Transformation in Trials
A podcast about the transformations in clinical trial. As life science companies are pressured to deliver novel drugs faster, data, processes, applications, roles and change itself is changing. We speak to people in the industry that experience these transformations up close and make sense of how the pressure can become a catalyst for transformation.
Transformation in Trials
The Ethical and Legal Challenges in Unapproved Drug Access: A Talk with Patti Zettler
Imagine being given a shot at a cure before it's even approved. That's the fascinating world of expanded access programs for unapproved investigational interventions that we're exploring today with our esteemed guest, Patti Zettler, law professor and chair of the International Society for Cell and Gene Therapies Expanded Access Working Group. We delve into the history of these programs, the FDA's role in their regulation, and the surge of interest they've seen in the last decade. Ever wondered why a patient would be willing to be a first mover on a yet-to-be-approved drug? Patti provides enlightening insights into this unique field.
We then delve deeper into the intriguing complexities of expanded access programs within the realm of cell and gene therapy. We navigate through the potential for these programs' misuse by pharmaceutical companies, and the tension between the need for scientific evidence and a patient's desire for early access. The conversation also explores the ethical and legal dilemmas these programs present, the doctor's role, and the challenge of effectively communicating associated risks to patients. We wrap up with a contemplation on the changes we hope to see in the industry. Patti's insights, coupled with our thought-provoking discussion, will leave you with a deeper understanding of this crucial aspect of modern medicine.
Guest: Patti Zettler
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You're listening to Transformation in Trials. Welcome to Transformation in Trials. This is a podcast exploring all things transformational in clinical trials. Everything is off limits on the show and we will have guests from the whole spectrum of the clinical trials community, and we're your hosts, ivana and Sam. Welcome to another episode of Transformation in Trials. Today, we're joined by Patricia Zettler and Patricia, would you tell us a little bit more about yourself?
Speaker 2:Sure, thank you so much for having me. I'm delighted to be here. My name is Patty Zettler, I'm a professor of law at the Ohio State University in Columbus, ohio in the United States, and I am the chair of the International Society for Cell and Gene Therapies Expanded Access Working Group. And just to give you a little bit of a sense of what ISCT, the International Society for Cell and Gene Therapy, is, it is an organization focused on preclinical and translational aspects of developing cell and gene-based therapeutics and has over 2,700 members across all sort of stakeholders industry, academics, scientists, regulators, ethicists across the globe. So it's a great, great global organization.
Speaker 1:Thank you for that, and today we're going to dive further into the topic of expanded access programs. And just to get us started, can you tell us more about what an expanded access program is?
Speaker 2:Sure. So you know, as I'm sure many, I'm sure all of your listeners are familiar, usually companies, developers, cannot distribute their products until they have the appropriate regulatory approval or regulatory authorization from the relevant regulator in their country. In the United States that's the US Food and Drug Administration, or FDA, and it takes a long time to get that approval because to produce the evidence of safety and effectiveness that's needed again, as your listeners will know, there's a long process of clinical trials and sometimes patients are willing to accept uncertainty about the risks and benefits of a product because they have an untreatable, serious terminal illness and they also cannot get into the clinical trial. And so expanded access refers to access to an unapproved investigational intervention outside of a clinical trial. It's our sort of regulated pathway to distribute a product outside of a clinical trial.
Speaker 1:And is this something that's new, or have we been able to do this for many years?
Speaker 2:Yeah, that's a great question. So expanded access is not new. Expanded access is the term that FDA uses, and has used since 2009 at least, and other terms that folks may have heard are things like compassionate use and or non-trial pre-approval access. Those are some of the other terms that get kicked around, but in the United States there has been at least there's been informal pathways for this kind of access, especially since FDA got its modern approval authority in 1962. And FDA has had formal regulations on the books for this kind of access since the 1980s, so it's been around a long time.
Speaker 3:Patti, we have a global audience. Is our similar programs available outside the US?
Speaker 2:Yeah, well, I'm always. I am a lawyer by training, so I'm always cautious about opining on things I don't know deeply. But there are similar pathways in other places in Europe. For example, there are similar pathways in the EU countries and I'm not as familiar with the details, but most places with a kind of developed regulatory regime for medicines have some kind of pathway like this.
