A Political History of Patient Safety and Human Subject Ethics in Randomized Controlled Trials

February 11, 2022

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February 2, 2022

Laura Bothwell, PhD, MPhil, MA

ID7444

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00:00Welcome to the program for Biomedical Ethics.
00:02Our Evening seminar series,
00:04and we're particularly pleased
00:05tonight because as you know,
00:07we try very hard to bring you
00:09experts in and and and leaders in
00:11ethics from all around the world.
00:13And then we realized that not
00:15infrequently we have some wonderful
00:16people right here at Yale that we'd
00:18like to highlight and bring to you.
00:19And so this evening it's
00:22doctor Laura Bothwell.
00:23Laura is an ethicist and historian
00:25of public health for research,
00:26examines social, historical,
00:28and ethical dimensions of epidemiology.
00:30With a particular focus on
00:32randomized controlled trials,
00:34she has an interest in in vulnerable
00:39subjects and participant diversity
00:42in randomized control trials as well.
00:44She also does work in climate change,
00:46epidemiology and ethics.
00:49Laura's education includes a PhD
00:51from Columbia, a postdoc at Harvard,
00:54and she is.
00:56She is a visiting scholar visiting
00:58appointments at the universe
00:59at Oxford University,
01:01the Fundacion Brocher and the Karolinska
01:03Institute and National Taiwan University.
01:05So she is in fact has visiting
01:08appointments all around the
01:09world and what she teaches public
01:12health ethics right here at Yale.
01:14Very very pleased to welcome Laura
01:16doctor Laura Bothwell this evening
01:18to let you folks know how this works.
01:20We will have about a 45 minute
01:22talk from Doctor Bothwell,
01:24plus or minus a bit,
01:25and then we'll have a conversation.
01:27I'll invite you to submit questions
01:29through the Q&A function INSZOOM.
01:31I'll read these questions to Doctor Bothwell.
01:33I apologize if advanced if I
01:35don't get to your question,
01:36we'll get to as many of them as we can.
01:39Then we will stop no later than 6:30.
01:41So we start now and we ended 6:30.
01:46And with that with no further ado,
01:48I thank you very much for joining
01:50us tonight and I welcome my friend
01:52and my colleague on the faculty
01:53and I'm so pleased to have you
01:55here as our guest speaker.
01:56Tonight, Doctor Laura Bothwell.
01:58Take it away, Laura.
02:00You're muted, there you go.
02:02There we go. Thank you so much.
02:05Doctor Mercurio,
02:06it is such an incredible privilege
02:08to be a part of this seminar series.
02:12I've been really enjoying and learning
02:15a great deal from last year's series,
02:18dealing with anti racism to the very
02:21pertinent and important topics that
02:23have been explored this year as well
02:26with regard to vaccination policy.
02:28So it's just a real privilege to
02:30be a part of this excellent series
02:32and to have had the opportunity
02:34to work with Mark Mercurio and
02:36Sarah Hull who I believe don't just
02:40explore bioethics but live.
02:43In the classic Aristotelian sense of virtue,
02:46ethics,
02:47in their professional dynamics here at Yale,
02:49and it's been just such a such a
02:52privilege and pleasure to be able to
02:55work with this incredible program.
02:58So I'm talking about a political history
03:00of patient safety and human subject
03:02ethics in randomized controlled trials.
03:04This is the subject of a book that
03:07I'm in the process of writing.
03:10To begin,
03:11I'd like to acknowledge support that
03:14I've been fortunate to receive for this
03:18project from the agencies listed here,
03:21and I also would like to acknowledge
03:24the image credits at the bottom
03:26from various archives.
03:27That have allowed public access to
03:31some really useful images that are
03:34being shown in the slides today.
03:37The framework of this talk first
03:39will examine historical influences of
03:42social settings, intellectual trends,
03:44culture, social movements,
03:46economics and regulations on
03:48the development of RCT's.
03:49And we'll examine key themes across time,
03:52methodological rigor, ethics,
03:54political context,
03:55and perspectives toward vulnerable
03:57research subjects.
04:01The format will involve looking at the
04:03origins and early history of clinical trials,
04:06the emergence of randomization,
04:08the expansion of RCTs, then limitations,
04:10and ethical standards in the early use of
04:14RCT's and limitations in unregulated research
04:16with a case study of fill it in mine,
04:18which I'm sure many of you are familiar with.
04:21The emergence of policies in the 1960s
04:23expanding required use of our cities.
04:25The role of the civil rights
04:28movement in advancing trial ethics.
04:30Recent historical.
04:31Improvement and attention to participant
04:33diversity and also recent challenges as
04:36RCT's have globalized and industrialized.
04:39So going into the early history
04:42of randomized controlled trials
04:45prior to the emergence of RCT's,
04:48there was the development of alternate
04:50allocation of patients in trials.
04:52So rather than randomly allocating
04:56participants to intervention
04:58and placebo arms,
04:59early trial is typically would
05:03alternately allocate participants.
05:04But prior to that we had a really.
05:09Disorganized system of of clinical research,
05:12which reflected a completely different
05:14way of thinking about evidence
05:16in public health and medicine.
05:18So clinical trials began to substantially
05:21expand in the mid to late 19th century as
05:25a as a result of shifts in the structure
05:29of medicine and scientific thinking.
05:32In part this was due to the
05:35expansion of hospitals.
05:36Medicine became institutionalized and
05:39shifted from being conducted in patients
05:42homes to collecting sick patients together.
05:46Many of the early hospitals were particularly
05:50targeting impoverished populations,
05:52and we're free hospitals
05:54and charitable hospitals,
05:57and is technology developed overtime
06:00hospitals themselves developed and appeal to.
06:03Patients of all economic backgrounds
06:06for the access to technology, and.
06:09In this process,
06:11medical thinking became more systematized
06:14and institutionalized in a physical sense.
06:19And for the first time we started to
06:21see very large numbers of patients
06:24coming together in the same place.
06:26For frequently the same diseases
06:29in rapid succession,
06:30giving researchers access to considerable
06:33sizes of populations for trials in ways
06:37that they hadn't previously had access to.
06:40So that was one dimension,
06:42but only one dimension of the changing
06:45ways that medical thinking was being
06:47done in the late 19th century.
06:50There was also an increasingly empirical
06:52approach to medicine and public health.
06:54We saw the development of the field
06:57of microbiology really advancing
06:59the germ theory, advancing,
07:01and just like other dimensions
07:04of the sciences, medicine,
07:06and public health began to be much more.
07:10Rigorous and systematized.
07:12And there was an effort in scientific
07:15thinking toward more empirical approaches.
07:18There was also a shift toward
07:21greater professionalism.
07:22In medicine and public health,
07:23which contributed to this more rigorous
07:27approach to thinking about disease
07:31at a more complex and systems level?
07:36And we saw a new biologic vaccine and
07:39drug industries emerge to confront the
07:41newly and recently identified germs.
07:43So now we had not only a better
07:46awareness of the diseases that were most
07:49commonly afflicting global populations,
07:50but we also had new industries and new
07:55interventions that medical practitioners
07:57were eager to test out on patients.
08:00And so all of this led to a conglomeration of
08:04events that made it quite.
08:06Likely for clinical trials to emerge,
08:09and of course, that's.
08:11What we saw happening, however,
08:13in the early days of clinical trials,
08:16there was an absence of regulation
08:18and absence of organization and
08:20a lot of significant problems.
08:22So at this time controlled clinical
08:25trials still conflicted with an
08:27intellectual culture and medicine in which
08:30individualistic ideologies dominated.
08:32This was a sort of transition
08:35toward evidence based thinking,
08:36and of course the field of
08:39evidence based medicine emerged.
08:41A century later, essentially,
08:43but during this time there was a
08:46a real predominance among medical
08:48practitioners that each individual
08:50patient should be treated as such,
08:53and you couldn't necessarily compare
08:55patients from one to the next.
08:58This was sort of the General practitioner
09:01ideology but scientifically minded.
09:06Physicians and researchers were
09:08starting to shift toward a concept
09:12of the common human where we could
09:15at least look at basic responses of
09:18individuals to disease and responses to
09:21interventions against those diseases
09:23and look at trends across groups of
09:26individuals and start to think about.
09:29Controlling for confounders.
09:32However, even when clinical trials occurred,
09:34there were problems.
09:35There were typically small
09:37patient sample sizes.
09:38Control groups were relatively rare.
09:41Methods were loose,
09:43there were poor ethics,
09:45typically no mention of informed
09:47consent or patient rights.
09:49There was really little if any infrastructure
09:51or support for clinical research.
09:54It was wholly unregulated,
09:55and at this time still expert testimonials
09:58and case studies were much more
10:00common in the scientific literature.
