Future Pulse Cardiology

Legal Aspects of FDA approval and implications for clinical research

April 20, 2022 Dr. Thomas Nero, Prf. Christine Coughlin Episode 4
Future Pulse Cardiology
Legal Aspects of FDA approval and implications for clinical research
Show Notes Transcript

Prof. Christine Coughlin of Wake Forest School of Law speaks with Dr. Thomas Nero on the FDA approval process, emergency use authorization, Right to Try Legislation and the implications for clinical research, diversity and health care equity.  Prof. Coughlin holds positions in the College of Medicine as well as the Law school and in the Center for Bioethics.  She has published extensively on the FDA approval process.

Legal Aspects of FDA Approval Process and Implications for Clinical Research

[00:00:00] Dr. Thomas Nero: Hello I'm Dr Thomas Nero And today we're going to be taking a shift from our normal podcast to talking a little bit about healthcare policy joining us today is professor Christine Coughlin professor Coughlin is a professor of law at wake forest university school of law . She has an appointment in the graduate school of arts and sciences and also the center of bioethics and health and society at wake forest in addition for full disclosure she is my sister So please don't hold that against her. Today we're going to be discussing some of the legal aspects of the FDA approval process , and its ramifications for research as well as specifically how it will affect diversity healthcare equity and ultimately healthcare outcomes Welcome professor Coughlin

[00:00:52] Prof. Christine Coughlin: Thank you for having me I'm very excited to have this conversation 

[00:00:56] Tom: So we've had a number of conversations over the years regarding health policy and the legal aspects of medicine And I know one of your interests is trying to create a dialogue dialogue between physicians physician researchers and the legal profession And tell me what really brought you into this initially 

[00:01:17] Christine: When I first started teaching at wake I lectured both in the law school and at the medical school One characteristic of that particularly when I was doing lectures at the medical school was the misinformation that physicians had about the legal system and about lawyers. I had the opportunity of running a fourth year Medical school rotation at the law school And teach them the fundamentals of the law And then I got to get law students and medical students together and do all these simulations where I would give them the opposite sides This led to so many amazing opportunities for the students to interact and dialogue and to kind of shift their positions both the lawyers and the doctors And hopefully we can see the law more as a guide to help people treat patients better instead of a barrier of what you can't do 

[00:02:18] Tom: Most recently you started writing on the FDA approval process and some of the other ramifications of our legal system on healthcare Why don't you walk us through FDA approval process as you see it and then talk to me a little bit about what its limitations are that you see.

[00:02:42] Christine: Whenever we think about the FDA approval process we need to first recognize the structure of our government And I know that sounds like I'm going back to a civics 1 0 1 course but in order to understand the FDA you need to understand the organizational structure So article two section two of the constitution and yes I am starting with the constitution as we all should Provides for a cabinet with vice-president all these department heads one which is the secretary of health and human services underneath the secretary of health and human services lie The two agencies the FDA and its sister organization the CDC I start there because whenever you're talking about FDA or FDA policy you have to recognize that it's going to be political. That doesn't mean it should or it needs to be partisan as we have really seen in the last few years but that they are political decisions because we're dealing with policy So when we're thinking about FDA and FDA policy I think the most important kind of concept to remember is this tension between safety and access And for a long time I thought that tension was more of a pendulum that the FDA swing back and forth from safety to access I've changed my thought process on that I now think that the best policy is that neither needs to be mutually exclusive and that we can have safety and provide for access within the current FDA framework If we're willing to understand the limitations of when we can give investigational drugs to people we cannot and if we're willing to provide both on a budgetary and political platform for ways to collect and gather data so that we can make meaningful observations about saftey 

[00:04:51] Tom: I'm sure that the COVID epidemic really affected your thinking For for how you're seeing this process can you give us some examples of know, using emergency authorizations and how that works for public trust 