Speaker 1:And has there been any development or evolution in this space since the 1980s? Do we see more expanded access programs? Do we see fewer? What does it look like?
Speaker 2:Yeah, that's another really good question. So are we seeing more programs? Have there been evolutions? There certainly have been evolutions in the pathway over the last 40, 50 years and in the US this is a space where there's been a lot of social debates around how exactly should we be providing this kind of access. There have been lawsuits brought against the government for patients seeking wider access or more clarity about the access. The government itself has tried to clarify and speed up and make more efficient the processes for companies to provide this kind of access. And in terms of, is interest expanding?
Speaker 2:It's a little bit hard to say across 40 or 50 years just because we don't have easy access to that information. But again, in the US we do know that the FDA publishes the numbers of requests that it receives and the numbers it authorizes and publishes back at least 10 years for both drugs and biologic products, and you can see that the numbers of requests are increasing. So that might be because patients are becoming more aware of this option. For example, during COVID, some of the products that were ultimately received emergency use authorizations and then subsequent approvals were first provided through expanded access. So I think people became more aware of this as a possible pathway. But also I think there's just, at least in the cell and gene therapy space, there's a lot of hope right now. There's some gene therapies that have been approved and patients and developers are pretty hopeful. That was a very long-winded answer to say. It seems like at least over the last decade or so, the number of requests is increasing a little bit. It's a bit hard to say going back 40 or 50 years.
Speaker 1:And are there any specific areas where it's more prominent? Is there a specific focus on cell and gene therapy, for example?
Speaker 2:Yeah, so that's also a bit tough to answer based on what's publicly available, just because companies and developers are not required to disclose necessarily all of their programs and the government doesn't necessarily disclose the details of what's been requested. But the office within FDA that deals with cell and gene therapies has seen a similar increase over the last 10 years the number of requests. So I do think probably there's increasing interest there and historically cancer has been a really big area. So a lot of oncology. There's a lot of interest in accessing investigational oncology interventions outside of clinical trials.
Speaker 1:That makes sense. I would also be curious from a patient perspective. What makes a patient want to be a first mover on a drug that is not approved yet?
Speaker 2:Yeah, so I'm not associated with a patient advocacy organization or beyond. Just we're all patients throughout our lives and at some point in our lives, but my sense is that it's patients when you're facing a serious or terminal disease for which there is no approved therapy or no good therapeutic option that's supported by strong safety and effectiveness information. Some people are willing or are interested in trying things with uncertain risk benefit profiles and if a patient can't get into a clinical trial, something like expanded access is the way for a company, if the company wants to, to provide access outside the clinical trial.
Speaker 3:I was going to ask that question actually, patty. I thought it potentially was a bit too much of an obvious question, but assuming that all avenues have been explored about available clinical trials before an expanded access option is investigated, or is that not necessarily the case?
Speaker 2:So that's a good question also. So, in general, fda's regulations and FDA sort of sister regulators in the EU etc. Expect that expanded access programs will not delay clinical trials, will not delay the development of the safety and effectiveness information that is needed to get marketing authorization to prove the product is safe and effective, which is ultimately what patients want, right? Patients want a safe and effective therapy, not just something that is, you know, we don't know if it works or not. Okay, all right, and so there are. But whether a patient has to exhaust every single possible clinical trial or just be ineligible or unable to participate in the clinical trial of the investigational product the patient is interested in, I'm not sure there's a clear, uniform answer there.
Speaker 1:Are we missing out on something as a society when we, when we make use of this avenue, missing out on some scientific rigor that we could have had in addition to the data that we collect from the clinical trials?
Speaker 2:Yeah. So expanded access, the the intent is treatment, so it's the intent is not to develop safety and effectiveness information about the product. So a bonus question is a good one, because the program is not necessarily designed to develop the kind of safety and effectiveness information we get out of clinical trials. So some folks, including myself, have argued that maybe, if there is interest in broader access, expanding clinical trials might be a more beneficial way to provide access and in a way that allows us to get better information. I think it's the patient populations that are typically interested in expanded access.
