Clinical trials demystified, part 3: Dr. Allegra, Dr. Wright & Dr. Weinstock (2024)

Manju George 0:00
Hello everyone. Welcome to Doc talks. I’m Dr Manju George, the Scientific Director at Paltown Development Foundation, the nonprofit that supports the 11,000 member colorectal cancer community Colontown. Today we have the third doctalk in the clinical trials demystified series, and which is titled, How the FDA, industry and the NCTN work together to bring treatments to cancer patients.

Manju George 0:33
I feel that patients experience of drug development is like the story of the six blind men and the elephant, the whole process seems this complex, mysterious, ginormous thing that’s just too huge for us to grasp, whether our exposure to it is in terms of participating in clinical trials or getting a new drug that has been recently FDA approved, or looking at Clinical Trials results. I feel that we have a very sketchy knowledge of the whole drug development process. So the the goal of this session is to shed some more light into this complicated process, so we have a better understanding of it, and then we can interact more effectively with it.

Manju George 1:19
Patients direct experience of drug development is mostly through their participation in clinical trials. If you look at the clinical trial landscape, there are several broad categories of cancer trials based on the funding sites, etc. So I’ve listed the main types of trials. For example, there are the NCI clinical trials, industry and pharma sponsored trials, then the smaller investigator initiated trials. And I also really recently realized that there are DoD (Department of Defence) run trials, and then, of course, there are trials run by foundations and patient advocacy organizations and the new agency under President Biden’s Moonshot. That’s the new agency who also run trials. So for colorectal cancer, the main categories are the NCI trials, the industry sponsored trials, and the investigator initiated trials, and also the ARPA-H trials.

Manju George 2:20
The plan for this session is to have these experts who we have with us today to tell us more about the different categories. We also have an expert from the FDA who will tell us about the drug development process. So the format of today’s session will be short talks about 10 to 15 minutes long by each of the panelists. And then we will look at the questions that you’ve already submitted. And then after that, the session will be open to audience questions. So with that, let us start with Dr Carmen Allegra. Each of the panelists will also introduce themselves at the start of their session. So with that, let’s start with the NCI clinical trials and the NCI perspective. Dr Allegra, welcome.

Dr. Allegra 3:10
Thank you very much. And good afternoon, everybody. Let’s go to the first slide. So who am I? You know, I ask this question almost every day, and I’m not sure I really know, but let me give you a little bit of sense of my background, so you’ll know who it is that you’re listening to, that you’re spending your precious time this afternoon. So I was a graduate of the University of Pennsylvania. I stayed there for a long time. I did my undergrad, medical school and residency training in internal medicine. Fellowship in the National Cancer Institute, and ultimately retired from the intramural program of NCI as the combined medicine Branch Chief. After about 20 years of laboratory and clinical experience in molecular pharmacology and clinical research in GI cancers, I’ve always focused on GI cancers my entire career. After that, I joined the University of Florida as chief of oncology and hematology, and ultimately retired from that position, as well as emeritus professor of medicine after 12 years of administration and clinical research in GI cancers. And currently I’m the Lead medical advisor for the National Cancer Institute, CTEP, the cClinical Therapy Evaluation Program, which you are hopefully familiar with for all of their GI studies. And I’ve done this now for about 8, and a half years or so.

Dr. Allegra 4:37
Let’s go next. So just a little bit of a trip down memory lane, just to tell you where the NCTN or the National Cooperative Trials Network came from. Many years ago, probably 50 years ago, the federal government started to fund clinical trials groups, and over the course of that time, let’s go back, please, many groups evolved. And you could see here that there were 10 different groups. And this is a system that was in place for many years, many decades, and it turned out that it was extraordinarily inefficient. And there wasn’t, although they were called to cooperative groups, there really wasn’t a whole lot of cooperation amongst the groups. There was a lot of political issues, if you will, but there was tons of redundancy, which is enormously inefficient. Each one of these groups had an operation center, a statistis center, a tumor bank. They had disease committees. So every group had a GI disease committee. So there were 10 different disease committee all vying for a clinical trial to get started in their particular group. Very, very inefficient.

Dr. Allegra 6:00
Let’s go next. So about a dozen years ago or so, the NCI decided to pull together a blue ribbon panel, and this was conducted by the Institute of Medicine at the time, to come up with a better way of doing our national clinical trials, a better network for doing it, and they did this, and these are some of the outputs from that. One is to incorporate innovative science and innovative trial design. They wanted to improve the speed and efficiency and development as well as the conduct of the trials.They wanted to facilitate the front office operations by ranking the groups with defined metrics on a similar timetable, and they wanted the back office operations to make progress in improvement in operations and organizational management as a priority. Improve trial prioritization, selection and support and completion, and they wanted to increase resources. Interestingly enough, doesn’t happen too often to the clinical trials program, and obviously, throughout this whole redevelopment process, to ensure that there was participation by patients, as well as physicians with input into the the ultimate system.

Dr. Allegra 7:25
Let’s go next slide, and this is what came from it is that those 10 groups now shrunk by half, and we now became the NCTN, the National Clinical Trials Network. And you can see that there are four adult groups, Southwest Oncology Group, Alliance, NRG and ECOG ACRIN. There’s a pediatric group, the Children’s Oncology Group, and there’s also a Canadian group that it’s independently funded by the Canadian government, all of whom participate now in the NCTN. And there was a centralization of many of the functions. One of the most important was the centralization of the IRB. So instead of having each of these groups have their own IRB, or each institution having to go to their own IRB. Now, there was one centralized IRB. The goal of this was really enhance efficiency. There was also a clinical trial support unit that provided a lot of support for registering patients, for following patients, and we’ll talk a little bit about that in a bit. And there was also an imaging radiation oncology core, which allowed us to collect images, to study those images make some sense out of them. Now, as was true in the past, each of these groups also had their operations, their statistical group, their tumor banks and their committees, Each of the diseases had their committees, but now it was far fewer than there was in the past. And there was also great participation by the NCORP. So this is the NCI Community Oncology Research Program, which is a gigantic network of community centers where patients can enroll onto the NCTN trials

Dr. Allegra 9:28
Go next. So these are the NCTN sites across the US. You can see there are many sites. There’s over 3000 institutions, 14,000 investigators, and they, as a group, enroll about 20,000 patients a year into a variety of clinical trials. And this has been relatively consistent. Interestingly enough, even during 2020 during the covid epidemic, the the numbers really didn’t change much. There was still about 20,000 patients, excuse me, that were enrolled during 2020, and 2021, every state basically has enrolling centers, some more than others.

Dr. Allegra 10:09
As you can see, go next, in addition to the US, you can see there are sites across the world. So there we have our Canadian colleagues, you can see there’s also good representation from the European Union as well as Japan, Korea, some sites in China as well as in Australia and New Zealand. So it’s really a pan World Organization, and the sites across the world participate heartily, and I’ll show you the numbers that are associated with their participation as well

Dr. Allegra 10:10
go next. So this is the accrual to our therapeutic trials. And as I said, it’s about 20,000 patients a year. And where did they come from? Well, by and large, the greatest number of 42% come from our member sites, or NCTN member sites, and these are by and large university sites, although some of them are not, they’re large community practices as well. The NCTN labs, these are academic centers that are lead academic programs, and they also contribute about a quarter of the patients. And the NCORP, these are the community sites, a little bit more than a quarter of the pool every year. And you can see that the Canadian sites are in this orangey color, and the international sites are in the purple right next to it, each contributing for 2% respectively.