[00:05:04] Christine: From like the 19 hundreds until about the 1960s seventies probably early eighties with the aids crisis FDA policy was very focused on safety but taking that kind of crisis and saying okay because of that we have to provide for ways to treat sick people quickly as a result we have Pathways where we allow drugs to either go to people who are sick or get approved more quickly based on surrogate endpoints So in addition to these other pathways we found that after 9 11 we also needed a pathway to deal with a public health emergency when we had emergency countermeasures that needed to go and be distributed to the public much more quickly so after nine 11 Congress passed what was called project BioShield of 2004 which allowed for an emergency use authorization of Medications vaccines et cetera that could be used in an emergency countermeasure so these were authorized to be marketed not approved because there's a lower standard which is what you had to show is it may be effective based on a totality of scientific information So the FDA allows more information in and allows it to be authorized at a lower level during the emergency 

[00:06:29] Tom: And my understanding is that that emergency is sort of opening up They can open or close that at any time but that at some point they should make a determination. 

[00:06:38] Christine: Right And that's a really interesting point that you just brought up So under the public health services act there is actually a time limitation but under the act for emergency use authorization it just stays open until Either the product receives full approval Which we've seen with Pfizer and Madonna and some other things. Two, We find information that would support the revocation because it is unsafe or ineffective such as we found out with hydroxychloroquine which was revoked 78 days after it was initially authorized under new UAE or the secretary of health and human services says the emergency is over I think that your point is something critical to our policy Right now we have had emergency use authorization now for about two years So what does that mean Things are coming to market very quickly and we can talk about the public trust part of that in a moment but is the public getting so used to that When we go back to the full approval process will people say no we want those drugs more quickly. 

[00:07:52] Tom: And also with that there are some caveats correct that when they give those emergency use authorizations that there is an expectation for a higher level of post-marketing follow-up 

[00:08:04] Christine: You are absolutely right That is there but you know think about the incentives that that provides A lot of patients if they can get the drug that they want through an EUA are not as willing to participate in clinical trials So it may be harder to get the supporting data. 

[00:08:24] Tom: I was reading in one of your papers and you were referring back to the ebola crisis and learned that one of the problems was that they allowed for emergency use authorization but they did not actually get the data that should have been required at the time And they missed a great opportunity 

[00:08:42] Christine: At some point we have to make sure that we have the mechanisms in place to either take that data and somehow making make it meaningful which I don't think we're at the point yet of having been able to optimize real-world data like we should to avoid what happened with Ebola 

[00:08:57] Tom: Talking a little bit about the other pathways for approval What other pathways are there currently now available 

[00:09:10] Christine: There's accelerated approval So accelerate approval allows FDA to I'll use the word conditional approval but I don't want anyone to get that mixed up with what happens under the EU framework which has a different framework for conditional approval but it allows The sponsor to market the product based on a surrogate endpoint the problem that we've found with accelerated approval Is that despite the fact that there are these post-market studying requirements we found that a lot of sponsors weren't actually abiding by them And there's been all sorts of studies that have come to light particularly in the past year that some Aren't having requirements until like the year 20, 26 to finish the clinical trials So these things would have been out on the market for many years and could potentially harm patients. As a result there's actually two bills in Congress pending a Republican bill which is more of a counter posable proposal to the initial democratic bill that would reform the accelerated approval pathway I think something will be happening in that area soon And we will see what that is and whether it happens before or after the midterms 

[00:10:25] Tom: Do both do both of those bills require extensive post-marketing surveys and post-marketing 

[00:10:32] Christine: Both do however the Democrat bill provides a specific time limitation by which you have to complete the studies or the drug needs to be withdrawn And the Republican counter proposal is a bit more friendly to pharma and allows the FDA to make rules that would promote 

[00:10:51] Tom: reporting it's quite interesting being part of a lot of clinical trials we see that the trials don't always go the way that we would like and We will often overestimate the effectiveness of drugs or or overestimate the severity of outcomes within a population And Realized that we do need more time or we need more patients or we need something more in order to prove to with a reasonable doubt that we're correct right Where the P value of less than 0.05 or whatever our standard is going to be for the trial so you know that I understand the need for increasing the length of When it's appropriate and I'm sure that that's one of those things where lawyers will talk about that in a lot in the future about how do we make sure that there is some flexibility because the future is hard to predict 

