Contemporary Pediatric Research Ethics: Lessons Learned from the COVID-19 Pandemic

January 25, 2021

January 20, 2021

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00:04OK, I think we're going to get started.
00:08Good evening, my name is
00:09Mark Mercury on director,
00:11the program for Biomedical Ethics
00:12and I want to welcome you tonight to
00:15our Evening Ethics seminar series.
00:17In looking forward to this talk for
00:19quite some time and I want to get to
00:22introducing our speaker in just a minute.
00:25Wanna welcome have myself on the associate
00:27director Jack Hughes and Serra Hall,
00:29as well as our program manager Karen Cole.
00:32Thanks so much for joining us to let
00:35you know how this works is we'll have a.
00:38Lecture someday the way it works is
00:39that we're on a big room together,
00:41eating good food,
00:42but for a little while longer we do
00:44it like this and we'll have a lecture
00:45that will last around an hour and
00:47then we'll have about 30 minutes
00:49or so for a question and answer.
00:51And and right now you're all muted,
00:53but when the time comes for Q&A will
00:55I'll explain to you how we're going
00:56to do that so you get a chance to
00:59ask your questions as we go sabi
01:01calling on you to ask the questions.
01:04We will stop at.
01:05We have a hard stop at at 5:30
01:07as those you excuse me.
01:09At 6:30,
01:09those of you who've done this with this
01:12before and no so I apologize in advance.
01:14Whoever has the best possible question at
01:16629 'cause you probably won't get to ask it,
01:19but come back,
01:19come back in a couple weeks and ask
01:22a question or the next session you
01:23can see in front of you there the
01:26calendar for upcoming talks and
01:27we're very excited about all of them.
01:29But then I want to talk about my friend.
01:32They only laventhol doctor Naomi
01:33Laventhol is a clinical associate
01:35professor of Pediatrics in the division
01:37of the United Perinatal Medicine.
01:38As well as in the Center for Bioethics
01:41and Social Sciences and Medicine at the
01:43University of Michigan Medical School,
01:45they only attended college.
01:47Indiana University and Medical School at LSU.
01:49She did her pediatric residency
01:51and neonatology Fellowship of
01:52Medical Ethics Fellowship an MPH,
01:54all at the University of Chicago,
01:56and since then,
01:57she's been up in Ann Arbor at
01:59the University of Michigan,
02:01where she's one of the leaders
02:03in the ethics endeavors there,
02:04as well as in neonatology.
02:07I am I've been working with Naomi
02:09off and on for years and I've been
02:12wanting to get her here and was
02:14delighted this year when she agreed
02:16to come such as it is to visit us.
02:19In this way they only,
02:21as part of the next generation of
02:23leadership in pediatric ethics.
02:24I will tell you that when the COVID-19
02:27pandemic was upon us in the spring,
02:29and several of us in pediatric ethics
02:31associated with the American Academy
02:33of Pediatrics decided that we needed
02:35to get together to try and write
02:37something that provide some guidance.
02:39With regard to triage,
02:40it was Naomi who led the
02:42effort and led the charge in coordinated US,
02:45and that was a work that was
02:47published with Naomi's first author.
02:49She's smart, she's hard working,
02:51and she gives a great talk.
02:53So we're in for a treat tonight.
02:55Tonight we're going to hear about
02:57contemporary pediatric research ethics
02:58lessons learned from the COVID-19 pandemic.
03:00Naomi I'm delighted you're here.
03:02Thank you so much for joining us take over.
03:06Well, that was a lovely introduction mark.
03:08Thank you so much.
03:09I'm going to go ahead and share
03:11my slides and get started.
03:12It is a pleasure to be here
03:14and you know when.
03:15When I was first invited to do this,
03:17I think we really were hopeful that
03:19that we would be able to do with this
03:22in person and that wasn't meant to be,
03:24but it's great to be here and you
03:26guys have a good setup. I am.
03:28Not able to see you guys right now
03:29so if something funny is happening
03:31someone beginning let me know.
03:33Can everybody see my slides OK?
03:37OK, I see you mark, thank you.
03:40Alright, so as I was saying before
03:42before the recording started,
03:43this is a new talk for me and it's a
03:45talk that I've really wanted to write
03:47for quite some time because it comes
03:49out of some ideas and questions that
03:50I've had throughout this pandemic.
03:52And I'll tell you that in other research
03:54I did to prepare this I thought I would
03:56find more answers than I ended up finding,
03:58and so I really hope that I leave plenty
04:00of time in the discussion for us to
04:02try to come to those answers together.
04:04I have nothing to disclose except
04:05as I mentioned earlier.
04:06I do have five and eight year old
04:08boys in the house right now, so.
04:10If you hear a loud crash, that's them.
04:12Um and I, did you know I've
04:14overtime is that given talks.
04:16I've tried to view this objectives.
04:17Idea is really not just like this is a
04:19thing I have to turn in for the CME,
04:21but you really think about what
04:23do I want to do with this time?
04:26And so today I'm really hoping
04:27that we explore key principles of
04:29research ethics that have emerged as
04:30important themes during this pandemic.
04:32And we're going to talk specifically
04:34about children and their unique
04:35aspects as a special population of
04:37research participants in general and
04:38in the context of this pandemic.
04:40And we're going to reflect a bit on
04:42the tensions related to racism and
04:43socioeconomic inequity as they relate to
04:45the historical context of research ethics.
04:47Clearly,
04:47that's several hours worth of
04:49talks unto itself.
04:49It's not my specific area of expertise,
04:51but I do think this is important as we
04:53think about the research ethics of this
04:55pandemic and about children in particular,
04:57even though the attention I will
04:59tell you hasn't really been
05:01on children with regard to.
05:02Uh, racial tensions and vaccine research.
05:06So here are the things we're going to
05:08do when I'm not necessarily going to go
05:10through through these things in order,
05:12but these are the ways we're
05:13going to talk about this.
05:15We're going to talk about
05:16principles that were reinforced.
05:17We're going to talk about new complexities
05:18that arose in public health ethics.
05:20We will talk a bit about race,
05:22racism and inequity,
05:23and will talk about children.
05:24I'm going to talk both about clinical
05:25trials and about pre approval access,
05:27which is something I had
05:28to learn a lot about,
05:30as as this pandemic going on.
05:31And if there's time,
05:32I'll talk a bit about research
05:33integrity and publication ethics,
05:35because there are some things that came
05:36out during this pandemic that are.
05:38I think are important,
05:39but if I have not gotten my timings
05:41right and it looks like that would cost
05:43us too much of the discussion time,
05:45I'll skip that for another day.
05:48Alright,
05:48so I start here with this picture
05:50of New Orleans.
05:51This is my hometown and what
05:52I'll tell you is
05:53that for the first time in about 20 years
05:55I was in this scrum with my family in 2020,
05:58and while we were in the scrum,
05:59at a certain point I looked around and
06:01I thought, gosh, it's a good thing.
06:03All these worries about
06:04coronavirus are overblown,
06:04or we're all really in trouble.
06:07And it turned out that we really
06:09were in trouble and I just have
06:11this year to sort of think about my
06:14own life is a private citizen and
06:15how this pandemic started for me.
06:17And, you know, we were lucky.
06:19We didn't get covid during this
06:20during Mardi Gras at last year,
06:22but a lot of people did because there
06:24wasn't a lot of warning about the
06:26seriousness of this pandemic as it was
06:28spreading out of Asia and there was
06:30there some public health opportunities
06:32that were missed in the lead up to Michael.
06:35But so to frame research ethics
06:37in the context of clinical ethics,
06:39my general way of thinking about
06:40this and this has really been my big
06:43approach to thinking about research
06:45ethics during this pandemic is that you know,
06:47as as Mark was saying,
06:49as we were writing these papers about
06:51resource allocation and workforce
06:52redeployment and shortages of PPE,
06:53those were things that we've
06:55never had to think about,
06:56or at least not so.
06:58Specifically,
06:58they were hypotheticals an we had to go
07:01back an do this normative re analysis
07:03of things that we thought we knew and
07:06rethink them in this modern world.
07:08And we this was really new and different
07:10for a lot of us and we had to pivot
07:12to thinking more deliberately about
07:14public health ethics that many of us
07:16have in our lifetime and children
07:18really occupied a unique and complex
07:20and often polarizing role in these
07:22considerations and the most polarizing
07:23role of children I can think of in
07:25this pandemic has been school closure,
07:27school reopening and what are we
07:28really talking about when we're
07:30talking about kids in this pandemic?
07:32And I do think that that recapitulates
07:34into the research ethics.
07:36So where is the clinical ethics
07:37in covid I think have let us into
07:40this really unchartered territory
07:41to mean research ethics has largely
07:43reinforced what we already knew and
07:45shown these principles that we already
07:47understood playing out logically in
07:48this modern time with modern technology.
07:50And I will say access versus protection
07:52several times in this talk because
07:54it keeps coming back to access
07:56versus protection an in my view,
07:58when you talk about yes.
07:59So
08:00sorry to do this, but I just got a
08:02text from a friend of mine in the
08:05audience that they can't see the slide.
08:07So I'm asking Kyle.
08:08Give us and give us just a few
08:11seconds here in Kyle if you could
08:13figure out why that is the case,
08:15I can see the slides just
08:17fine. Yeah, I can tell.