10:03In clinical trials and you can see in
10:06this image here that renting Psyche
10:09Psychiatric hospital in New Jersey,
10:11where Henry Cotton became well
10:13known for removing patients teeth,
10:16tonsils,
10:16colons,
10:17and other organs under false
10:19claims of curing mental illness.
10:21And this was one of numerous examples
10:24within the scientific community that
10:27really got those who are thinking
10:29about evidence to move toward having.
10:34Higher standards to hold their
10:37colleagues accountable for
10:38what they believed was the.
10:41The the evidence for their interventions.
10:46Still we saw a predominance in this
10:49era of interventions that were promoted
10:52by either medical practitioners or
10:55by the proprietary companies that
10:59were producing drugs and various
11:03treatments that really had no overall
11:08accountability beyond the claims of.
11:11Those producers and also the physicians
11:14who they periodically paid to promote
11:17their products in medical journals.
11:19And here are some other examples
11:22of descriptions of proprietary
11:24drugs in the early 19th century,
11:26just to give us a real contrast of what
11:29life was like when we didn't have a
11:33robust Food and Drug administration.
11:36So I I like the description here,
11:39of sarsaparilla as something that
11:42is uniformly successful in certain
11:46in its remedial effects it produces.
11:49Rapid and complete cures of a
11:52whole range of indications for all
11:56diseases arising from the impurity
11:58or deficient vitality of the blood,
12:00blood or from mercurial poison is a powerful,
12:04safe and certain remedy,
12:05and this is,
12:06I think,
12:07striking simply for the language
12:10in terms of
12:12how. How much liberty?
12:14The producer of this drug was able
12:18to take in proclaiming perfect,
12:22perfect treatment.
12:24And you know, a power that is.
12:28Available for a variety of conditions
12:31and we don't really have that level of
12:34liberty for producers of products anymore.
12:36As a result of shifts that
12:39we're going to talk about.
12:41So at this time there were other
12:43problems in scientific thinking that
12:46were really affecting the the development
12:49of the field of clinical trials.
12:52There was the eugenics movement
12:55and arguably accomplishing or
12:58accompanying poor research methodology.
13:01There were also dangerous social prejudices
13:04that were influencing scientific thinking,
13:07and so even for those who are starting to.
13:11Think about conducting clinical trials.
13:15There were some real ethical problems
13:18that resulted from the influence of social
13:22context and social prejudices on science.
13:26In a system that was without
13:29regulation and without policies for
13:31protecting vulnerable populations to.
13:33So, to give you a sense of
13:36the early clinical trial,
13:37subjects who we've seen in in.
13:41The number of scenarios of our
13:45more advanced clinical trial
13:47methods in the early 20th century.
13:51The populations that they drew upon
13:55were frequently institutionalized,
13:57impoverished, and marginalized.
13:59For example,
14:00there were cholera inoculations
14:02tested on inmates and it's this
14:05penal settlement in India.
14:07Quinine tested against malaria among inmates.
14:12In the prison labor camp that
14:14undermines penal settlement,
14:15prison label Labor camp in the Bay of Bengal,
14:18Antipyretics were tested among
14:19Burling mothers in a British line
14:22in hospital for low income women.
14:24Tuberculosis treatments were tested among
14:27Native Americans on Western reservations.
14:29The diphtheria antitoxin was tested at
14:32Wheeler Parker Hospital for infectious
14:34diseases among underprivileged
14:36children in New York City and orphans,
14:38also in the hope it all days on fonts Milad.
14:42In Paris,
14:43and so this is a real trend that
14:46we saw occurring in trials in this
14:50in this time period.
14:53OK, now I'm not sure if I should take.
14:56I see there is a hand raise.
14:57I don't know if I should take
14:59questions now or wait until the end.
15:04I I would leave it up to you.
15:05We can. We generally wait till
15:06the end for these things Laura,
15:07but why don't we go ahead and do that?
15:11Great, OK, well we'll be sure that
15:15someone is asking about a recording.
15:16And yes, there is a recording
15:18which we made available later.
15:21And we will. We will absolutely.
15:26We'll absolutely get to the
15:27questions right after Loris talk.
15:29Perfect, yeah, I.
15:30I would love to return to this period
15:34as we move to the end of the talk.
15:36I'd love to come back to this,
15:38so I look forward to those questions.
15:41So there was a sort of really seismic
15:44shift in the way that scientists were
15:47thinking about clinical trials with
15:50the development of the work of Sir
15:53Austin Bradford Hill and the creation.
15:56Of statistical methods,
15:58there's a real overlap in the
16:00history of infectious disease and
16:02the history of the development
16:04of randomized controlled trials.
16:05Austin Bradford Hill himself was
16:09struck ill with tuberculosis and in
16:13his illness he was bedridden and spent
16:16a good deal of time thinking about
16:19medical statistics and developing a
16:22series of articles for The Lancet on
16:24Principles of Medical Statistics.
16:26That could be applied to clinical trials,
16:29and he shifted his professional
16:32focus from work in the in practicing
16:35medicine to becoming an epidemiologist
16:38and thinking about medicine from
16:41a more distanced stance in terms
16:46of the focus of his professional
16:49work from a day to day basis, and.
16:54He developed a series of ideas for
16:57randomization that at the time were
17:01considered completely unethical.
17:03Physicians and researchers felt that
17:06when a new scientific development emerged,
17:09it was not ethical to allocate
17:12patients to a placebo arm,
17:14particularly at random when there
17:17was an opportunity to provide
17:20a cure for for those patients.
17:23And.
17:24A real significant historical moment
17:28occurred following the Second
17:31World War when in London there was
17:35a real economic deficit and there
17:38was not a capacity from it for the
17:43government to provide streptomycin.
17:45This newly developed antibiotic to all
17:48of the patients with tuberculosis who
17:52would stand to potentially benefit from this.
17:55Experimental therapy and so.
17:57Austin Bradford Hill saw this as a a
18:02really opportune moment to conduct
18:05what really has been celebrated as
18:08the first institutionalized very
18:11rigorous multi institution studied.
18:17Applying randomization in a
18:20clinical trial and so.
18:23There's the streptomycin study
18:26for tuberculosis involved.
18:28A placebo group of patients who were
18:31receiving the existing standard
18:33of care for to tuberculosis,
18:34which was bed rest and then an
18:38intervention group who received
18:40streptomycin and it studied these
18:42patients over the course of four
18:45months and looked at the outcomes
18:48for the control and intervention
18:50group and found a significant
18:53benefit from streptomycin and again,
18:56this study was only considered ethical
18:58because the government could not provide.
19:00Enough streptomycin for everyone
19:03who they would have liked to have
19:06provided it for and so as a result,
19:10inevitably there was a percentage
19:12of the patient population that was
19:14not going to receive anything beyond
19:17the existing standard of care.
19:19And so it was deemed ethical to
19:22allocate this placebo group to
19:24the existing standard of care.
19:27At random to conduct this trial,
19:30given the lack of access to resources.
19:33But what was interesting is
19:35that after four months of study,
19:38it became clear that resistance
19:41began to develop to streptomycin,
19:44and so the researchers realized
19:47that it would
19:49be necessary to provide combinations
19:52of antibiotics to really cure
19:55tuberculosis and nice discovery.
19:57Proved to the medical community
20:00that there was some real value
20:02of him having a a rigorous study.
20:05With randomization to the control and
20:08intervention group so that we could
20:11develop more rigorous scientific knowledge
20:14to better treat populations overtime.
20:17And at this point in history,
20:20the concept of clinical aquacise
20:22had not been specifically named,
20:24but this was sort of the genesis
20:27of the concept of clinical aquacise
20:30in scientific thinking that allowed
20:33generations of researchers too then.
20:36I think we feel that it was appropriate
20:40to allocate participants to an
20:42intervention and a control arm at
20:44random when there was no clear
20:47sense that there was necessarily a
20:50benefit of an intervention and that
20:52it was then ethical to continue to
20:56conduct a randomized study until a
20:58preponderance of information had
21:00accumulated sufficient to convince the
21:02clinical community that it was appropriate.
21:06We shipped to a new plan of action,
21:08whether that be the new intervention
21:10or in the case that the intervention
21:13proved iatrogenic reverting to
21:15the existing standard of care.
21:18So there was a process of shift that
21:21occurred in the years following
21:25the original streptomycin study.
21:28First,
21:29you can see historically this is a
21:32chart that I've created from looking
21:35at around 1000 RCT's in the published
21:38literature,
21:39overtime and trends of where trials
21:41have been conducted in various
21:43factors and trials that will be
21:45looking at throughout these slides.
21:47But you can see originally there was a trend.
21:50Trials coming out of the UK.
21:53The group that Austin Bradford
21:55Hill worked with with the Medical
21:58Research Council in the UK did a
22:01series of studies on interventions
22:04for tuberculosis and increasingly
22:06a variety of other interventions.
