0:10

Hello, and welcome back to

0:12

Talk Evidence. We've got Nick

0:14

writing program for you this week, we start with some

0:16

new data on colorectal cancer screening

0:19

using colonoscopy.

0:21

We then turn very excitingly to

0:23

listener request. You've been itching

0:26

for someone to send in their evidence

0:28

request. And finally, we have

0:30

one, so you can hear more about

0:32

that. And in fact, it tends to a bit of feature

0:34

then. This this episode

0:37

feels very dedicated to diabetes

0:39

and and of prediabetes, and

0:41

there's not a bit of COVID insight. And

0:43

we're going to finish off with a little bit of news

0:46

about clinical academics behaving

0:48

badly.

0:50

I'm

0:50

Helen McDonald's, research integrity editor

0:53

for the BMJ and BMJ journals, and

0:55

I'm joined today by Joan.

0:57

Hi, Joan. Do you want to introduce yourself?

0:59

Hi, everyone. This is Joe Ross. I'm

1:01

a professor of medicine in public health

1:03

at Yale and also an associate editor at the

1:05

BMJ.

1:06

I sounded very timid to that, Joe. And

1:08

I'm also joined by Juan. Juan,

1:11

do you guys introduce yourself?

1:12

Hi, everybody. I'm Juan Franco.

1:14

I'm a firm position. I'm

1:16

currently a researcher at the Heineken

1:19

University in Dusseldorf Germany, and

1:21

I'm the Attorney Chief of BMC Evidence

1:23

by medicine.

1:26

In short, a very important people.

1:34

Right. Let's get on to our first

1:36

item for today, which is colorectal cancer

1:39

screening and Juan, you

1:41

volunteered to take a closer look at this one.

1:43

This is a new study that came out in the New

1:45

England Journal of Medicine. A

1:47

few days. Okay?

1:49

Wait

1:49

a second, Helen, isn't this the B and J

1:51

Talk Evidence podcast? Why are we talking about

1:53

a paper in the England Journal of Medicine?

1:55

I'm gonna see if we can bring it back to

1:57

the MJ at the end. But we're we're open to

1:59

all evidence here. It's

2:02

evidence motivations not journals.

2:04

So Juan, tell us about this paper.

2:06

Well, I think it's it

2:08

was very popular in the

2:10

news this past

2:13

days because there is

2:15

one of the first randomized

2:18

control trials that put colonoscopy

2:21

in the under

2:23

scrutiny. And It

2:25

was a a large trial between

2:27

two thousand and nine and twenty fourteen in Poland,

2:30

Norway, Sweden, and Netherlands with

2:34

follow-up data from more than

2:36

eighty four thousand participants. And

2:41

and pay participants were randomized

2:43

to be invited to

2:45

undergo a single screening colonoscopy

2:48

or no invitation to screening.

2:51

So the

2:52

And that will be an important point later, why

2:54

don't you plan? because they were invited to

2:57

come. You didn't hear anyone's gentle

2:59

gentle voice, but I will stress that. So it's not

3:01

necessarily that they actually came. They were invited

3:04

to come. Carry on.

3:04

No one had to describe my voice as gentle

3:07

before, but thank you. I

3:11

yes. And the

3:14

the invitation part is is

3:16

crucial not only because I couldn't

3:18

imagine a trial of people being coerced to

3:20

having colonoscopy, but also

3:22

by the fact that only forty two percent

3:24

of those invited

3:27

under with screening. So very

3:30

little well, like,

3:33

I wouldn't want to put it as subjective

3:37

tone to it, but let's say it's not

3:39

an optimal uptake for

3:41

something that you're randomizing people into.

3:43

And during

3:46

the medium follow-up of ten years, Basically,

3:49

in the main analysis, the

3:54

risk of colorectal cancer

3:56

was point ninety eight

3:58

percent in the invited group and point one

4:00

two in the usual care group. So

4:02

there are say some absolute

4:05

risk reduction and the confidence interval

4:08

is between zero point seven and

4:10

zero point eight three. and

4:12

– but the risk of death

4:14

from colorectal cancer was

4:18

zero point two eight in the divided group

4:20

and zero point thirty one in the

4:22

usual care group and the confidence

4:24

interval for the risk ratio is from

4:26

zero point sixty four to one point

4:28

sixteen. And

4:31

so this is the main analysis.

4:33

And the interpretation is basically

4:35

that And

4:37

it's as consistent with these

4:39

types of screening that identify

4:43

precursors of the disease, which

4:45

is also common in cervical cancer,

4:48

so you remove the polyps, and

4:50

you therefore, you estimate that the

4:52

risk of the disease will be lower.