08:20OK so my buddy who knows who he is is
08:23something with your connection I guess.
08:26Thank you and I'm sorry to interrupt
08:28Ono trouble. Call you OK. Art over
08:32your doing. I won't so access
08:35versus protection again and again,
08:37and the unique vulnerabilities of
08:39children imparted moral and regulatory
08:42challenges to research ethics
08:44research uncovered for children.
08:46And our history and current
08:48struggles with racism and inequity
08:49wear sailing as they've ever been.
08:51But so so when I started writing this talk,
08:54I really thought there's nothing new here.
08:55But then I thought more about
08:57this public health ethics issue,
08:58and I think even in research ethics,
09:00there is a lot that's new.
09:03So after I've done all this myself,
09:05I found out that someone had published it,
09:08and after I've done my own
09:10diving into clinicaltrials.gov,
09:11I found exactly the figure
09:12that I was hoping to make,
09:14which is this dismal and hopefully
09:16drawing realization about how few of the
09:19interventional studies in for COVID-19
09:21have included children under the age of 17.
09:23I'll tell you almost none of them
09:26included children under the age of 12,
09:28but this to me as a pediatrician
09:30is really depressing.
09:31We just.
09:31Didn't include children in these trials
09:33and I think there were a few reasons
09:35about for that that will get to, but
09:37I want this is the framing of my talk is why?
09:40Why is this true?
09:41Was it the right thing was at the wrong
09:43thing and could we have done better?
09:45And so I'll say the thing I'll say
09:47again and again in this talk is that
09:49children should be protected by research,
09:51not from it.
09:51And I could kind of stop here,
09:53and we could probably spend the
09:54next hour and a half talking about
09:56whether or not we agree with this
09:58and how to make it so if it's true.
10:00One thing I want to be clear
10:01about is I read this phrase,
10:03sort of in relation to pregnant
10:04women saying that pregnant women
10:05should be protected by research,
10:06not from it, and so it's very clever,
10:08and I wish I'd said it first,
10:09but I want to be a friend
10:11that I didn't say it first.
10:15So this is a slide that I actually
10:18use quite a bit when I do.
10:20My introductory talks for students and
10:22learners about pediatric research ethics,
10:23and I've beautified it a little bit for you,
10:26but I'll start by saying this in the
10:29contemporary research environment.
10:30Enrollment in special populations
10:31is usually required, by which I
10:33mean it's a regulatory requirement.
10:35It's necessary morally,
10:36and that are the integrity of our science.
10:38Depends on it and that sometimes it
10:41really can be procedurally difficult.
10:44The big picture principle here is
10:46that research should be done with
10:48participants who stand to benefit
10:49or who represent populations
10:51that could benefit in the future.
10:53Now ethics,
10:53we say good ethics rely on good
10:55facts and I think it's also true that
10:57good medicine relies on good facts.
10:58And generally I think it's true
11:00that patients are better off when
11:01their medical care is informed by
11:03high quality scientific evidence.
11:04We shouldn't be excluding unique
11:06populations with unique complexities
11:07because it's difficult we shouldn't
11:09be excluding them.
11:10For convenience,
11:11we should be getting over that
11:13inconvenience and bringing them in.
11:14There are some specific regulatory
11:17and institutional considerations
11:18that we have to take into account.
11:20So again,
11:21access versus protection when you
11:22think about vulnerable populations.
11:24It's and research.
11:25The question is always going to be
11:26is research this fundamentally good
11:28thing that makes us all healthier?
11:30That's that we should want to be involved in.
11:33Or is it at its core dangerous
11:35and a little bit scary,
11:36and we should all be wary.
11:38And the answer clearly is yes,
11:40but you know to both.
11:41But I think this is the tension
11:43that comes up again and again.
11:45And as we've thought about this
11:47in the context of Covid an in the
11:49context of children that access
11:51versus protection balance.
11:52Stasin but.
11:57But um.
11:57There's also this other tension
11:59which suddenly I've lost the
12:01ability to show you hang on.
12:04Between individual child health
12:05and an public health more broadly,
12:07and I mean public health and
12:09the really big picture here.
12:10And thinking about what is the role
12:12of children in this pandemic and what
12:14moral obligation to children's have
12:16towards population health in general.
12:18In most situations.
12:18We don't think of children
12:20as owing adults much,
12:21but in this pandemic,
12:23in some sense kids were asked
12:25to do a lot for adults,
12:26and I think that's one of the most
12:29interesting ethical issues that
12:30come out of this pandemic for me.
12:33So I won't talk about all these populations,
12:35but just to remind you,
12:37there are some very specifically bend
12:39categories of special populations when
12:41it comes to research that children,
12:42pregnant women,
12:43incarcerated individuals,
12:44individuals with cognitive
12:45and motor disabilities,
12:46and we're increasingly aware
12:47of economically and socially
12:48disadvantaged persons as also
12:50being a special population.
12:51And when we say special population,
12:53I think it's important to be
12:55cognizant of what do we mean?
12:56We're generally talking about
12:58medically medical complexity or,
12:59for example, in the for the patients
13:02that mark and I take care of.
13:04Physiologic vulnerability,
13:05one thing I say about premature infants
13:07is that all of their organ systems are
13:10immature and that makes them vulnerable.
13:12Now vulnerability in a more legal and
13:14social sense has to do with the patients
13:16risk of being exploited or coerced,
13:18and this violates the fundamental
13:19principle that I'm sure we
13:21all in this group know about,
13:22which is that research should be voluntary.
13:24We also want to be clear that the
13:26people who are taking on the burdens
13:28of research are the same people who
13:30benefit and that we're not burdening
13:32one group while benefiting another.
13:33And this really I don't talk
13:35about can't very much,
13:36but this is where in our
13:37hearts we talk about cotton.
13:39We think about how people shouldn't
13:41be used as a means to an end.
13:43The problem with this is that once
13:45you get designated as vulnerable,
13:46that makes it harder for you
13:48to be in a study.
13:49That means you're not recruited,
13:50and that means the care that
13:51you get isn't informed by data
13:53that involved people like you,
13:54and that makes her care less good.
13:57The other thing is that we have to
13:59be really careful not to conflate
14:01vulnerability and stupidity,
14:03and I think one of the things that
14:05his anger pregnant women over the
14:07centuries is that pregnancy and it's
14:09sort of designation is vulnerable.
14:11Got misclassified as a state of
14:14cognitive impairment as opposed
14:16to physiologic vulnerability.
14:17So I'll talk very briefly about oversight.
14:20This is pretty dry,
14:21but I do think you have to
14:23think about this a little bit,
14:26especially as you think about vaccine shop.
14:28And generally speaking,
14:29HHS empowers individual institutional
14:31review boards to approve three categories
14:33of research involving children.
14:35This should be familiar to most people,
14:37but as we think about,
14:38we think about this in terms of
14:40balancing risk and potential benefit.
14:42An as a general rule,
14:44we don't get to do research that's
14:46risky for children and less they
14:48stand to benefit an in all situations.
14:50Research needs to be accompanied by
14:52formal informed consent by parents and
14:55a sense of children when possible.
14:57Now there are lots of situations in
14:59which we do allow for more risk than minimal,
15:02but here we have this pretty stringent
15:04requirement that there's anticipated
15:05benefit that's proportional to that risk.
15:07This is in my gut where I think most
15:09of the vaccine trials have fallen,
15:11although I will tell you I had
15:13a heck of a hard time finding
15:15that written down anywhere.
15:16There are other types of
15:18vaccine research which have,
15:19which has specifically not
15:21falling into this category.
15:22Finally,
15:23there is this funny sort of
15:24case in which there's a minor
15:25increase over minimal risk,
15:26and books and articles and seminars have
15:28been given over how do you quantify
15:30what exactly is a minor risk over minimal,
15:32and what does that look
15:33like and what kind of
15:35kid are we talking about?
15:37But we do allow for this little
15:39caveat of ultraism by children,
15:41and say that children can take on a
15:44little bit of risk to benefit children
15:46who are like them in the future.
15:49This is, I think,
15:50a really interesting idea and we do
15:52know from some studies that young
15:53kids are able to articulate a notion
15:55of altruism and understand this.
15:57So I think this is fundamentally good,
15:59but it's also quite nuanced.
16:01So I'm gonna pause here for a little
16:03bit of humor and tell you a story
16:04that just happened to me last week,
16:06and I thought this is great and
16:07I got permission from my friend
16:09to use these screenshots of text
16:11messages to send me in this talk.
16:12So this is my good friend who had
16:14her second vaccine a couple of last
16:15week and she said it was no joke.
16:17I had chills and muscle aches.
16:18I felt terrible,
16:19and it felt like a head covid.
16:20And before you get all mad.
16:22So I got mad all the time.
16:23When people say that having the flu
16:25shot is worse than having the flu.
16:26And I will tell you that this friend
16:28is my friend from Mardi Gras who
16:29actually did have covid so she didn't
16:31know what she was talking about,
16:32but you.
16:33So she tells me this and then she tells me,
16:35now blurted out,
16:35I've blocked out the name of her son here,
16:37but she says I'm trying to convince
16:39my son that he wants to do good
16:40for humanity and participate
16:41in the pediatric vaccine trial.