Speaker 2:It's tough to get useful information in some cases because typically they're so sick already. You know adverse events. Fda published an article maybe five or six years ago, looking back at its own internal records, and it found, I think only, if I'm recalling correctly off the top of my head, only two instances were an adverse event and an expanded access program led to a hold on an adverse event or any sort of action. And that's kind of understandable, right, because if you're talking about a super sick population, adverse events aren't likely to be attributable to the intervention versus just the natural course of the disease. So I would leave it up to my scientific colleagues about whether there's a way to design expanded access programs that serve that purpose of treatment but also enable better information collection. I mean there there is information collection, that happens. I'm just, you know I'm. I think it's outside my expertise to know if there's a way to like sort of design the programs better to get better information.
Speaker 3:I'd like to spend a bit of time on ISCT. Perhaps you could talk to us a bit more about. Isct is an organization, and I understand that you're involved in a working group related to this topic of expanded access, so perhaps you could share with our listeners a bit more information about that.
Speaker 2:Sure, yeah. So, um, isct is the International Society for Cell and Gene Therapy and it is comprised of over 2,700 cell and gene therapy experts and they come from kind of a bunch of different areas within the cell and gene therapy field, including academics and basic scientists and folks doing clinical trials, and physicians and developers and industry and so on, and they're located across the globe. So it is. If you have listeners out there who are in the cell and gene therapy field, it is a really wonderful organization and you know there is an annual meeting.
Speaker 2:This year was in Paris, so nice location to have an annual meeting. And you know a lot of in between the annual meetings, a lot of smaller meetings or webinars, opportunities to connect with colleagues and learn about what's going on in the field. The expanded access working group was is a subgroup of the committee. There's a committee on the ethics of cell and gene therapy and the expanded access working group was formed in recognition of this seemingly increasing interest in expanded access in the cell and gene therapy field, given the kind of recent gene therapy approvals, the hope that all of the great scientific work that's been going on is going to translate into, you know, promising new therapies and to try to sort of get ahead of the game and provide some guidance to the field on best practices.
Speaker 1:That sounds really interesting and very needed for this field. I am a little bit curious. This seems this could be perceived as a loophole to get your drug on the market earlier than you could otherwise get. Have we seen any indications of misuse of this program by pharmaceutical companies?
Speaker 2:Yeah, I mean, I think that is one really big concern, right? We don't want providing access to unproven products to to mean that we never get to learn about whether the products ultimately are safe and effective for the relevant disease. So there's this sort of tension between the need to develop rigorous scientific evidence on the one hand and patients understandable desire for early access in some cases on the other hand. I think that's why FDA and similar regulators around the globe tend to have a requirement that an expanded access program not delay the clinical development of a product, because you know, we don't, we don't want to undermine the ability to learn about the safety and effectiveness of a product. Typically, there are also limits on what companies may charge for their product.
Speaker 3:So in the.
Speaker 2:United States, developers are allowed to charge, are allowed to recover costs of providing their product and, in some instances, of kind of the administrative costs of running the program. But you know, nothing's perfect right. So I think that's one thing that is important to keep an eye on, as to whether entities are using expanded access as a means to commercialize unproven products, unproven interventions. But there are, you know, there are some regulatory guardrails in place that are intended to prevent that. Whether I don't, nothing works perfectly. So you know, I suspect that is also the case here.
Speaker 1:Do you know if there would be any implications for functional companies who would misuse this no-transcript?
Speaker 2:I think it depends right.
Speaker 2:There, of course, are legal implications and penalties if any laws or regulations are violated.
Speaker 2:I think the challenge from a sort of policymaking and lawmaking perspective is how do you allow sufficient cost recovery so that companies are not completely disincentivized from providing access if they choose to, without opening the door to full-blown commercialization without you know, in a context in which the company would not have safety and effectiveness evidence that we would typically expect?
Speaker 2:And I do think that's, you know, an important thing to note, which is that companies, developers are not compelled to provide expanded access, and I think it can actually be a pretty difficult decision as to whether to grant any given expanded access request from the company's perspective. You know, at certain stages of development and for certain products, there may not be very much of the product itself, even if the company can't see a direct way, the clinical trials will be undermined. There might still be concerns about slowing enrollment in clinical trials or otherwise undermining the clinical trials, and the company may wanna prioritize conducting the trials faster and getting the product to market faster. So I think you know there can be difficult questions on the developer company and about whether expanded access is the right thing to do or not.
Speaker 3:I was gonna ask actually, Patti, is expanded access available for investigational products at all stages of clinical development? Because obviously the further you go through development the more rigor has been applied to safety and efficacy. So I would imagine the risk is obviously differs dependent on the stage potential.