4:55

and this is what we see in one of the

4:57

outcomes. But unfortunately, we

4:59

can't really identify a

5:02

change in colorectal cancer

5:04

mortality. Most

5:07

of this could be explained by the

5:09

low uptake would reduce the

5:11

power of the study to

5:14

detect this

5:16

difference. And as a matter of fact,

5:18

the authors go into

5:21

an adjusted a per protocol analysis,

5:23

trying to see those people

5:26

who would have undergone screening

5:29

And in that case, they

5:31

identify a difference

5:34

in colorectal cancer mortality. with

5:38

zero point one five percent in the invited group and

5:40

zero point three percent in the usual

5:42

care group, which is an - of

5:44

an estimate of half of

5:46

did that form

5:48

colorectal cancer? So

5:50

you're trying to tease out the does

5:52

the screening program work and what the

5:54

effects are versus if you actually turn up

5:56

for this screening, does

5:58

it does it work then?

5:59

the

6:00

Joe, I can see what it to say something.

6:02

Yeah. I mean, Juan, it was great that you

6:05

brought this to our podcast discussion

6:07

this week because it really was a

6:09

heated discussion throughout Twitter and

6:11

other social media forums. There's a bit of a,

6:13

you know, a roshock test

6:15

of of sentiment. It has it gone down,

6:17

Jay. Well, at that's what I mean. Like, it was

6:19

a bit of a Wireshark in the sense that, like,

6:21

people saw in it what they wanted to see in it. There

6:23

were the people who, you know, saw

6:25

the you know, the low participation

6:27

rate and that means that

6:29

screening programs, you know, aren't likely to

6:31

work. You know, we knew that, you know, we're probably

6:34

there's too much over diagnosis, too much

6:36

testing and treatment. This is just

6:38

one more kind of nail on the coffin for screening

6:40

programs. Others people were like, hey,

6:42

now, hey, now, like, it's more complicated than that.

6:44

And, you know, when you do do the intention

6:47

to treat or, sorry, the

6:49

per protocol analysis focused on the

6:51

people who actually underwent

6:53

screening. Right? It actually it's

6:55

it's effective at the individual level.

6:58

And to me, this raises what I think is an interesting

7:00

question. So My understanding is that in

7:02

Europe, for the most part, people don't

7:04

do colonoscopy unless they have

7:06

some symptoms of disease. But in the United

7:08

States, the sort of,

7:10

like, the ground level for colorectal

7:12

cancer screening is colonoscopy. And

7:14

I wonder if the participation rates would

7:16

have been much higher in a population of

7:19

people who are accustomed or like

7:21

prepared at age fifty or now at age

7:23

forty five, I'm supposed to undergo a

7:25

colonoscopy. And if we had seen participation

7:27

rates in the eighty percent as opposed to

7:29

the forty percent, might the results of

7:31

the trial look different?

7:33

Well, that's very interesting. And I did say that

7:36

I was going to bring it back to the BMJ didn't

7:38

I? Because a while ago, a couple of

7:40

years ago, we published

7:42

a paper in a rapid recommendation

7:45

series that looked at screening

7:49

options for colorectal cancer. And

7:51

Joe, you went back to look at that

7:53

paper to see

7:55

how to see how this

7:58

latest study might impact on those recommendations.

7:59

Yeah.

8:01

Well, so first I would just say for listeners,

8:03

you know, we'll put a a link in the show notes

8:05

to the rapid recommendations page

8:10

in the BMJ And I would encourage people to go

8:12

and look at it because the team at

8:14

the you know, at the journal do a really

8:16

terrific job of creating infographics that

8:18

people can engage with in order to look

8:20

through and sort of identify, you know, what

8:22

pathway to go down. And given the time and

8:24

effort they put into it, more people should use it.

8:27

But essentially, what you see,

8:29

right, is you know, that

8:31

when the fifteen year risk of colorectal

8:34

cancer for an individual is

8:36

below three percent there's,

8:38

you know, weak evidence

8:41

that favors no screening. But

8:43

when you when there that fifteen

8:45

year risk is above three percent there's a weak evidence

8:47

that favors screening. And of course,

8:49

that three percent risk is

8:52

estimated using the acute cancer calculator

8:54

that's also right on the site for

8:56

people to look at. Now, how

8:58

is this trial going to change it?

9:00

Well, it will probably move it

9:02

even further away in the sense

9:04

that it

9:05

one will

9:06

disfavor

9:07

colonoscopy and screening

9:10

even a little bit more.