Dr. Allegra 11:45
Let’s go next. That’s where the patients come from. And as I said, there is a shared infrastructure to support these five adult groups and the pediatric group as well, called the CTSU, the Clinical Trials Support Unit, and they provide centralized services to our trials. They centralize, there’s a centralized registration and enrollment. They provide regulatory support. They they also facilitate site access to the trials across the groups to reduce burden to the investigators. And as I said, most importantly, there’s a centralized IRB, which is critically important in in trying to enhance efficiency here.

Dr. Allegra 12:31
Next, there are several, NCI sponsored Clinical Trials Network, one we’ve been talking about the National Clinical Trials Network, or the NCTN is really focused on late phase treatment trials. So these are the randomized phase twos and the phase three trials. But there’s also an ETCTN, which is the early phase clinical trials network, where they focus on Phase One trials and also smaller single arm or even randomized phase twos as well, but generally using agents or combinations that are earlier in their development before they get to the NCTN, but it serves as a feeder network for the NCTN. The NCORP, as I said, is kind of a sister organization to the NCTN, made up of the Community Oncology sites, and they conduct primarily, not therapeutic trials. That’s the purview of NCTN, but they conduct prevention and cancer control clinical trials, symptom management studies and trials, screening trials and cancer care delivery studies. So it’s a different focus for the NCORP and course the NCTN groups participate in the NCORP studies, and likewise, the NCORP sites participate in NCTN, so there’s a crossing of all of these trials for all of the groups,

Dr. Allegra 14:03
Go ahead next please. So this is the relationship between NCORP and NCTN. You can see that there is, a great deal of collaboration between these two networks. Their focus are different. One is more in prevention and control trials, while the NCTN is more in therapeutic trials, but they cross with patient accrual to any of the trials conducted by either of these two networks.

Dr. Allegra 14:33
Next please. So just as a snapshot, these are the ongoing NCTN trials in colorectal cancer. So I spared you the long list of other GI cancers because of our focus today, but you could see there’s a number of trials that we currently have open in the colon or rectum or both, depending on the stage of the disease, as well as anal cancer.

Dr. Allegra 15:03
Let’s go next. And likewise, there’s also a number of trials that are in very early development. So these are mostly phase one trials. And actually I think almost all of these are phase one trials, but these are all trials that are conducted through the the Early Clinical Trials Network, so the ET CTN, and you can see the sorts of combinations that they’re investigating. And mostly these are drugs that, perhaps as single agents, have some known activity. But the question is, how do you better put them together for greater activity? And ultimately, if these show promise, they would be escalated to a much larger study. Let’s go next. Okay, I think that was the last of my introductory slides, so I’ll pass it back to you Manju.

Manju George 15:53
Okay, thank you. So we’ll skip these two slides, because these are the set of questions. And then thank you so much, Dr Allegra for that broad overview. With that, let’s go to the next speaker, who will tell us about the industry perspective and talk about industry trials. Welcome, Dr Wright,

Dr. Wright 16:15
Thanks. Yeah. So hi everyone. Thanks for your time. I’m Jennifer Wright. I’m a physician currently with Eli Lilly and Company. I’ve been here for about seven and a half years. My history is I was a practicing oncologist. I was in the Salt Lake City area at the University of Utah and Huntsman Cancer Institute seeing sarcoma patients, both pediatric and adult patients. While I was there, I enrolled patients on lots of clinical trials, some pharma trials, some of the NCTN groups that Dr Allegra mentioned, Alliance and Children’s Oncology Group, for example. And also I served on the IRB, the institutional review board there for 10 years. And so now what I do at Lilly is I’m the medical lead for a couple different programs. One, that’s one of our early phase, phase one two programs, and also some work in our phase three trials, where, how Lily sets it up is the medical lead helps design the trial, and once the trial’s up and running, we serve as the point of contact for the physicians who are enrolling patients, so that we can help answer any questions about, you know, if a patient experiences a side effect or or what else, whatever other questions investigator may have. Then when we get the results of those trials, and I help analyze those from the medical perspective, and then prepare submission packages to be sent to the FDA and their counterparts around the world to help try and get the drugs approved. I also, sort of, again, because of my pediatric experience, help provide some expertise for other drug teams in our company as to their pediatric trials. And so today, I’m not representing Lily per se, but I’m here to kind of talk/show my experience on kind of both sides, as both an investigator in the past and now working for a pharma company.. I don’t know that we’ll completely demystify the whole process today, and in the short time, we have hopefully shed a little bit of light on some of the more confusing aspects of clinical trials. So thanks, Dr George. Next slide.

Manju George 18:27
Okay, thank you. So with Dr Wright’s section, how we have organized, is that we have put a bunch of questions here that many of them we got from colontown. So the hope is that through these questions, we get to learn a lot about how pharma handles these trials. So then let’s get to the questions. So the first question is, what is different with pharma run trials? What do you want patients to know about this group of trials?

Dr. Wright 18:55
Right? So this obvious, I could probably say before everything I answer, well, it kind of depends, right? There are so many, there’s such a broad range of situations that can come up in the pharma run trials. But I think the most obvious difference, or the most common differences, compared to the NCTN trials, for example, is that pharma does tend to do more of the early phase, first in human studies. Dr Allegra obviously mentioned the ET CTN part of the group that does the earlier studies on drugs. But pharma will, you know, we go through lots of potential compounds that hopefully eventually one day turn into medicines, but most of them don’t, right.? The failure rate is much higher than the success rate and so I think if you look very broadly, there are more phase one and two studies run by Pharma. Pharma definitely runs phase three, later stage trials. But because there’s so many of those first in human study trials where the drugs don’t work, that swings the average toward towards smaller and earlier phase trials. I think that that’s probably the biggest difference within those trials.

Dr. Wright 20:17
Then I think this sort of runs into the next question about enrollment for those first in human especially trials, is that I would say, in general, the the rules are a little more restrictive, right? We’re we’re a little choosier about which patients we allow. For the most part, that’s a safety reason that you know, in the first few patients who receive a drug that’s never been given to human before, they take on a little bit more risk, right? We obviously have checks and balances in place to try and minimize that risk. And obviously, if we know a patient isn’t going to be safe, we don’t proceed down that path, but there the first in human trials tend to be smaller and stricter, a little bit healthier of a population. We’re looking for less other medical problems. Part of that is because of the other medications patients are on for, you know, heart disease or diabetes, etc, we want to try and minimize the potential for drugs interacting until we get a little more information on the new drug being studied.

Dr. Wright 21:30
It also because of, again, that safety, those safety checks we will enroll, usually, 2, 3, 4, 5, patients and then stop, right? And then we let those patients be exposed to the drug for a while. Make sure it is safe like we think. Or sometimes we’ll discover side effect and say, Oh, this patient needs a preventive medicine to go along with this, etc. And then we’ll reopen enrollment, enroll a few more patients. Okay, check again and see, you know what the rate of severe side effects now or at a higher dose, etc? And so there’s a lot more stops and starts in enrollment, right with these phase one first in human trials.

Dr. Wright 22:16
Occasionally, when the with these global studies that this tends to be more for the later phase studies, sometimes there’s restrictions on what geographies can enroll when, that’s a pretty complicated process. I won’t go into a lot of detail about that, right now, I think another big difference, then again, for the pharma- run early phase trials. And Dr. Allegra pointed to this a little bit. A lot of them are just what we call single arm, or open label single arm. So everybody is getting the drug. Everybody knows that they’re getting the drug. There aren’t as many of these days where patients are randomized to a control arm, or, for example, standard of care treatment, to be compared to the drug. So that’s one of the other major differences why these are more that’s more common in pharma-run studies.

Manju George 23:12
Okay, thank you. Then the next question is, how long does it take for a pharma led trial from concept to resulting out? And then, if you could provide a broad overview of, like, what are the things that pharmaconsiders is different?