22:08And then this team started to promote
22:12our success internationally and in
22:15the 1950s and 1960s in the United States,
22:18there was a huge investment in
22:21science in response.
22:22Through the Cold War,
22:23as the US was trying to win the
22:26science race and the NIH received
22:28a an enormous amount of funding
22:31and colleagues at the NIH were very
22:34keen to embrace the methods that
22:37Austin Bradford Hill was promoting
22:39in lectures around the world.
22:42And at this time there was a period for,
22:46you know, the 1960s to the late 1980s, when.
22:52The NIH was a leading funder
22:55of clinical trials worldwide,
22:57and then you would see a shift
23:01toward trials being located in
23:05different nations around the world.
23:07And this was a period when shifts
23:11in trial sponsorship moved toward
23:14industry funding and multinational
23:16trials became much more common.
23:19From this period forward.
23:21But we're following the history of RCT.
23:24Where they have occurred in this
23:26talk and so this also aligns with.
23:29Some significant moments in the
23:32history of bioethics and the patient
23:35protections that we saw develop
23:37for participants in RCT's in this
23:40in this time period,
23:41so I'd like to explore this
23:43a little bit more,
23:44and you can also see on the next slide.
23:48Fairly similar trends in terms of funding,
23:51so the UK Medical Research
23:53Council was an original funder.
23:55Then we have the US Public Health service,
23:57DHS taking a significant role and
24:00then pharmaceutical companies taking
24:02a larger role in more recent history
24:05so RCTs became institutionalized
24:08and expanded in the 1950s.
24:10But they were not required by any regulators,
24:14and they were also not regulated
24:17in terms of ethics.
24:18And any any standards for patient
24:22protections and all of this
24:24would eventually come to a head.
24:26We had post war ethics that had expanded,
24:30but these were not required
24:32or regulated in any sense.
24:34So the Nuremberg code of 1947 has been
24:37historically celebrated celebrated as
24:39a watershed moment for establishing
24:42the requirement of informed consent,
24:45and indeed,
24:46the World Medical Association passed
24:47the resolution on human experimentation.
24:50The principles for those in research
24:52and experimentation in 1954,
24:54which implemented the informed consent
24:57requirement of the Nuremberg Code.
24:59But this was not put into significant
25:02use internationally.
25:03It predated the development of the
25:06intellectual field and discipline
25:09of bioethics,
25:10and also there were no ethical or
25:13regulatory infrastructures to put
25:15the Nuremberg Code into place.
25:17So what happened following the Second
25:19World War is that those scientists?
25:21Who are keen to follow the code?
25:24Did so and those who were not
25:27particularly seeing this as their
25:29primary objective scientifically
25:31continued to do business as usual,
25:34which led to some real significant
25:38problems for patient protections.
25:41So unregulated research came to a
25:44breaking point in the late 1950s
25:47with the solidified crisis,
25:49and here you can see an ad.
25:52From a Swedish.
25:54Producer of solid amide claiming
25:56that it was safe for children.
25:59The drug quality mind was sold
26:03around the world.
26:05And it was widely distributed in
26:08numerous countries and it was sold.
26:12Or it was it was not sold.
26:13It was available in the Dominican Republic,
26:17France, Hungary, in the United States,
26:19which meant that doctors who were
26:23distributing the drug to patients
26:25could do so for experimental purposes.
26:29But it was not yet approved for
26:33Sale by pharmacies. So, uh.
26:37This drug was being widely used
26:41by pregnant women to assist with
26:45warnings sickness.
26:46And a Doctor Who is prescribing this drug.
26:51Doctor Videocine lens in Germany
26:54started to notice a significant
26:57exponential spike in.
27:02Phocomelia, which is a.
27:06A birth defect of children
27:08being born with deformed limbs,
27:11he also saw a rise in stillbirths
27:14and pregnancy is not going to
27:17turn to term and he identified
27:19the link between the rise and the
27:22consumption of The Little Mermaid
27:24and the rise in these birth defects.
27:27And he was ridiculed by Kenny Grunenthal,
27:29the drug company who had created
27:32solidified as a half wait intent
27:34on murdering a drug by spreading.
27:37Rumor but I soon became clear
27:41that he was right,
27:42and the thalidomide epidemic
27:46broke out throughout the world.
27:50It started to be documented
27:53within the medical literature.
27:58And. Alarms really started to be
28:03raised in the US. Frances Kelsey,
28:06who is a pharmacologist and reviewer
28:07for the Food and Drug Administration,
28:10also was concerned about
28:13thalidomide exposure.
28:14And she kept the drug from
28:17being approved by the FDA.
28:20And as news of the crisis
28:22broke out around the world,
28:24she was really celebrated for
28:27having prevented the the drug
28:30from reaching populations.
28:31More broadly, in the United States,
28:33she received the President's
28:36medal for distinguished service.
28:39And in response to all of this,
28:42government leaders realized that we
28:44needed to see some more robust controls
28:48to prevent some sort of epidemic
28:52like this from occurring again.
28:55It was really the determination
28:57and stubbornness of Kelsey who
28:59prevented a broader epidemic in
29:01the United States than occurred
29:03in other parts of the world, but.
29:08Smartly,
29:08the regulators at the time were
29:10seeing that they needed a more robust
29:13infrastructure to prevent this sort
29:15of thing from happening again.
29:17We couldn't simply rely on a plucky
29:21individual in the FDA to to prevent
29:24this sort of incident from occurring,
29:27and so this led to the 1962
29:30Kiefaber Harris amendments.
29:31The Food and Drug Act,
29:33which led to the requirements for
29:35adequate and well controlled studies,
29:37and this was the creation of the
29:39requirement in the expectation that RCT.
29:42Be used for drug approval,
29:44but it also led to the first
29:47legal requirement of informed
29:48consent for research subjects,
29:51so this was a significant moment for
29:54the transition from the Nuremberg Code.
29:58Ideas into an actual regulatory
30:00reality so that studies that were
30:03being brought to the FDA had to
30:06demonstrate that they had obtained
30:09informed consent from research subjects.
30:12And in response to this,
30:13the FDA held a conference on the
30:16amendments and you can see that it was
30:18extremely well attended with standing
30:20room only from members of the drug industry,
30:23and this led to a complete shift
30:25in the way that drugs were approved
30:28and the expectations of having
30:30RCT's before drug approval.
30:34The regulation of research expanded
30:36globally at this point in history,
30:38with a new emphasis on
30:40research ethics as well.
30:41The World Medical Association
30:44Declaration of Helsinki.
30:46Was adopted by the 18th World Medical
30:50Association General Assembly in 1964.
30:52This enshrined the main principles of
30:54the Nuremberg Code demanding informed
30:56consent and respect for research subjects,
30:59and this was incorporated into the
31:01FDA informed consent requirements and
31:04also into other international ethics
31:06regulatory requirements around the world.
31:08So the declaration of Helsinki.
31:12Is ethically binding on physicians,
31:14and that obligation overrides any
31:16national or local laws or regulations.
31:18If the declaration provides
31:20a higher protection,
31:21it requires all research involving
31:23human subjects to be discussed by
31:25a committee with members other
31:27than the researchers,
31:28and this was really a direct reflection
31:30of the problems of the thalidomide crisis.
31:33Because Kenny Groenendaal had been
31:37developing a drug at studied it
31:39internally and it didn't have any sort of.
31:42External review of the research
31:44that the company was doing
31:47on this drug and then the drug was
31:50distributed without any sort of external
31:53accountability and the ethical problems
31:56of this had become very apparent in
31:58the results of the the ELIMITE crisis.
32:01And so this was a time of a shift toward
32:06creating the concept of external review.
32:11So the declaration of Helsinki
32:13also established the principles
32:15of respect for the individual
32:18self-determination and informed consent.
32:20The investigators duty to the
32:21patient or the volunteer.
32:23The subjects welfare must
32:24always take precedence over the
32:26interest of science and society,
32:28and it also had allowances for vulnerable
32:32research participants and so in
32:35response to this regulatory shift and
32:38the requirement of informed consent.
32:41And the incorporation of the
32:44Declaration of Helsinki into clinical
32:47research standards by regulators.
32:49We also saw a significant rise in a
32:52stated use of informed consent in
32:55published RCT's that only increased
32:58overtime until more recent years,
33:01when perhaps it became simply assumed.
33:05We also saw following this period a
33:09significant decline in prisoners and
33:12psychiatric inpatients as research
33:15subjects in RCT's reflecting a
33:18shift in thinking among researchers
33:21that vulnerable populations needed
33:24to be protected and could not just
33:27be relied upon and exploited,
33:31particularly given their vulnerability
33:33relative to the broader population.
33:37So simultaneously the civil rights movement
33:40was also motivating new regulations,
33:43protecting minorities in research.