16:43But after seeing me yesterday,
16:44he's unwilling.
16:46This friend is not a pediatrician and
16:47I'm really proud of her because she
16:49really understood in her core that
16:51this thing called child dissent is a
16:52thing and her child isn't more than 10 or 11.
16:55But he had this sense that this was a choice
16:57that he was allowed to make and he said,
16:59Nah,
17:00I don't want to do it and she said
17:02I can't make you and I was proud of
17:04her and I was really pleased to have
17:06this very real life example of this
17:08kind of intuitive ascent discussion
17:10between a child and his mother about
17:12participating in research study.
17:13And so I once gave a 90
17:15minute talk on a sense,
17:16so I've gone way down this rabbit hole
17:18before and I've only got 1 slide on it here.
17:21But this is just to remind you
17:22that ascent in Pediatrics in 2021
17:24is much more nuanced than just
17:26getting a nod from the kid,
17:27or determine at what age you do
17:29this and what age you don't.
17:31What age you don't,
17:31and if you're going to be in the business
17:34of enrolling children in research,
17:35you really do have to think about how
17:37you're going to engage that child,
17:39how you're going to determine their
17:40assessment of what's going on,
17:42and how you're going to allow
17:43them to be active
17:44participants in this decision.
17:46And just to be very clear,
17:47ascent forms are not the way to do this.
17:51But getting back to the regulatory bit,
17:53there is this other category and
17:54this comes up with some versions
17:56of some sorts of vaccine research,
17:58which is why I wanted to bring it up,
18:00which is there are situations in which
18:02an IRB can look at the protocol for
18:04a child research study and say, wow,
18:06this doesn't fit neatly into any of
18:08those three categories and say HHS,
18:09you have to help me.
18:12There are two mechanisms by which HHS
18:14can then approve a study like this.
18:16One is by saying, actually no.
18:18On further review,
18:19this does mean one of the previous
18:21categories and the other is by
18:23saying the potential to address
18:25the health and welfare of children.
18:27In this scientifically sound study is
18:29so great that we will allow some risk,
18:31even though this doesn't meet some of
18:33the other categories we talked about.
18:35So I think that this is a really again
18:38interesting nod towards this sense that
18:40there are some cases in which children.
18:42Can do things for the good of community,
18:44even if there's a net risk
18:46to them in doing it.
18:48So to recap,
18:49all of this background stuff
18:50in pediatric research ethics,
18:52children should be protected by research,
18:54not from it.
18:55Healthy children may not participate
18:57in research protocols and telling more
18:59than minimal risk most of the time,
19:01but sick children may be permitted to
19:03participate in protocols involving
19:04slightly more risk if they may receive
19:07direct benefit or a vital information
19:09about their disorder can be gathered.
19:10Pediatric research requires
19:11stringent oversight is.
19:12I've just reviewed an this nice quote quote
19:15from her friend Renee Boss in Baltimore.
19:17Pediatricians,
19:18researchers,
19:18Arby's and parents must work
19:19together to refine and apply the
19:21principles of respect for persons,
19:23justice and medicines to children.
19:24I really couldn't say that better myself,
19:26so I didn't try.
19:29So I want to move now out of this classic
19:31example of clinical trials though,
19:34and talk about investigational
19:35therapies in pre approval access,
19:36because I think probably many of you
19:38like me got a crash course in pre
19:41approval access as this pandemic is gone
19:43and forgive me if this is too basic for you.
19:46I found that I really had to go back
19:48and understand this and there's some
19:50great folks at Penn who work on this
19:53a lot and this does apply to children.
19:55There are emergency use authorizations
19:57that have been granted for children,
19:58usually older kids.
19:59But I won.
20:00I distinguish expanded access
20:01and early use authorization as
20:03two mechanisms by which the FDA
20:05authorizes pre approval access.
20:06There are other ways that pre
20:08approval access can happen,
20:10but the other thing that's important
20:12here is this is not FDA approval
20:14and I encourage you to be really
20:16careful in which words you use
20:18when you talk about this because.
20:20An early use authorization,
20:22for example, is not an approval.
20:25So expanded access usually allows a
20:27drug or device that is currently under
20:30some kind of systematic evaluation
20:32to be made available to someone for
20:35who suffer who for some reason is
20:37not eligible to enroll in the trial.
20:40We often refer to this as compassionate use.
20:43Usually the way this works is that the
20:46drug company directly supplies the the.
20:48The drug of the device to the prescriber,
20:51without a middleman like the federal
20:53government, through some sort of
20:54boarding and four agreements,
20:56and even though this is technically speaking,
20:58not research and does not require
21:00an informed consent,
21:01there is usually you do need to
21:03get your IRB to sign off on this,
21:05and there's some reporting to
21:08the IRB that's required.
21:10And what I just learned is that the
21:11manufacturer can actually quite
21:12require additional information
21:13that the FDA isn't interested,
21:15but it's still not considered to be research.
21:17This is also not the same
21:19thing as right to try,
21:20which I'll come back to in a minute.
21:24So early,
21:24this authorization is
21:25actually pretty different.
21:26It's a different form of pre approval
21:28access in which that the FDA concludes
21:30that a product may be effective and
21:33that it's known and potential benefits
21:35outweigh the risks with a pretty low bar.
21:37And one thing that's really clear
21:39about this is that for a patient
21:41to get something under an EUA,
21:43this is a clinical decision.
21:45This is not a research decision,
21:47you know,
21:47as we're all getting our vaccines
21:49that are released under anyway.
21:51We're not signing.
21:52Research consents were not
21:54participating in a research study.
21:56And in the case of vaccines,
21:58Pfizer and Moderna for example,
21:59are supplying millions of doses to the
22:01federal government were supplying it to
22:03states who are supplying it to institutions.
22:05So the supply chain is also really
22:08different than under expanded access.
22:11So in the time of kovid,
22:13institutions about to decide whether
22:14or not they want how they are going
22:17to make EUA approval UA authorized
22:19interventions available to their patients,
22:21and they can choose to say we're only
22:23going to our patients to get this in
22:26the context of which about clinical
22:28trial and then this nice paper that
22:31accorded here at the bottom the authors
22:33talk about about appropriate limitations too.
22:35Too easy way use,
22:37and when it's justifiable to
22:39you to limit this to a trial.
22:41And usually this has to do with,
22:43you know,
22:44my favorite word and research ethics.
22:45Equipois.
22:46We're really not sure whether
22:47or not there's a net benefit to
22:50be derived from getting this.
22:51This can also be a way to make
22:53sure that these trials happen,
22:55because one thing we always have
22:56to worry about is once everyone
22:58can get something before the
22:59trials have been done to finish
23:01scientifically validating it.
23:02It's really hard to go back and
23:04randomize people after that,
23:05and so if you think it's really
23:07important that at some point
23:08this trial needs to be done,
23:10the way might be your only chance to do it.
23:14The problem with this is,
23:16on the one hand, you potentially answer
23:19the unanswered questions by bringing
23:21a higher level of scientific rigor,
23:23but there's concerns about
23:25voluntariness and fairness here.
23:28And so, particularly when we're
23:29thinking about using any UA in
23:31the context of limited supplies.
23:32So the only way you can get
23:35this is if you're in the trial.
23:38The plus side is that it solves your
23:40problem that FDA does not tell you
23:43anything about resource allocation.
23:44You know when when there isn't.
23:46Any way for convalescent plasma,
23:47and you know we had six doses for
23:49300 people who needed it or my.
23:52I don't want to send it,
23:53but might have benefited from it.
23:55FDA didn't tell us how to allocate
23:58our six doses.
23:59Using a trial can be one way to
24:00bring some structure and fairness and
24:02criteria to how to distribute those,
24:04but it does raise access to raise
24:07questions about whether there really
24:08is fair access to that trial and
24:11whether or not people are going to.
24:13Inadvertently be coerced into participating
24:14because they really want the thing.
24:15And that's the only way they can get it.
24:19So do you want to distinguish
24:21this from right to try?
24:22Because I think right to try is
24:25when people talk about only plus
24:27lay press and I had to go back
24:29and remind myself how this works.
24:31So right to try is even less regulated
24:34than an expanded access in which
24:36terminally ill patients can get things
24:38after a phase one trial without any
24:40further communication from the FDA.
24:42So there's no,
24:43there's no communication information back.
24:45This isn't I.
24:46There's no IRB checkpoint on this,
24:48and I think this was viewed as a
24:51strong thing for patient advocacy.
24:53My take on this is that we have
24:55to be really careful and I liked
24:57this description about it,
24:59but fundamentally,
24:59right to try had a lot to do with
25:02politics and not a lot to do with science.
25:05And if you think critically about
25:06the benefits from this,
25:07it's not really clear what right to try
25:09ads in the setting of compassionate use.
25:12An easy way,
25:13and there's been some really interesting
25:15and compelling writing I think about.
25:17About the unintended consequences
25:19of Rachel tries.
25:19So I really like this piece
25:21talking about how right to try
25:23can inadvertently exclude people
25:24from the kind of comprehensive and
25:26really high quality palliative care
25:28that's available in the 21st century
25:30and just a lot of writing about.
25:33When we start to make these drugs
25:35available like this in this unregulated way,
25:36are we really undermining what
25:38we owe to patients in terms of
25:39science and regulation of new drugs?