Dr. Wright 23:27
Yeah, so when we were emailing back and forth about sort of my draft answers, I said, Well, it depends where are you starting, you know, what time point are you starting from, right? So, concept, and so I think of it as there’s really two phases, concept to getting the study open, and then the time the study opens to the readout. Because that concept to opening the trial can, again, is the, I think, the more variable part. We have chemists, right, they’re the first piece in this puzzle in terms of starting and developing a drug really, at the bench in the lab, right? And so they may have three or four starts and stops. They develop something. We find out it’s not going to be safe, or it’s not going to work, etc. And so that can add a long time on to the front end of study. Once we hit all the checkmarks, we think where it’s appropriate to move into a clinical trial, there the time to read out as it’s a little more clear, those usually fall into what I think of as three buckets. One, there’s a first in human trial where we find out either the drug just doesn’t work or it’s not safe, and therefore that ends pretty early, usually within a year to 18 months, I think of the time the first patient enrolls, we can say, Nope, we’re not going to develop this any further and publicize those results and take that step. And so that’s kind of the shortest but the most unfortunate, right?

Dr. Wright 24:58
And there’s a lot of ways you want it to take a little longer for certain reasons. The next, I think, is then the longer lasting Phase one/ two study, where you do start to see some positive results and you find it’s safe and manageable for the patients. Then those can be kind of extended, because as you start to see data where the drug is working, you maybe want to add more patients to the trial, or add certain subset of patients where you need more information in. Say, again, if it’s a more broad population, you really want the colorectal patients, or you really want pancreatic cancer patients or etc, right? So those may take longer for kind of good reasons.

Dr. Wright 25:44
Then usually, once again, the earlier phase studies read out, and you know, they’re positive, and we’re moving into Phase Three and later studies, those take longer to enroll. They’re bigger, right? So it takes more time to find all the patients to enroll, and so those will be the ones that generally take years, three, four or five years, sometimes to get potentially even longer for final results. Most of the time, there will be what we call interim results. So midway through, at some checkpoint that’s planned ahead, in advance, before we see the data, we’ll take a stop and look and see, and there’s lots of reasons to do that, but often there’s a peek at the at the midterm results, before the very end. But the final data often takes years, multiple years, to get to so but again, even in that case, the longer the trial, that means it’s better, right? The outcomes for the patients are better. Usually, the measurements are, again, how long are patients going without having their disease return or progress and so you actually want them to be longer. That’s that’s good news for patients.

Manju George 26:54
Okay, okay, thank you. So the next question is, what factors are involved in decision making around pharma clinical trials, about the different steps, design, what endpoints and all of that. Could you give an example to illustrate the different steps?

Dr. Wright 27:08
Yeah, yeah. I mean the in terms of when you decide to start a trial, right? Obviously, you have to have a there’s science involved, right? You have to have a good rationale for the medicine you’re developing, you think that it’s going to work. There needs to be a need, right? for patients. While there’s some space for different specific drugs that all work largely the same way, you don’t need 18 drugs that all work the same way, right? That that’s just crowding a space unnecessarily. So you may have something, but you’re kind of too late to the game, so you may decide not to move forward. In that case. There’s obviously, again, safety, there’s technical issues sometimes. So is there a new kind of device that’s involved in delivering the drug? There’s different implications there. Some of you may be aware of this newer method called Radio ligand therapy, where I’m super simplifying this, but it’s essentially a radioactive type medication. There’s really a lot of criteria, where that drug can degrade within days of it being made. So getting it to physically the hospitals, there are a lot of decisions around, how can we do that, and how is that feasible?

Dr. Wright 28:34
There’s, again, competitive landscape. How many other drugs like this are out there? What’s the standard of care? There’s regulatory implications. Is there a way forward to get this drug approved, and in whatever countries where we’re seeking that. And then, Pharma is for profit businesses, right? And so there are sometimes pressures outside of just the science that will influence those decisions. Sometimes, even at a company that that makes more than just cancer drugs, sometimes it’s influences, broader, even outside the cancer situation, that can can impact those. So again, like everything else, kind of complicated.

Manju George 29:25
Okay, so are pharma run trials more expensive than NCTN run trials? And if yes, then where is the additional expense coming from?

Dr. Wright 29:34
Right? So I didn’t compare notes with Dr Allegra beforehand, but I’m going to say yes, in general, that’s probably true that pharma run trials are more expensive. There’s a few different things. Part of that is, again, your cost for even the benchwork that’s going on, right, the development of and the chemistry that goes into to developing the drugs. That’s part of it. Part of it is the trials that we run with the intent, again, to submit data to the FDA and other regulatory agencies tend to require more extensive collection of data. So this sites the investigators where patients are, have to put more information in the database and travel expenses are sometimes paid for patients by pharma run trials, that I think is probably not the case for most NCTN run trials. And another component is that, again, academic centers can charge different rates for industry versus cooperative group type trials. I think that’s completely fair, right, an IRB submission, for example, for pharma costs more than than for other groups and and so there’s, again, lots of factors in this. Again, the,if I understand the NCTN correctly, like Dr Allegra said, their shared cost on the back, the behind the scenes, right? the operational sort of thing, whereas that’s I’m going to assume, funded by tax dollars to a degree, right? So that’s just something that pharma does. Has those support assistance, etc, as well, that that are add cost to the trial.

Manju George 31:32
Okay, from a cancer center perspective, are pharma run trials more interesting than NCT run trials? And if yes, why?

Dr. Wright 31:39
So I kind of think probably the answer might be no. So maybe the more interesting part, if you have a brand new class of a drug, yeah, then that Pharma is bringing, okay, yes, that would be more interesting, maybe. But in general, pharma studies are answering a couple of questions, right? Does this drug work? Is it safe? Right? Because our goal is getting the drug to a more regulatory goal, right? We’re trying to get this drug approved. NCTN run trials, I think in my experience, answer some more interesting questions, sometimes about, well, what’s the right order to give drugs like, what’s the sequence, a patient with colorectal cancer should they get FOLFOX first or something else, right? And so, actually, I think sometimes the questions being answered can be more interesting, but the on the converse, the advantage, I think, to pharma trials sometimes, is again, the newness and again, just access for patients who have exhausted standard of care options, new drug clinical trials brought by pharma are just attractive because they’re an option that doesn’t otherwise exist. So I think it depends on the situation.

Manju George 33:02
Okay, thank you. With earlier phase trials giving efficacy signals, what sort of considerations go into designing larger phase two or three trials?

Dr. Wright 33:12
The biggest,– a lot of them are the same considerations that you take just from starting a trial in general. But if you see efficacy in the early phase trial, the big questions, I think, are, again, how is this going to work into the current treatment landscape? In general, in early phase, you’re testing the efficacy of the drug by itself. So then in our phase two or three trial, well, do we want to combine it with a standard therapy? Or do we think that’s safe? Can we do that ? Again, the next question talks about control arms, right? And so when you’re planning a phase two or three trial, you have to really think through the control arm. How will that work? Again, how many patients do you need? So this is a statistical thing, right? That if your drug has a big effect, so makes a big improvement, you need fewer patients to kind of prove that again and support that. If you have a smaller or moderate sort of improvement over the baseline or standard of care, you need a bigger trial. You need more patients to really confirm that efficacy. So all sorts of considerations going into those as well.

Manju George 34:30
Okay, the next question is about control arms, they are something of concern to people. How does industry typically choose control arms? What considerations to keep in mind from the industry perspective?