[00:11:40] Christine: Who would have predicted we would have been where we are 

[00:11:42] Tom: today true enough with both of these issues one of the Interesting conundrums is this one about liability protection, But as we're going especially in emergency use authorizations that we're giving some liability protection to the pharmaceutical companies how do you see that sort of working for us and how do you see that working against us 

[00:12:06] Christine: I see it primarily working for us. I think that if you go back and look at the history What happened when we thought that there was going to be another Spanish flu like epidemic in 1976 , we tried to deploy a national vaccine program. We saw that manufacturers weren't really wanting to take part in such a large deployment without some type of liability protection especially if we're asking them to do it quickly so as a result we do have for early childhood vaccines we have a vaccination program that can help to provide compensation for people who have been injured We have the same type of thing with COVID and we also provide liability protection for sponsors and manufacturers I think that the marketplace and the incentive of wanting to be a big player in the vaccine world also promote safety the big question is what is the con People will be trying to cut corners Well we have the FDA regulations and all the oversight We have significant oversight with vaccines and then you know we just have market controls And so I think that that kind of counteracts any kind of manufacturer liability issues. 

[00:13:22] Tom: But in a way also though this can be a negative because as we look at COVID but also happened with the Spanish flu is that people started not trusting the vaccines because it appeared like it was being put out too quickly that there weren't going to be protections there and that they were going to protect big Pharma and not worry about the individual patient 

[00:13:43] Christine: And that's all in my humble opinion a result of ineffective messaging On the part of public health and also especially in COVID the

partisan nature of the public health messaging 

[00:13:58] Tom: Another piece to this is the larger question of health equity and a separate question about how we grant access to investigational drugs. how do you see that affecting research in general and healthcare policy 

[00:14:13] Christine: So in order to address that I need to finish the kind of framework that we started a few questions ago So we started talking about accelerated approval there are also additional pathways so there's expanded access Which I can get to in a moment Right Try And then there's a lot of incentive-based programs that might not necessarily provide for earlier approval or you could be used in connection with accelerated approval but will provide tax credits or other incentives for rare or orphan drugs So in order to answer that question you need to look at the whole spectrum of the laws and how they work together because FDA laws are extremely precise and complex and integrated area of law 

[00:15:09] Tom: And pulling up this legislative framework as a whole when we talk about those things specifically you start talking about identifiable lives versus statistical lives And as researchers we are very interested in statistical lives Because that's how we figure out what's really effective and how effective it is 

[00:15:33] Christine: We talked already about the safety and access conundrum the false dichotomy from 1901, 1902 until probably the Seventies, Eighties we were more in this protective framework And then after the aids crisis we started saying okay we also have to provide for sick patients And this is where I think identified lives really come in so when you had all of these aids patients lying down in front of the FDA office you started to seeing this is happening As a result of FDA policy people are dying FDA is worrying about these obscure standards of safety for future patients And we have patients dying now and the news media was covering it and so as a result we said we need to start allowing people who are of these identified lives allowing people who are sick to take the risk and gain access to these medications So we had expanded access which is a pathway through the FDA in which either an individual a small group or a larger population of sick individuals may have access to unapproved medications And then we had another case of identified lives We had Abigail burrows who was a UVA student who hadn't had neck cancer And even though there was a experimental treatment out there for head and neck cancer she was not eligible to be in any clinical trials or to get it in any other way she ultimately passed away Her father created Abigail Alliance which sued the FDA Years of litigation ensued It was unsuccessful but afterwards it created a movement basically to get these right to try laws passed And so sick patients and their advocates would have an avenue outside the FDA to try to gain access to investigational medications And to say I feel like I'm worth the risk I want to take that So what are the problems with that If you're going within the spectrum of the FDA through expanded access 99% of all request for investigational drugs are approved Sponsors can direct costs to patients So the drugs aren't necessarily free, But they're not going to gouge the patients because it's within the FDA there are more controls and we're able to access treatment data more easily. In the right to try scenario which I do think it's a good thing to always have these opportunities but again that's an identified life but on a statistical lives basis having this alternative pathway does not depend upon clinical trial participation can also have us lose data And we don't know then whether or not this treatment is going to be effective for the larger popular So I I use those two stories to try to illustrate the fact that identified lives and trying to show somebody who is sick can be a really powerful motivator to change policy But the only way that we're going to be able to use it in in an appropriate way is to consider it on a statistical lives basis. 