Speaker 2:Yeah, in the United States, yes, through FDA's expanded access pathway, a product could be provided at any stage of development. Typically, it's later in development, as you know, for the reason you noted, which is at that point there's you know, at least more evidence of safety and it's, you know, in some cases there may be better evidence of effectiveness. And the overwhelming majority of the expanded access programs are what's known as single patient programs, where we're talking about like one to maybe 10 patients. When you get to the larger scale expanded access programs, where we're talking about maybe hundreds of patients, even stronger there that typically we're talking about a product that's already in phase three or maybe phase three trials have been completed and you know everyone's pretty confident approvals coming and expanded access is kind of a stop gap between the end of the phase three trial and the approval.
Speaker 2:But there is some. I don't want to get too deep into the weeds but, as folks may have seen in you know, in news reports and things there, in 2018 there was a new law enacted in the United States known as the right to try law, which creates a second pathway for this outside of clinical trial access the United States. Under that pathway, a drug must be, must have successfully completed phase one, whatever that means. But so there is some nuance there. But in general, under FDA has expanded access regulations, a drug could be available at any stage, though typically we're talking about a drug that's further along in development.
Speaker 1:And what role does the doctor play in expanded access? Are they the ones that apply for specific patients access or yeah, it depends.
Speaker 2:Typically, there's an expectation that the physician will have made an assessment that the patient does not have any approved available treatment options, and often it is a physician that's working with the regulator to get the authorization, particularly if we're talking about, you know, one patient, not a kind of larger program. So there is a lot of, there can be a lot of physician involvement.
Speaker 1:And in that case, how does it differ from an investigator with study?
Speaker 2:Well, I think the main difference is the goal is treatment and not to develop safety and effectiveness information. So we're not gonna have randomization, you know there won't be blinded, obviously, but the, you know, it's just not part of a formal sort of scientifically valid protocol to develop safety and effectiveness information.
Speaker 3:That makes sense, patti. Where have the ISCT and the working group landed on this whole topic of expanded access? Have you come to some conclusions yet, based on some of the investigative work that you've been undertaking?
Speaker 2:So the ISCT expanded access working group we published a paper in cytotherapy a couple of months ago that did not come to any conclusions, that just talked a little bit about the history of expanded access, why it's important for the cell and gene therapy field, and highlighted a few issues that are not unique to cell and gene therapy but maybe particularly salient and worth exploring.
Speaker 2:And one of those issues was the one Ivana raised, which is is this, our expanded access programs, a situation where we might see efforts to commercialize unproven interventions and in this LNG therapy field we see a lot of that in some instances, like stem cell clinics that market unproven interventions directly to patients and you know so what you know. How do we kind of avoid that risk of you know, commercializing, maybe exploiting patients hope when there isn't the evidence to back it up? We are actively working on sort of studying these questions and coming up with something that's a bit less exploratory and more guidance focused in a subsequent publication. So unfortunately I don't have a, I don't have an answer on where we've landed exactly yet, but it's, we're working on it.
Speaker 1:I would also be curious to learn more about your background into this space. How did you end up focusing on this specific topic?
Speaker 2:So I'm before I was an academic, I was an attorney at FDA and I worked on this topic when I was at the agency, but you know I was actually interested in it and and writing about it before I even went to FDA, you know.
Speaker 2:I think this is just an area where expanded access is an area where we really it pushes us to think hard about the value of an approval process that requires the demonstrated evidence of safety and effectiveness that you know many approval processes around the world require, and how to balance that need to develop evidence, which takes time, against individual people's kind of understandable desire to try anything in certain circumstances. And it's one of those questions that's been around kind of as long as there have been approval processes for medicines and there's no right line, right answer perhaps about what's the exact right way to do things. So I just think it's a difficult legal and ethical question and an important one. So that wasn't a specific moment I got interested in it, but I think it's one of those questions about how you regulate medicine, how you regulate science that's really challenging. So it's interesting from that perspective.
Speaker 1:In this podcast. We usually love a nice and hairy subject where there is no right and wrong and there are many nuances and many ways of looking at it, and I think this is a perfect example, because we want patients who are willing to take the risk to have the drugs available for them to try, but at the same time, we want to make sure that they are safe and that we do conduct the rigorous investigations we need to do to reduce the drug. I think it's super fascinating.