25:41So this is just food for thought.
25:43I haven't heard a lot of talk about,
25:45right,
25:45right to try in the context
25:46of covered specifically,
25:47but I thought this was a good opportunity
25:50to review pre approval access.
25:52And the question that has been bugging me
25:55for the last six months that I thought
25:58I was going to have answers for you.
26:01For as I came to this talk was how do we
26:04feel about kids and expanded access anyways,
26:07in particular for for COVID-19 infection
26:09and what do we think about kids getting
26:12recipe or convalescent plasma or
26:14monoclonal antibody as under anyway and
26:16I expected to find this deep and rich
26:19seam of writing by all the ethicists I
26:22know who are so much smarter than me.
26:25To explain this to me and I found that
26:27this really just hasn't been front and
26:29center in the minds of bioethicists
26:31right now, and there's a lot of potential
26:33reasons for that is one is no mark described.
26:36We've been really busy doing other things.
26:38You know.
26:39The other is that a lot of these trials
26:41do include kids as young as 12 in the
26:43ways usually don't grant permission to
26:45use the drug outside of those and ranges,
26:48so the other is just.
26:49It's not really an issue,
26:51but you do wonder about whether we
26:53should be imposing. I think different.
26:55Thresholds or what's the role of assent?
26:57For example,
26:58for a teenager to get experimental,
26:59convalescent plasma,
27:00and so I'm hoping that you guys
27:02will engage with me on this one.
27:04We're able to talk at the end of
27:06the session because I have been
27:08really trying to think about what is
27:10a framework to think about guiding
27:12pediatric clinicians about use of
27:14of pre approval access.
27:16Outside of the confines of cancer,
27:17which is when we usually talk about it,
27:19but unfortunately I don't have 10 nice
27:21editorials to share with you about this.
27:23'cause it doesn't seem like
27:25people are writing them.
27:27So now I wanna really shift
27:28gears and talk about the vaccine.
27:30'cause if you want to think about where is
27:32the money in pediatric research ethics,
27:33it is in vaccines which are at
27:35the heart of every pediatrician.
27:38So.
27:39I will admit that I have bristled at the
27:42term operation warp speed this whole time.
27:44There's something that about it that
27:46I don't like, a feel like it kind of.
27:49Is antithetical to what you want and
27:52methodical and careful research and
27:54that nothing involving human subjects
27:56research should be happen at warp speed.
27:59But now with two doses of vaccine in
28:01my arm and looking at this figure,
28:03I'm starting to wonder if maybe my
28:05approach to this is a little antiquated
28:07and I should view this as a good thing
28:10and a bad thing and I'll get back to
28:12operation warp speed in a minute.
28:14But this is just a comparison of
28:16previous historical viral epidemics
28:17and the time from first observation
28:19of the disease to having a vaccine.
28:21Ann and I just it really did happen
28:23at warp speed for stars coming too,
28:26and I think this figure shows it really well,
28:28I'm sorry.
28:29If the person who can't see it still
28:31can't see it, but the idea here is,
28:33you know, we've known about Merge for six
28:35years and we still don't have a vaccine.
28:38It was 15 years from it,
28:39took 15 years to get A Bola vaccine approved,
28:42and it wasn't like the laughable outbreak
28:44was the first of all app, right?
28:45We knew about it for a long time after
28:48that before that, and so this is really
28:50happening in an unprecedented way.
28:51And of course the research ethics
28:53was going to be a little different.
28:56So this is a refresher,
28:58an vaccine development and testing isn't a
29:00ton difference than other new drug testing,
29:02and then it goes through many phases,
29:05including laboratory and animal studies,
29:06in which you do in vitro and
29:08then in vivo and animals,
29:10and you apply for your Ind.
29:12An vaccine studies have the same Phase 1,
29:15two and three that other drugs do the
29:17same process for approval and licensure,
29:19but there are some additional
29:21steps here and a lot of these come
29:23out come from in the time of post
29:26licensure monitoring in vaccines.
29:28So we think about the classic
29:30phase four trials,
29:31in which we look at how these
29:33vaccines are functioning in public.
29:35But we also have systems in place for
29:37adverse event reporting for vaccines.
29:39There's a vaccine safety data
29:41safety data link,
29:42which is like spotty and told,
29:44but allows for this real coordination
29:46of vaccine adverse events.
29:48And there's also this really interesting
29:50history about the vaccine court,
29:51but so thinking about this you sort of
29:55wonder how warp speed can this possibly be.
29:58Some of the reason this happened quickly.
30:00Apparently in the time of Comet isn't
30:02just because we were so so so motivated,
30:04but also because of the nature of
30:06the RNA vaccine and just ability to
30:08speed this up in a different way.
30:10But it really is.
30:12Amazing and astonishing to think
30:13of how fast we went from first
30:16observation of COVID-19 disease to
30:18a vaccine in the arms of millions
30:20of people around the world.
30:24So this is where it starts
30:26to get really interesting.
30:27I think for children in vaccines and
30:29immediately when we think of vaccines
30:31are supposed to be for kids, right?
30:33That's this intuitive sense that
30:35vaccines are supposed to be for kids
30:37and our kids are home, darn it.
30:39And. And they can't go to
30:41school because of this pandemic.
30:42And couldn't we get them
30:44vaccinated and send them to school?
30:46And so this was so apparent so early.
30:48And it was so painfully out clear,
30:50so early that we were going to
30:52have a vaccine for adults months
30:54before we had it for kids.
30:56Amen, I learned a really
30:57interesting thing here.
30:58I learned this term called
31:00the age D escalation,
31:01which wasn't a term that I knew
31:03specifically which describes
31:04this intuitive walking down the
31:06age spectrum of vaccine testing,
31:07and I want to work through this with you,
31:10'cause I think it's kind of
31:12tricky and important,
31:13but generally speaking,
31:14it's the case for vaccines that Phase
31:161 two trials are conducted first
31:17in adults than in older children,
31:19and finally in progressively younger
31:21children as it becomes relevant.
31:22So for example,
31:23there's not a lot of reason to.
31:26Test HPV vaccine in the youngest kids
31:29right now. Epidemiology of the disease.
31:31The risk benefits of the vaccine.
31:33There's need to be calculated
31:34for each age group.
31:35The safety profile of all the
31:36factors need to be taken into
31:38account in deescalation,
31:39and this is due to this classic thing
31:41that we say in Pediatrics all the time,
31:44which is the kids aren't just little adults.
31:47Now,
31:47there are situations in which it really
31:49makes sense to vaccinate young children,
31:51because young children those are
31:53the ones who get this and so there
31:55you can raise a moral argument
31:57against testing a vaccine in
31:59an older patient population.
32:00If that population really won't
32:02derive any benefit from it.
32:03There are some situations,
32:05Interestingly,
32:05in which adults can do this for
32:07an altruistic reason,
32:08and a group of adults can say we
32:10think it's worth having some safety
32:13data in adults before we test this.
32:15In kids,
32:16understanding that we will
32:17never benefit from this.
32:18I don't have a good modern example of this,
32:21but I think this is an
32:23interesting moral idea.
32:25And there are some situations in which
32:27there just isn't a lot of scientific
32:29or moral validity in testing a
32:30vaccine in adults or older children.
32:32Some of this has to do.
32:34For example,
32:34if adults are previously vaccinated
32:36or previously immune to it exposures,
32:37there might be situations in
32:39which you can make a scientific
32:40case that you really have to
32:42test younger children first.
32:46And just drive home this point about
32:48children not being little adults.
32:50There's some data that they express
32:52different antibodies in different ways,
32:54and this is important in thinking
32:56about things like vaccine.
32:58It's also thinking important thing
32:59about the clinical trials for testing
33:02and I will say that I didn't find
33:04anything really in the in the literature
33:07talking about child participation
33:09in vaxin in the test in the clinical
33:11trials of covenanting tests,
33:13I just didn't see that anywhere.
33:16And there have been a lot of studies.
33:18If you look at what's currently
33:20in clinicaltrials.gov,
33:21there are a lot of studies of particularly
33:23rapid antibody type tests of children,
33:25and this difference an antibody
33:27expression might be a really good
33:28reason that you would want to include
33:30children and say an antibody test.
33:32Generally, the testing is pretty low risk,
33:34so it doesn't generate a lot of controversy.
33:39But this is where to me this
33:42gets so so interesting so.
33:44We are now desperate to get children tested
33:47and were desperate for a couple of reasons.
33:50One is that I think as people think
33:52about kids with unique vulnerabilities
33:53and even if the overall never.
33:56I haven't said this explicitly,
33:57but even if the overall burden of
34:00this epidemic seems to be low on
34:02kids and the kids don't seem to get
34:04sick and die as much as adults,
34:06parents of kids with a lot of magic
34:09medical frailty are terrified of this
34:11and really worry about about what if
34:13my child with chronic respiratory failure.
34:15Gets a terrible case of COVID-19 and
34:17becomes really sick and you can imagine
34:19how sailing at this was particularly
34:21the beginning of pandemic when it also
34:23wasn't clear that we were going to have
34:25ventilators for all those children.
34:27And so we do see a lot of push
34:29from parents who want this vaccine
34:31for direct benefit for their kid
34:33because they're so desperate for
34:34the child not to get covered.