Dr. Wright 34:43
Yeah, it’s a super complicated question. Again. I think it’s different for every disease state. What are the other options that could be the control arm? Again, are you trying to add to something? Or is your new drug going to be by itself? It’s almost easier if you’re adding to something then, because in the control arm is usually the standard of care regimen without your drug, usually with placebo. If you’re doing a global study, sometimes what’s the standard of care is different in different regions, so you have to figure out how to work with that. You have to think about is the standard of care the norm today? Is that going to be a standard in four years when this trial reads out? We’ve certainly seen lots of times where that landscape changes pretty quickly, and then that can impact your control arm greatly.

Manju George 35:47
Okay, for pharma led international trials with multiple arms open at many locations, countries, how does enrollment work?

Dr. Wright 35:54
Each company kind of can have a different approach to this. Again, part of it depends on early or late phase. And if you’re having to do these stop and starts for waiting to clarify the safety status of the drug. But in general, once a study is widely open, it can be that there are restrictions for geographies, you need a certain number of patients from a different region or need other countries to catch up. You do also, again, with multiple arms, sometimes you’re adding to a standard therapy, and you have to do that in bits to pieces of regimen to prove safety. The other thing is that when we say, Okay, we are opening this trial, not all sites or hospitals open at the same time, right? So we have the ability to, even if we start at the same place for all sites in the US and Europe and Japan and China, or wherever we’re enrolling. Those countries all have different processes. And so my experience in general is that the US is the fastest to get open. And so patients in the US have a little bit of advantage that they’ll be able to enroll earlier on most international trials than other countries. But again, lots of it depends on the trial.

Manju George 37:27
Okay, thank you very much. So we will stop here with Dr. Wright, and there are lots of questions, and my hope is that through all of them, we will get more information. But then here I want to go back to Dr Allegra, and then we will look at some of the questions that we had posed to him. And then we will go to the FDA, because this will give us a more idea of the the two main sets of trials. So thank you, Dr Wright, Dr Allegra, you’re back on

Dr. Allegra 37:58
Okay. Well, thank you.

Manju George 38:01
So these were the set of questions. So, how long does it take for the NCTN trial from the concept to the results?

Dr. Allegra 38:14
Yeah, so I think we asked Dr Wright similar question about the pharma trials. And you know, everybody has to go through the same steps, essentially, to get a trial from a concept to being open for accrual. I think, though the difference is when a trial becomes visible, at least to the investigators, is really what makes the difference. So for the NCTN trial, the investigators create the trial. The concept work comes from their experience, their thinking. So right from the get go, the clock starts for the NCTN. So the investigator, goal one, has to recognize an opportunity or an idea based on, whatever– either clinical or laboratory observations, and then that idea is vetted through one of the cooperative groups. I showed you, the adult cooperative groups. They all have committees, and the committees have to look at that and think about it and give input, and massage it and and iterate on it, and eventually it comes out of the other end, and then it gets presented to a disease specific task force. So for GI cancers in the NCTN, there are six task forces, one for rectal-anal, one for colon, one for pancreas, one for hepatibiliary, esophagogastric, etcetera. So the idea for colon or rectal idea would have to go to the either the colon or the rectal Task Force. It’s a group of experts from around the country in that particular disease. And again, the concept gets presented and it’s discussed and it’s reviewed, and something comes out the other end that hopefully is a better product than than when it was started. And then it gets presented to a steering committee, a disease specific. So in this case, would be the GI steering committee of of CTEP. And again, it’s reviewed by a group of experts, and input is given, and either the concept is either approved disapproved or is given a pending–If you could fix these things, come back and we’ll look at it again. And it’s in either up or down the second time– it’s either approved or not. But once it’s approved, then protocol authoring begins, and this actually one of the longest steps. It takes a while for that protocol to get written, because it’s in an excruciating detail. These are very, very long documents, and every group has their own little template. And once that protocol is completed, it goes through CTEP revision for approval or revision, and then eventually the protocol is approved. Now with industry and Dr. Wright, correct me if I’m wrong at this step, the protocol, the concept of the protocol, becomes visible to the investigators, to the outside world. All of the steps prior to that are not visible that they’re all done internally by industry. So you don’t know how they’re thinking appropriately so, for obvious reasons, until, it gets to a protocol stage. But once it’s approved by the CTEP, it gets reviewed by the central IRB. It gets reviewed by the industry sponsor, because there’s almost always an industry sponsor associated, providing the agents, and it also gets approved by the FDA, if it’s an IND study or it has registrational intent. And then with those approvals and revisions by each of the stakeholders, the protocol gets activated for approval. That’s a pretty quick process. And then how long does it take? And Dr Wright went through this as well. Depends on the size of the study. If it’s a randomized study, and looking for really big differences, maybe the study is not so big and it could get accrued with a couple 100 patients, or you might be looking for some very small differences, and that may take a large number, maybe a couple 1000 patients, so it would take longer to enroll all of those patients. And once the patients are enrolled, that’s just the beginning of the end, because it’s the number of whatever the end point of the trial is– whether it’s how long people live, which is kind of usually the major endpoint. You have to wait for that endpoint to occur in a significant number of patients, and that, depending on the disease, could take a very long time. Something like colon cancer, for example, patients live for 2, 3, 4, years. So you have to wait for those patients to reach that end point before you can count them on your clinical trial. For other diseases like pancreas cancer, that may occur a whole bunch sooner. And so those trials are a lot quicker. But that’s kind of the route that we go through. And I would say that once the trial is approved, it generally takes about a year for then to be activated, andthat is almost entirely protocol authoring. And then how long it takes to approve patients depends on the size of the trial, which varies enormously. So I hope that answers some questions.

Manju George 43:41
Okay. Thank you very much. So the next question is, what is needed to open and accrue a trial– like patients already have questions like why can’t we have a ton of trials? Why do we have only so many?

Dr. Allegra 43:52
That’s a great question. It’s a great question. And of course, it’s a complicated question, but the first bullet there is probably the most important piece. It takes financial resources to open and accrue to a trial. It takes every trial that that is done, regardless of who’s doing it, whether it’s industry, or it’s a investigator initiated, or it’s one that’s federally sponsored, is a very expensive proposition. So there are limitations on how many dollars you can spend on a given disease, and numbers of trials and so forth. So to do a trial, you need financial resources. You need an interested investigator, clinical investigator, that has an available and an adequate amount of effort to develop and supervise the the trial. And this is a difficult part, because the investigators you’re talking about are doctors in clinic. And if you know anything about hospitals, they want the doctors in clinic seeing patients for obvious reasons. They want to generate revenue. They don’t want you spending time developing a clinical trial. So, there isn’t always a lot of support for the clinical investigator to do the job they need to do to develop and actually supervise a clinical trial. But assuming that you have that, then you need an entire infrastructure to support the conduct of that trial. You need clinical trial coordinators, data managers, statisticians, regulatory and billing personnel, contracting personnel, a scientific review board, a data safety and monitoring board to make sure things are are safe, an IRB. All of these are, relatively expensive. It’s a huge expense. And I would say that the amount of revenue, let’s say we’re working with an industry sponsor, the amount of revenue that comes from that sponsor doesn’t nearly cover the cost, or maybe just barely covers the cost of all of these, all of these infrastructural needs, and this is especially true of government run trials. So for CTEPrun trials, for each enrollment, the site gets about $2,500 which is a very tiny fraction of the amount needed to run all of the infrastructure necessary for that trial is probably a 10th, maybe 15% of what’s truly needed. So they’re very, very underfunded, I would say, from a federal perspective. I think industry does a whole lot better, and that they fund much more aggressively than than the government does. And then the clinical trial has to be attracted to patients, and it also enhances the credibility of the organization. So hospitals and practices do like to have trials so they can offer them to their patients for financial reasons, but also just because it’s it’s good medicine to be able to have these trials available for our patients. They do constitute probably the best available care, and they’re very important for individuals to participate in, because it’s kind of the point of the realm. They’re very important for promotion and tenure of clinical investigators. There’s no other way that you can get promoted in an academic system other than to do your science and publish in high quality journals. So they’re very important for that reasons. And I think you know for patients, they should be very, very aware that the kind of therapy that’s given on clinical trials really does represent the best available here, even in the control arm, what we’re trying to do is improve on that best available care with a new agent or a new group of agents.

