0:00:04.480,0:00:09.440 Okay so thanks very much for that uh  for that kind of introduction and uh 0:00:09.440,0:00:17.600 thank you for the invitation, I'm blessed to see  some of your faces as well. so what I'm going to 0:00:17.600,0:00:23.040 talk about today um I hope my voice holds up and  I assure you it's not COVID I just have laryngitis 0:00:23.040,0:00:29.280 and what i want to talk to  you about today are a few things that i've been 0:00:29.280,0:00:35.360 thinking about recently with respect to how we  evaluate risk in the context of public health in 0:00:36.320,0:00:43.120 pandemic so i'm sorry this is yet another COVID  talk, i'm sure there have been but if there is 0:00:43.120,0:00:48.800 any silver lining that it provides us with much  food for ethical thought and the work that i'm 0:00:48.800,0:00:53.680 talking about today has also been done under  the auspices of the UK Pandemic Accelerator 0:00:56.560,0:01:04.320 so it's going to be a talk in three parts today so  first i'm going to talk about challenge trials so 0:01:04.320,0:01:09.360 some of you may have have come across this concept  challenge trials are the deliberate infection of 0:01:09.360,0:01:15.120 human participants with an infectious agent in  its case covered for the purposes of the search 0:01:15.120,0:01:19.440 and i'm going to be asking whether the risks are  ethically justified with particular reference 0:01:19.440,0:01:25.600 to the challenge trials that are currently going  on in the uk and then going to move to something 0:01:25.600,0:01:31.840 else that i've been thinking about which is  differential allocation of different vaccines to 0:01:31.840,0:01:38.560 groups of populations of patients based on their  risk profile so in particular i'm going to look at 0:01:38.560,0:01:44.320 the way in which decisions were made around which  vaccine was allocated to which groups in the uk 0:01:44.320,0:01:48.560 and some of the risks that were talked about  in relation to these presenting the vaccine 0:01:48.560,0:01:53.840 and question what factors differential  vaccine allocation should be based on 0:01:54.720,0:01:58.720 and then i'm going to try and bring those  two things together to present us with some 0:01:58.720,0:02:04.720 considerations for how we think about risk and  relative risk in setting public health policy 0:02:04.720,0:02:12.000 across this whole area so i'm going to attempt to  argue that at least some forms of challenge trials 0:02:12.000,0:02:18.400 are not ethically justified i'm going to  argue that stratifying populations for vaccine 0:02:18.400,0:02:25.280 allocation by their risk profile can can in some  cases result in unjust distribution of risk so we 0:02:25.280,0:02:31.360 shouldn't be doing that and then i'm also going  to say that comparing these cases and looking 0:02:31.360,0:02:36.160 at the ways in which they have used relative  risk to make public health decisions reveals 0:02:36.160,0:02:43.040 some flaws in our overall approach to that so  that's an overview of how i hope it's going to go 0:02:45.600,0:02:49.920 okay so the first part of the work that i'm  going to talk about is something i've been 0:02:49.920,0:02:55.440 working on with a PhD scholar and research  assistant at Edinburgh Emma Nance who's been 0:02:56.400,0:03:00.880 working with me as a student on the one  health models of disease PhD program 0:03:01.600,0:03:05.840 and also doing some RA work with  the pandemic ethics acceleration. 0:03:07.840,0:03:15.200 so Emma has conducted the literature  review and synthesis of the ethical issues 0:03:15.200,0:03:19.840 and has also done some work developing  arguments with me on challenge trials. 0:03:23.840,0:03:28.880 so what are challenge trials as i said  challenge trials involves the deliberate 0:03:28.880,0:03:33.440 exposure of participants to an infectious  agent so they're also known as controlled 0:03:33.440,0:03:39.680 human infection trials i'm going to be referring  to them as challenge trials or CT for short and 0:03:40.240,0:03:44.640 the idea of challenge trials has been hotly  debated particularly over the last year 0:03:45.200,0:03:51.440 in particular the idea of challenge trials as a  tool for vaccine development has received quite a 0:03:51.440,0:03:58.400 lot of ethical attention so with respect to COVID  particularly the idea is that if you are trialling 0:03:58.400,0:04:06.000 a vaccine and you have to wait for people simply  to become infected about the lack of control over 0:04:06.000,0:04:12.320 those situations means it's going to take longer  and require both more time and more people to to 0:04:12.320,0:04:18.240 see what the effect is on the other hand if we  take vaccinated participants and we deliberately 0:04:18.240,0:04:23.200 expose them to infection then we can see hopefully  in a much shorter time how effective they're given 0:04:23.200,0:04:28.880 vaccines so the the idea there is that they will  expedite the development of vaccines and of course 0:04:28.880,0:04:34.880 given that an effective vaccine against COVID is  something that from the outset has been one of 0:04:34.880,0:04:40.160 the public health goals we know that vaccination  reduces the disease burden results in lives saved 0:04:40.160,0:04:46.080 etc and the argument has been that in fact  we need to conduct vaccine challenge trials 0:04:46.080,0:04:51.120 in order to speed up the development of the  vaccine and i think estimates have ranged from 0:04:52.320,0:04:57.440 several in the thousands or hundreds of thousands  of lives that could be saved when we just speed 0:04:57.440,0:05:04.160 up vaccine development even last few months so  challenge trials have also previously been applied 0:05:04.160,0:05:08.800 in the cases of a number of other diseases  and the ethics of this has also been 0:05:08.800,0:05:13.120 hotly debated COVID is perhaps not  like some of the other diseases for 0:05:13.120,0:05:17.280 which challenge trials have been conducted  in the past for reasons that i'll go into. 0:05:19.280,0:05:24.000 so what are some of the ethical considerations  in relation to challenge trials or controlled 0:05:24.000,0:05:31.920 human infection as i said the prime justification  cited in favor of carrying out challenge trials 0:05:31.920,0:05:38.240 is their social and their scientific value so it's  argued that we'll be able to build knowledge about 0:05:38.240,0:05:43.680 disease about the mechanics of infection about the  progression of the disease about immune response 0:05:43.680,0:05:48.720 about transmission dynamics and so forth and  that both through increasing our understanding 0:05:48.720,0:05:54.240 of disease biology and immune response but  also with that specific aim of challenge 0:05:54.240,0:05:58.880 trials for vaccinated individuals we will be  able to accelerate the development of vaccines 0:05:58.880,0:06:04.080 we'll be able to accelerate the development of  therapies and will save lives so the classic moral 0:06:04.080,0:06:13.200 relationship now of course the big objection too  many buttons the big objection to challenge trials 0:06:13.200,0:06:16.640 is that they pose a risk to participants  so you're going to take a bunch of people 0:06:16.640,0:06:22.880 and deliberately infect them with something  known to known to be harmful and too dangerous 0:06:24.560,0:06:30.480 so the major objection is well hang on it  involves a risk to participants and not just 0:06:30.480,0:06:35.280 the risk because of what says that exists we know  that everything involves some degree of risk but 0:06:35.280,0:06:42.080 the queries about whether the benefits that are  claimed on the basis of these trials would justify 0:06:42.080,0:06:50.160 the risks that that will be imposed so it's been  argued that it's questionable whether the benefits 0:06:50.160,0:06:56.720 of of these trials will actually manifest so even  if we are able to speed up vaccine development 0:06:57.680,0:07:03.600 will we actually gain