33:46So in 1965 we saw new policies resulting
33:52from the 1964 Civil Rights Act,
33:54so that no person in the United
33:57States on the grounds of race,
33:59color, or national origin could
34:01be excluded from participation in,
34:03denied the benefits of or subjected
34:05to discrimination under any.
34:07Program or activity.
34:09Receiving federal financial
34:10assistance and this required,
34:12therefore,
34:13that grant and award programs of
34:16the Public Health service.
34:18Would operate in compliance with
34:20civil rights laws,
34:21so this was a significant moment in
34:24the history of a trial ethics and
34:28protections of research subjects because.
34:31At this time,
34:32the United States was the leading funder
34:34of clinical trials around the world,
34:37and the attention to nondiscrimination
34:42was having a significant impact
34:45on the overall norms of research.
34:49First affecting trends in trials
34:51that were funded by the government,
34:53but then also having a ripple effect
34:57on trials conducted by other funding
35:00entities who started to follow
35:02a new scientific norm.
35:04We also saw an eye NIH grant request
35:09for proposals shifting to have
35:12basic civil rights requirements of
35:15occurring in non segregated facilities,
35:19but this was all really insufficient
35:22with regard to addressing the influence
35:25of racism on scientific research,
35:28and this became very clear when
35:31the Tuskegee syphilis experiment
35:33became public and this was.
35:35Again,
35:35another watershed moment for
35:36the field of bioethics,
35:38so we all know that antibiotics were
35:41first used to treat syphilis in 1943.
35:44However, in 1972,
35:47Tuskegee was exposed as the
35:51US Public Health service,
35:52studying individuals for 40 years for
35:55the natural progression of the disease,
35:57despite treatment being available and
36:01the sort of ethical justification
36:03that the scientists.
36:05Of the Tuskegee study made
36:07for themselves was a very
36:09utilitarian arguments.
36:11They felt that because the
36:13populations that they were studying
36:15didn't have access to medical care,
36:18it was appropriate for them to study
36:21this population because they were
36:24following the existing standard of care
36:27that this population would be receiving
36:31and not having access to to treatment.
36:35Not having access to to health insurance,
36:38but of course society felt very
36:41differently about this and felt
36:44that we should be holding our health
36:47researchers to the standard of
36:49treatment that is generally practiced
36:51within medicine and not discriminating
36:54against research participants who are
36:57low income and taking advantage of
37:00their lack of access to care in order
37:03to exploit them for for research.
37:05Purpose is preventing access to treatment
37:08that that others in society are receiving.
37:12But this is a trend that has not gone
37:15away and will talk about even in recent
37:18years in relation to the COVID-19 trials.
37:21So the ethics response to Tuskegee
37:23was first the 1972 creation of what?
37:25What is now the Office for Human Research
37:28protections in DHS and then in 1974,
37:31the US Department of Health and
37:33Human Services passed Title 45 code
37:35of federal regulations per 46,
37:37creating the requirement for
37:39institutional review boards.
37:41Then you can see here.
37:44Two senators,
37:45Mondale and Kennedy,
37:46who were particularly instrumental
37:49in creating these institutional
37:52policies in 1974.
37:53They helped to pass the
37:55National Research Act,
37:57creating the National Commission for
37:58the Protection of Human Subjects of
38:01Biomedical and Behavioral research,
38:02and then also at an international level.
38:05In 1975,
38:06the World Medical Association
38:08made its first revision to the
38:10Declaration of Helsinki in Tokyo.
38:13So in 1978,
38:15the National Commission for the
38:17Protection of Human Subjects of Biomedical
38:20and Behavioral research created the
38:22Belmont report and after many years,
38:24four years of meeting at
38:26the Belmont Retreat Center,
38:28this group of leading bioethical
38:32thinkers had deliberated.
38:34What government policies should
38:36look like with regard to the
38:39guidelines for institutional review
38:42boards and they considered.
38:44At length,
38:45whether they should promote very
38:48detailed guidelines and they ultimately
38:50came down to some very core simple
38:53principles that could be broadly and
38:56generally applied because they felt
38:58like it was inappropriate to try
39:02to specifically prescribe specific
39:05research ethics for what they could
39:08not necessarily predict would be a
39:10number of different studies scenarios,
39:12and rather it was more appropriate.
39:14We have a broad set of general principles
39:17that should be considered in every context,
39:21regardless of of the variations
39:23that that can occur,
39:26so these principles included respect
39:28for persons that we should protect.
39:30All people with voluntary and informed
39:33consent that researchers must be truthful.
39:35There should be no deception that we
39:38should protect those whose decision
39:41capacities are limited and you
39:43can see in this language a direct
39:45reaction to the Tuskegee study.
39:47That researchers must be truthful
39:49that there should be no deception.
39:51This is really the reverse of what
39:54the Tuskegee researchers had done,
39:56and so we could see historically the
40:00alignment of developments in
40:02the civil rights movement.
40:04Having a direct influence on
40:07our development of bioethical
40:09regulations for clinical trials.
40:11So the next principle that they developed
40:14was beneficence doing no harm maximizing.
40:17The benefits and minimizing the
40:19risks to the research subjects.
40:21Third, the principle of justice that
40:23burdens and benefits of research should
40:26be distributed fairly and equally.
40:28Again, this was really a direct
40:32response to Tuskegee because that
40:35was a very clear case in which the
40:38burdens and benefits of research were
40:41not distributed fairly and equally.
40:44So in response to the creation
40:48of the Belmont report and all of
40:52the bioethical regulations that
40:54we saw come out of tuskeegee,
40:57we saw a real significant rise in reference
41:02to institutional review boards being
41:05consulted for RCT's that were published.
41:09However, we've also seen some substantial
41:13and meaningful critiques of this
41:16historical process of development.
41:19So, for example,
41:20Patricia King has written
41:22in American bioethics,
41:23individualism, self-determination,
41:24and autonomy are paramount,
41:27paramount, other values,
41:28and other ethical issues have historically
41:31enjoyed lesser status even today.
41:33The failure to obtain informed consent
41:35of the Tuskegee subjects continues
41:37to receive greater attention.
41:39And the social and economic conditions
41:41in which the subjects found themselves,
41:44which is a really critical entrenchment
41:47observation that will carry forward,
41:50as we're looking at the problems that
41:53have recurred again and again with
41:56regard to social and economic conditions,
41:58leading to desperate research,
42:01treatment overtime.
42:02Susan Reverby that as the ethicist and
42:04historian has also written that we need
42:06to avoid just thinking about a simple,
42:08good and evil while we pretend that
42:11the structural factors that create
42:13problems in the 1st place can be ignored.
42:18So this brings us up to the more recent
42:21history of advances in bioethics,
42:25and we've seen a greater attention recently
42:28to diversity and inclusiveness, so.
42:32Following this period in the
42:35late 1970s and into the 1980s,
42:38when there was a concern about
42:41exploitation of minorities in research,
42:44we saw a shift in our public health
42:47systems leadership so that more
42:50women and minorities were taking
42:53positions of leadership in the NIH,
42:56and the FDA and within Congress.
43:00And really this professional transition.
43:04Lead to greater discussion,
43:07not just of nondiscrimination,
43:10but also of inclusion in research
43:13so that throughout the 1980s
43:15a series of working groups and
43:19conversations were held about what
43:21would make sense at a policy level,
43:24not just with regard to non discrimination,
43:26but with regard to having research
43:29reflect the broader population so
43:32that researchers were becoming.
43:35Very aware of the trends toward white
43:39men being studied more frequently than
43:42they were members of the population,
43:45and so by the early 1990s,
43:48NIH funded RCT's were then required
43:51to include people of different
43:53ethnic and racial backgrounds.
43:56Women, children, and the elderly,
43:59and this was really a result of the work
44:02of women and minorities drawing attention.
44:05To these issues at a governmental level
44:08so that the NIH Revitalization Act of
44:121993 institutionalized the expectation
44:14that these populations be included in
44:18trials that were funded by the government,
44:21and then the FDA soon followed suit
44:24by also requiring that drug sponsors
44:27of trials include diverse populations
44:30in order to obtain drug approval.
44:34This was also a time when
44:38scientifically thinking shifted so that.
44:42Inclusiveness of diverse populations was
44:44not just seen as ethically appropriate.
44:47It was also seen as scientifically
44:51more rigorous and race and other
44:56demographic backgrounds started to be
44:59included in study design in order to
45:03make our scientific findings more useful.
45:08So we stopped shifts overtime with
45:11increasing discussion of defining
45:14the race of trial subjects.
45:16You see, there was a spike in attention.
45:19Uh,
45:20aligning with the the civil rights
45:23movement and then in more recent years
45:26we saw a significant rise in in at
45:29least defining the race of trial subjects.
45:31But we can talk in the Q&A about
45:35the significant limitations of
45:37the existing regulatory structure
45:39with regard to trial diversity.