9:12

But there are more trials

9:14

coming and I hope that

9:16

the next few years will have a much better

9:18

sense of the role of colonoscopy

9:21

in colorectal cancer screening. I don't know, Helen,

9:23

if you to talk about Well,

9:24

what I can say is that

9:26

the that sounds like a politician doesn't

9:28

know. What I can say is

9:30

that the team that produce the

9:33

rapid recommendations are going

9:35

to have a look at that

9:37

study in more detail and add

9:40

an update to

9:42

describe the the latest

9:44

evidence and to give some preliminary

9:46

indication of how things might change. But I think

9:48

they might hold on a bit longer for

9:50

those other studies that you mentioned, Joe, to

9:52

do a fuller update of

9:54

that guidance in light of that

9:56

new evidence there.

10:06

Now, let's turn diabetes or prediabetes,

10:08

I should say, and our very exciting

10:10

listener request. So

10:13

here in the KB NHS

10:15

spends about ten billion a year

10:17

on diabetes, apparently. I love this reading around,

10:19

and that's about ten percent of the entire

10:21

budget. And

10:24

our query relates to prediabetes.

10:26

And here it is. It's from

10:29

a UK GP who happens to

10:31

work in Bath, which is actually where I'm

10:33

based. So here we are.

10:37

Hi.

10:37

My name is Nicole House, and I'm a GP

10:39

in Bath. I would like more information

10:41

on the evidence for the National Diabetes

10:44

Prevention Program to discuss with my

10:46

patients living with obesity. We've

10:48

had local education Sally Day

10:50

where the team presented their

10:52

program but with no clinical outcome

10:54

data. Can the talk

10:56

evidence team tell me what is

10:58

the evidence these programs prevent,

11:01

reduce or delay the onset

11:03

of diabetes. Many

11:05

thanks.

11:09

So that was Nicole's message. For

11:12

those people who are not listening in

11:15

the UK or in England, this

11:17

is a program

11:19

that's offered through the NHS.

11:22

It's a mixture of some

11:24

coaching

11:25

information. It's delivered digitally.

11:27

It's centered around education.

11:30

An educational intervention and to try

11:32

and prevent or delay people from developing

11:34

type two diabetes, and it focuses on

11:36

healthy eating, lifestyle,

11:38

help to lose weight and physical

11:41

exercise programs. And the

11:43

program both says that these have been

11:45

proven to reduce the risk of

11:47

develop up in type two diabetes. And

11:50

so what I've done when I

11:52

gave Joe and Juan the homework

11:54

on this is thought of kind

11:56

of two questions One is

11:58

what is the evidence

11:59

that programs a

12:00

bit like this work, so sort of

12:03

lifestyle and event to prevent

12:05

people from going from having

12:07

pre diabetes to diabetes. And then

12:09

we'll come back to this specific one.

12:12

that's run-in England. So

12:14

Juan, with your connections

12:16

to Cochrane and systematic reviews,

12:18

I thought you would be the perfect person

12:20

to tellers first, where the program's a

12:22

bit like this work?

12:25

Well, yes, there's

12:27

a Cocon review from

12:29

twenty seventeen

12:31

about diet, physical

12:34

activities are a combination

12:36

of both in different

12:38

programs to prevent or delayed

12:40

type two diabetes. They

12:43

included different

12:45

studies. And especially, it's it's

12:47

it's important to have, like, a different time

12:49

points with different different credentials

12:52

of diabetes. But the

12:54

main gross evidence

12:56

from eleven trials highlight

12:59

that this these

13:01

programs may reduce slightly

13:03

some of the risk of

13:05

diabetes. As particularly

13:07

in numbers, there's moderate

13:09

sense, you have evidence of every

13:13

for a thousand people, that

13:15

do not go out this program with

13:19

a two hundred and fifty seven will

13:21

get diabetes. And with

13:23

the program, one

13:24

hundred and forty six. So

13:28

a reduction that, of course, has

13:31

a pretty high confidence interval.

13:34

And what kind of time

13:34

period is that over one? Is that sort of

13:37

The

13:37

median the mean duration follow-up is

13:40

three point eight years. Okay. So

13:42

we're looking more at this sort of delaying

13:44

rather than Life

13:45

time prevention of

13:47

disease. It's difficult because most of

13:50

this study is not had

13:52

very long follow-up time.