34:36And in fact there are some some
34:38interesting claims coming out of China
34:40that one of their vaccines is testing.
34:42Really young kids,
34:42and I read this and my first response
34:45to this was why can they do it?
34:46And we can't and why clearly other
34:48people have got this right and have
34:50figured out that we should be trying
34:52to find a way to test younger kids.
34:54This is where I think this tension
34:56of individual and public health
34:58gets really interesting,
34:59and the quote on the right of the
35:01screen comes from that article about
35:03the Chinese vaccine and the trials
35:05of early kids and what they're really
35:07thinking of is how can we control
35:09this epidemic in our population?
35:10And is one way to do that to get
35:13younger kids vaccinated with quick?
35:14And this, I mean,
35:16talk about ripped from the headlines,
35:17this article.
35:18On the left I found yesterday
35:20talking about when we can expect
35:22results of the vaccine,
35:23but I just want to call
35:25your attention to this.
35:26For that, I've highlighted,
35:28which is vaccinating.
35:29Kids could be key to halting,
35:31spread and herd immunity.
35:32And this to me,
35:34that might be true,
35:35but I think that we really need
35:37to stop and reflect on this,
35:39because then we're not really talking
35:41about kids getting vaccinated,
35:42so they don't get covid and they
35:44don't get sick.
35:45We're talking about kids getting vaccinated,
35:47so their teachers and their parents
35:49and their grandparents in the bus.
35:51Drivers don't get sick and we
35:52can certainly make arguments for
35:54why children are better off when
35:56their parents are healthy and are
35:57better off on their parents have
35:59financial stability because they're
36:00not losing their jobs.
36:02So there are certainly.
36:03Lots of lines to direct benefit to
36:05kids for having this pandemic ends,
36:06but it's a little more direct and
36:08I really hope we can talk about
36:10this because in the in our
36:11discussion 'cause I find this to be
36:14incredibly complex and thought provoking.
36:16So again, you know I threatened
36:19to talk about this a lot and
36:21I'm talking about this a lot,
36:23but there's a great article
36:24that's still in the all you can
36:27get is the Word document version,
36:29but it's free access in Pediatrics
36:30from some of our lawyer friends
36:32talking about different ways
36:34that our regulatory body could
36:35approach vaccinating children,
36:37and at what stage of safety and
36:39efficacy should we be including
36:41children in these trials?
36:42And I think they find this really
36:45nice and tabular way of.
36:46Weighing out the pros and cons
36:49of a very conservative versus a
36:51very effective approach and the
36:53tradeoffs of slowing down vaccine
36:55into the arms of children, but.
37:00That on the one hand,
37:01but potentially having more risks,
37:03on the other hand.
37:05And I thought this was a great read.
37:08I thought this was really interesting
37:09and particularly this point about
37:11the risk to lots of public trust.
37:12If you get this wrong,
37:14and so there's really not one answer
37:16to what should the regulatory approach
37:17be to enrolling kids in vaccine trials?
37:19Or when is the right time to do it?
37:22But I think that some really smart
37:24and interesting people are starting
37:25to tease this out in a systematic way.
37:27That's going to help us think about this.
37:31So now I have to talk about the part
37:34of this that's the hardest for me,
37:36and it's the hardest for me.
37:38I think both because it's not a
37:39strong area of expertise for me,
37:41but also just because this has been so
37:44painful in America over the last year,
37:46and not only because we've seen
37:47these disparities now,
37:48but was we've been forced to contend with
37:50how long they've been there and how long.
37:53Race,
37:53racism and inequity have played a
37:55role in American research ethics.
37:57So this started coming out really early.
38:00This was a slide I made for my very
38:02early talks on Covid in the spring
38:04and summer when we were really talking
38:07about how are we going to grapple
38:09with the historical unease that the
38:11black community has with research
38:13in America and how are we going to
38:15be trustworthy and be transparent
38:17and make sure that we come up with
38:20a vaccine that people want to take?
38:23Informed by by studies that reflect
38:25who we are as a country,
38:27and this this has been such a
38:29deeply held fearing concern.
38:31I think even though most of the
38:33writing about this isn't about kids,
38:35but we really can't skip this part.
38:38And no where more than I think
38:41in this issue of recent research,
38:43is this issue of access versus
38:45protection more salient?
38:46And one thing that kind of gets under
38:48my skin a little bit is when I see
38:51these headlines that really boil
38:53this down to something like black
38:55community won't be in research trial,
38:58because Tuskegee and distrust.
38:59And that's not to downplay that deep
39:01and painful history of test Kyan,
39:03that mistrust that's been so so
39:06hard to recover.
39:07But I really think it's important
39:09to think about.
39:10Other ways that we have created and
39:12allowed for barriers of historically
39:14disadvantaged groups to be part of trials.
39:16And if you think about hidden costs
39:18of participating in research such as
39:20coming back to the hospital for extra
39:23research, paying for extra visits,
39:25paying for parking is a huge
39:27issue at my own institution.
39:28Buying lunch when you're at the hospital.
39:31If you have to travel far.
39:33Concerns about access to to poor health
39:35literacy or lack of information,
39:37and various ways that implicit
39:39biases play in this.
39:40It is certainly about mistrust and
39:42certainly about a nasty history,
39:44but it's also got a lot of other things.
39:47And the other thing is,
39:48it's about the funding pipeline,
39:50and it's about who gets funded an
39:52WHO is in a position to be funded,
39:55an how lack of diversity
39:57among principle investigators.
39:58Is part of the problem that.
40:00Impacts what gets funded,
40:02particularly the NIH.
40:03And so the issue of bringing the
40:05diversity to our trials and having
40:07our trial populations represent
40:09who we are in the country.
40:11It's really thorny and complicated,
40:13and all of the things that we've
40:15been talking about in this really
40:17complicated time in American
40:19history play out in research ethics.
40:23And one more thing to kind of bring this
40:26point home is just thinking you know.
40:29So black people make up about
40:3113% of the population in the US,
40:33but have accounted for 21% of
40:35the deaths of covid. And sadly,
40:37only 3% of enrollees in vaccine trials.
40:40This threatens the validity and
40:41generalizability of the trial, and.
40:44And you know, I won't belabor this any
40:46further, but this is not a small issue,
40:49and so I really like this.
40:50You know, I harped earlier about my dislike
40:52of the phrase operation warp speed,
40:54but I really liked this phrase.
40:56Trust could be earned more quickly by
40:58a collaboratively designed operation.
40:59Build trust with worthiness that matches
41:01the seriousness and scope of operation,
41:02Warp speed.
41:03And again,
41:03I couldn't have said it better myself,
41:05so I didn't try.
41:08But the sad so sorry before my sad thing.
41:11One of the things that's been really
41:13interesting is I think different
41:14approaches that that leaders in the black
41:17community have taken to addressing this,
41:19and one strategy has been to people
41:21in positions of leadership and sort of
41:23figures of respect and authority have said
41:26we're going to volunteer for these trials,
41:28and we think we owe it to ourselves
41:30and one another to be in these trials.
41:33And there's a big case that cost my eye.
41:36'cause I'm from Louisiana.
41:38But the presidents of two historically
41:40black universities in New Orleans said
41:42we were going to enroll in these trials,
41:44and we recommend that our student
41:46bodies do this too.
41:47And this was not met without controversy,
41:49and there was some some significant
41:51bash backlash from parents of
41:53students at these institutions.
41:54So this wasn't universally welcomed
41:55as a as a way to address this issue,
41:58but I find this to be interesting
42:01and thought provoking.
42:02But for all this,
42:04unfortunately the news isn't very good
42:06and this was a figure I found that
42:08thought I thought laid out really nicely.
42:11The proportion of people in different
42:12states who have been vaccinated
42:14who are black set up against the
42:16proportion of residents of that
42:18state for black and importantly,
42:20of the proportion of health care
42:22workers in that state who are black.
42:24And that's important when the people who
42:26have been vaccinated for health care workers.
42:28And as you can see here,
42:30we're not doing great here and.
42:32There are some states where
42:34we're doing better than others,
42:35but even in states where a huge proportion
42:37of health care workers are black,
42:39there are a very small fraction
42:40of people who've been vaccinated,
42:41and so to me,
42:42this says that our fears were warranted
42:44and we've got a lot of work to do.
42:46You know,
42:47we didn't solve this on the 1st pass,
42:49and we have a lot more work to do
42:52to figure out how to do better here.
42:54So if your question is what on Earth
42:57does this have to do with pediatric ethics?
43:00That's fair and I didn't find
43:02anything in the literature
43:03specifically in or in the Lane press really
43:06about children of color and vaccine trials,
43:08but I think there's no reason to think
43:10that they would be immune to this,
43:13and that the forces that impact their
43:15parents aren't going to infect them.
43:17And in the really compelling letter
43:19from the AP to the to the Health
43:22and Human services and the FDA.
43:25This difference in mortality among black
43:27Matlack Latin X children was highlighted,
43:29and I thought said really nicely.
43:31The population studied must reflect the
43:33racial and ethnic diversity of the US
43:35population and not exclude populations at
43:37risk that may greatly benefit from Maxine's,
43:40including children.
43:42So we know this is a vulnerability for us.