the benefit of that it's  dependent on factors including whether vaccines 0:07:04.160,0:07:09.040 having been developed are efficiently produced  and distributed we might actually depending on 0:07:09.040,0:07:13.200 where and how challenge trials are carried out  and where and how that exercise the development 0:07:13.200,0:07:18.400 of vaccines we might face further problems of  justice and widening inequities in terms of 0:07:18.400,0:07:24.560 who has access to the vaccines i think  there is a particular question over 0:07:26.320,0:07:32.480 whether and how that's vaccine candidates once  tested become distributed so there's there are 0:07:32.480,0:07:38.080 questions over whether the claimed benefits the  social and scientific work will actually manifest 0:07:40.800,0:07:45.600 beyond this there's the ethical  problem of researchers intentionally 0:07:45.600,0:07:50.320 causing harm so if we think about the  progress of a vaccine challenge trial 0:07:51.040,0:07:56.240 we can split it into two steps the first is the  the administration of the vaccine candidate now 0:07:56.240,0:08:00.480 that of course is also a risk because one of the  things that we're looking at when we when we test 0:08:00.480,0:08:05.120 new vaccines or new drugs is safety so there's a  risk involved in that but we hope that the payoff 0:08:05.120,0:08:11.280 the benefit is uh inducing immunity so there's  both the scientific and wider social benefit of 0:08:11.280,0:08:16.560 developing therapy but we also hope that there  will be some benefit to the person immunised of 0:08:17.120,0:08:23.280 becoming becoming immune to the disease once  we've got to the point of having administered 0:08:23.280,0:08:28.720 the vaccine however further exposing  the further exposing participants to 0:08:28.720,0:08:33.360 the infectious agent can be nothing but powerful  so there's absolutely nothing in that for them 0:08:34.720,0:08:39.680 and emma has worked particularly on a paper  of hero considering whether researchers are 0:08:39.680,0:08:45.200 authorized so is it legitimate for researchers  to intentionally cause harm through the second 0:08:45.200,0:08:51.840 step of the process where they where they expose  the participants to the infectious agent and she 0:08:51.840,0:08:56.320 argues that actually for a number of reasons we  shouldn't see researchers as being authorized 0:08:56.320,0:09:01.040 for this uh i don't have a quote from what she's  written up here but uh she says something like 0:09:01.680,0:09:06.000 people may volunteer to become fire fighters but  that doesn't mean we should go about setting fires 0:09:07.680,0:09:13.680 okay there are i think a wide range of  issues around the intentional infliction of 0:09:13.680,0:09:18.160 harm by researchers that i think raise serious  ethical problems i won't go in depth into them 0:09:19.200,0:09:26.560 but further further justifications so we might say  well it's it's dangerous there's too much risk to 0:09:26.560,0:09:30.720 participants we don't know if the benefits are  certain and you're deliberately causing harm to 0:09:30.720,0:09:35.920 our systems supporters of challenge trials would  turn around and say yes but they're volunteered 0:09:35.920,0:09:41.360 for it they consented to it the arguments that  were raised in particularly in the uk around 0:09:41.360,0:09:45.280 whether we should allow healthy young people to  volunteer to be infected with program as part 0:09:45.280,0:09:50.720 of challenge trials also focus very much on  the idea of altruism and the idea that people 0:09:51.280,0:09:57.040 people may want to do something good if they  want to do something so defenders of challenge 0:09:57.040,0:10:04.640 trials would say informed consent means that those  the risks and the harms involved are acceptable 0:10:06.560,0:10:10.720 they might also say well let's see  what the risks actually are and 0:10:12.800,0:10:18.960 it has been argued that the risks involved  in participating in challenge trial for 0:10:18.960,0:10:23.280 within the threshold of what might be  considered acceptable risk so there's 0:10:23.280,0:10:28.800 a range of literature out there again on what  acceptable risk is in the course of research 0:10:29.840,0:10:37.040 and i think particularly when it comes to risk  benefit balance um partly this is going to be 0:10:37.040,0:10:42.720 an empirical question about how risky actually  is it what are the dangers of being exposed to 0:10:42.720,0:10:49.920 and infected with a particular disease now  with um with cloverd some of those risks are 0:10:50.960,0:10:57.600 increasingly known so the argument has been  that it's fewer than one in i think 3 000 0:10:57.600,0:11:02.480 healthy young people are likely to die from or  have serious effects from kerbin and so that's 0:11:02.480,0:11:10.640 a that's a very small risk but we might say  that actually given the newness of this disease 0:11:11.440,0:11:16.320 given how much there is that we still don't  understand about the disease progression and 0:11:16.320,0:11:23.840 especially its long-term consequences that in fact  we can't say we can't claim that it is within the 0:11:23.840,0:11:28.000 threshold of acceptable risk and furthermore we  can't really say that people are giving informed 0:11:28.000,0:11:33.360 consent because the understanding of risk that we  have and what the risks and potential harms are 0:11:33.360,0:11:38.320 is insufficiently well characterized so simply  telling people you have only a zero point 0:11:38.320,0:11:46.080 um 0.03 chance of death doesn't take into  account what the other risks might be what 0:11:46.080,0:11:50.000 so what other harms are not accounted  for particularly things like long code 0:11:53.360,0:11:59.200 against that again proponents of challenged trials  might say yes but we're reducing the risk as much 0:11:59.200,0:12:05.920 as we can by selecting young healthy subjects  so we know that younger people people without 0:12:05.920,0:12:12.720 pre-existing or other health conditions are  much less likely to die as a as a result of code 0:12:14.240,0:12:21.440 and yes i think that reduces the risk but  then it also brings up another point of 0:12:21.440,0:12:28.720 fairness so is it right that young healthy  people um sacrifice themselves in order to 0:12:29.600,0:12:32.960 produce knowledge that may  save the lives of other people 0:12:34.400,0:12:39.760 okay so in reviewing the wide range of literature  that's out there on the ethical considerations 0:12:39.760,0:12:44.320 around challenge trials and particularly  those that emerged around vaccine child 0:12:44.320,0:12:48.720 trials in other words where you vaccinate people  and then see if they could fairly become infected 0:12:51.120,0:12:58.720 a range of conditions under which challenged  trials or controlled human infection would 0:12:58.720,0:13:05.920 be considered ethically acceptable have emerged  so amongst those include the idea that that 0:13:05.920,0:13:12.320 subject selection is fair that the risk benefit  balance is appropriate that consent is given and 0:13:12.320,0:13:19.360 that they stakeholder engagement then again this  this is from the literature produced this year 0:13:20.800,0:13:25.200 so in terms of fair subject selection  i think there are serious questions 0:13:25.200,0:13:31.120 about fairness in in this context so um nera al  for example has proposed that we should reduce 0:13:31.680,0:13:38.560 both the risk itself by selecting young  healthy adults but that we can also compensate 0:13:38.560,0:13:43.760 um the the risk of participating in a way by  selecting those subjects who are already at a high 0:13:43.760,0:13:49.120 baseline risk in other words if you're already  50 likely to become infected with covered in a 0:13:49.120,0:13:54.720 given period of time giving you a hundred percent  chance of covered is not as much of a risk to you 0:13:55.360,0:14:00.400 as it were as it would be when you take