and what drives you, and then maybe we'll talk a little bit about some of your thoughts and vision for improvements in clinical research. And just for those of you that may be new to this podcast, we talk about the truth behind the medicine. We like to explain to people what we know about a particular therapeutic area or a particular medical problem, what we don't know about it, and then the process of learning about the stuff that we don't know, and Norm has certainly been a facilitator during the course of his career in helping us learn more about the stuff that we don't know. So, Norm, with that introduction, thank you for joining me here on MedEvidence and tell the audience a little bit about yourself. How did you get involved in clinical research?
Norm Goldfarb:
2:14
Okay, so back in 2000, I was the CEO of a startup company technology company, and the internet bubble burst and our investor decided they was a bank and they decided they did not want to be in the venture business anymore. So we shut down the company the next day and I started looking around the things for things to do and, uh, I was contacted by some people that had an idea for patient recruitment I didn't know anything about it at the time, for clinical research, of course and um, they wanted me to be CO for that. It was a terrible idea. They wanted to hand transcribe patient files at doctor's offices, like get somebody to type all that stuff in. So I thought that would take a long time, but I passed on that opportunity. I think it didn't happen, but I did like the clinical research idea in general and the mission was fabulous.
Dr. Michael Koren:
3:11
And that was your first exposure to clinical research or medicine, or did you have stuff in your previous past that influenced you?
Norm Goldfarb:
3:20
That was the first medicine thing I've done. I did start a biotech company, which worked out well many years ago, but that was in agriculture and didn't have much to do with biopharma, and I thought it'd be an opportunity to work with him on a site that he had one study going. I thought we could make a professional site and we ended up doing that. So he was handling the physician stuff and I was handling all the business and operational stuff.
Dr. Michael Koren:
3:54
Where was that? Was that in California? Do I remember that correctly?
Norm Goldfarb:
3:56
It was in San Francisco, which is clearly the worst place in the world to start a clinical research site because of the expense of medical costs here. So that was just super hard. And it's not just the budgets that were hard, it was just clinical research in general. That's really hard. So it took me a couple of years to figure out that I would rather run conferences and publish a journal on clinical research and help other people figure out how to do it rather than doing it myself. I really admire people that are able to do clinical research, the sites I don't know that much about the sponsors and CROs, but it's just amazing that people can make successful sites.
Norm Goldfarb:
4:39
Based on my personal experience, which is pretty bleak personally-
Dr. Michael Koren:
4:45
yeah, cros for the people who are uninitiated are contract research organizations and they're vendors to groups that help run clinical trials. Sorry to interrupt. We like to just define initials as much as possible, because it's easy to get lost in jargon.
Dr. Michael Koren:
5:03
Yeah.
Norm Goldfarb:
5:03
So one thing I noticed was that it was taking months to negotiate a clinical trial agreement and it occurred to me that if I was trying to do a real estate deal, I could get two lawyers in a room with the principals in and we could knock out a contract in three hours for like a $30 million real estate project.
Norm Goldfarb:
5:28
But we're spending three months knocking out a clinical trial agreement for a $30,000 study. So that just doesn't make any sense. So I started Magi, the model agreement group initiative, to try to develop a standard template for contracts, and we developed a good one actually multiple ones depending on the situation and we were not able to get it adopted as a standard, but it was used extensively when the parties were stuck on a negotiation, a particular term, they could refer to it as an educational tool, because when you know, back in 2000, a lot of sites were very unsophisticated on contract negotiation and also sponsors were referring to it when they were creating a new CTA template for themselves, so they were using it as a source document. So I think it made some contributions, but it's hard to tell how much. Yeah.
Dr. Michael Koren:
6:47
Pharmaceutical companies, device manufacturers, sometimes government, sometimes now hedge funds and private equity firms provide funding or all different types of parties will get into a contract with a site, the location when the research is actually done, and typically you'll say well, you have $100,000, and we expect you to get us data on 50 patients, and that's our job is to find those patients, make sure that they experience the study per the protocol and then ultimately deliver the data to the party. So that's basically how our business works. Sorry to interrupt, but I just want to help people understand that.
Norm Goldfarb:
7:19
So I think of you as a clinical research wizard and I forget about all your other medical expertise, and I'm probably going to keep doing that today. And then, fortunately, I stumbled into taking over a conference on clinical trial agreements and budgets and that became the Magi conferences, which worked out really well. We worked up to about 800 attendees twice a year, which was unusual for and still unusual for conferences, and we actually had 12,000 unique individuals attended those conferences over the years and had a lot of chances to learn about what the issues are in clinical research by talking to potential speakers. Say, what do you think the issues are? And then also, I was writing articles and I got tired of uh, the review process of the uh magazines and journals. So I said, well, I'll start. This is the internet world, I'll just start my own journals. That was became the journal of clinical research best practices and uh ended up writing uh.