43:45We know that health disparities
43:47impact children in devastating ways,
43:49and we seem to not have quite,
43:52not quite not at all figured out what to do
43:55to realize the dream of the vaccine trials.
43:58Reflecting the diversity of this country.
44:02So I wish I had happier news on this.
44:04This is a little bit of a
44:06dark place to wrap up my part.
44:07My talking about vaccines but but I
44:09think this is this is part of what
44:11we've got to do together as ethicists.
44:13So finally,
44:14because I think I've got time to do it,
44:16I want to talk a little bit about research
44:18integrity in public publication ethics.
44:19I spent a lot of time on this for
44:22those folks who are who do this,
44:24I don't know if your program
44:25is is where people get this,
44:27but if you have a K award you're
44:28required to get 10 hours of in
44:30person training on research,
44:31ethics and integrity.
44:32Um and so at University of Michigan.
44:35RC TSA takes responsibility for making sure
44:37that all our categories get that training,
44:39and I teach it with my good friend Kate
44:42Spectre Baghdadi and we always have
44:44a lot of fun talking about research
44:46ethics and integrity and in the covid
44:48vaccine then the covid era I would say
44:52it wasn't fun but it was relevant.
44:55So when I teach people about falsification,
44:58plagiarism, fabrication,
45:00I use this like you know this lingo
45:05of too long didn't read and.
45:08Really. Just don't steal ****.
45:10Don't make **** up,
45:11don't change it and I've got
45:13permission from Doctor Mirror to swear,
45:15but I think it's important for this
45:16to be funny because it really needs
45:18to go in 'cause everyone says I
45:21would never do this.
45:21This could never happen to me.
45:23I know better this this won't happen and it
45:26happens and it happens over and over again.
45:29So we use the example of hydroxychloroquine,
45:30so all of you guys will remember
45:32the great hope about this at
45:34the beginning of the pandemic,
45:35and this cheap,
45:36widely available drug was going
45:37to be the Savior for this thing.
45:39And then you look at the cumulative
45:41trials and you see a peak in the
45:43spring of new trials and it starts
45:45to go down and you know.
45:46And then our hopes came crashing
45:48down and this just wasn't the panacea
45:50that we thought it was going to be.
45:53And if you follow this,
45:54it was super dramatic, right?
45:55It works, it doesn't.
45:56It works it doesn't it see if it's not,
45:58you know, and it ended up being
46:00this sort of 1 two punch of.
46:01It's not clear that it works,
46:03and it's also not clear that it's safe,
46:05but in the middle of all this.
46:08I started paying attention
46:09to this delightful website,
46:10an organization called Retraction Watch
46:12that is a group that that sort of its
46:15aim is to share with the public sort
46:17of the process of Journal retractions.
46:19How many get retracted and what
46:22happens when they get retracted
46:23and what I want to point out to you
46:26here is this is refreshed a couple
46:28of days ago Journal retractions
46:30to date an we had gotten to 62.
46:32This is a lot of retractions and
46:35this doesn't include some more
46:36benign versions of this and.
46:38People behind Retraction Watch have
46:40been looking empirically to say.
46:42Is there really an uptick in this?
46:44And it really seems like there
46:46is an that in this race to learn
46:49more about this pandemic.
46:51We've gotten a little sloppy sometimes.
46:54And if what you're thinking is,
46:56this happens to those disreputable journals
46:58that email me saying dear Leventhal,
47:00Naomi T.
47:01We would love to review your
47:03paper and publish it in two days.
47:05Think again.
47:06This happened to the New England
47:08Journal in The Lancet and you know,
47:10not too shabby journals.
47:11The you know the source of respect
47:13and dignity around the world.
47:15And both of them got into trouble with
47:18datasets that couldn't be verified
47:20and had to retract their papers.
47:22And this is a big deal.
47:24This is an overwhelmingly big deal.
47:27And.
47:27One of the other ways that this
47:31is a big deal is that.
47:34Retractions don't necessarily mean
47:35that people stop citing the articles,
47:37and there's a couple of reasons for this.
47:39Summer has to do with the whale.
47:41It searches show you whether or
47:43not something has been retracted,
47:44so like if you go to The Lancet it
47:47says in huge letters that it's red,
47:49but people cut corners in this area.
47:51A lot of the time,
47:53and it's actually the case that.
47:57Citing a reference that you haven't
47:58actually gone to and verified yourself
47:59is on the spectrum of plagiarism,
48:01but people tend not to think
48:02about it this way, and sort of,
48:04you know,
48:05if you if you're trying to cite something
48:07and you're in a hurry and you don't have it,
48:09'cause you know the reviewers
48:10wanted to decide it.
48:11You're like alright,
48:12fine.
48:12You might not follow those links
48:14to their logical end,
48:15and you might well be citing
48:17something that was retraction and
48:18not realize that you're doing it.
48:20And that's problem.
48:21If there is a question about the
48:24scientific integrity of the the.
48:26Of the paper that you're signing,
48:27I'm gonna pause just to say there's
48:28somebody in the waiting room.
48:29I'm happy to let them in but I don't know
48:32if I'm supposed to be the one doing that.
48:34So to wrap up on this,
48:36you know don't feel stuff,
48:37don't change stuff,
48:38don't mix them up the stuff up,
48:40but the other thing about research
48:42integrity that I just want to stay here.
48:45And this is true in so many ways
48:46as you are responsible for your
48:48own stuff and what happened with
48:50these retractions in The Lancet in
48:52the New England Journal was that
48:54they contractid with private data
48:56sources and then couldn't vouch for
48:57the sanctity of those data sources.
48:59But the same thing happens when you
49:01cite something that you haven't read.
49:03That's a failure to be responsible
49:05for your own check.
49:06And that, I think,
49:07is another is a is a authentic
49:10problem with research integrity.
49:12So thanks for granting me that it's a
49:14little outside of the scope of I think
49:16probably what you expected me to talk about,
49:17but I do think it's part of the cadence
49:19of research ethics of this pandemic,
49:20and so I'm I'm glad I got
49:23a chance to fit it in.
49:25But so I think this is where I can wrap
49:27up and we can have lots of time to talk.
49:30So to conclude,
49:31the COVID-19 pandemic is required.
49:33Reexamination of long established
49:34principles of research ethics,
49:35largely reinforcing the fundamental
49:36tension between advancing population
49:38health through rigorous science and
49:39acknowledging the inherent risks of research.
49:43I hope that you'll take away if you hadn't
49:46already that pre approval access requires
49:48particular attention and understanding.
49:50Come and join me in re examining the
49:53foundational ethical principles that inform
49:55the way we do research and think about
49:58this harsh light on the historical record.
50:00Version of children from research and
50:03the entrenched racism and injustice
50:05problems that have plagued our society
50:07for a long time and persist in 2021.
50:09Um public health crisis is also demonstrated.
50:12The complex role of children and
50:14infectious epidemic and raises
50:15questions without easy answers.
50:17It's really hard to know
50:19what our children owe us.
50:21And finally, when we go too fast,
50:23we make some mistakes and sometimes those
50:25mistakes are really deeply regrettable.
50:28So I'm going to wrap up there and
50:29leave my email address up for a second
50:31and my Twitter handle up for a second
50:33and then I'll stop sharing so I can
50:35see your smiling faces and hopefully
50:36we can have a great discussion.
50:45Thank you Naomi, that was terrific.
50:47Children should be.
50:49Make sure I remember this.
50:50This quote which is memory children
50:52should be protected by research,
50:54not from research that was at the exact.
50:57That's that's very memorable.
50:58I'll take the prerogative I get
51:00of asking the first question,
51:02but then I'm going to invite others in the
51:06way we're going to do this is you can.
51:10How you can raise your hand and then I will.
51:13Then my friend Kyle will then
51:15enable you to unmute yourself.
51:16Right now everybody's muted,
51:18but if you raise your hand that
51:20I call on you then you'll be able
51:22to unmute yourself and you can ask
51:24Naomi your question directly or
51:26share your comments about this.
51:27Lots of people on this call with
51:29with expertise in this area,
51:31so we're interested in hearing
51:32from all of you.
51:34Then I'd love to see people are
51:36formulating their questions is
51:38one of the things that struck me.
51:40During the early part of the pandemic
51:42and still to this day was the
51:45remarkable lack of centralized guidance.
51:46There was no president's Commission
51:48on Bioethics that there had better
51:50had been in the past.
51:52There was nothing like that to
51:53guide us in terms of how we write
51:56our critical care protocols right?
51:58Our triage protocols.
52:00Or our allocation protocols?
52:01Is there an analogy to be drawn here?
52:04When we try to figure out how much is
52:06a minimal increase in risk you know is there,
52:09is there a place that we could go in
52:11New Haven that people in Ann Arbor
52:13could also go to where someone is kind
52:16of made this judgment or adjudicated?
52:18Or is it every man for himself?
52:21Well, I think the answer is
52:22kind of in that there is,
52:24I think, our renewed pathway.
52:26An interest in centralized IRB,
52:28at least for multicenter studies,
52:29because one of the things that happens
52:32when each institution is on their own.
52:34Deciding. Well, I think this is a more
52:36than a minor increase above minimal risk,
52:39and you know, as one center will say,
52:41that another center will say
52:43it's not right because it is so
52:45subjective and it is hard to know.
52:47So at least within one multicenter trial.