Manju George 47:51
Okay, thank you. The next question is, why do NCTN run trials take a long time to accrue and result out when compared to pharma run trials?

Dr. Allegra 47:59
Yeah, so I don’t think this is the case. I think once a trial is accruing, it depends on the number of patients you have to put on that trial, as to how long it takes to accrue and and ultimately to read out. But there are differences, and one is when the timeline starts. So I explained to you before that pharma trials, the timeline starts much later than an NCTN trial, when it becomes visible very, very early. And I think one of the most important differences between a pharma trial and a government trial is how much financial support the government gives versus industry, industry supports their trials, very, very well. The government does not, unfortunately, and that’s just because there’s a limit to how much funding that there is available, but there is a financial incentive through to an industry trial and so, and I think that makes a big difference if a given institution has, let’s say, competing trials or options to open this trial or that trial. One is an industry trial, one’s a government trial. You’re probably going to pick the industry trial unless it’s not a very interesting trial. But that’s that’s rarely the case. So, you know, I think that’s where the time difference counts.

Manju George 49:23
Okay, thank you very much. So with that, we will now move on to the FDA part, and I invite Dr Weinstock to give her talk. Welcome, Dr Weinstock,

Dr. Weinstock 49:37
Hi, thank you. This has been so great. I’ve really learned so much from the other speakers, and it’s such a great concept. So hopefully I can add to the understanding of how things work at the FDA. So my name is Chana Weinstock. I’m a medical officer, medical oncologist, work at the FDA. Next slide, please. So a little bit about me. I trained as a medical oncologist and hematologist at the University of Maryland. I stayed there for about four years as an attending, and I also worked at the Baltimore VA. I joined the FDA. It’s hard to believe I’m coming up on 10 years there, I joined as a medical officer originally, was promoted to a team leader in 2017 and I served as the Acting Deputy Director of division of oncology three, which deals with GI malignancies in April of 2024. So one of the most rewarding aspects of my work at the FDA has been really just the outward facing part of my job, where we’ve developed workshops on clinical trial design and end points in oncology. I’ve had the opportunity to interface with thought leaders in oncology in terms of planning ASCO meeting sessions, chairing them, speaking at ASCO. I was the educational committee member and track leader for one of the GU oncology tracks over a few years. I’ve been involved in ASCO GU planning and some of the other advocacy organizations, annual meetings. So that was really great. And there’s a question in the chat about how to better pool data across clinical trials. And I think one of the things I heard about when I was interviewing for the job at the FDA, which I really was not aware of beforehand, is that the FDA is a repository of so much clinical trial data, because any drug company that’s looking for approval of their drug submits all the patient level data to us to analyze and to verify the benefit and the safety of the drugs. So what happens is we’re left with just an enormous amount of data, and I think we’re in this unique position to do pooled analyzes across trials to address questions regarding, safety, efficacy, that are pertinent to the US population. So I’ve done a lot of those. I’ve been involved a lot of those sorts of analyzes to address overriding questions in the field of oncology, and that’s been very rewarding.

Manju George 52:21
Okay, thank you.

Dr. Weinstock 52:25
Okay, so the way I structured my talk, I took some of the questions that were submitted to me in advance, and I worked a little bit of an introduction to the FDA, what we call an FDA 101 style talk around these questions. So these are the questions that were submitted, and I’m happy to go through them and tell you a bit more about the FDA. So the first question was, tell us about the Oncology Center of Excellence. Going to refer to this from here on as the OCE, and what the goal of the Oncology Center of Excellence is. So basically, we are, and you could advance through all the way through this slide. Yeah, thank you. So the Oncology Center of Excellence is a center within the FDA that involves about almost 100 medical oncologists, in addition to colleagues of mine, who are trained in other disciplines, and we’re involved in the review and approval of new drugs. And it’s a great group of people. It’s very collegial, very helpful. There’s just a ton of brain power and expertise in this group. As you can see, we have a campus physically located in White Oak, although, since the pandemic, a lot of what we do is virtual. It used to be that companies would fly down or drive down to White Oak to meet with us. Now I would say 95% of our meetings are virtual, and we, this was during Covid. We did have some get togethers back when we weren’t in the office. That’s us on the top right corner. But it’s been a really wonderful place to work. There’s a lot of engagement with the oncology community, with advocacy communities, and really a lot of efforts to really move the field forward.

Dr. Weinstock 54:23
Next slide, please. So really, our role is to ensure the safety and efficacy and security of drugs. The FDA also deals with the food supply, cosmetics and radiation emitting products. One thing we don’t take into account when we look at regulating drugs or other products is pricing information. So that’s not something that we take into account when we look at the risk benefit of a drug. Next slide, please. So back to the Oncology Center of Excellence. So. With the Cancer Moonshot Initiative that was started, I think, in 2016 what happened was there was a realization that there were a few different centers within the FDA that were involved in regulating products related to treatment of cancer, but they were not all in the same place. So there’s the Center for Drug Evaluation and Research, which deals with drugs. CBER is the center, and that’s called CDER. CBER is the Center for Biologics, so any vaccine or cell products, like car T cells, those are actually housed in a different center and reviewed by different reviewers. And then there’s the Center for Devices. So devices that are used in the treatment of cancer are regulated also in a different center. So the Oncology Center of Excellence, brought all of these centers into the same umbrella and really got us talking to each other. We’re always talking to each other, but this is a very unified approach to regulating cancer products. Now within CDER, which is where I live, at the FDA, with the Center for Drug Evaluation and Research, we have five different disease specific teams,Division of oncology, one, two and three, and then two hematologic malignancy review divisions. So what this does is it really concentrates and focuses the expertise of the medical oncologists and the other teams who work at the FDA so we can give the best possible advice to sponsors and drug companies, etc, who come to us for advice. So colon cancer and other GI malignancies, like I said earlier, are regulated within the division of oncology three but again, we’re all part of the Oncology Center of Excellence, the same umbrella.

Dr. Weinstock 56:50
Next slide, please. So like I said, there’s almost 90 of us. It’s a very academic type environment with disease specific teams, and this enables us to give the best guidance possible. Next slide, please. And this is just a snapshot of what we did last year, for example, with 14 new drugs approved or biologics approved for the treatment of cancer, and then many, many supplements. So supplements are when there’s a drug that’s already on the market, approved for a new indication. So we do a lot of that as well. Next slide please. Okay, so next question that came up, so what are the steps in the FDA approval of a drug, and then what happens after a drug is approved? What’s the FDA role then? So I would say the FDA involvement in approving a drug starts very, very early with a lot of interactions between the FDA and the companies running clinical trials. You know, we start very early in drug development, even at the pre IND stage. So an IND stands for an investigational new drug. That’s when you’re looking at a drug in a first in human or early phase clinical trial. And what our role is, we look at the preclinical or the animal data. We look at the dose that a sponsor is proposing to use for the first time in a human. We look at the dose escalation that they’re planning when they escalate the dose in humans, and how they’re planning to do that, and we provide input on whether we think that’s going to be done in a safe way. Once that phase one trial is done, we continue to interact with sponsors, and we talk about phase two trials. As you know, there’s early signs of efficacy. We talk about the dose that looks like it’s going to be the best dose to move forward into later phase drug development. And then we talk about trial design and what we think a good trial design would look like to demonstrate safety and effectiveness of that product. So we’re very, very involved in all the phases of drug development, not just at the point where a clinical trial reads out and is ready for us to be reviewed. And then even once a drug is approved, there’s post marketing surveillance that FDA is very involved in, although that happens in a different section of the FDA, but we talk to them all the time about safety, surveillance, post market and can move forward.