45:42You can see here there was also
45:45an increased attention overtime
45:47to enrolling pregnant women and
45:50considering the myriad ethical
45:53dimensions of that in clinical research.
45:57But the past several decades
46:00have really given us a lot more
46:03thought and attention to issues of
46:06participant participant diversity.
46:08From an ethical perspective.
46:10We've also seen a recent issues
46:13with regard to child globalization,
46:16so global RCT policies to
46:19the extent that they exist,
46:21tend to reflect competing interests.
46:24The International Council for
46:26Harmonization was created in 1992,
46:29attempt to regulate basic standards
46:34of drug trials around the world,
46:37but this is really been critiqued
46:39for having an industry focused and
46:41also for its non inclusiveness.
46:43Of diverse populations around
46:45the world at a policy making
46:48level, this has started to
46:51shift in more recent years,
46:53but as we've seen this trend toward
46:57clinical trials being conducted globally,
47:00the issues of patient protections
47:02and human diversity take on new
47:06valences that require attention at a
47:08policymaking level that really has
47:11not been sufficiently addressed.
47:13And unfortunately,
47:14history is tended to repeat itself,
47:18so as trials have globalized
47:20social inequalities continue to
47:22have ramifications for our cities.
47:24For example,
47:25there were the scenarios of the ACTH
47:29HIV trials in which participants in Sub
47:33Saharan Africa were allocated to a placebo,
47:37whereas participants in
47:39developed settings were not,
47:42and this received significant.
47:44Ethical debate and criticism for
47:47repeating the same assumptions that
47:50had occurred in the Tuskegee study,
47:53which is that the existing standard
47:55of care of lack of access was used
47:59to justify studying participants by
48:02not providing the standard of care
48:04for medicine that existed elsewhere.
48:07We've also seen contract research
48:09organizations a multibillion dollar
48:11annual industry being critiqued for
48:14targeting middle income countries,
48:15often with ethnically homogeneous
48:18populations.
48:19Looser regulatory oversight,
48:20sneaker systems, ethical review.
48:24And as a result of this we've seen
48:28patient interchangeability questions
48:29so that we're asking frequently.
48:31Now,
48:32are the populations being studied in
48:35our clinical trials internationally,
48:37really reflecting the ultimate consumers
48:40of the products that are being tested?
48:44This has also raised questions
48:46of post trial treatment,
48:47access to interventions that
48:50are being tested in populations.
48:54Globally and this has really come
48:57into public awareness again recently
49:00with the COVID vaccine trials.
49:02So despite hosting a clinical
49:04trial of the Astra Zeneca vaccine,
49:06South Africa was unable to secure
49:08a fair pricing agreement for
49:10vaccines quite recently,
49:12and the country procured its first million
49:15doses of the vaccine at $5.25 per dose,
49:19more than double the
49:23$2.60 per dose.
49:24Paid by the European Union countries
49:27to this same company and so we've
49:30seen this significant concern being
49:33raised at an international level
49:36with regard to the individuals who
49:39are being tested in clinical trials,
49:42not necessarily being treated fairly
49:46and having access to the products
49:49that are are being tested on them
49:53during the course of a study.
49:54Once that study is completed.
49:57So I'd like to close by
50:00highlighting some key findings.
50:03First trial design study location ethical
50:06safeguards for research subjects.
50:08Participant diversity investigator,
50:09accountability,
50:10and even the likelihood of favorable
50:13trial results have all been
50:15historically influenced by social,
50:16political, and economic context.
50:18Ongoing trends in RCTs indicate
50:21that intellectual developments have
50:23tended to be insufficient alone to
50:27change normative research practices.
50:30We've seen this over and over again where?
50:33Scientific advances have been
50:35adopted by those who are interested.
50:39Ethical developments have been
50:41incorporated into the research of those
50:44who value those at the goal developments,
50:47but without some sort of
50:50regulatory infrastructure,
50:51there hasn't been a normative shift
50:54toward overall embrace of scientific
50:58and ethical standards that have
51:02arguably been necessary to have.
51:04Optimal and ethical science.
51:07However,
51:08once precedents are established through
51:11the leadership of regulators and through
51:15the leadership of funding agencies,
51:18there have tended to be cultural
51:20shifts in research ethics that have
51:22perpetuated and become normative.
51:24So we've seen this,
51:25for example,
51:26with the development of the Declaration
51:30of Helsinki being incorporated
51:32into regulatory structures.
51:34And the leading drug developing
51:37locations around the world first
51:40and then being adopted by countries
51:43that were following suit of of
51:47leading regulators internationally.
51:49So at once informed consent started
51:53to be required by some countries.
51:55It started to be increasingly required by
51:59others as a sort of normative standard.
52:04Finally,
52:04as new challenges emerge,
52:05history is provided examples of
52:07how science has been dramatically
52:10transformed through the work of
52:12individuals committed to ethics
52:13and scientific integrity over
52:15other competing interests.
52:17So we've seen a lot of recurring
52:20problematic themes overtime,
52:21but I'd also like to end on this
52:24point of optimism that we've
52:27seen some really significant.
52:29Game changing.
52:32Work coming from individuals who have
52:35been committed to scientific rigor
52:38and to ethical standards that have
52:41led to major changes in improving
52:43the quality of science and the
52:46quality of ethics for the broader
52:48population and so moving forward,
52:51I would like to think that we can
52:53learn from history in this regard as
52:56well that it is quite possible for
52:59committed individuals who are determined.
53:02To change the way that research,
53:05ethics and their overall
53:08research process operate,
53:10but you know it,
53:12it takes time and it takes political
53:16will and support as well.
53:18So that's a sort of broad overview
53:21of this history,
53:22and I I look forward very much to
53:25discussing with you all whatever
53:28is of interest within this.
53:32Thank you so much Laura.
53:33That was outstanding. Water.
53:34Wonderful review. I learned a lot.
53:36I'm sure most folks on the call did.
53:39I would invite you all now folks if you
53:41have questions or comments to put him
53:43through the the Q&A function on zoom,
53:45and I will just take something,
53:47take a quick one while while some
53:48questions go in there, Laura,
53:50it was interesting when you.
53:53You commented on the the I saw President
53:55Kennedy signing up signing the law
53:57when when it became federal law in
53:59the United States about regarding
54:01informed consent for these trials and
54:03about the end of Tuskegee and and the
54:07progress has been made ethically.
54:10And it it struck me and I,
54:12I think that you this was perhaps
54:14part of your message is that that it
54:17really wasn't the medical or academic
54:20community that finally had to say, listen,
54:24the way we've been doing about this.
54:25And of course,
54:26it wasn't just testing the way we've
54:27been going about clinical research,
54:29human subjects,
54:30the absence of really good human subjects
54:33protection is really not appropriate.
54:36This is really not good.
54:37We need some stricter rules that
54:39I get the sense that this.
54:40It really didn't happen at the.
54:44This really wasn't brought about so
54:46much by either medicine or academia,
54:47but really more by the public when it
54:49went when it published the New York Times.
54:51Is that a fair assessment?
54:53Yeah, I think so.
54:55You know there's been some really nice
54:59scholarship on how this transition
55:02occurred and behind the scenes,
55:04which I wasn't able to cover in this talk.
55:07There was also.
55:09A significant effort over the
55:11decade prior to the fiber Harris
55:15amendments in which senators
55:17could favor and Harris had tried
55:20to reform the FDA unsuccessfully,
55:22and so sadly,
55:23what seems to have been a trend
55:26in the history of bioethics
55:28is that it took the public,
55:31becoming aware of a huge violation of
55:36patient rights and giving that public.
55:41Outcry having having that provide
55:46impetus to the policymakers to
55:48actually carry out the objectives that
55:51they had been hoping to carry out.
55:54That's I think not to say that it
55:58isn't possible for change to happen
56:01without a crisis, but there was.
56:06In this case, and in a number of cases,
56:08historically a conglomeration of effects
56:12where public outcry and political will.
56:18All moved toward making shifts that,
56:21as you point out,
56:22we're not really being made by
56:25the scientific community itself,
56:27and I think we're in a moment
56:29now historically as well.
56:30Where we have some major crises
56:33of public trust in science
56:36with regard to drug profits,
56:39and you know the recurring issues of
56:42who is being tested in our in our trials
56:45and their access to treatments where.
56:49There there is sufficient public
56:52concern and you know the question
56:55is whether we can find the leaders
56:58to make the changes at a policy
57:01level that we've seen historically.
57:02Because we're now in a in a period
57:04that is much more challenging from a
57:07global perspective where we need to
57:09see some sort of international standards
57:11implemented at a national level.
57:14But that takes a lot of first
57:17international agreement for
57:18what those standards are.
57:19And then advocacy at a national level,
57:23from from policymakers to
57:25to implement those changes.
57:28Sometimes, perhaps in addition to the
57:31political will and the leadership.