Norm Goldfarb:
8:19
I'm personally writing over a thousand articles, book reviews and columns over the years, and you'll have to so for about when I was writing an article for about a week I'd be the world's expert on one specific little topic and then I'd start forgetting about it and then it's back like everybody else. And there again, I've been working with a lot of authors and figuring out what their thinking is on these problems. And the bad news about clinical research is there's a ton of problems, but from my point of view that's really good news because that's what conferences and journals help solve. So lots of grist for the mill in solving problems and developing insights on all these various topics.
Dr. Michael Koren:
9:03
Yeah Well, the biggest problem from my perspective is we need more folks to take advantage of all the benefits of clinical research, including the incredible opportunity for information sharing that occurs both between the patient and the local folks that are running the trial, as well as the local folks and the national or international people who are ultimately putting together the results. And the neat thing about you, Norm, is that you have an understanding of all elements of that data exchange and communication and have certainly weighed in on multiple areas within that realm.
Norm Goldfarb:
9:39
Yeah, let me give you an example. So first, with all the problems we have in clinical research, the number one problem in my opinion is we have a transactional way of looking at the world. Each study is a new transaction. The study sponsor, the pharma, puts together a new team of solution providers and the CROs and the sites, and they all have to figure out how to work together very fast and very complex problems, which has gotten only more complex with all the technology that's now available and everything's transactional. And then, after the study's over, the sponsors say thank you very much to the sites and everybody else, and then maybe they talk to them in the future, maybe they don't sites and everybody else, and then maybe they talk to them in the future, maybe they don't.
Norm Goldfarb:
10:26
And in general, the sites say goodbye to the patients that participated in the studies, which so I like to call the people that participate in a clinical study, the participants, as opposed to the patients, because many studies have placebo arms where they're not actually getting a treatment that's going to help with their condition. So participant is much more neutral. It's more neutral to help with that concept. So in any case, after a study, many sites just forget about the participants in the study and then if they need them again in the future, then they go contact them again. But there's no, it's a transaction again. So what we need is long-term relationships, and one of my favorite hobby horses now in terms of patient recruitment even though it's really participant recruitment is long-term community engagement. There are studies where the sites engage with community, find people that have the particular condition that that study is designed to treat, but then after that study, that community engagement goes away. What's really needed is long-term engagement with community. So it's not disease-specific, it's just people in general, and particularly people that are going to have some medical condition in the future or haven't currently, and there's really no—go ahead.
Dr. Michael Koren:
11:49
Yeah, I was going to say connecting people with clinical trials in general and specifically through a particular disease that they're concerned about is certainly one of our initiatives at MedEvidence, and I think you've been very, very helpful to move that concept forward in a number of scenarios.
Norm Goldfarb:
12:11
Thank you. So what we need to—now those community engagement exercises, going to health fairs and visiting churches and all that kind of stuff. That's very time consuming and the people that typically do that at sites are the study coordinators who do most of everything else at the site and they don't really have time to do that. They have to spend their time on the studies and finding people for the specific studies they're working on. So this longer term stuff is a really big drain on their time and if they're going to hire somebody to do it, that's very costly. It adds up. So what we really need is a source of funding for that activity, and the source of funding ultimately has to come for the sponsors. So we have to find some mechanism where the sponsors say sure, well, you're a good site for us, we will contribute to the funding of community engagement at your site. So one of the projects I'm working on, which I think we'll get together, may free up some funds for long-term community engagement.
Dr. Michael Koren:
13:14
Norm was talking about how he is an industry engineer. I love that term. That's fabulous. So why don't you break it down a little bit more for us? Tell us about some of the things that you're really passionate about right now from a general standpoint, and then get into a little bit more of the specifics, as how that makes things better for clinical research sites and for physicians like myself. Find and attract the right patients for clinical research and ultimately create these experiences for patients in our community that people tend to enjoy so much so that they're likely to do a second clinical trial once they've done a first clinical trial, at a rate of over 97%, which I find quite remarkable.
Norm Goldfarb:
13:55
I think one of the most important things for the public to understand is the people that are doing clinical research are doing it because they're dedicated to the mission of clinical research. They see the opportunity of, instead of helping one patient at a time like a doctor or a nurse would, the ability to help thousands or millions of people at a time in a cardiology study or a COVID vaccine study. And they're willing to endure lots of complexity, incredible amounts of headaches to do this job. And it's really because they care about the mission, they care about the patients, they care about the people and you can't really understand why people in clinical research are putting up with all the nonsense until you understand the reason for that dedication.