Dr. Weinstock 59:38
So the early stage development, late stage development do answer different sort of questions, and we’re involved in determining some of these answers. Early stage development looks at the safety of a drug and preliminary activity. And then as later stage development happens, we’re really looking at whether there’s a meaningful benefit provided. And once a drug has gone through a late stage clinical trial and is ready to be submitted to the FDA, the data to be submitted to the FDA for review, it’s submitted through what we call a new drug application, or an NDA, so that’s the actual application that’s submitted to the FDA, or a biologics license application, which is a BLA so those are the name of the submission when it comes in the late stages. That’s as opposed to in the early stages when there’s an IND submission, which stands for investigational new drug. Next slide, please. And like I said, there’s a lot of interaction points between drug companies or sponsors and the FDA. You know, at the beginning, some of it is voluntary, a pre-INDmeeting. You know, we, we can have that. It’s not necessary. But a lot of times, companies will ask our advice in the early stages, and then as the lifecycle of the drug progresses, and a phase three trial requires design and it reads out, we get very involved in questions about trial design, questions about interpreting data and all of that. So that’s sort of a snapshot of where we come in this process. Next stage, please.

Manju George 1:01:26
What is the EOP meeting?

Dr. Weinstock 1:01:28
Oh, end of phase. End of phase. So an end of phase meeting is so if a company has conducted like, a phase two trial, and they’re like, oh, you know, the data looks promising for this drug, and this indication, we have data on, I don’t know, 50 patients, and here’s what we think, we want to launch a very large clinical trial where we’re looking at this in 500 patients. So that’s an end of phase meeting.

Manju George 1:01:52
Okay, thank you.

Dr. Weinstock 1:01:55
So what sort of input does the FDA have on earlier phase trials, like phase one and two and how they’re run. So, I think, and you can advance through this slide as well. There are a lot of points where we can meet with sponsors, but I think the main thing that we look at in early phase drug development is safety, certainly in the phase one setting. You know, are you choosing the right dose to start with in your first in human trial based on the animal data, are you dose escalating appropriately? Are you choosing the right doses? Are you monitoring your patients? Are you including patients who can get this drug safely, etc? And so we do have a lot of interactions. And we get questions about how to run phase two trials all the time. And what I do tell sponsors in general, either through talks like this, we’re happy to meet and consult essentially on trial design issues. I think the the earlier you involve the FDA, the better it is, because we can address some of the issues that might come up later, earlier in the drug’s life cycle, and hopefully get ahead of issues that might come to the front in later stage trials. And one great example of this is something called Project Optimus, which is where we’re really looking at getting the optimal dose earlier in drug development, rather than having a trial readout, and you say, well, you know, the dose looks like it was probably too high or too toxic. What do we do now? So there’s a lot of that as well. you can advance.. then these are just some of the many, many colleagues of mine who are involved in drug development advice. You know, there are a lot of things that patients on a trial don’t even think about. But like, you want to make sure that the drug that they’re getting is delivering the right drug, and there are product quality considerations and things like that that come into play. So there’s a multidisciplinary team looking at all of these INDs from the very early stages, and we all work together.

Dr. Weinstock 1:04:24
So how do we improve trial accessibility for patients? And this has been a very big focus of the FDA, certainly since I’ve joined. Next slide, please. So this was touched on before, but we really do feel that patients enrolled in clinical trials have better outcomes than those who are not treated in the context of clinical trial, and that’s been shown through various studies. The care that a patient gets on a trial is really the optimal care, and that’s why we want clinical trials available to as many patients, and as broad a patient population as possible. But then another consideration is that you really want the trial population to reflect the population of patients who will be receiving a drug once it hits the market. So both of those things are very important in terms of opening the trial and enhancing equity and trial enrollment to as many patients as possible. And to that end, the FDA has been involved in a lot of efforts to open up eligibility criteria. So for example many years ago, I think some trials capped the upper age of patients enrolled in clinical trials at 65 and many patients who are taking these drugs are older than 65 and if you don’t have data on how old older adults do on your trial, that’s a big concern, right? So we’ve addressed some of these eligibility criteria. Some patients were excluded just by virtue of having HIV, hepatitis B, hepatitis C, even if they were very well controlled on medications. And you see here, we’ve published guidances to really encourage enrollment of a broad patient population in terms of age, in terms of comorbidities, brain metastases, in terms of diversity, and in terms of older adults as well.

Dr. Weinstock 1:06:20
And I’ll briefly touch on some of our expedited programs. I got a question about what Fast Track is and what it means for trials and patients. Yeah, so expedited programs exist within the FDA with the goal of hastening the approval of safe and effective therapies in cases where there are serious and life threatening conditions for patients. So there are a few categories: Fast track, Breakthrough, Priority review and Accelerated approval. There are also other categories of expedited programs that apply to biologic products and devices. I won’t go through those, next slide. So Fast track is a designation that we give to a drug once you know the company provides us preliminary data that demonstrate the potential to address an unmet need, and this is usually pretty early in drug development, and that’s expedites the development and review of the drug and really hopefully increases the interaction between the FDA and the drug company once that designation is applied.

Dr. Weinstock 1:07:32
Breakthrough therapy might sound similar, but it’s actually somewhat of a higher bar to qualify for breakthrough therapy, because it involves us reviewing data that’s been demonstrated by a drug, and the drug has to demonstrate preliminary clinical evidence that’s a substantial improvement over available therapy. So this is, like a therapy that seems to be really promising, and then we work really, really closely together to get that drug onto the market. The other two expedited programs involve Priority review, which is a designation that shortens the review clock once the data from a clinical trial is submitted for review. And Accelerated approval is an approval pathway that is granted based on earlier endpoints in a clinical trial. And then just Fast track and Breakthrough are usually earlier in the drug development than Priority review or Accelerated approval. So depending on the stage of the life cycle of your drug we can talk about different expedited programs based on where you’re up to in drug development. And that’s it from me. We do have, I just wanted to highlight Project Facilitate, which is a way that patients can or that we can help patients access single patient INDs, which is Expanded Access for patient with cancer to get access to a drug under a special type of IND. And we have a very fast process to turn those over. And thank you. I’m happy to take more questions. Yeah,we have many different programs going on in our office, a lot of innovation and innovative thinking, and hopefully we can really move the field forward for patients.

Manju George 1:09:30
Okay, and then we have a couple of I’m keeping my eye on the time, so we will see how we’ll do, but I have some questions for Dr Weinstock, like, when a drug is approved for an indication, what specific things should patients also keep in mind about the approval?

Dr. Weinstock 1:09:46
Yeah, so I would direct patients and providers to the label that’s approved along with a drug approval, because we really do put a lot of effort into informing different sections of the label that talk about which patients were enrolled in the trial that led to approval, who the drug is indicated for. So I think those are specific things that you can think about, and the label is a really good resource to really capture all the data that you should keep in mind when you’re prescribing the drug or using the drug.

Manju George 1:10:28
Okay, so we’ll skip the next one, because I think you went through some of it in your slides. Then what other information besides trial data does the FDA take into account while making decisions? Real world data registries, those sort of things.