someone  who has very little chance of being exposed 0:14:00.960,0:14:04.320 and then expose them so again  this is about relative baselines 0:14:04.320,0:14:07.760 and we're going to see this issue appear  again when we talk about that same 0:14:07.760,0:14:13.680 vaccine allocation because of course if you think  about taking those populations who are more at 0:14:13.680,0:14:19.280 risk of being infected with code in the first  place you can see that we're probably going 0:14:19.280,0:14:24.640 to end up disproportionately targeting perhaps  disadvantaged communities those who work in roles 0:14:24.640,0:14:29.840 where they have a high risk of exposure often  in more insecure socioeconomic situations etc 0:14:30.400,0:14:36.320 um so i think there's a there's a very much  question there over whether the proposals to 0:14:37.200,0:14:41.280 mitigate the risk exposure are going  to result in unfair subject selection 0:14:43.040,0:14:46.720 i think there are also problems with  saying we're going to mitigate risk by 0:14:47.360,0:14:52.720 focusing on the healthy young adult population  in terms of the validity and applicability of 0:14:52.720,0:14:57.040 the scientific knowledge so how much can we  extrapolate about disease progression about 0:14:57.040,0:15:01.600 immune response about the effectiveness  of vaccines for the whole population 0:15:01.600,0:15:07.120 when we've only targeted young healthy adults to  the experience we know very much from looking at 0:15:07.120,0:15:14.080 clinical trials and subject selection over the  past several decades that subject selection has 0:15:14.080,0:15:18.720 resulted has resulted in the generation of  knowledge that isn't necessarily applicable 0:15:18.720,0:15:23.280 across the population in other words we have  knowledge gaps when it comes to underrepresented 0:15:23.280,0:15:29.200 sections of the population in clinical research so  children pregnant women minority ethnic groups etc 0:15:30.000,0:15:35.360 so is the result is the result of the research  actually going to be valid when we've concentrated 0:15:35.360,0:15:43.360 just on a certain specific population for  recruitment when it comes to evaluating the risk 0:15:43.360,0:15:48.480 benefit balance as i said there are questions over  whether the benefits will actually be realized 0:15:48.480,0:15:53.520 whether the risk is acceptable furthermore  the risk benefit balance has to take into 0:15:53.520,0:15:58.080 account whether there might be other ways of  generating that knowledge so all things considered 0:15:59.040,0:16:02.800 would there be less risky ways or ways of  generating that knowledge that have a more 0:16:02.800,0:16:09.760 favorable risk benefit balance again some have  argued that standard clinical trials without 0:16:09.760,0:16:15.200 infection challenge would actually pose a more  favorable risk benefit ratio in this case and once 0:16:15.200,0:16:21.840 again that's not likely to come down partly to an  empirical evaluation of the risk benefit fractures 0:16:24.080,0:16:30.080 i think when it's so the other conditions um i  talked about consent and about whether informed 0:16:30.080,0:16:36.000 consent can truly be possible in the case of a  new and largely uncharacterized disease but i 0:16:36.000,0:16:41.600 think the other another important factor that was  identified as necessary for challenged trials to 0:16:41.600,0:16:47.280 be ethical and stakeholder engagement and i think  we need to consider seriously the possibility that 0:16:47.280,0:16:52.000 such trials might have the potential to  compromise trust in science and healthcare in 0:16:52.000,0:16:55.680 other words the kind of engagement that we might  generate is actually going to be a negative one 0:16:56.240,0:17:01.280 and that might be the case either if someone  suffers an adverse event as a result of 0:17:01.280,0:17:05.280 participating in trials so the vaccine  isn't effective they contract covered and 0:17:05.280,0:17:12.240 they have serious ill health or death as a result  but in fact in itself the fact of researchers 0:17:12.240,0:17:18.880 intentionally inflicting harm on on participants  so that the fact of challenge file themselves 0:17:18.880,0:17:24.640 might be something that could compromise trust  in science okay so that's the sort of ethical 0:17:24.640,0:17:31.600 background for the discussion as i said the  ethical discussion around covert challenge trials 0:17:31.600,0:17:39.680 intensified particularly last year in november  2020 we had a few kind of media and blog pieces 0:17:39.680,0:17:46.960 these ones from the science museum asking should  we infect young people with copenhagen and in in 0:17:46.960,0:17:52.400 this piece they go into some of these ethical  concerns but overall uh and julian said last 0:17:52.400,0:17:57.040 year's quoted in this they come down very much on  the side of because of the scientific and social 0:17:57.040,0:18:02.000 benefits because of the public health benefits in  the livest we ought to conduct challenge trials 0:18:03.360,0:18:09.040 in february this year the first human challenge  trials were coded were approved in the uk so 0:18:09.040,0:18:15.360 that's the government uk press release um  interestingly although a lot of the justification 0:18:15.360,0:18:21.680 in november was around we must do this in order  to develop vaccines the the first studies that 0:18:21.680,0:18:27.760 were approved were not actually vaccine trials so  they weren't taking vaccinated people necessarily 0:18:27.760,0:18:32.880 they were aimed not at testing the efficacy  of vaccines and remembered by february we 0:18:32.880,0:18:37.200 already had a number of vaccine candidates  becoming available and being being rolled up 0:18:37.200,0:18:43.680 and they were instead intended to establish  characteristics of the of the coronavirus such as 0:18:43.680,0:18:49.120 the minimum amount of virus needed to establish  infection to look at transmission dynamics to 0:18:49.120,0:18:54.400 examine the duration of infection to look  at immune response etc so from what i 0:18:54.400,0:18:59.520 understand that was the aim of the first set of  challenge trials to actually receive approval 0:19:01.040,0:19:05.200 so let's look at this scenario  more specifically then 0:19:05.920,0:19:11.920 particularly in the way that risk and benefit  have been evaluated in improving these trials 0:19:12.480,0:19:16.720 so once again the overwhelming claim and  support of carrying out challenge trials is 0:19:16.720,0:19:22.000 that the benefit of these experiments justifies  imposing the risks on participants and i think 0:19:22.000,0:19:27.600 the first trials were i think about 90 people  were scheduled to be deliberately infected with 0:19:29.680,0:19:38.080 so i am not convinced as you can probably tell  that the the risk benefit evaluation in this case 0:19:38.080,0:19:44.880 was correct i wondered whether it's actually  necessary so is it necessary to expose 0:19:44.880,0:19:49.440 participants to these risks in order to realize  the benefits of understanding more about the 0:19:49.440,0:19:55.040 disease and particularly if you think in february  in the context where there were thousands of 0:19:55.040,0:20:01.680 new infections already occurring every day is it  actually necessary to go and invent 90 more people 0:20:01.680,0:20:07.040 in order to gain that data could we not instead  have used more real world evidence in order 0:20:07.040,0:20:12.000 to to generate these results across a more  diverse population in a real world context 0:20:13.680,0:20:18.320 i think the actual public health benefits  of this research also needed to be further 0:20:18.320,0:20:25.360 clarified so for example is quantifying the  exact viral load required to reduce infection 0:20:25.360,0:20:30.560 in a controlled environment likely in any way to  influence public health policy in a beneficial 0:20:30.560,0:20:39.520 way so if we find out that um that a