[00:19:15] Tom: Certainly there's an aspect to this about raising awareness that I think that can't be lost here that we'll be talking about these head and neck cancers People may get earlier detection because they're hearing about it and also it does motivate some of the pharmaceutical companies in order to do some other development but I also worry about the possibility that what it does is focus our attention on And individual or one class of individuals you know a middle-class white woman versus everyone else And that it then makes other people feel that the healthcare setting and the healthcare system is not working for them And that they're not being cared for 

[00:19:58] Christine: My coauthor Nancy King and I in for one article we really looked at a lot of the top stories that have been able to move policy And one of the things we commonly found you're correct Generally middle to upper-class white individuals who would like attractive in a social media campaign that were the basis of the identifiable viable life movement for that particular condition So stories are being left out and that's what's really important especially when we have the healthcare disparities that we have. 

[00:20:34] Tom: One of the issues that we're looking at is this question Diversity and getting more people into research trials and getting them involved in our healthcare writ large getting them to the offices and making sure that people trust us as physicians and healthcare providers to be able to care for them. And, if they don't see us as being their advocate then we're going to fail because we will never have that opportunity 

We're going to shift gears here And I did want to talk about what you see as some of the barriers to performing clinical trials and diversity and how that fits within the framework of the things that we've been discussing.  Diversity has become one of the most important aspects of how we're going to do Um perform our clinical trials because it's really important for us to make sure that the trial covers the population whom we are treating And we can't be treating people if they're not in these trials we have to recognize that there may be Um populations that respond differently from a legal aspect. Do you see that there are specific barriers to involvement in clinical trials and maybe they're their ideas that you have thought about that would decrease those barriers?

[00:21:57] Christine: I wish there was a simple answer And I think like any issue of structural racism it's insidious and longstanding I think the biggest issue is that of public trust And when we have the history that we do with respect to medical research and unfortunately All of the atrocities that have been done in the name of science especially to people in communities of color is going to be hard to gain that trust back particularly if those who are running the clinical trials and those physicians tend to be white or Caucasian males or females so what needs to happen I think that Public education going into communities making sure that our teams are as diverse as possible and inclusive as possible do believe that we need to be talking to people on the ground and getting people in the communities to help us with the efforts in clinical trials to show that we are interested in creating therapeutics or treatments that are going to help with some of the things that this population is dealing with I think that's key a lot of people say that the pandemic has exposed a lot of the health disparaties have been there. They haven't exposed it What's done is it's magnified it and we need to be looking and we need to be listening and we need to be acting. 

[00:23:32] Tom: That is a great idea to end on because as you said there's no clear answer here except that we do need to be putting in more effort into our trials Research divisions into how we communicate with all the populations that we're treating and making sure that we don't don't limit ourselves so that we can be certain that we have good outcomes 

[00:23:56] Christine: And I think if I if I could say one more thing one thing that I think is key is that we need to look back at our history whether it's on FDA policy whether it's with clinical trials and not expect change when we haven't reckoned with what has happened in the past 

[00:24:15] Tom: I can't thank you enough for taking your time today to talk about these issues I think that this is just the beginning of many conversations Probably many conversations that you and I will have but more conversations that we'll need to have in the future so that we're not continuing the systemic problems that we've had in the past and that should help to improve health care equity overall 

[00:24:37] Christine: Well thank you for the opportunity it is wonderful to have these kinds of discussions And I think that only through having discussions with people in different kinds of professions and looking at the problems from a different perspective are we actually going to create a kind of solutions that will effectuate change 

[00:24:57] Tom: Well thank you and have a great day