57:34Again, I think the fact that the
57:36that the that we sometimes require
57:38public scrutiny before we kind of
57:40come to our senses as a profession.
57:43I had a boss years ago when I worked New
57:45London, used to talk about the New London
57:46Day rule that was the paper out this.
57:48We call it the New Haven Register
57:49rule or the New York Times rule.
57:51Her basic rule was she says, you know,
57:53if you wouldn't want to see it
57:55on the front page of the paper.
57:56You got to think very carefully
57:57before you do it and or make it a
57:59policy for what we do in this House.
58:01Is it is that there are so many
58:03things at once.
58:04Once there's been a light shined on them,
58:06people realize now we really
58:07can't be doing that.
58:09I'd like to think and hope that we
58:10can kind of be a step ahead of that.
58:11But of course one of the things about.
58:13About these meetings and and getting
58:15scholars like you to speak to us is
58:17that there are many scholars and members
58:18of the health care in the audience.
58:20But there's also members of
58:21the public in the audience,
58:22so all of us are hearing and benefiting from
58:25from your wisdom here, Doctor Bothwell.
58:27Now I have some questions please.
58:30The statistical work that you
58:33referred to early on.
58:34Sir Hills work.
58:35Was someone asked how does the
58:37statistical work of Florence Nightingale
58:39fit in you familiar with that at all,
58:41or?
58:42Yeah it's very funny 'cause I
58:44was preparing for this talk.
58:46I was thinking about I visited.
58:51The British National Archives and.
58:56Actually held some documents by Florence
58:58Nightingale in her in her penmanship,
59:01which was an incredible experience
59:04looking at her thinking on on statistics,
59:08and I think that there's
59:12room for scholarship too.
59:14Better describe the contributions that
59:17she's made into this sort of evolution of
59:21of thought and clinical trial history,
59:24but certainly she Tran she was a part
59:27of that transition from thinking about
59:29patients on an individual level to
59:32thinking about science more in medicine,
59:36more systematically that you know
59:39was occurring in the in the sort of
59:42thought transition toward the modern.
59:44Era, but I I think that that's a
59:47that's a really important point
59:50to raise for contributions.
59:52Thank you, could you say something
59:55about the historical development and
59:57ethical concerns that have arisen in
59:59the social and behavioral sciences,
01:00:01including psychology and psychiatry,
01:00:02about the historical development
01:00:04and the ethical concerns,
01:00:06psychology and psychiatry?
01:00:07Have you have you seen something specific
01:00:09about that that you could speak to?
01:00:12Yeah, I love that question because
01:00:16actually I've looked at, you know,
01:00:18thousands of trials now overtime
01:00:20and there was this period when
01:00:22antipsychotics were being developed
01:00:24in the 1950s and being tested in
01:00:28early RCTs on populations who
01:00:32are considered now vulnerable,
01:00:35but they were being widely tested
01:00:39on institutionalized populations,
01:00:40oftentimes without.
01:00:42Consent and without even any real
01:00:45awareness on the parts of the researchers
01:00:49that they were engaging in research
01:00:51with with a set of vulnerable subjects.
01:00:55In a post Second World War period.
01:00:59Psychiatric and research and antipsychotics
01:01:02were one of the leading areas in
01:01:05which RCT's were being conducted,
01:01:08and so I think this is a fairly
01:01:12unfortunate period historically
01:01:14when it was after the development
01:01:17of the scientific methods of RCTs,
01:01:19but before the implementation
01:01:22of bioethical protections for
01:01:24patient populations,
01:01:25and there was a lot of research done in this.
01:01:29Period when we saw this emergence
01:01:31of a broad range of antipsychotics.
01:01:34And the the participants were were not
01:01:37necessarily being treated as they as
01:01:40we would like to to see them being treated,
01:01:44and so that is shifted over time.
01:01:47And we've realized that it's possible
01:01:50to conduct research on patients in
01:01:52a way that is bringing them into
01:01:56the discussion and ensuring that
01:01:58they want to be studied.
01:02:00But there's certainly a
01:02:02problematic history in that.
01:02:04Field,
01:02:05particularly in that period before
01:02:08the Declaration of Helsinki
01:02:10and the Belmont report.
01:02:13Code of federal regulations.
01:02:15You know 45.
01:02:17So yeah, that's that's the you know.
01:02:19It's it's.
01:02:20It's a very interesting history.
01:02:24Next question, some of estimated that
01:02:26humans challenge trials and didn't
01:02:28really refer it to refer to that during
01:02:30your talk human challenge trials early
01:02:32in the COVID pandemic could have
01:02:34expedited vaccine development and
01:02:36potentially saved millions of life years,
01:02:39but historically is challenge trials
01:02:41have been problematic, to say the least.
01:02:43What are your thoughts on humans
01:02:44and could you define for us that
01:02:46whether you I assume this refers to
01:02:48the deliberate deliberate exposure
01:02:49of individuals to the disease?
01:02:50What are your thoughts on human
01:02:52challenge trials in Houston
01:02:54pandemic? I love that question as well
01:02:56because this has been a recurring
01:02:59theme in the history of bioethics.
01:03:01I mean, we have the modern field of
01:03:04bioethics developing in the second
01:03:05half of the 21st or the 20th century.
01:03:07But prior to this point.
01:03:11It was not uncommon for researchers
01:03:14to expose themselves to diseases
01:03:17and then test agents on themselves,
01:03:20and I think there's some really
01:03:24compelling ethical literature talking
01:03:27about informed participation in
01:03:30challenge trials being akin to.
01:03:34Serving the public in other ways.
01:03:37For example, firefighters,
01:03:40police officers,
01:03:42individuals who expose themselves to
01:03:45risk and potential harm for the broader good.
01:03:49I think the the most important
01:03:51dimension of these trials,
01:03:53of course,
01:03:54is that individuals going into
01:03:56them don't have an unrealistic idea
01:03:59of the benefits and the risks of
01:04:03of what they're being exposed to.
01:04:07But should they be fully fully
01:04:10aware and informed,
01:04:12I personally find compelling the
01:04:15arguments that compare these two
01:04:18to other forms of public service.
01:04:21But I know there's there's a range
01:04:23of opinions on this well,
01:04:24but I appreciate that,
01:04:26but but the questioner,
01:04:27and I've interested in your
01:04:28thoughts or your thoughts have
01:04:30the fully informed individual
01:04:32that a properly designed study if
01:04:34the subjects were fully informed.
01:04:36You think that'll be
01:04:38ethically acceptable? Informed
01:04:39of the risks. I I know someone who
01:04:41volunteered for Edge challenge trial
01:04:43and was very proud of doing that.
01:04:46Actually who was a low risk individual
01:04:49who is willing to to be exposed and.
01:04:54I I I I admired that individual.
01:05:00But I don't think that we
01:05:03should ever compel anybody.
01:05:05Have to be extremely voluntary.
01:05:07Family volunteer.
01:05:09You know if we offer incentives.
01:05:12I think I would be problematic
01:05:14at the same time.
01:05:15There's the argument that
01:05:16individuals who do that deserve to
01:05:19receive some sort of compensation,
01:05:21but I think I think when you get
01:05:22into the realm of of compelling
01:05:24individuals to expose themselves
01:05:26to potential harm using financial
01:05:28means that that gets really funny.
01:05:30Well, right,
01:05:31they're they're in there in lies.
01:05:32The problem with a certain
01:05:33amount of coercion revenues.
01:05:34If we see that that that that
01:05:36individual deserve some compensation
01:05:37for making that sacrifice.
01:05:39Just like firemen get paid,
01:05:41so we say that someone.
01:05:42Does this deserve some compensation?
01:05:44So this of course means that that if
01:05:46the compensation if it's a if it's a
01:05:49financial compensation that to a poor man,
01:05:51that's a that's a very different
01:05:53level of coercion than to a rich man.
01:05:55And and so this is potentially problematic.
01:05:58But I, but I hear you, Laura,
01:06:00and I actually had a member of my
01:06:01family who was young and strong,
01:06:03and who said, well, you know,
01:06:03let's try it on me.
01:06:05Let's try it on me and my friends,
01:06:06you know, let's let's do that at this thing.
01:06:07Gonna kill my grandma.
01:06:10So so that I I get the sense what
01:06:12your sense is that under the right
01:06:14circumstances this could be acceptable.
01:06:16A follow up question to that question
01:06:19was more generally there are other
01:06:20other other changes we should
01:06:22consider to speed the development of
01:06:24new medications and interventions,
01:06:26particularly lifesaving intervention.
01:06:27So other things we should be considering.
01:06:32Yeah, I think this is a great.
01:06:35Question and it's an objective of of science
01:06:37to speed the development of research.