thousand  instead of a hundred virus particles are required 0:20:39.520,0:20:43.760 or ten thousand seven thousand are required  even if we establish the order of magnitude 0:20:44.400,0:20:48.960 are we going to be able to say based on that while  social distancing should go to 1.5 meters instead 0:20:48.960,0:20:53.680 of one meter what practical difference are we  going to introduce into public health policy 0:20:53.680,0:20:59.280 that comes from quantifying that exact viral load  given all of the messiness and the variability of 0:20:59.280,0:21:03.920 real-world situations how does the data from  that very controlled environment how is that 0:21:03.920,0:21:09.040 going to translate into public health policy in  a timely way so as to actually save the lives 0:21:10.720,0:21:15.360 similarly when it comes to studying transmission  dynamics my understanding of these studies 0:21:15.360,0:21:20.160 were that they didn't plan to infect people and  then release them back into the community release 0:21:20.160,0:21:24.480 them into the wild but instead to keep them  isolated so they didn't see even more coping 0:21:24.480,0:21:30.000 infections but of course again what we want  to understand when it comes to public health 0:21:30.000,0:21:34.240 is how is this disease behaving what's happening  with the epidemiology in the real world 0:21:35.280,0:21:40.400 so is it the case that studying transmission  dynamics in a very carefully controlled group 0:21:40.400,0:21:44.960 of people in an isolated environment  going to give us that understanding 0:21:44.960,0:21:49.760 or would we be better off looking at the  thousands of real world cases devoting more 0:21:49.760,0:21:55.280 evidence for example to uh things like context  tracing and understanding real world transition 0:21:56.960,0:22:04.960 as i said i think the the challenge trials pose uh  certainly further risks to public trust in science 0:22:06.080,0:22:11.840 and this to me is one of the most compelling  reasons that there might not be a favorable 0:22:11.840,0:22:17.280 risk benefit balance because recall the  risk benefit balance the benefits are that 0:22:17.280,0:22:21.520 we understand the disease better we develop  vaccines faster we develop therapies faster 0:22:21.520,0:22:25.840 that only results in the public benefit if  there is actually uptake of those vaccines 0:22:26.560,0:22:31.040 now either if adverse events occur or if  people get the idea that scientists are 0:22:31.040,0:22:34.080 deliberately infecting people with  covert and that's a bit of a worry 0:22:34.720,0:22:40.320 compromising trust in science which has already  become increasingly fragile during this pandemic 0:22:40.320,0:22:46.400 is probably going to lead to further health harms  so if it makes 10 of people less likely to have a 0:22:46.400,0:22:51.760 vaccine because they don't trust what scientists  are doing in the development of vaccines if people 0:22:51.760,0:22:54.640 refuse to have vaccines because they don't  want to have something that's been tested 0:22:54.640,0:22:59.280 by deliberately trying to infect people that's  actually going to damage rather than improve 0:23:01.280,0:23:07.120 i think there's also a question over the times  of these trials or rather the lack thereof 0:23:07.120,0:23:11.920 vaccines were already starting to become  available from late 2020 so the justification of 0:23:11.920,0:23:15.280 we need challenge trials in order to  speed up the development of vaccines 0:23:16.400,0:23:22.400 certainly not the first wave of vaccines and  although we know that there are questions over 0:23:22.400,0:23:27.600 different variants of coronavirus emerging and the  efficacy of the vaccines that we currently have 0:23:28.320,0:23:31.760 the testing that was being done in  those early phases was of course with 0:23:31.760,0:23:36.160 the variants that were available the variants of  the virus that are available so it's questionable 0:23:36.160,0:23:40.240 whether that's going to be useful to if  you like future proof vessels to give us 0:23:41.760,0:23:46.240 to give us an advantage in the development  of future vaccines against the new variants 0:23:46.240,0:23:49.120 which have not necessarily been  studied in the challenge trials 0:23:49.680,0:23:56.240 so overall i felt that the benefits of at least  this first wave of trials were insufficiently 0:23:56.240,0:24:04.320 clear to justify the risks and i think that given  the very high stakes involved the onus of proof 0:24:04.320,0:24:10.240 for establishing what the benefits are that are  going to be realized from the research so not 0:24:10.240,0:24:13.760 just we will know more but what are the public  health benefits that that's going to lead to 0:24:14.480,0:24:18.880 and the pathway by which that research  is going to produce those benefits 0:24:18.880,0:24:22.080 the onus of demonstrating that i  think needs to be on the researchers 0:24:23.120,0:24:27.120 some of the criticism at the time around the  uk trials were that they were insufficiently 0:24:27.120,0:24:31.360 transparent about their protocol but i think we  need to call for equal transparency when it comes 0:24:31.360,0:24:36.560 to what's this research meant to do why what  are the benefits and why do they justify risks 0:24:37.920,0:24:43.280 okay a bonus extra thought so i questioned the  timeliness of the current round of challenge 0:24:43.280,0:24:47.520 trials and i said well we already have  vaccines the bonus extra thought of course 0:24:47.520,0:24:54.000 is whether even though the challenge trials that  started in february didn't necessarily help us 0:24:54.000,0:25:01.360 develop the vaccines we have now any faster is  promoting the challenge trials establishing the 0:25:01.360,0:25:07.040 lines of ethical arguments that might support them  and also attempting to gain public acceptance for 0:25:07.040,0:25:12.240 challenged trials public acceptance for it's all  right to do in fact people with career virus is 0:25:12.240,0:25:18.080 this actually a form of building ethical or maybe  unethical preparedness for future pandemic crisis 0:25:18.080,0:25:22.960 so these these trials were too late for the first  wave of covert variants and vaccines but will the 0:25:22.960,0:25:27.920 payoff come later when we don't have to debate and  we can just say look we've done it before we've 0:25:27.920,0:25:32.880 done challenge trials before let's go in swinging  let's get back seats okay i don't have time to 0:25:32.880,0:25:39.040 explore that further now but i thought i thought  i would drop in there for people to reflect let 0:25:39.040,0:25:45.360 me move on then to the section of my talk about  differential vaccine allocation and this is yet 0:25:45.360,0:25:50.320 another case in in which i think we need to  look at the way that we are evaluating risks 0:25:50.320,0:25:56.080 and using that and making decisions about public  health policy and healthcare and research as well 0:25:57.840,0:26:05.600 so it was great that we got a vaccine for  coronavirus so fast so towards the end of 0:26:05.600,0:26:10.400 last year as it became clear that we were we were  going to have vaccines that happened pretty soon 0:26:10.400,0:26:16.160 one of the big success stories was it took us  less less than a year to get to a covered vaccine 0:26:16.880,0:26:24.560 but of course we didn't have just a vaccine we  had many vaccines and so therefore oh and i have 0:26:24.560,0:26:31.680 proved this picture which is i think  clearly photoshopped off somewhere okay so 0:26:32.960,0:26:38.480 late last year those of us who are looking at this  we're also saying well hang on it's great that we 0:26:38.480,0:26:43.520 have vaccines but the availability of different  vaccines and the fact that they are going to have 0:26:44.720,0:26:52.240 different safety and efficacy profiles different  adverse effects different availability different 0:26:52.240,0:26:56.480 national interests backing them or