13:54

And most of all, most

13:57

of this study is did

13:58

not

13:59

provide enough data

14:02

for other type of

14:04

important outcomes. For example, complications

14:06

related to diabetes or health quality

14:08

of life. or

14:11

possibly adverse events, which

14:13

one would expect that there would

14:15

be minor But for example, even if you take

14:17

cardiovascular mortality, that

14:20

seven studies did report on cardiovascular

14:22

mortality, the evidence

14:25

was too uncertain to

14:29

to to to figure out whether there's a

14:31

difference or not between those

14:33

receiving receiving the

14:35

program or not. So, basically,

14:39

one of the questions perhaps,

14:42

I see, I have as a

14:44

clinician thinking about this, is

14:46

how much of these programs are trying

14:48

to prevent like the chemical

14:50

diagnosis of diabetes or how much

14:52

are we preventing the actual morbidity

14:54

that is related to

14:56

diabetes and the burden of the disease?

14:58

So

15:00

yeah.

15:01

I I would I I

15:04

think that there is some is

15:06

that is positive one.

15:09

But I I mean more.

15:10

Well, it's it's really interesting. I mean, I

15:13

think much of these programs that

15:15

while, you know, that cochrane review

15:17

summarizes a wide breadth of

15:19

evidence, but the seminal

15:22

study that was actually

15:24

published a long time ago in the the Journal, I

15:26

think two thousand two, two

15:28

thousand three, something like that.

15:30

You know, that was the first three year follow-up,

15:32

you know, in the diabetes prevention program.

15:34

I identifying folks at high risk, those with

15:36

pre diabetes, you know, as

15:38

assessed by elevated

15:40

fasting and post load plasma

15:43

glucose concentrations. So they were randomized

15:45

to placebo metformin

15:47

or lifestyle interventions. And the people who were

15:49

randomized to lifestyle interventions did better

15:51

even than those who started taking metformin

15:54

in terms of the incidence

15:56

of diabetes and with weight loss.

15:59

that Lancet published their ten year outcome rates

16:01

in the lower incidence

16:04

of diabetes persisted. But

16:06

again, they don't look at cardiovascular

16:09

outcomes like WAM Notes. But it it

16:11

was those studies that actually

16:13

led in the United States

16:15

a big program evaluation led

16:18

by Medicare, the Centers for Medicare

16:20

Medicaid Services. So Medicare did this big pilot

16:22

demonstration project essentially

16:24

say, well, everyone, you know, should

16:26

have access to lifestyle

16:28

interventions as part of, you know,

16:30

diabetes prevention. Among those, quote

16:32

unquote, with prediabetes. Right?

16:34

And that's actually been a large

16:37

rollout that I think is now

16:39

mirrored in terms of what's happening in

16:41

the UK. And the

16:43

evaluation of that effort

16:45

is gonna be like what happened with the

16:47

colonoscopy trial we just discussed. So

16:49

they're gonna offer lifestyle, interventions,

16:52

and or metformin. I'm not sure if

16:54

that's even part of the program. And then it'll

16:56

depend on participation rates to know if

16:58

it actually works at the population

17:00

level as opposed to an randomized trial.

17:02

And I

17:02

did find a couple of papers, which will

17:04

put in the notes of the episode,

17:07

which were largely service evaluations

17:09

and people's experiences of having

17:11

been in the program. So I think

17:13

the answer to the precise answer in

17:16

Nicole's question is I don't

17:18

think we entirely know

17:20

the outcomes for this

17:23

program or necessarily the

17:26

answers about for how

17:28

long it might delay diabetes

17:31

or ultimately whether it fully prevents it. But I

17:33

think Joe and

17:35

Juan, I feel

17:35

I feel persuaded that

17:38

there is at least some evidence

17:40

of these programs having an

17:44

effect,

17:45

certainly feels like they're unlikely to

17:48

do harm when targeted at people

17:50

who

17:51

have pre diabetes.

17:53

And and, also, in general, right, they're

17:55

focused on lifestyle modifications

17:58

-- Yes. -- which are general -- I'm saying

17:59

wow. -- not just decided,

18:02

but for lots of lots of

18:04

reasons. So, yes, I think, you know,

18:06

feel pretty good about that. Well, we can

18:08

look forward to Nicole's feedback maybe.

18:11

on whether we have

18:13

helped her remotely have a conversation

18:15

with her patients. You

18:16

know, perhaps I would add

18:19

is how this affect the whole system

18:21

in the sense.

18:22

When you shift the

18:25

resources and time and

18:27

efforts into prevention, I would have

18:29

to be absolutely sure that the

18:31

people with the condition in this case with

18:33

diabetes are receiving the

18:35

most option care because if and

18:37

so thinking about the whole system,

18:39

if you if you're a policy communicator

18:41

have to allocate money, where

18:44

would you put it in this case?