Dr. Michael Koren:
14:47
Yeah, that's very well said and thank you. I think you're right. I think there's something that certain physicians have in their blood that drives them towards clinical research this great desire to want to learn things, want to find out about things and ultimately communicate those learnings to other people. Thank you, well said.
Norm Goldfarb:
15:07
So currently my main vehicle for doing industry engineering is something called the site council. I find the most interesting part, the most challenging part of clinical research is the interface between the pharmaceutical companies, the sponsors in the study, and the hospitals and clinics and other places where clinical research is actually performed, which is called the sites. And that's a very problematic area and it consumes a lot of resources and I'll give you a good example.
Dr. Michael Koren:
15:40
Yeah, just to add to the fact that it's not just pharmaceutical companies, but there's all kinds of research going where device manufacturers. There's social science research, there's laboratory method research, there's a lot of other things, but in general the sponsor is the ultimate party that's funding the research. But go ahead. Sorry to interrupt.
Norm Goldfarb:
15:57
Clinical research has some big peculiarities to it. One of the things that's inherited from its history in academia is that the study sponsors have the primary responsibility for making sure that the quality of the data that's collected during a study is accurate, and we've worked our way into a situation where study sponsors spend about as much on inspecting the data as the clinical research sites spend on generating the data. So it's a lot. It's unbelievable. It's a lot like in an assembly line having an inspector standing behind every single production line worker. Well, that's obviously not a practical way to do it.
Norm Goldfarb:
16:44
So over the last few years, a number of clinical research sites have been developing the technology and the systems to produce much higher quality data than was produced typically in the past and still produced at a lot of sites currently.
Norm Goldfarb:
17:03
And they do that with something called a quality management system which covers all the bases of quality, starting with qualified people, train them properly, instruct them properly. You inspect the work they did, like spot checks, but not every single thing all the time, and when there is a problem you have to go do a root cause analysis, determine how you can fix the problem so it doesn't happen again. So there's a whole lot of different things in the quality management system. You can fix the problems. It doesn't happen again. So there's a whole lot of different things in the quality management system and the most advanced sites and also what groups of sites, called site networks, are becoming very sophisticated in that. Now, coincidentally and very happily, for the last 10 years or so the Food and Drug Administration has been making a big push on something called risk-based monitoring and something else called quality by design.
Dr. Michael Koren:
17:54
Yeah tell us about that these are important phrases in our industry, and even the people in our industry don't really fully understand them. So yeah, break that down for everybody.
Norm Goldfarb:
18:05
So risk-based monitoring means that when a study sponsor sends out what we call a site monitor, which is an inspector, to take a look at what's going on at the site, review the data that the site's been collecting, that they ought to spend that time at the sites that are more likely to have problems with the data.
Norm Goldfarb:
18:26
So it's risk-based. So if a site produces really high-quality data, you do less. If a site has problematic data, you do more. And that applies to other things besides the data, for example, the safety, because the number one priority in clinical research is the safety of the participants and everything else is second. And if it looks like a study is not safe for a patient, for a particular participant, then the responsibility of the investigator to say, no, you shouldn't be in the study anymore or we should do something differently to make sure it is safe for you. And that gets communicated to every other site on that study too, by the way. So everybody knows that there's been a problem and it should not happen again. Not every single problem, but the ones that are important, yeah.
Dr. Michael Koren:
19:12
And serious problems are fortunately extremely rare. But, to your point, norm, the number one responsibility of the physician as the investigator is to make sure the patient has a safe experience and to report any adverse condition as quickly as possible through the system and then, using this communication leverage that we have, letting people around the world know what's going on. So if there is a serious problem with a medicine that we're looking at literally within 24 hours, people around the world should be on notice, and we do have that system in place, and the physician part of that system is an extraordinarily important part of our role as clinical investigators.
Norm Goldfarb:
19:51
So that's risk-based monitoring and quality by design, as goes by acronym QBD, is building quality into the system as opposed to testing the defects out of the system. So why not design a system that generates high-quality products, rather than one that finds all the problems with the products and then has an efficient system for fixing the problems? That's just a lot of extra, what's called rework and, with Toyota, invented lean manufacturing back in the 70s maybe, and that's basically where that came from. So build the quality and the quality management system, which I mentioned a minute ago, employs quality by design concepts. So the quality is built into the data, is built into the safety and built into the other things that are done in a study
Dr. Michael Koren:
20:45
and we have lots of internal training programs, and I've led a program to train clinical investigators at all different levels. These are novice physicians as well as people who are sophisticated to get to that exact point that you mentioned quality by design. And when certain principles are repeated over and over again in terms of safety, in terms of making sure that you protect the primary endpoint, which is ultimately what is delivered to the scientific database, and that's ultimately what makes a difference in terms of knowledge sharing. Well, when all these things are part of your DNA, then you're much more likely to get a good result in terms of interpretable data and high-quality data and good use of the patient's time.