not backing  them all of this is going to create a very complex 0:26:56.480,0:27:03.760 landscape for eventual vaccine distribution i  think we saw what we have seen and continue to see 0:27:04.320,0:27:09.120 some of the global dynamics and the international  politics of medical innovation play out 0:27:09.120,0:27:15.440 in terms of which vaccines get made available  where and now particularly with schemes for 0:27:15.440,0:27:23.120 vaccine certification coming in the possibility  that actually there will be forms of vaccine 0:27:23.120,0:27:29.040 nationalism in terms of favoring certain vaccines  based not only on on scientific evidence but also 0:27:29.040,0:27:33.840 on national interests but that's not what i want  to talk about today what i want to talk about is 0:27:35.600,0:27:41.440 yeah what i want to talk about is the way that  we handle the different risk profiles associated 0:27:41.440,0:27:49.520 with the vaccines i won't talk so much about some  possible differences in in efficacy although those 0:27:49.520,0:27:56.640 of course have also been um on people's minds and  might and for individual opinions and if we had 0:27:57.760,0:28:02.880 the choice might inform individual decision making  uh most of us in in the uk have not necessarily 0:28:02.880,0:28:09.440 had the choice but so they would inform both how  as individuals regard we regard the prospect of 0:28:09.440,0:28:15.440 getting vaccinated at given time in a given place  for example uh just to give a personal example 0:28:15.440,0:28:20.000 i know that in edinburgh different vaccination  centers were said to be giving out different 0:28:20.000,0:28:24.640 vaccines and so if you wanted one or the other you  have to know which which center to go to i went to 0:28:24.640,0:28:35.360 the one closest to me that had these are the sorts  of things so the main vaccine candidates that were 0:28:35.360,0:28:41.360 being made available in in the uk in the early  part of this year were the astrazeneca vaccine 0:28:42.240,0:28:49.200 and the flysa vaccine we have had some some of the  others be available but the the main discourse if 0:28:49.200,0:28:56.320 you like in the main choice not that there wasn't  much choice was between should you have and as we 0:28:56.320,0:29:02.240 all know um the the rollout was going reasonably  successfully but then in around march or april of 0:29:02.240,0:29:08.320 this year concerns started to emerge over adverse  events associated with the astrosenica vaccine 0:29:08.320,0:29:13.440 specifically a rare plotting disorder that  had been observed in a very very small number 0:29:13.440,0:29:24.320 of astrazeneca recipients and i believe i saw  this reported first from from germany but rapidly 0:29:24.320,0:29:30.480 reports emerged from from different countries  of small numbers of of these adverse events 0:29:32.720,0:29:41.440 in people who received the astrozenica vaccine as  a result several countries suspended their role 0:29:41.440,0:29:48.480 out so decision was made at a at a sort of higher  level to to wait and to pause and to re-evaluate 0:29:48.480,0:29:55.680 so the ema did an evaluation of the safety  of the vaccine um beyond that as well though 0:29:55.680,0:30:03.520 we need to think that not only at a sort of public  health level decisions were made about whether to 0:30:03.520,0:30:07.760 to hold back on the roller but also that  this news and the way that it was reported 0:30:07.760,0:30:14.800 will have had some impact on people and their  willingness their eagerness or their hesitancy 0:30:14.800,0:30:20.960 to be vaccinated so this news may well have  slowed some people down by a week a couple 0:30:27.040,0:30:31.040 very common amongst people i know i might  just wait a little bit longer and see 0:30:31.040,0:30:37.360 we're not really sure and again bearing in  mind those claims about the longer we delay 0:30:37.360,0:30:42.960 people being vaccinated even if it is by a month  or a few weeks that could still be costing lives 0:30:42.960,0:30:49.360 so this um this concern over the risks associated  probably did hold up the process persistent 0:30:49.360,0:30:53.920 vaccination role out and that may have had real  consequences in terms of human life and health 0:30:55.920,0:31:04.240 so in the wake of thinking that astrazeneca  perhaps had particular risks associated with it 0:31:04.240,0:31:11.680 a number of health authorities in different  countries decided to change their policy 0:31:11.680,0:31:19.520 on vaccine allocation and yeah when i was when  i was searching for the advice on this i didn't 0:31:19.520,0:31:24.560 find the document that i originally wanted  to to find which had actually taken comparing 0:31:24.560,0:31:30.960 what they thought the relative lists were  but rjcbi in the uk uh in april issued 0:31:31.520,0:31:39.680 the guidance that certain age groups so under 30s  as well as those 30 to 39 year old who are not 0:31:39.680,0:31:46.480 in a clinical priority group at higher risk of  severe program should be offered an alternative 0:31:46.480,0:31:51.360 to astrazeneca and they said that that's based  on available data on current epidemiology 0:31:51.360,0:31:56.880 benefit risk profile by age my highlight of that  because that's i think i want to look at multiple 0:31:56.880,0:32:02.720 predictions on disease and the current forecasts  on vaccine supply so they thought um we're going 0:32:02.720,0:32:08.720 to be able to get alternative vaccines in good  time and therefore we should be able to offer 0:32:10.400,0:32:15.760 so if i've understood it correctly and this is  still research in progress in a sense like so 0:32:15.760,0:32:24.640 i'm trying to to bottom out some of the some of  the facts in this my understanding of the way 0:32:24.640,0:32:31.840 that these decisions were being made at the time  was that the recommendation that that younger age 0:32:31.840,0:32:38.000 group should be offering alternative was based  on different background risks for different age 0:32:38.000,0:32:44.640 and disease status groups of getting kubern and  getting severe orders from it so in other words 0:32:44.640,0:32:50.320 they were treating the risk of an adverse  event particularly the risk of plotting as a 0:32:51.840,0:32:58.560 fixed figure across all groups they were saying in  some cases if you're very young your your risk of 0:32:58.560,0:33:03.120 getting covered actually falls below that and  therefore would recommend an alternative whereas 0:33:03.120,0:33:08.320 if you're older you're at a higher risk and  therefore the risk of adverse events is lower 0:33:08.320,0:33:12.800 than your background does that have i explained  that in a way that makes sense to everyone 0:33:12.800,0:33:18.880 yeah so it wasn't based on different risk of  adverse event of adverse effects it wasn't based 0:33:18.880,0:33:23.840 on if you're 60 you have a less risk of plotting  than if you're 20 you have a greater interest 0:33:24.480,0:33:28.480 it's based on if you're sixty you have a greater  risk of code and therefore your relative risk 0:33:28.480,0:33:35.840 profile is more favorable to give you um a  supposedly risky encouragement now i think 0:33:35.840,0:33:42.080 there were a lot of books i think there are a  lot of problems with the whole way that this 0:33:42.080,0:33:48.800 um these adverse events and the evaluation  of what the risks actually were were reported 0:33:48.800,0:33:55.040 and thought about and that there was quite a  lot of um quite a lot of ethical discussion at 0:33:55.040,0:34:00.000 the time saying we really shouldn't be pausing  that the kinds of magnitudes of the risk we're 0:34:00.000,0:34:05.040 talking about are so small that actually we're  doing far more by pausing than by just caring 0:34:06.960,0:34:12.480 so it was extremely low numbers of events that  were reported even to the point where it was hard 0:34:12.480,0:34:16.240 to say whether this was an adverse effect or just  