52:49If you can have an expert IRB that.
52:52Is going to think about that
52:54one way for the whole trial.
52:56I think that can at least deal
52:58with that Inter institution
53:00variability in the way that people.
53:03And the way that people make
53:05these determinations about
53:06what's going to be approved, but.
53:08But to your point.
53:10I mean,
53:11I think what we had before for the this was
53:13the President's Commission on Bioethics,
53:15and that you know,
53:16the last,
53:16the administration that ended
53:18this morning was the first one
53:19in a long time that didn't have a
53:21president's Commission on Bioethics.
53:22And I do think that one thing that you
53:25could do is if it rose to the interesting,
53:27they serve at the pleasure of the president.
53:29But things could make it to
53:31the desk of that Commission,
53:32and they could do a deep dive
53:34and give a report.
53:35And so they did that, for example,
53:37when there was talk of testing
53:38a smallpox vaccine in children.
53:40And they wrote 150 page report on
53:42the ethical considerations of of the
53:44vaccine of a smallpox vaccine trial for kids.
53:47So you know,
53:47I think that this is an area where
53:50organizations like the AP can help.
53:52I haven't seen us too much of that,
53:55but you know,
53:55maybe mark you and I already stated.
53:58Now you know, I think some of the
54:00child advocacy organizations can,
54:01and there are some organizations within
54:03NIH that really focus on the research ethics,
54:06but.
54:07The every man or woman for them self.
54:11IRB approach to this I
54:13think is a huge problem.
54:15An contemporary research.
54:16So we, Marcella Nunez
54:18Smith is on our faculty.
54:20And who is President Biden's Co.
54:22Chair for his COVID-19?
54:23Will then transition communities
54:25for the leadership for the COVID-19
54:27effort we we've made this point
54:29with her an hopefully it eventually
54:31finds its way to the ears of some
54:33people who can respond and give
54:35us some of that central guidance.
54:38I want to invite Doctor Tom Murray too.
54:40Hung up on mutual here or
54:43askyouthere.com if you can.
54:45If you can unmute yourself,
54:46please ask your question.
54:50Hi I'm I was trying to show my face,
54:53I apologize I I can't do that.
54:55My name is I'm on my infectious
54:57disease physician who's been
54:58working a lot with covid.
55:00Thank you for such a thought provoking talk.
55:02Two different areas that really struck me.
55:04The first is I think one of the
55:06issues around vaccination and kids
55:08for this particular infection really
55:10relates to the quote you showed about
55:12who's getting the sickest and who
55:14is bearing the burden of disease.
55:15And so I actually have been one
55:18of the pediatricians in favor of
55:19starting with the adults because
55:21they bear the burden of disease and
55:23kind of working it back because.
55:25I don't think children are where the money
55:27is in terms of stopping this pandemic.
55:30I think there are other reasons
55:32around school and things like that,
55:34and I'm all in favor of vaccination
55:36of children. But I do think.
55:39The Epidemiology of this disease is very
55:42different than something like influenza.
55:44Where we know kids are the cesspool.
55:47The second thing.
55:48So this is going to be totally
55:51unrelated thing,
55:52but with respect to the EUA data,
55:55I just pulled it up while you were
55:57talking about the distribution of who
56:00were in those trials and they did do
56:03a reasonable job of representing the
56:05US population in the Moderna trial
56:08it was 10% black and 20% Hispanic.
56:10The challenge I think has been
56:13translating that and helping.
56:15Get people to trust that we
56:17can provide this vaccine.
56:19So even if you're doing a better
56:21job of enrolling the right
56:23people in the clinical trials,
56:25it's not translating to getting those
56:28populations that need the vaccine the most.
56:31To have the trust to get it so
56:33I'm wondering what your thoughts
56:35are around even when you have a
56:37reasonable distribution of population,
56:39how to translate that into
56:41better vaccine uptake?
56:43Thanks for both of those comments,
56:45which are both really good and and helpful.
56:48And yeah, I think that.
56:51It does seems you know,
56:52the more we know about this,
56:54the more it seems like the people
56:56you know lives are saved by keeping
56:59adults from getting COVID-19.
57:00And I I didn't exactly mean to give
57:03the impression that I think it was a
57:05miscalculation not to include children.
57:07I actually think the most
57:09interesting thing is that even now,
57:11as we're including children that still
57:12with an eye on general infection
57:14control more than saving child lives.
57:17But so now your point about
57:20that as well taken.
57:22And you know that thanks for the
57:23clarity on the way for the moderna,
57:25I think that that is.
57:27That to me I think is such a recapitulation
57:29of what a major problem we have.
57:31In that quote I shared about,
57:33you know,
57:33sort of that operation.
57:35Build trust that should have gone along
57:37with operation work speed so you know
57:39my thoughts about this is is a bit that.
57:42We still have so far to go.
57:44I do think some of these you
57:46know these public campaigns I I
57:47didn't have time to fit this in,
57:49but there's a big push among black
57:51physicians to tweet out their
57:52pictures of themselves getting
57:53their vaccines and key leaders.
57:55You know,
57:55I think that was really what drove those
57:57presidents of Xavier and Dillard to say.
57:59We're going to be in these trials.
58:01And this is this is good for us.
58:03So I guess you know,
58:05if you look at that figure I showed
58:07about just the uptake rates.
58:08I guess it hasn't been as fruitful as
58:10we were hoping it was going to be, but.
58:13I think that needs to come from
58:16every angle we can think of to,
58:18really.
58:20Think about how do we move on from
58:22this really painful history and and
58:25overcome the barriers to getting
58:26our whole country to believe that
58:29this vaccine is safe for them.
58:32You know Stephen Thomas at University
58:34of Maryland was a speaker in
58:35this forum earlier this year.
58:37It's a name that either or both
58:39you might want to consider in
58:41terms of rebuilding trust.
58:43And he is. Interested in an,
58:47he's actually piloted a program
58:48going into particularly of Barber
58:50shops that are primarily for African
58:52American men and also salons for
58:54there primarily for American women.
58:56And he thinks that this is where so
58:58much of the culture happens where so
59:00much of the trust is actually built,
59:03and so he's actually piloted.
59:04This program. It's, and it was.
59:06It was about trying to get people
59:08to participate in clinical research
59:10projects about trying to get
59:12people to get tested for kovid,
59:14and so he gave a great presentation here,
59:16which I think is available on our website.
59:19But but stay tuned,
59:21you're going to hear from more from
59:23from Stephen Thomas on this in the
59:25work he's doing to rebuild that trust.
59:27And there are some interesting,
59:28you know when you think about a
59:30disease where the hallmark of of of
59:33saving lives is not congregating,
59:34how do you get that sort of community
59:37participation when people aren't going
59:38to church and they're not there aren't
59:40as many of them in that barbershop,
59:42and you know, not being able to get
59:44groups of people together to sort
59:46of rally that enthusiasm? That's it.
59:48That's another barrier to doing that, but I.
59:51My intuition is that he's on the right.
59:53You know him clearly knowing much
59:55more about this than me that getting
59:57to people where they are in settings
59:59that they feel comfortable is how you.
01:00:00Start to build that
01:00:02trust again. Yeah,
01:00:03that seems to show promise now.
01:00:04Charles Hughes has a question for us
01:00:06here so I'm gonna unmute Charles.
01:00:12Charles, you should be able to
01:00:13unmute yourself now and then.
01:00:18I'm trying to hear me.
01:00:20Yeah, OK we can. My question is,
01:00:22even if you get kids to consent to
01:00:25being tested to be affecting trial,
01:00:27what about the power relation?
01:00:29I mean you got a kid being confronted
01:00:31by parents and doctors saying you
01:00:33believe we really need you this
01:00:35the population here with do they
01:00:37really have conformed consent
01:00:39or or do they feel pressure?
01:00:43Yeah, I mean that I think is,
01:00:45you know we got lots and lots
01:00:46of ethics concepts about this.
01:00:48I think that. This.
01:00:53This is where ascent has to
01:00:55be a meaningful process.
01:00:56Just like informed consent
01:00:58isn't signing a form,
01:00:59it's a conversation you know.
01:01:01Really, I think taking the time if you can,
01:01:04if you can achieve it.
01:01:07Getting that child sort of alone in
01:01:10the room like we do in our lesson
01:01:12visits and sort of asking them and
01:01:14giving them that opportunity to.
01:01:16To the eye,
01:01:17the contemporary thinking about
01:01:18ascent really has to do with this
01:01:20read back and that it's not that
01:01:22the kid nodding is insufficient and
01:01:24that they need to sort of tell you
01:01:27these affirmative things you know,
01:01:28and I think that that is always.
01:01:32That is always an issue,
01:01:33whether the parent really does want
01:01:35the child to enroll or not is sort of.
01:01:37Can that child really say no,
01:01:38but that I think the onus of that
01:01:40is mostly on the research team
01:01:41to be as careful and thoughtful
01:01:43about about that as they can,
01:01:44and also weighing risks.
01:01:45So when someone pointed out to me
01:01:47about my friends example about,
01:01:48you know my son doesn't want
01:01:50to be in the vaccine trials.
01:01:52'cause he saw me being so miserable.
01:01:56She probably you know he's going to
01:01:58get vaccinated eventually, right?
01:01:59And so on.