Norm Goldfarb:
21:30
Yes, and one of the things that study participants probably don't understand, and our patients, is that, rather than picking some random way they think is a good way to do something, today they refer to these standard operating procedures to make sure it's done properly, based on 30 years of experience that a lot of investors like Michael have in this industry, and those evolved across the industry to become very important elements to quality by design. Yeah for sure, okay, so in any case. So here we have a lot of sites are developing very high quality processes, minimal defects, and we have the FDA saying, well, let's not spend much time monitoring the sites that have high quality. And it then occurred to me well, what if a site was producing basically perfect quality? So why does it have to be monitored at all? And why is that important.
Norm Goldfarb:
22:34
It's important because 20% or more of the cost of a clinical study is spent on site monitoring, about the same cost that is spent on the sites who collect the data in the first place, and that's just an absurd expense and it also just consumes a lot of time as well.
Norm Goldfarb:
22:52
So if we can get that 20 or more percent down to a couple of percent, then we can develop drugs much more inexpensively, which means they can be made more affordable to the patients and the sponsors can afford to develop more drugs in the first place. So now there's more drugs available more affordably to the patients, if we can solve this one problem of wasted time on site monitoring and, by the way, it doesn't just waste the time of the site monitors, it wastes the time of the study coordinators and other site personnel so I asked the FDA that you can actually they're very nice people, it turns out. You ask the FDA, well, what do you think about this? And they basically didn't have any objection and they reeled off a bunch of information about risk-based monitoring and quality by design and they didn't object. So that a really good opportunity.
Dr. Michael Koren:
23:53
There's two fascinating things about that. One is you can just email or call or contact the FDA, ask them a question and they actually respond. So I think that's pretty cool. And number two, to your point, monitoring is a huge part of the cost of developing drugs and, again, monitoring has its role.
Dr. Michael Koren:
24:13
We love our monitors. They come in, they make sure that all the paperwork is signed appropriately, etc. Etc. But the truth is is that they also spend a lot, a lot of time, and do they really need to go over every single word in every single document? Well, I'm not sure that needs to happen, and in many cases, when the monitors come in and spend all this time, it's time we're not spending on talking to our patients, reaching out to the communities and doing other things that are important to getting these trials done and ultimately get new products to the market, which will ultimately save lives and reduce suffering. So, to your point, there's a huge opportunity here for efficiencies, and it starts with just asking the question to the FDA do we really need to monitor every piece of data? And the answer is no. And the other question is can sites do some of their own monitoring? And it sounds like the question is the answer is yes.
Norm Goldfarb:
25:09
Yes, and what they need to have is their own quality management system, which includes a whole lot of different things the qualified people, the training, the standard operating procedures, the inspections, the monitoring and then all the sponsor needs to do is inspect the quality management system itself, not the data, which is a much smaller task. Now, this is only for the sites that have those high-quality QMS systems in place, but if I'm a study sponsor, those are the sites I'm going to want to work with, because I'm going to get better quality out of them and it's going to cost me 20% less or more when I do the studies at those sites. So it's a big motivation for the sponsors. So it's a big motivation for the sponsors and it's a big motivation for the sites. And it helps the patients because we get better quality data, faster and cheaper, so more drugs faster and cheaper and medical devices too.
Dr. Michael Koren:
26:04
That's so interesting. So, norm, thanks for sharing those insights. Any other big initiatives you've been working on to share with?
Dr. Michael Koren:
26:11
the audience.
Norm Goldfarb:
26:11
Let me go back to the FDA for a minute. So FDA has a Q&A line for clinical research people to ask questions, and they've been doing that for about 12 years or so, and so I thought that'd be interesting data to have available to clinical researchers. So I asked them if I could get a copy of it. They weren't crazy about spending the time on it. I filed some Freedom of Information Act requests and they eventually gave me all those Q&As which the site council has now put online, so clinical research professionals can find all those answers to all the questions over the past 12 years that anybody's ever asked the FDA on what's called good clinical practices, which is this general area we're talking about, and the people that appreciate that most are the FDA. People have to answer those questions because they use the site council website to find out how they answered questions in the past.