something that was happening at a background rate 0:34:16.960,0:34:20.960 as i said the risk benefit balance was  still i think in favor of taxation overall 0:34:21.680,0:34:25.840 and to me one of the biggest concerns  is that the reporting of these effects 0:34:26.640,0:34:34.000 i think it's undoubted that it did to some extent  increase vaccine hesitancy or vaccine delay over 0:34:34.000,0:34:38.000 people who were slated to receive the  astonishing vaccine and that's the case even 0:34:38.000,0:34:41.840 i would say among groups who wouldn't  be considered traditionally hesitant 0:34:41.840,0:34:49.760 so people who who you might think would be um  would be enthusiastic vaccines would say yes i 0:34:49.760,0:34:54.560 think that that you should be vaccinated but then  they might just say well but maybe i'll just point 0:34:56.240,0:35:03.760 and again anecdotally i saw this quite a  lot on social media uh younger well-educated 0:35:05.280,0:35:10.640 good groups you would not think of as necessarily  being traditionally what would say vaccines 0:35:12.160,0:35:15.200 i think there were further if we  look on the international scene 0:35:15.840,0:35:22.960 there were questions about which figures ought  to be used for risk calculation so the rates at 0:35:22.960,0:35:28.080 which these events were being detected with water  were quite variable amongst different populations 0:35:29.280,0:35:37.040 i think a lot of um a lot of what i saw was  health authorities within given countries using 0:35:37.600,0:35:44.240 the rate per vaccination in their country to  decide what the risk was so i think at one point 0:35:44.240,0:35:48.560 uh the uk was talking about one in a hundred  thousand i think at the same time australia 0:35:48.560,0:35:53.520 was talking about one in two hundred and fifty  thousand so using different uh different rates 0:35:53.520,0:35:59.280 based on what had occurred within their particular  population um i think for whatever reason 0:35:59.280,0:36:04.240 germany had at a proportionally higher rate even  in the uk so they were more skeptical about it 0:36:05.120,0:36:10.400 but when we're talking about such low numbers  i mean i think that there are reasons to use to 0:36:10.400,0:36:15.280 rely more on your own country data because there  could be environmental and population reasons 0:36:15.280,0:36:21.120 why populations in the uk versus australia might  respond differently but with such low numbers it 0:36:21.120,0:36:27.200 might just also be statistical errors so is it  valid to perform the kind of comparative risk 0:36:27.200,0:36:32.000 calculations that were what was being talked about  at the time you know your risk of diet or getting 0:36:32.000,0:36:39.120 indian code is this your risk of getting blood  clot is this um one in 50 000 is more than one in 0:36:39.120,0:36:43.600 a hundred thousand so you should have you should  have the vaccine is it valid to be doing that 0:36:43.600,0:36:49.120 kind of comparison when you've actually got such  tiny numbers and really still such a positive data 0:36:50.160,0:36:55.760 so i think there are a lot of problems even with  recognizing this as a risk event and the way it 0:36:55.760,0:37:00.800 was responded to by public health authorities  in terms of what they then did with vaccinations 0:37:01.440,0:37:09.040 but a number of countries did introduce age-based  stratification for different vaccines so that was 0:37:09.040,0:37:14.640 then rolled back on in quite a number of cases but  to begin with the policy tended to be well you're 0:37:14.640,0:37:20.960 a high risk older adult you can have the higher  risk of accident i think that's fundamentally 0:37:20.960,0:37:27.280 problematic um and here's why i think it is so  there's a report experiment that i call botulism 0:37:27.280,0:37:32.880 on the beach uh it's it's not very complicated but  imagine where she cracked on an island community 0:37:32.880,0:37:37.680 she threatened an island we've only got two crates  of tin food one's being contaminated with botulism 0:37:37.680,0:37:42.160 and if you if you eat tea food from that  it's a 30 chance that you're going to die 0:37:42.880,0:37:48.000 our chance of rescue within the next month are  slim a container ship might pass by but we reckon 0:37:48.000,0:37:53.680 it might be a month before we rest now i'm happily  overweight and i'm i can i reckon probably survive 0:37:53.680,0:37:59.920 the mom i don't eat i can go half rations um but  doug's not doug is fighting fit but can't can't 0:37:59.920,0:38:04.160 survive a month without food so he'll probably  starve if he doesn't eat some of the chicken fruit 0:38:04.160,0:38:10.320 how do we allocate the crates now if we were to  go with that approach of relative risk my risk 0:38:10.320,0:38:15.280 of eating the contaminated food is higher  than my risk of just waiting out the month 0:38:17.440,0:38:22.640 so you might say well you know doug's almost  certainly going to die let's give him the crate 0:38:22.640,0:38:27.760 with the botulism because 30 chance is better than  an almost certain day and i'll have the safe food 0:38:28.880,0:38:33.680 but i don't think that's fair right i don't think  that is the right way to allocate the crates of 0:38:33.680,0:38:40.000 food in circumstances so it's a bit of a silly  thought experiment but it kind of gets to my my 0:38:40.000,0:38:45.200 intuitive i don't feel that the right response  about saying you're at higher background risk so 0:38:45.200,0:38:50.320 we'll give you the riskier treatment we'll give  you the the and i hesitate to say this because 0:38:50.320,0:38:54.960 i don't actually think that the astrazeneca  treatment was in any way second best i think the 0:38:54.960,0:38:59.920 sorts of risks we're talking about are so small  that the debate was almost nougat but it did raise 0:38:59.920,0:39:04.000 this question of is it right to say well you're  at a higher risk so we'll give you the riskier 0:39:04.880,0:39:10.560 and we'll preferentially allocate less risky  treatment to those who have less background risk 0:39:10.560,0:39:17.120 of disease those who are probably going to survive  so i don't think that it's just to do that i think 0:39:17.120,0:39:24.240 that by saying that you're placing the burden of  the higher risk treatment on those who are already 0:39:24.240,0:39:29.440 disadvantaged in terms of the existing background  risk um please tell me if this is just um 0:39:30.400,0:39:34.160 you know am i missing something huge or is  or is this flying in the obvious but i was 0:39:34.160,0:39:39.360 just like i don't think this is right what  they're suggesting now it might be in some 0:39:39.360,0:39:44.800 cases justified to differentially allocate  different treatments to different populations 0:39:44.800,0:39:49.520 if the actual risk of adverse effects themselves  were different and i started trying to think of 0:39:49.520,0:39:54.080 ways to extend my thoughts experiment and say well  what if i'm resistant to botulism etc and then it 0:39:54.080,0:40:01.600 just all became very but if the actual risk of  whatever adverse effect we were worried about 0:40:01.600,0:40:06.000 was lower in in the older population then  it would probably be justified to do that 0:40:06.960,0:40:12.560 and then the other situation in which it might be  justified to give someone a second best treatment 0:40:12.560,0:40:18.400 when they're in a high risk group that might be  justified if the group who is scheduled to receive 0:40:18.400,0:40:23.120 the second best treatment just has no other option  and that doesn't mean being given no other option 0:40:23.120,0:40:26.400 it doesn't mean the jcbi said  you can only have this one 0:40:27.360,0:40:32.640 but if they're for whatever reason if there is  actually no other option then a second best then 0:40:32.640,0:40:38.320 it could be ethically justified to give them that  now the ethics of second best treatments and the 