Dr. Weinstock 1:10:43
Yeah, this is a really important topic. You know, there’s been a lot of focus on real world data, and there’s actually within the Oncology Center of Excellence, there’s a team that specifically just looks at how to incorporate real world data into clinical trials and how to interpret that data. So I think the short answer is that clinical trials, based on the patient data in the conventional way that you’re used to conducting trials, are really the gold standard and are here to stay. We can use real world evidence for a lot of other things in sort of in a supportive manner. And it’s something that I think is evolving and that we’re really interested in being on the cutting edge of as we get better and better at registry data and interpretation of real world data.

Manju George 1:11:36
Okay, okay. Thank you very much. I think that is the panel talks. So now we have a ton of questions, so I’m kind of thinking how we’ll get through all of them. So these questions whoever wants to answer, can answer, and then we will kind of look at some of the questions, because there is about 25 of them. So I think some of the questions in chat are already covered here, so we look at that pretty quickly. So the first question is, and you know, whoever wants in the panel to answer these questions, they’re welcome to start with. So the first question is, what steps can be taken to accelerate the time to trial for drugs, particularly upon a successful phase one trial, why does it often take up to an year to get a phase two open?

Dr. Wright 1:12:20
It’s more of the same that we’ve kind of talked about, right? Um, sometimes, again, you want to meet with the FDA and say, are these plans appropriate? Are we going to get to where we think we’re getting with this phase two trial, and then it’s just a lot of operational Dr Allegra mentioned it takes a long time to write a protocol and make sure you get that done well. I will say, I think this is one area where competition is good, right from the industry side, we feel pressure if another company we know is developing a drug in the same class, this will inspire us, maybe, to to move a little faster and set internal goals to be a little more aggressive than we might if there’s not competition.

Manju George 1:13:10
Okay. Okay. So can trials make use of synthetic control groups, given that a large number of patients currently and historically in treatment with standard of care, the challenge getting a patient to enroll in and stay in a trial that is not with their local oncologist, if they’re randomized to a control group. So what does the panel think about synthetic control groups?

Dr. Wright 1:13:32
I know of an example again at Lilly, where this was used. I think that the concern for most industry again is, will this be acceptable to the regulatory you know, not just FDA, but again, we’re working with Europe’s version, and around the world. So I think for rare populations, especially, we have done this at Lilly for a couple of our pediatric trials. But again, you have to work with the agencies in advance to make sure you’re using the appropriate control group. It’s a lot of statistics work that is much above my head. I don’t know. Dr Weinstock, if you have other thoughts on that.

Dr. Weinstock 1:14:14
Yeah. I mean, there’s a few different things that are covered in this question. I think synthetic control groups, or control groups based on, historic control that kind of thing. I think people have tried to do it. There are many challenges. And I know some of my statistical colleagues have addressed those. Yeah, I think thinking creatively about control groups, one of the things we’ve tried to encourage is sort of a combined control group where there’s a few trials running in the same indication, like, maybe everybody could get together, and if you really are all using the same control and it’s pretty much the same population, maybe, you know, different trials could cooperate and use the same patient data for for those control arms. But, you know, I think there are efforts underway to decentralize trials. So you could decentralize trials, so maybe you’re not traveling to an academic center to get what would be a standard control therapy that a patient could get closer to home. So there are a lot of different ways to think about control arms that are more creative that we’ve been involved in discussing.

Manju George 1:15:22
Okay. How do trial set just for changes in related treatments while midstream? Like, for example, a new SOC for the control arm?

Dr. Weinstock 1:15:31
Yeah, I can take this one, because there’s been a lot of thought about this recently and and there’s been an FDA Advisory Committee dealing with this as well. Like, what happens when one trial reads out and it affects the perceived, especially when there’s, like, an accelerated approval or something, and something’s on the market, but then there’s a confirmatory trial going on, and there’s a control arm that patients might think, or providers might think, is not optimal. So I think from our perspective, this is mostly a problem when there’s an overall survival advantage that’s been demonstrated when one trial reads out. How do you handle that? Do you consent patients? Is that enough? Do you really have to change the control arm in the middle of a trial, I don’t know that that’s always the case. So, those are discussions we could have. There’s also something called equipoise, right? So every time you open a trial, equipoise is a big concept. It basically means equilibrium. You want both arms to be perceived as possibly being able to win, right? You know, there are a lot of trials that fail, right? Because the control arm actually is superior. So we don’t know that just because we’re opening a trial that we’ve picked the winner. Otherwise we wouldn’t be doing the trial. But you want there to be a perception that the control arm is adequate. So a lot of that goes into it. You want to make sure that the control arm is perceived as being a good option, even when data comes out from other trials. And there are mitigation strategies to ensure that even if you know there’s a new standard of care that happens in the middle, or if patients don’t want to go on the control arm for some reason, or they drop out early, how to build that into your trial design, etc. And this isn’t exactly what you asked, but there are ways to offer the the Investigational agent, through crossover, that’s built into a clinical trial, so that there are a lot of different things you can do to kind of work around the control arm issues.

Manju George 1:17:39
Okay, thank you. So I’m going to skip a few things. So what happens to learning from failed trials? This issomething that lots of patients are interested in knowing, because they want to know, like, it’s not that a trial, when it’s fails, it does not benefit anybody. There’s a small subset of people that are benefited. But what happens to all of that? Anybody wants to take that?

Dr. Allegra 1:18:00
So I could start with that one. So every trial that’s run is reported to clinical trials.gov a centralized database of all trials that are ongoing, and at the end of the trial, there is a mandate to provide data of the outcomes of that trial to that website. So that’s one thing that happens to all trials, whether they’re failed or successful. I’m guessing the person who asked this is more interested in what happens in terms of publications in journals, and there is no question, there is bias of journals to not publish failed trials, which is not that interesting, but the reality is that’s very important information to know what doesn’t work. It’s almost as important as knowing what does work in many cases, not all cases, but it is an important piece of information and needs to be published. And there are some journals that specifically will publish trials that didn’t meet their primary endpoint, that were essentially failed trials. So there are avenues to get trials published, as long as the sponsors, the authors, etc, want to do the publication, you have to have somebody who is going to be willing to write the paper, and go through the steps to get it published, of course, but assuming that’s available, there are plenty of journals that will accept failed trials that they should be in the literature and searchable.

Manju George 1:19:28
Okay, okay. Dr Allegra, since you’re answering this, I’ll ask the next related question, how does clinical trials.gov fit into all of this? Who’s tasked with keeping it up to date?

Dr. Allegra 1:19:39
So the principal investigator of the trial is ultimately responsible for completing all of the data that goes into clinical trials.gov, and there are teeth to this. The government can find people, and they could even incarcerate if it gets to that point, but, it is the PI’s responsibility to do that. Now the reality is that the PIsgenerally delegate that responsibility to someone, a data manager or someone at the institution that willmake sure that the that the information is kept up to date in clintriles.gov, to the extent that it’s exists. But it is not the responsibility of that data manager. It’s the responsibility of the PI to make sure that it actually happens. And I think over the course of time, this requisite has become more and more stringently upheld.

Manju George 1:20:33
Okay, so the next two questions are about adverse events and monitoring. So what guidance does the FDA offer for reporting of adverse events? And then the next question is when a patient looks at results reported from early phase trials, what are some of the things to keep in mind in terms of side effects? This is for Dr Weinstock.