01:06:40I think the history of randomized
01:06:43controlled trials has revealed
01:06:45numerous scenarios in which we've
01:06:48been too eager to develop new products
01:06:52and not sufficiently tested them,
01:06:54and then ultimately needed to remove them
01:06:57from the market as a result of post approval,
01:07:00adverse events becoming known.
01:07:03So it's a really delicate balance.
01:07:05I've written about.
01:07:08You know different means
01:07:10of of speeding trials,
01:07:12and I think that history has shown us
01:07:16that we really have to ensure trial rigor.
01:07:21In order to advance our scientific progress,
01:07:26otherwise sometimes we move so
01:07:28quickly that we then have to go back
01:07:31and and correct our mistakes, but.
01:07:35There are a lot of arguments
01:07:37being made about the regulatory
01:07:40infrastructure slowing down the
01:07:43process of developing new therapies.
01:07:46Which. You know is is a concern.
01:07:51At the same time,
01:07:52if we compare our own Food
01:07:54and Drug Administration,
01:07:55for example to other regulatory
01:07:58agencies internationally,
01:07:59we actually have one of the
01:08:02fastest org approval processes.
01:08:04So it's it's a real delicate
01:08:07balance in terms of speeding
01:08:10delivery of of new therapies,
01:08:12and then also ensuring that those
01:08:14therapies are safe and effective.
01:08:19Can you comment on the political
01:08:21transition from concerns about bias
01:08:23toward studying vulnerable minorities
01:08:25to more recent concerns about bias
01:08:28toward excluding vulnerable minorities?
01:08:30Both are problematic, of course,
01:08:32but is there a tension in this
01:08:34pendulum that's often overlooked?
01:08:38That's a really great question, so.
01:08:43I think that there is there is a
01:08:46tension in the pendulum and it often
01:08:49comes out in the question of how do
01:08:52we even measure diversity so you know
01:08:57we saw this valuable transition from.
01:09:02Major problems in our research on
01:09:08drugs and different interventions
01:09:09and even health outcomes outside
01:09:12of clinical trials where we just
01:09:14didn't have information on broad and
01:09:17diverse populations and we were making
01:09:20claims about therapies and women
01:09:22that had only been studied in men,
01:09:24sometimes, even when those therapies
01:09:26were designed to treat women.
01:09:28So we we have seen this shift.
01:09:32To learn more.
01:09:34You know, consider it treatment
01:09:37of of broad populations.
01:09:39But then we've seen major discussion
01:09:42of how can we even measure something
01:09:46like rates where it's many argue
01:09:51in part a socially.
01:09:55Articulated concept that reflects.
01:10:00A wide range of of social factors
01:10:03and race is also connected to social
01:10:06determinants of health and a very
01:10:09complex way and ethnicity can sometimes.
01:10:13Correspond to other social determinants
01:10:15of health and then changes in the social
01:10:19determinants of health mean that those
01:10:22ethnic variations could potentially change.
01:10:25We've also seen some really great
01:10:27research by David Williams.
01:10:28For example, looking at the impact
01:10:30of racism on health outcomes.
01:10:32But we're in a stage now and looking at
01:10:36diversity of clinical trial participants
01:10:39that I think is quite inadequate.
01:10:41We have.
01:10:43Decades now of regulators developing policies
01:10:46to try to promote inclusion in trials,
01:10:50but then we don't have any significant
01:10:53forms of accountability to statistical
01:10:56significance of what we find or a very clear
01:11:00sense of how we define different categories,
01:11:03particularly for race,
01:11:05race and ethnicity.
01:11:08And and even within that,
01:11:10particularly for multiracial individuals
01:11:13and people from different backgrounds.
01:11:16So typically,
01:11:17when you look at the trials that are
01:11:20approved by the FDA for new therapies,
01:11:23they they'll measure race and
01:11:26ethnicity and other variables
01:11:29but beyond male and female sex,
01:11:33typically you see frequent claims that
01:11:36there is not statistical significance.
01:11:39To support.
01:11:41Any significant outcomes in terms of.
01:11:47Saying there's from one group to the next,
01:11:50even though oftentimes they
01:11:52measure differences that should
01:11:53they have broader populations,
01:11:55they might be able to find
01:11:57something statistically significant,
01:11:59so I think that there's a place
01:12:02right now for post approval.
01:12:04Pharmaco epidemiological research
01:12:06that is looking at trends out of broad
01:12:11population level of interventions by race,
01:12:15ethnicity and different.
01:12:18Demographic backgrounds that can hopefully
01:12:20help to better inform the science.
01:12:25But that's just one dimension,
01:12:27and I think that the question is
01:12:30also getting at what is fair,
01:12:32right from an ethical standpoint.
01:12:35So the question of exclusion to the
01:12:39question of inclusion then also
01:12:41makes us think about how can we
01:12:44make that inclusion process fair,
01:12:47and you know appropriate in how we're
01:12:51we're drawing populations into our studies,
01:12:55particularly when we see trials.
01:12:57Being conducted in multinational settings,
01:13:00you know how can the the diversity
01:13:04categories really truly represent the
01:13:06broad populations of the world who
01:13:08will be consuming a product and then?
01:13:11Also how can we ensure that the
01:13:14individuals that we are using in
01:13:16our studies as proxies for race and
01:13:18ethnicity were drawn into the studies
01:13:20in a way that is fair and you know,
01:13:25not tokenistic and also.
01:13:28Not repeating scenarios of the past
01:13:32where people of diverse backgrounds
01:13:35have been relied upon to produce
01:13:39study results that are not then
01:13:42informing medical treatment in
01:13:44their local communities so.
01:13:46I, I think a lot of the issues that
01:13:49we face historically were still we're
01:13:51still grappling with today because
01:13:53we haven't seen the next phase of
01:13:56ethical development from a regulatory
01:13:59perspective with regard to clinical trials.
01:14:03Thank you given the experience
01:14:04of black people in Tuskegee,
01:14:06how would you enhance the
01:14:08participation of black people in
01:14:10randomized controlled trials today?
01:14:14So I think the. The issue you know with
01:14:19Tuskegee was of course most importantly
01:14:23with deception and not offering the
01:14:26existing standard of care to the community.
01:14:30But I think what we see over and over
01:14:33again is that this trend recurs, and I,
01:14:37I think that there there was a really
01:14:39powerful debate in the New England
01:14:41Journal of Medicine in the early 90s,
01:14:45in which really respected ethicists
01:14:47on both sides of the debate.
01:14:49We're making arguments for and against
01:14:52having a placebo in the AZT trials.
01:14:56I think bio ethical thinking
01:14:58has tended to shift since then,
01:15:01so that there is a general.
01:15:05Discussion in a lot of the international
01:15:09policies that are being made that
01:15:12state that we need to offer post trial
01:15:15access to care for all populations
01:15:17who are participating in trials.
01:15:21But the problem is that we see
01:15:24the United Nations, the WHL,
01:15:26different that icah different
01:15:28organizations coming up with
01:15:30statements that this should be done.
01:15:32But then we don't see
01:15:34any regulatory policies.
01:15:35Requiring that that we
01:15:37ensure post trial access,
01:15:39I think we've done a better job
01:15:42of avoiding deception in trials
01:15:45and having informed consent,
01:15:46but even there,
01:15:48you know there's some great thinking
01:15:50coming out of Yale in terms of asking.
01:15:53Is informed consent always truly
01:15:56informed and how are we ensuring
01:15:59that participants aren't simply
01:16:01signing a very lengthy document,
01:16:04but they're being made fully
01:16:06aware of the scientific process?
01:16:09The way that we are developing knowledge
01:16:13and the true risks and benefits of
01:16:16of what they're being exposed to.
01:16:19In this study, so you know,
01:16:21I, I think in terms of.
01:16:25Populations who have been subjected
01:16:28to racism by medical practitioners.
01:16:32There's definitely a lot of room
01:16:36for improvement with regard to.
01:16:38Building up trust and having full
01:16:43accountability for for researchers for
01:16:46distributing the benefits of their research,
01:16:48but then also for ensuring that
01:16:53participants in trials are having you know,
01:16:58a sufficient discussion of risks
01:17:01and benefits that that will allow
01:17:03them to be truly informed decisions.
01:17:05And this this applies of course across.
01:17:08Populations, but as a result of teskey,
01:17:12there's been a significant distrust.
01:17:17In the medical community that is has
01:17:20emerged within African American communities,
01:17:23which is quite understandable
01:17:25and his you know,
01:17:27also been the subject of some really
01:17:29useful ethical discussion in terms of how
01:17:32to rebuild that trust and have you know,
01:17:37fair and appropriate dynamics.
01:17:39We at the School of Public Health have
01:17:42Doctor Angela Parrott who teaches on
01:17:45the subject of racism and health.
01:17:47Has done some really useful work on
01:17:51community engagement and talking about,
01:17:54you know,
01:17:55participate in community engagement
01:17:57and participatory research where
01:17:59community members are paid for
01:18:01their time to consult and inform.