0:40:38.320,0:40:43.360 idea of minimal risk has been explored in relation  to medical research and i'm thinking particularly 0:40:43.360,0:40:52.400 of the the kennedy krieger led paint contamination  um i think it's a it's not an easy one and 0:40:54.080,0:40:58.880 i think that there can sometimes be good  reasons to both carry out research on second 0:40:58.880,0:41:04.800 best especially where there is no other option  and it can be sometimes justified to you second 0:41:04.800,0:41:12.480 best i don't think that only on the basis of risk  is is that case but then i also want to say that 0:41:13.040,0:41:20.000 the whole um the whole relative risk of  astrazeneca was a bit of a risk for fee 0:41:20.000,0:41:24.160 and that we ought to be talking about the  treatments in terms of best and secondary 0:41:25.360,0:41:32.400 um but other factors that this brings up further  problems with the idea that we're going to look at 0:41:32.400,0:41:39.280 background risk and allocate people to receive  different vaccines based on background risk is 0:41:39.280,0:41:45.840 that it's a very narrow approach and i did see  a lot of um justifications and figures at the 0:41:45.840,0:41:51.680 time given numbers the risk is one in a hundred  thousand so really relying on the numbers there 0:41:52.640,0:41:59.280 but background risk is also dependent on a whole  host of other factors including either existing or 0:41:59.280,0:42:05.760 prospective public health policies so australia  particularly so australia because they had 0:42:06.320,0:42:13.520 different numbers of plotting cases and they  had a different background risk to the uk had 0:42:13.520,0:42:18.560 a slightly different policy to begin with or who  should receive astrazeneca so they i think said 0:42:18.560,0:42:24.640 nobody under 50 knew that off the top of my head i  hope that's right but their age special was higher 0:42:24.640,0:42:30.000 because their evaluation of both background risk  and the risk of adverse effects was different 0:42:30.000,0:42:34.720 and so they first said no no nobody over  the age of 50. now of course what's your 0:42:34.720,0:42:39.040 background risk i said that the background risk  of contracting covered in australia was lower 0:42:39.760,0:42:44.080 both because of the population size and the  incidence occurred but also because they were 0:42:44.080,0:42:48.720 having very severe lockdowns and also not  letting anybody into or out of the country 0:42:49.600,0:42:57.280 now okay so what your background risk is is  what it is that that can change where was the 0:42:57.280,0:43:02.320 evaluation for example how much would the risk  go up were we to open up international travel 0:43:03.040,0:43:06.240 how much would that change the background  risk and how does that have a barrier 0:43:06.240,0:43:12.160 on our decisions about which vaccines to  allocate so the australian the australian 0:43:12.160,0:43:16.960 health ministry came under quite severe criticism  for holding back a little bit on the vaccine 0:43:18.080,0:43:22.400 when in fact they didn't take into account would  people prefer to be less locked down and more 0:43:22.400,0:43:28.080 able to travel and very slightly more at risk from  from a vaccine that wasn't being made as available 0:43:30.160,0:43:35.760 okay so there are other public health policies to  think about that the simple comparison of 100 000 0:43:35.760,0:43:41.360 150 000 a simple comparison of numbers of existing  risks just totally fails to take that into account 0:43:43.360,0:43:46.960 of course another thing that conditions  what the background risk is is the rate 0:43:46.960,0:43:52.960 of vaccination itself so we're talking here  background risk is not only the risk to yourself 0:43:52.960,0:43:57.760 but the risk you pose to other people and the  percentage of the population who are vaccinated 0:43:57.760,0:44:01.520 affects what that background risk is so  any measures that encourage some of the 0:44:01.520,0:44:07.440 population to put off vaccination or reduce the  availability of vaccination to the population 0:44:07.440,0:44:11.360 are going to increase the background risk for  everybody and that's going to have a feedback 0:44:11.360,0:44:17.920 effect right on whether or not you decide to make  um make vaccination available so there was some 0:44:17.920,0:44:23.120 not really i think an evaluation of the  wider factors that contribute to what the 0:44:23.120,0:44:27.600 background risk is and are thinking about  how what public health policies as a whole 0:44:28.160,0:44:34.320 should feed into what the vaccination seems um  something else that affects the background risk 0:44:35.600,0:44:41.120 no sorry this affects the the risk of the adverse  effects awareness that they exist and timely 0:44:41.120,0:44:45.440 treatment so once it started to be known that  there was this very rare possible side effect 0:44:45.440,0:44:51.440 and they started issuing symptoms to look out for  your chance of dying from that probably went down 0:44:51.440,0:44:55.520 so all of these things needed to be factored  in um but i don't think they're sufficient 0:44:57.200,0:45:02.880 okay so um i think i'm getting almost the  end of my time so let me move on then to 0:45:02.880,0:45:08.880 what can we draw from these two cases for  thinking about how we treat relative risks in 0:45:08.880,0:45:15.680 setting pandemic public health so to summarize  so far i have tried to argue that i think 0:45:15.680,0:45:20.160 the risks of deliberately exposing volunteers  to covered in at least the current iterations 0:45:20.160,0:45:24.000 of challenged trials in the uk aren't  justified by the supposed benefits 0:45:24.640,0:45:29.520 and i've tried to argue that the risks of  adverse effects and vaccines don't justify 0:45:29.520,0:45:32.960 stratifying the allocation of treatments  based on different levels of background 0:45:34.560,0:45:41.280 so they've argued that and yet challenge trials  have been approved and in a number of countries 0:45:41.280,0:45:47.200 they did stratify vaccine allocation and say  astrazeneca young people you know you can't 0:45:47.200,0:45:53.360 have that so this to me just presents a bit  of a puzzle why is it acceptable to expose 0:45:53.360,0:45:58.720 healthy young people to a significantly higher  risk of undergoing challenge trials with the 0:45:58.720,0:46:03.600 justification being well we're going to develop  vaccines and vaccines but then when the vaccines 0:46:03.600,0:46:08.000 come out we don't want to expose younger people  to the much smaller risk of having the vaccine 0:46:09.600,0:46:15.200 now the pragmatic but unsatisfactory explanation  for this apparent paradox is that decisions about 0:46:15.200,0:46:19.760 vaccine allocation and decisions about research  approval get made in totally different ways by 0:46:19.760,0:46:25.200 different bits of our policy making bodies and  of course that's not joined up and this is why we 0:46:25.200,0:46:30.560 have what looks like a bit of a paradox so that's  pragmatic but it's not really very satisfying 0:46:32.560,0:46:36.880 we could try and think of some possible  differences that that mean that we can't just 0:46:36.880,0:46:43.120 compare virtual cases like this so we might  say well um challenged climate participants 0:46:43.680,0:46:48.160 are low risk for coviz so you know  we are trying to reduce the risk 0:46:48.720,0:46:54.800 but the comparison of the relative risk in the  process of vaccine approval vaccine recommendation 0:46:54.800,0:46:59.040 is with the overall background risk so it's not  just the chance that you get to if you catch 0:46:59.040,0:47:04.080 go with it it also factors in what's the chance  that you catch code in the first place the risk 0:47:04.080,0:47:08.960 involved in in challenge trials is much higher so  you're probably going to get invented the point 0:47:08.960,0:47:13.920 of the challenge funds they try to infect you so  the actual risk