Dr. Weinstock 1:20:59
Yeah, so for early phase trials, like I said, we look at the protocols very carefully to make sure that adverse events are collected and reported to us. And we get safety reports all the time, and we review them to make sure there’s nothing out of the ordinary going on in drug development. And like I said that’s most relevant in early drug development, but in terms of reporting toxicities from later stage trials. And, oh, I’m sorry, this was about early trials. So I think early trials, the toxicity reports are not always public through the FDA. I think you can look at published trial results to get an idea of early phase toxicities, but I will talk about later phase toxicity and how you can get a little bit more information about that through FDA resources. So when a drug is approved and we review the toxicity information from basically all the information that was submitted to us. There’s a lot of information that goes into our review, which is published on a website called Drugs@FDA, and when you look at that drug, you can get the clinical review, which is where we review all of the safety data and efficacy data that was submitted. And a lot of times there’ll be very detailed information about some of the adverse events thatoccurred to patients on the trial, including like, when they happened, and did they resolve, and things like that that might not be otherwise available. So I think that’s a very good resource to know about, andnot everybody is aware of that. Sometimes we’ll include information in Section Five about some of the toxicities, and some of the time to resolution and things like that, or time to onset, or more detailed data. But I think the label and our reviews on Drugs@FDA can be very valuable resources about some toxicity information.

Unknown Speaker 1:23:04
Okay,

Dr. Wright 1:23:04
The other thing I think I’ll just mention again, from pharma side, we there’s a couple of ways we try and disseminate this information to the investigators before it’s publicly disclosed, right? So even though it’s at the time, confidential information to the company, we work with the investigators to make sure they’re aware of anything that might impact them, the patients they’re treating at their sites, and sometimes that protocol is updated to require additional monitoring, something like that. But we’ll have investigator meetings very routinely. Again, the earlier on in development, the more frequent those meetings are to share that information amongst investigators and so again, trying to just make consent forms. If any of you participate in trial, you get the original consent, but those get updated as new information comes along, and that consents are in a lot of cases need some work, but they are good source of information for sort of fresh, really up to date, sort of things about toxicity.

Manju George 1:24:10
Okay, okay, thank you. So then I’ll go to question number nine, why do phase one and two trials with impressive results fail to impress with phase three results, like, Who wants to take that? Some general reasons.

Dr. Allegra 1:24:24
Yeah, I mean, these are small trials. So the sample size, the number of patients on the trials, is very small. And so the error bars, how what the response rate is, or the progression free survival is, you know, it’s a very broad range that you end up with, because the the numbers of patients on the trial is is pretty small,and so you can get false positive at a higher extent, at a higher level, than you do when you tighten up your statistics in your later stage, in your later phase trials like a phase two trials, and that’s why they often don’t translate. But that’s why we do phase three trials, because we, we have to have an adequate statistical plan to to know whether something truly is beneficial and safe versus, maybe it isn’t but mostly, if you have a positive phase two trial, it often translates into a positive phase three, but certainly not always.

Dr. Wright 1:25:23
I think the other thing that can have a big impact again, like I mentioned, your first in human trials are more narrow for inclusion criteria, right? You’re you’re selecting a somewhat healthier population often, whereas then when you get to phase three, as Dr Weinstock mentioned, you want more broadly applicable information to the people who are going to get this drug if it’s prescribed. And so some of the difference, I think, is also related to that. There is a difference in the populations, I mean, intentionally, but some this is an unintended consequence of that, I think sometimes,

Manju George 1:25:59
Okay, so then I’ll skip to some of the last questions, because we are close to time. This is about after the drug gets approved what is the process to get insurance to approve the drug? I’m trying to see what number it is, 22

Dr. Wright 1:26:20
I probably should take that one. It’s a bit of a mysterious hole for me as well. We because we have a different part of our company that works on that. But our goal, obviously, is to work to get as many companies as we can to cover the cost of it. So there is a group that works on that and that group is global. So we do that in the US, but also in other countries as well. Their processes are can be quite different, especially when there’s national health care programs, but the process involves us, again, submitting the data, some publications and that sort of thing to again, just essentially the proof what they need is, what’s the benefit? Where is the balance of the cost of the drug with the degree of improvement, and that can be sometimes a long and painful process,

Dr. Allegra 1:27:23
But I’ll add that once the drug is approved by the FDA, Medicare, by law, is obligated to support that. It’s the independent, the private insurers who can, you know they can make decisions. They usually follow Medicare, but not always.

Dr. Wright 1:27:39
And then sometimes, yeah, their their percentage of coverage, right is sometimes the challenge, right? It’s, it’s covered, but with the copay that is really not sustainable for most people.

Dr. Allegra 1:27:51
yep, yep.

Manju George 1:27:52
I think there were some questions about insurance, and I’m hoping that that is covered. So then we’ll kind of move to the last few questions. For the trials that are not registrational, how does a new drug or regimen become part of part of standard of care? Is it also kind of similar process?

Dr. Wright 1:28:11
So one, one route, is through regional or national treatment guidelines. So for example, there’s the NCCN guidelines ESMO guidelines in Europe, etc. And that is an independent group that will review data from new trials and rank the quality of the data and the strength of the data. And so a smaller trial, for example, that may not be registrational, can get into those guidelines. And there are some insurance companies that can use those guidelines as support to provide a drug for a patient. That’s just one way.

Manju George 1:28:59
Okay, thank you. And then the last question for all three of you is based on your experience, what’s one thing you want patients considering trials to keep in mind?

Dr. Weinstock 1:29:09
I can take this, I mean, I think really emphasize, and I mentioned this briefly, Project Community, there’s alot of emphasis in partnering with us at the FDA as patient advocates to really let us know what the issues are in the clinical trial space, in the treatment space. We’ve really tried to make an effort, but we welcome as much patient advocacy participation as possible to really know what’s going on. What are the unmet needs. Which communities feel underrepresented? I remember going to a breast cancer metastatic mini symposium where the metastatic breast cancer patients with metastatic breast cancer were saying that they felt like clinical trials were not addressing their needs as much as earlier states, things like that. We really want to hear that kind of feedback. And things about patient reported outcomes and things that matter to patients, tolerability versus toxicity, impact on patients, daily lives ofdrugs and toxicities that aren’t reported. Maybe patient’s ability to work, to function, that kindof thing, like we want to hear all that. So, I can provide my email address. I welcome input and feedback and engagement from patient advocates.

Manju George:
OK, thank you very much! what about from the other two? Dr. Allegra?

Dr. Carmen Allegra:
The question that I often get asked is in consultations, especially for early phase trials is people who have got the standard of care, they have advanced disease, and they wanted to do something else, they are in good shape, good performance status, they don’t want to give up, they want to continue with the fight. And they want to know what should I do next? And if you direct them to clinical trials.gov, putting in all the specifics about the person, you come up with 20 or 30 trials, with possibilities throughout the country. Then the question is how do I figure out what to do? And unfortunately, the question is nobody knows. My advice to patients is to pick the institution and the doctor they are most comfortable with. And have a conversation with that individual as to which trial makes the most sense to you that are available at that institution. As opposed to trying to shop around different doctors at different institutions because nobody knows the answer because we wouldn’t be doing these different trials. But often, a point for huge frustration for patients.

Manju George:
OK, thank you! Dr. Wright, do you have anything to add?

Dr. Jennifer Wright:
Yeah, I think ask. So clinicians get super busy. And they can get into routines, and it is very understandable. But you can be your biggest advocate and just ask. Is there a trial that’s appropriate for me? Hey, I hear trial patients do much better than non-trial patients. You have to make them stop and think. and I say that. I was a practicing physician and got super busy. It’s really interesting that in the pediatric landscape, almost all patients will go on a clinical trial, if one is available that’s appropriate for them. Just a different mindset and so, help remind the physician that you need these options presented to you.

Manju George:
Thank you so much! This was wonderful! I so appreciate you guys taking the time and spending the last one and a half hours with me, with all of us. A recording of this session will be posted in Colontown University and thank you again, once more!

Dr. Carmen Allegra:
Thank you! take care everybody!

Dr. Jennifer Wright:
Bye!

Dr. Chana Weinstock:
Bye!