01:18:03Research that is done on them,
01:18:06and I think that's really the
01:18:07direction that we need to be taking
01:18:10our clinical research overtime and
01:18:12to make sure that you know we're
01:18:15we're whoever we're studying that.
01:18:18Representatives of that community
01:18:20are brought into the process
01:18:22of of conducting the research.
01:18:26Thank you.
01:18:28A comedy which I wish I will share.
01:18:31Thank you for informative talk.
01:18:33Its share of a large university IRB.
01:18:35I'm aware that European standards
01:18:37for research are much stronger.
01:18:38Incidentally, I'm a psychiatrist and
01:18:40clinician and keenly aware of how
01:18:42vulnerable patients can be at risk.
01:18:44I urge IRB's to consider
01:18:46social determinants of health.
01:18:47Also present risks and widens the group
01:18:50of so-called vulnerable participants.
01:18:57A direct a direct a simple question if
01:19:00if an organization seeks to perform
01:19:03a clinical trial in a country that's
01:19:07an impoverished country and says,
01:19:09well, we are going to bring this
01:19:10drug and you talked about the
01:19:12post trial availability of drugs,
01:19:14what would be the answer to recognizing that?
01:19:16That seems to be the accepted standard?
01:19:18What's the direct response?
01:19:19If if a pharmaceutical company says
01:19:21we're going to go into this country
01:19:23and we're going to trial this now,
01:19:25this there is no treatment
01:19:26available right now.
01:19:27Of this population, wherever it is,
01:19:29if we bring this drug in here and
01:19:31we do a randomized control trial,
01:19:3350% of the people are going
01:19:35to have access to this.
01:19:36If we don't,
01:19:36zero percent are going to have access to it.
01:19:38That population that we study.
01:19:40So therefore we're doing net
01:19:42good by bringing this here,
01:19:45even if we don't make it available
01:19:46to everybody after the trial.
01:19:47If it's shown to be effective,
01:19:49what would be the response to that?
01:19:51I've seen a trend in a lot of the
01:19:55leading ethicists in this area moving
01:19:58towards some sort of standard of an
01:20:01expectation for post trial access.
01:20:03Of course, you can't realistically provide.
01:20:08Interminable post trial access
01:20:10for a population because that's
01:20:13not financially feasible,
01:20:15but at least conducting a study
01:20:19on a population should not
01:20:21simply end the moment the trial.
01:20:24And but there should be some
01:20:28benefit for some period of time.
01:20:31Month, years after the completion of a trial.
01:20:36So that.
01:20:37People living in that population can
01:20:40still have access to the treatment,
01:20:43particularly trial participants,
01:20:44so that they can have continued
01:20:47access to the treatment that they
01:20:48were exposed to in the trial,
01:20:50particularly should improve
01:20:51beneficial to them,
01:20:52but also having some period
01:20:56of access for the community.
01:20:59There has been an argument
01:21:00that that is a sort of.
01:21:02Social obligation.
01:21:04I think that those arguments have
01:21:07been fairly ethically compelling.
01:21:10The exact amount of what is offered,
01:21:13I think, is of course.
01:21:15Relative to what is being studied,
01:21:18the profits of that intervention there.
01:21:20There's so many dynamics that would
01:21:22go into figuring out what is fair,
01:21:24but simply going in and testing and
01:21:28intervention and then leaving I.
01:21:30I think that there's there's been
01:21:32a shift among ethicists that that
01:21:34just doesn't seem quite right.
01:21:36We have to do a little bit better than that.
01:21:39Well, I I, I agree, but I but now
01:21:41I gotta find you don't know about
01:21:42anymore but I got a very wealthy
01:21:45pharmaceutical company that I that I
01:21:46also run in my spare time and I say,
01:21:48well, you know if you say
01:21:49there's a social responsibility.
01:21:51So if I say well, why should I have
01:21:53more of that social responsibility?
01:21:54I'm gonna go in there.
01:21:55Make this drug available to half the
01:21:57people running around in my eyes
01:21:59this we're going to do this we're
01:22:00going to get out now why do I have
01:22:03more social responsibility than
01:22:04anybody else stored that population?
01:22:08You're benefiting from it, right?
01:22:10And you're you're getting something,
01:22:13something significant, probably,
01:22:14particularly if your intervention.
01:22:17If they are helping to prove that
01:22:19your intervention is effective,
01:22:21you're going to make some money off of that,
01:22:24and so they had they stand to
01:22:27benefit from their contribution to
01:22:29the development of that knowledge.
01:22:33There we go.
01:22:37This will be our final question.
01:22:38Is there an ethical framework you
01:22:40would invoke around the recent pfizers
01:22:42application for vaccine use in age group
01:22:44in which the data is not yet available?
01:22:50Yeah, that's a great closing question.
01:22:57I think that you know,
01:22:59sort of the emergency use
01:23:03authorization questions. Wait?
01:23:05They raised a whole host of
01:23:08of different issues because.
01:23:10If we make something available
01:23:13before it's been sufficiently tested,
01:23:15that can corrupt the results of our studies.
01:23:21You know, so it's it's.
01:23:25Is it possible to pollute,
01:23:26pollute the data and then there
01:23:29are so many questions you know
01:23:31that come up with regard to?
01:23:33What is fair and appropriate?
01:23:36Should we be be allowing access to something
01:23:38that is being tested on individuals
01:23:40where we have a placebo involved?
01:23:43Or you know there are certain
01:23:45risks involved in the research and
01:23:48then we're allowing individuals
01:23:50outside of the research enterprise
01:23:53to bypass that that process.
01:23:56It's it's really,
01:23:58I think this this should be a seminar
01:24:01inning of itself because there.
01:24:03There's so many issues that emerge,
01:24:06UM, there are a lot of scenarios
01:24:09when historically,
01:24:10particularly with HIV drugs,
01:24:12we saw expanded access to treatment
01:24:16being allowed for people whose lives
01:24:19were on the line and there was a
01:24:22strong argument being made for this.
01:24:24But then.
01:24:26Subsequently those who were involved in the.
01:24:33Activism in obtaining access to drugs
01:24:36outside of trials realized that there
01:24:39was a certain benefit to the drug companies,
01:24:43and.
01:24:44Providing expedited access and.
01:24:50Stale of a product that had not been
01:24:53sufficiently proven to be safe and effective,
01:24:56and ultimately was not having the
01:24:59clinical outcomes that were promised.
01:25:02I think with regard to the backs,
01:25:04the COVID vaccine is a different story.
01:25:06Because, you know,
01:25:08we have seen.
01:25:10Widely established safety and
01:25:12efficacy for older populations,
01:25:14so you know it's it's not a question
01:25:18of whether this is likely to be.
01:25:21Useful to other age groups.
01:25:26But it also just it.
01:25:28It's it's challenging to to
01:25:31bypass the scientific process.
01:25:34You know it's.
01:25:37This is this is a question that I'm
01:25:39not sure I have a complete opinion on,
01:25:42but I think that it deserves a lot
01:25:44of attention and at least I can
01:25:46describe what needs to be considered
01:25:49from an ethical perspective,
01:25:51which you know are the questions
01:25:53of fairness to the participants
01:25:55in the trial and ensuring that we
01:25:59are adequately developing a fully.
01:26:04Useful scientific assessment of of
01:26:06the vaccine in this population.
01:26:09Because we've seen you know,
01:26:11again over and over.
01:26:13Historically scenarios where products
01:26:15have come into the market too soon
01:26:17and they're not fully vetted,
01:26:19and so you know, it's.
01:26:24It's it's. It's important that we
01:26:27whatever expanded access there is that
01:26:30it doesn't interfere with getting a
01:26:32full and accurate assessment of safety
01:26:34and efficacy because without that then
01:26:37we're getting into an experimental
01:26:38realm for the entire population,
01:26:40which is arguably less out of
01:26:43the ethical than having it.
01:26:45Your experimental group in which you're
01:26:47testing something out before it's before,
01:26:49it's broadly distributed.
01:26:52Thank you, thank you.
01:26:53Well, I promise the heart stop at 6:30.
01:26:56Doctor Laura Bothwell thank you so much.
01:26:58This is really been quite informative.
01:27:00There are and and and there are some terrific
01:27:03questions and comments that follow on.
01:27:05People are very much engaged in this
01:27:07and I and I do appreciate everybody who
01:27:09was on the call and who was submitted.
01:27:11These terrific questions and the marvelous
01:27:13information you've shared with us, Laura.
01:27:15This has been a terrific evening.
01:27:17Thank you so much.
01:27:18Such a pleasure. Thanks to
01:27:20everyone who participated.
01:27:23Thank you all very much.
01:27:24We'll see you again in a couple of weeks.
01:27:26I have a goodnight thank you Doctor Bothwell.