Dr. Michael Koren:
27:08
Oh great, I love that,
Norm Goldfarb:
27:09
and it didn't take a lot of work, but it's a valuable resource. It's the kind of thing that if you just think about what's missing in the world, particularly in this industry, you say, well, how do we fix that problem? It turns out there's a fairly simple way to do it and it didn't cost a lot of money, it didn't take a lot of time, and now it's available. And at a conference earlier this year I was talking to people at FDA They'd actually worked on that, coincidentally and they took a selfie with me. They liked it so much. That's great, nice people.
Norm Goldfarb:
27:42
Nice people.
Dr. Michael Koren:
27:43
Yeah absolutely Well. The commissioner of the FDA is Rob Califf, who's a cardiologist, and as a cardiologist I'm a big fan of that idea and Rob actually was somebody who was a mentor of sorts to me. He was running the Duke clinical trial program for a while when I was a freshly minted cardiologist and I was part of a group called the Ducks Group, which was a group of people mostly out of Duke, but I didn't go to Duke. But I became friendly with that group and learned quite a bit from Rob Califf and his group at Duke over the years and Duke has been a wonderful resource for moving clinical trials forward in a number of different therapeutic areas. So we're thankful for Rob and we're thankful for Duke and we're thankful for the openness of the FDA on making the process of getting people involved in clinical trials better, which again ultimately provides really good outcomes for the patients and for knowledge sharing and ultimately saves lives and reduces suffering. So it all comes together at the end.
Norm Goldfarb:
28:46
Let me tell you about just one last initiative we're working on. In clinical research there's certain studies, like vaccine studies, where a lot of study participants need to be recruited on a short timeline. Vaccine studies are a good example where there might be 50,000 people need to be recruited for a study. Traditionally the way this is done is the study sponsor rounds up a bunch of sites they've worked with in the past that they think will do a good job on the study. They get them set up to go and they say ready, set, go. And all the sites start racing as fast as they can to enroll these participants in what's called a competitive enrollment. And it's like the Oklahoma land rush, which is just chaos. The wheels are falling off the wagons, the wagons are crashing into each other. It's just a mess and there's a lot of stress. A lot more chaos is needed. And if you're a site and your site doesn't get initiated so you can start the study for a couple weeks because the person who does that is on holiday or something on vacation, then you miss out on a lot of the opportunity to enroll patients in those studies. So it's really aggravating to those sites and it creates this big chunk of work for everybody, that goes down the snake. You know it's a big lump and it's not an efficient way to work. You know it's a big lump and it's not an efficient way to work.
Norm Goldfarb:
30:12
As it turns out, if you do something called managed competitive enrollment where you give all the sites an opportunity to enroll a certain number of patients in a certain time period, like the first time period, and then you have a second time period you give them another chance, that means that it's done over a period of time, a lot less chaos.
Norm Goldfarb:
30:40
Everybody knows they have, say, a month to enroll. You know, a thousand patients or a hundred patients at that site and they can do that in a methodical way. They're not rushing through and I think it might have some patient experience benefits too, because there's much less pressure on the SICE-2 process. The participants through the study as quickly. So I think the participants have a better experience and I don't know if any of these sites have safety problems, but theoretically there could be safety problems if they're rushing it through too quickly. But by doing controlled competitive enrollment they can do it in a managed way, in a more organized way, without the chaos. And it turns out, if you do the math, the study gets done the same amount of time as it was done before just without the chaos.
Dr. Michael Koren:
31:34
That sounds good to me. Yes, there can be vaccine frenzies when all of a sudden we're asked to get 100 patients into a program in a week, but the truth is that rapid enrollment is important to the sponsors to move the timeframe as quickly as possible. But to truth is is that rapid enrollment is important to the sponsors to move the timeframe as quickly as possible, but, to your point, you don't necessarily have to lose time and still manage the numbers. Give all of the participants in different markets the opportunity to be part of things, and I would wholly endorse some of the concepts you're putting forward. And, by the way, this is just an example of the many ideas Norm has come up with over the years to try to make this industry better.
Dr. Michael Koren:
32:18
So, norm, with that, thank you so much for participating in this MedEvidence podcast. You've been fabulous, you've been insightful, and we'll do it again sometime. And I'll definitely follow up on that FDA question and answer website. I don't even know about that. So the reason I like doing these webcasts is I always learn something, and that's one of the things I learned today. So thank you for sharing that.
Dr. Michael Koren:
32:39
Yeah, and I learned some things from you. I always learn things when I talk to you, michael, so a pleasure for me as well, always a pleasure talking with you, and it's just amazing how much stuff you know. It's just amazing how much stuff you know. It's just astonishing.
Dr. Michael Koren:
32:52
Well, thank you All right. Well, norm yours in good health.
Announcer:
32:57
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