01:02:00Some level like the I worry a
01:02:02little bit less about coercion for
01:02:04something that he will get eventually.
01:02:07But yeah,
01:02:07I think that that is an
01:02:09incompletely answered question,
01:02:10but the age of modern
01:02:13understanding of assent and really.
01:02:15Sufficient by and I mean I
01:02:17still see things about like.
01:02:18This is our sent former.
01:02:19This is where they sign or
01:02:21they have to be 14.
01:02:23So I think as we lean into this
01:02:25more nuanced and sort of laborious
01:02:26way of determining a child's
01:02:28emotional readiness to give assent
01:02:30will get better at better and
01:02:31screening for that sense of this
01:02:33kid doesn't really want to do this,
01:02:35but it's a.
01:02:36It's a good question that I
01:02:38don't have a short answer for.
01:02:41Thank you.
01:02:45OK, thank you. Still thank you.
01:02:48Um, I'm looking at that.
01:02:50I see no other questions at this point.
01:02:54This is a. This is a huge problem going
01:02:58forward and what I think is an important
01:03:01thing which I think most people on
01:03:04this call can appreciate is is this
01:03:06isn't this isn't just about COVID-19,
01:03:08but COVID-19 is afford us the opportunity
01:03:11to take a hard look at how we do
01:03:14things and you know, we sometimes,
01:03:16especially when we're really under the gun.
01:03:19You know the old thing that there
01:03:21are no atheists in foxholes.
01:03:23I have used the comment as we
01:03:25were rushing in the spring.
01:03:27To try and get a triage protocol
01:03:29prepared very quickly as you don't,
01:03:31it seems that there's no
01:03:32contents in foxholes, either.
01:03:33We all became utilitarians in hurry.
01:03:35We changed the way we looked at things.
01:03:37Some of us did I think,
01:03:39to some extent,
01:03:40but we felt the pressure of the enormity
01:03:42of the problem as well as the the
01:03:44speed at which we needed the answers.
01:03:46So so many people in publications
01:03:48and their clinical research.
01:03:49It's the same thing.
01:03:50So the lessons here, Naomi as your title is,
01:03:53is that if you talk to so actors,
01:03:55it's not just about COVID-19,
01:03:56but lessons learned from that.
01:03:59It will apply to other things
01:04:01as we move forward.
01:04:03So much to be learned.
01:04:04This has been a great
01:04:05talk and a great evening,
01:04:06and I want to thank Doctor Leventhal
01:04:08so what's supposed to happen now?
01:04:10Naomi's I'm supposed to take
01:04:11out a few of us taking up for
01:04:14a wonderful New Haven dinner.
01:04:16So now we officially owe you 1 when you
01:04:19already you will recall owed me a.
01:04:21What was it? A pina colada?
01:04:24So sad, because that was in the spring
01:04:26when we were scrambling all of us to
01:04:28get the prepared for the charges,
01:04:30and I said well by the fall
01:04:32meetings this is fall of 2020.
01:04:33I said well, by the fall meetings,
01:04:35which were going to San Diego,
01:04:36the AP meetings were all going
01:04:38to relax and have Pina coladas
01:04:40and talk about the war,
01:04:41and you know and how it went,
01:04:43but as it turned out in the fall,
01:04:45we were still not even all
01:04:46the way into the war, much
01:04:48less through it. Yeah, so Mark,
01:04:49I think our talk about drinking
01:04:51together has prompted someone else to
01:04:53make us stop and ask another question,
01:04:54good. Let me see if I can if I can
01:04:57get myself to this and he would have.
01:05:00It's Tom OK Tom please. Yeah,
01:05:03I'm sorry I I would much rather go
01:05:05out drinking, but there was one other
01:05:07thing you brought up that I thought
01:05:09was really interesting and I love your
01:05:12insight on and that is even in the.
01:05:14Slide that you showed with
01:05:16the retracted papers.
01:05:17Several of them were from metrics
01:05:20and from the non peer reviewed.
01:05:23Journal depositories that
01:05:24you can make anything on.
01:05:26It's not peer reviewed,
01:05:28and then it goes on and gets cited
01:05:30subsequently in peer reviewed literature.
01:05:33I just wondered.
01:05:34Kind of what you think about that,
01:05:37and whether those are good.
01:05:38I mean, I know why they're out there,
01:05:41but I also see a potential downside.
01:05:44Yeah, I mean it's really.
01:05:47We are in this very strange time of I
01:05:49think publication integrity and ethics,
01:05:51and you know, I I spend time talking about
01:05:54how we came to have peer review at all,
01:05:57which came out of when scientific
01:05:59proceedings stop being housed
01:06:00in monastic libraries, right?
01:06:01So we got a printing press.
01:06:03We can circulate the the mark.
01:06:05You would enjoy this I think
01:06:07for your historical history,
01:06:08medicine stuff.
01:06:09But we gotta we gotta printing
01:06:11press suddenly everyone can share
01:06:13their scientific findings widely
01:06:14in the scientific community
01:06:16and a little bit of like.
01:06:17Slobbering, snobbery,
01:06:18and wanting to control this says,
01:06:19no, no, we gotta make sure we're
01:06:21controlling the quality of this.
01:06:23And the interesting thing is the move
01:06:24to an even more accessible format,
01:06:26right?
01:06:26So, like you know,
01:06:28one as the print Journal has been going
01:06:29down an online only journals or only
01:06:32everywhere you know the democratization of
01:06:34this might end up being our undoing right?
01:06:36And you do have.
01:06:37I mean, I really do.
01:06:38I mean, I'm sure you guys get them too.
01:06:41I get, I think 10 to 20 invitations today,
01:06:43too.
01:06:43You know, they will,
01:06:44too.
01:06:45Submit my article that they seem
01:06:46to think I just have ready to go
01:06:49that they will peer review and
01:06:51get me a decision on in 48 hours.
01:06:53Right,
01:06:53and so whether it's peer reviewed at
01:06:55all or fake peer reviewed, I think.
01:06:59How do you?
01:07:01What is the history of the good
01:07:03quality lit review with sort
01:07:05of like all these walls down?
01:07:07But again, I mean if you're.
01:07:10I mean,
01:07:11when I read a paper I look
01:07:13at where it was published,
01:07:15write an when I'm deciding
01:07:16on citing something,
01:07:17I look at where is published
01:07:18and I try to discern between,
01:07:20you know,
01:07:21'cause sometimes things by
01:07:22famous people on important topics
01:07:24or publishing really weird
01:07:25journals and you know.
01:07:26And sometimes I think like wow,
01:07:28they must have just like submitted
01:07:30and resubmitted until they found
01:07:31someone to take this and that
01:07:33happens to everybody versus
01:07:34what's wrong with this paper
01:07:35that this is where it is right?
01:07:37And so I will say that when
01:07:40you write up the sort of.
01:07:41The right answer is when you write a paper,
01:07:44you're responsible for your citations.
01:07:48My dismay is that.
01:07:50Editors seem to have put the
01:07:54job of looking for this. Um?
01:07:58An entirely on the backs of peer
01:08:00reviewers and not taking a lot
01:08:01of responsibility for themselves.
01:08:03And so when you look at this,
01:08:04it seems like so now as a peer reviewer,
01:08:07I'm supposed to run every
01:08:08single citation myself,
01:08:08and you know, see if it it checks
01:08:10out as a real publication.
01:08:12I mean, like I don't have time
01:08:13to do that as a peer reviewer,
01:08:15I do a lot of peer review.
01:08:17You know,
01:08:17I'm I'm reading the paper to see if
01:08:19I think it's good and if I happen
01:08:21to Nova reference that I want to see
01:08:23or I'm curious about a reference outlook,
01:08:24but I can't cross reference all that,
01:08:26so I think.
01:08:27We're gonna have to answer the
01:08:29question of whose job is it?
01:08:31And you know,
01:08:32my sense is we're headed for some rules,
01:08:34and that journals will start to
01:08:36say these are our requirements
01:08:38for your bibliography.
01:08:40Um, but I hadn't thought about
01:08:41that much from that perspective,
01:08:43so thank you for that.
01:08:44'cause I think that is a.
01:08:47It's so hard to know now what's a
01:08:50quality reference and what's not.
01:08:54It's a little bit scary
01:08:56asking these things. Yeah,
01:08:58I think so too.
01:08:59Publication ethics is like super
01:09:01interesting stuff these days.
01:09:02There's like a lot of.
01:09:04Cool things to do in that area, I think.
01:09:07And there's just so many ways to mess up and
01:09:10so many ways to mess up by accident,
01:09:12I think, is the other.
01:09:14Other big thing you know,
01:09:16I think when people cite a reference
01:09:18that they haven't checked.
01:09:19That's sloppiness, not malice.
01:09:21Right, and so an it's a sort of
01:09:24particularly problematic kind
01:09:24of Attribution that we all do.
01:09:26'cause we're in a hurry, right?
01:09:27Not because we're trying to
01:09:28pull one over on someone.
01:09:32Excellent point, excellent point.
01:09:34Well, I think.
01:09:35Are scanning quickly over my list here?
01:09:38I think folks who wanted to speak
01:09:40at the opportunity to speak it was a
01:09:43wonderful talk and they only we look
01:09:45forward to hosting you in person.
01:09:47New Haven after the storm.