of challenge trials is still high 0:47:15.120,0:47:19.040 we might say well it's different because  challenge trials are research and people 0:47:19.040,0:47:23.200 have volunteered for this and it's aimed  at generating knowledge whereas vaccines 0:47:23.200,0:47:27.360 our treatment and their expectations  around risk in exposure to treatment 0:47:27.360,0:47:30.400 and whether a lot of people have properly  consented and whether they can be said to have 0:47:30.400,0:47:35.440 volunteered to undertake the risk are different  when they think they're receiving them but 0:47:35.440,0:47:42.000 in a sense in many senses indeed the rollout of  normal vaccines during a pandemic is both research 0:47:42.720,0:47:49.200 and healthcare or treatment so we're ongoing we're  generating evidence on vaccine safety and efficacy 0:47:49.200,0:47:53.680 through the rollout and that's in fact the way  in which we're identifying some of the rarer 0:47:53.680,0:48:01.200 side effects or some of the the data around the  sort of um duration of immunity and so forth so 0:48:02.320,0:48:08.880 vaccines that roll out of vaccines and pandemic  is also research i think there's surely more 0:48:08.880,0:48:14.000 justification for it than for the challenge  trial research alone so it's a trial even if 0:48:14.000,0:48:18.000 not such a controlled one it's a much bigger  scale it's potentially to generate much much 0:48:18.000,0:48:21.680 more evidence and there's a therapeutic benefit  so surely there's more justification for that 0:48:22.720,0:48:27.200 and then we might say well it's a different the  consent given to participate in a challenge trial 0:48:27.200,0:48:32.960 differs from the consent of vaccination as i said  we might think that volunteering to participate in 0:48:32.960,0:48:37.600 a challenge trial means you're more informed we  might have different patients and expectations 0:48:38.400,0:48:45.920 but consent is irrelevant when it comes to vaccine  allocation now i did say if people have choices 0:48:45.920,0:48:50.880 that various factors might influence their choices  but in fact most of us aren't really given a 0:48:50.880,0:48:56.240 choice we receive the vaccine that is allocated to  our age group or we don't get vaccinated so when 0:48:56.240,0:49:02.080 the decisions about who gets what vaccine are made  at a higher level there's no option to consent 0:49:02.080,0:49:06.480 there's no option to to consent to undertaking  the risk of the more dangerous treatment 0:49:07.680,0:49:12.400 so i wondered whether it might be instructive  to think about that ethical framework that we 0:49:12.400,0:49:17.040 saw for challenge trials and to see how  that pans out when it comes to vaccine 0:49:17.040,0:49:21.120 allocation so remember this is the what sorts  of things would make a challenge trial anything 0:49:22.400,0:49:28.080 so is there sufficient scientific and social value  well there's clear social and public health value 0:49:28.080,0:49:33.600 in vaccination and as long as the overall risk  benefit balance and vaccination is favorable 0:49:33.600,0:49:38.880 that continues to be the case which was a fair  subject selection i pointed out that i think 0:49:38.880,0:49:43.840 there's a problem of fairness in allocation if you  give higher risk treatments to higher risk groups 0:49:45.600,0:49:50.160 is there an acceptable risk benefit balance well  again i think in the case of vaccination the 0:49:50.160,0:49:55.440 absolute risks from vaccination themselves were  very very timely the risks of challenged trials 0:49:55.440,0:50:00.400 were much higher and there was also a failure  to consider the wider public health context 0:50:00.400,0:50:03.920 that affected what those risks were  what the risk of balance would be 0:50:05.200,0:50:10.000 informed consent as i said you can't consent if  you're not of the treatment and i think australia 0:50:10.000,0:50:13.680 finally got this partly right because after for a  while saying no you can't have it if you're under 0:50:13.680,0:50:18.000 50 they went to saying oh well actually you can  have it if you've talked to your gp and you are 0:50:18.000,0:50:22.720 properly informed about it um but they got it a  bit wrong because they insisted on through small 0:50:22.720,0:50:29.360 sorts of um extra uh extra regulations around all  the world doctors shouldn't be shouldn't be sued 0:50:29.360,0:50:35.120 if they give it to you and you have a cross and by  exceptionalizing it in a way by saying all but you 0:50:35.120,0:50:39.760 must be properly informed i think they actually  may have contributed to the scare mongering around 0:50:39.760,0:50:44.240 astrazeneca and that probably again would have led  to people not having the treatment they otherwise 0:50:44.240,0:50:51.520 would have when it comes to stakeholder engagement  i think the messaging on risks um when when we 0:50:51.520,0:50:57.520 talk about vaccines and about adverse effects like  the messaging is being pretty cool i think people 0:50:57.520,0:51:02.400 are much more scared about clots from estrogenic  than they ought to be and no matter how many 0:51:02.400,0:51:07.840 infographics you see on being eaten by a shark  and struck by lightning that just doesn't seem to 0:51:08.480,0:51:13.760 you know that doesn't seem to sink in but i  think oh and this is something i've said in um 0:51:14.320,0:51:20.000 in my work for the pandemic ethics accelerator  elsewhere there was a lack of engagement with 0:51:20.560,0:51:27.440 publics on which risks matter in what ways so you  know do people yeah you might be more likely to 0:51:27.440,0:51:32.720 be struck by lightning than from an um than die  from a blood clot after astrazeneca but would you 0:51:32.720,0:51:38.560 rather be struck by lightning would you rather not  have to say oh i wish i hadn't had that vaccine so 0:51:39.360,0:51:43.920 risks are not just about numbers risks aren't  created and there was also a lack of engagement 0:51:43.920,0:51:48.240 on the other factors that conditional risk  particularly the other public health policies 0:51:48.240,0:51:55.280 and how those intersect with a vaccination plan  for illegal culture okay so a few conclusions i'm 0:51:55.280,0:52:02.880 just about to finish um i think the conclusions  from my individual analyses about challenge trials 0:52:02.880,0:52:08.480 with emma and the analysis of vaccine policy i  think challenge trials need much more careful 0:52:08.480,0:52:12.240 justification especially when it comes to the  benefits that are claimed and how they've been 0:52:12.240,0:52:18.160 realized i think and i apologize if this was just  a no-brainer but allocating higher risk groups to 0:52:18.160,0:52:23.760 high-risk treatments may be unethical in many  cases it is but overall when we compare these 0:52:23.760,0:52:30.880 two cases i think it's clear that in pandemic  public health policy we need a much more joined 0:52:30.880,0:52:36.000 up approach so we need a more joined up approach  to evaluating and distributing risk across all 0:52:36.000,0:52:40.880 aspects of public health not just between research  and treatment but also across other public health 0:52:40.880,0:52:46.160 policies such as behavioral interventions  masking block downs travel restrictions etc 0:52:46.160,0:52:49.760 we also need a more joined up approach to  knowledge production so we need to recognize 0:52:50.400,0:52:55.040 more explicitly that the role of treatments  continues to be researched and to think about 0:52:55.040,0:52:59.920 what that means for people who are receiving those  treatments as research participants we need to be 0:52:59.920,0:53:04.640 connecting the collection and use of real-world  evidence with our research so if challenge trials 0:53:04.640,0:53:08.560 are designed to this particular research  aim could real-world everything students say 0:53:10.480,0:53:13.840 and that is all i have for you today  thank you very much for your attention