Speaker 3:Right, is there a rigour around how patients can understand the risks of expanded access to? Because obviously with the clinical trial you've got the whole informed consent process and you'd like to think that's pretty rigorous and everybody goes into a clinical trial for the understanding what they're getting themselves into or not and for expanded access to something I would imagine some consent has to happen. But yeah, curious on that.
Speaker 2:Yeah, so for expanded access there are similar regulatory requirements for informed consent.
Speaker 2:One thing the ICT's expanded access working group is grappling with is I think it could potentially be much more difficult for patients to understand the deep uncertainty and the extent of the uncertainty we may have about investigational products that are available for expanded access.
Speaker 2:You know, partly because at least in a clinical trial, you know you're enrolling in research, whereas with expanded access your physician saying this is you know it is treatment, it's just an unproven treatment. And then, on top of that, you know there are efforts to promote and make sure patients are aware of expanded access as an option which could be good from an equity perspective. But you know, how do we promote it? How do we talk about it? Are there ways that people are talking about it that might imply to patients, kind of regardless of what's in the informed consent form, that this is something that's more proven than it is or that we know more about than we do? So I think it's, you know, a challenging, a challenging question, one we're grappling with, about how to talk to patients about it, how to make sure information is available in a way that isn't promotional or isn't unintentionally misleading.
Speaker 3:Yes, I always find it quite amusing that I always reflect on the fact when I go to the US and turn on the TV in my hotel room, there are adverts about pharmaceuticals in the UK. That never happened.
Speaker 2:Does a pharmaceutical company is allowed to promote expanded access, then so they are not allowed to advertise products, investigational products, in the way they advertise approved products, and there's a whole, that's a whole separate conversation about why there's granted consumer advertising and prescription drugs in the.
Speaker 3:United States.
Speaker 2:But one short answer is the First Amendment in the US Constitution limits the government's ability to prohibit it. But hospitals, might, a cancer center might say, well, we're cutting edge, we've got all these different programs and might rightly want to make sure patients are aware of expanded access programs. So it's not just the most sophisticated patients or the sort of the patients with the most know-how or who are aware of the programs. But we might worry about the ways in which that information is communicated, if it suggests it's a proven therapy or equivalent to a proven therapy or something like that.
Speaker 3:Yeah, it really is like one of those topics where there's just so many kind of gray areas and you can see like the perspectives from multiple different stakeholders and you try and put yourself in the position of a patient and think about what they're thinking, and then the regulator, and then the healthcare provider. Yeah, you've got your work cut out for some time, I think, patti.
Speaker 2:Yeah, well, luckily I have a whole working group that's working with me of scientists and physicians and ethicists, so I hope we'll have something out sometime in the next six months or so.
Speaker 1:Oh, would be super keen to read whatever you publish. As we start rounding off, we always ask her guess the same question, and that is if we gave you a magic wand that would give you the ability to change one thing in our industry, what would that be?
Speaker 2:One thing to change in the industry. So I think of myself a little bit, I guess, as an industry outsider, given that I'm a lawyer by training and a former regulator. But I think the one thing I would change which isn't necessarily about the industry but maybe about how people understand the scientific process is that there kind of is no silver bullet, like there's no magic way to just know something is safe and effective without doing the hard work that I'm sure many of your listeners do, running clinical trials or sort of running other kinds of evidence generation mechanisms. So I think I would, I would love to see sort of better understanding of the scientific process and just how difficult it is to translate, to come up with things that are genuinely good therapies.
Speaker 3:Patti, we've covered a lot today. Are there any other messages you'd like to get out?
Speaker 2:I think I would just say, if there are listeners who are in the cell and gene therapy space, to check out ICT's website. There's lots of resources there. It's a great organization. Get involved. And I also want to thank both of you for such a wonderful conversation. This was really a true delight to be on.
Speaker 3:Likewise really appreciate it.
Speaker 1:Thank you so much. You're listening to transformation in trials. If you have a suggestion for a guest for our show, reach out to Sam Parnell or Ivana Rosendahl on LinkedIn. You can find more episodes on Apple Podcasts, Spotify, Google Podcasts or in any other player. Remember to subscribe and get the episodes hot off the editor.
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