18:46

So there's some

18:48

let's look a bit of

18:50

an equity situation. Right? So

18:52

it depends on the system. Since I'm not in the NHS,

18:54

I cannot say that.

18:56

So but I I would argue that

18:58

in other systems, which people with

19:00

with diabetes are struggling to

19:03

get their medication or

19:05

or have a strong pathway

19:08

of care, allocating

19:10

resources to the prevention of the

19:12

condition may seem slightly

19:15

You are

19:15

really confusing everyone's CPT

19:18

now, hon.

19:27

So

19:27

coming up in December, we've got BMW

19:29

Research Forum at BMA House. And

19:31

joining me is dot to Helen Serrano from the events team.

19:33

Hi, Helen. Hi, Helen. Helen's

19:38

meet. So tell us a bit about this

19:40

event. You're speaking. So

19:42

the event is to bring together

19:44

the research community. We

19:47

recognize that there's loads of people

19:49

involved in research, not just

19:51

the people who submit to us and the people

19:53

who edit the journals here at B and J.

19:56

But there's funders, there's policymakers,

19:59

patient experts,

19:59

But of course, the researchers are the main part

20:02

of that. And we're just having this

20:04

event alongside the B and J

20:06

editors meeting to make

20:08

sure all those people are talking with each other

20:10

about the same things rather than

20:13

just to their own groups. Some of the

20:15

speakers we've got are

20:17

from some of the big funding organizations.

20:19

We've got Ken Gabriel

20:21

from Welcome Leap, who

20:24

is talking about how they fund for

20:26

impact by using big amounts

20:29

of venture capital money

20:31

alongside investment from organizations like

20:33

welcome. We've got

20:35

Chris Witty, the Chief Medical Officer, talking

20:37

about how research happens in

20:39

the UK and how governments involved

20:42

in it. And we've got a

20:44

really interesting panel

20:46

from

20:46

from

20:47

researchers and funders and

20:50

patients talking about Parkinson's disease

20:52

research and how that is becoming

20:54

a real spectrum and

20:56

a virtuous circle of patients

20:59

getting involved with research

21:01

questions and funders looking

21:03

at impact as well as

21:05

basic science research and further

21:09

clinical

21:09

research as well. So there's

21:11

loads, there's something for everyone

21:13

involved in research, and

21:15

there's some detailed workshops

21:16

and sessions along

21:19

different lines for different groups

21:21

as well.

21:23

Well, I will certainly be there and you've got

21:25

a special offer I understand for

21:28

our loyal listeners of

21:31

Talk Evidence we have. Well, we know that

21:33

the talk evidence community

21:35

are very interested

21:37

in how research gets done. So

21:39

we really hope that some of you will be able to

21:41

join us. And we've got a twenty

21:43

percent discount code, which

21:45

you can use when you

21:48

register at the website. The website

21:50

is BMJ research forum dot BMJ

21:52

dot com. That's all one word. And the discount

21:55

code is BMJRF

21:58

twenty two. So

21:59

that's BMJ research forum is the thing

22:02

you need to remember. And from that, you'll be able to

22:04

remember the website and the

22:06

discount code. so we really hope to see loads of your listeners

22:08

there. Well, thanks for

22:09

dropping and telling us all about it, Helen. Brilliant.

22:11

Thanks for having

22:12

me.

22:18

We are going to stay with

22:20

diabetes for

22:21

our next item. and

22:24

Joe, we discovered that you are a

22:26

co author of a paper that

22:28

has recently been published

22:30

and with your big

22:33

data obsession, you

22:35

have tried to emulate

22:37

a trial looking at the effectiveness

22:39

of adding different

22:42

second line drugs to

22:45

metformin, which is often use first line

22:47

for type two diabetes

22:49

because that's not enough for

22:52

many people. Tell us about your paper and

22:54

what you did.

22:56

Yeah. So

22:56

and thanks for giving the chance to talk a

22:58

little bit about it. So among

23:01

the many hats I wear,

23:03

one is I lead a research

23:06

group at Yale that

23:08

jointly works with folks at the Mayo

23:10

Clinic to collaborate with the FDA

23:12

on regulatory science research projects

23:14

that are a priority for the agency

23:16

And as you both are

23:19

aware, there's a

23:20

the

23:22

deep interest in

23:25

leveraging real world data sources

23:27

to try to better understand product,

23:29

medical product, safety and

23:32

effectiveness, particularly once products are approved

23:34

for use. And so how can

23:36

we, you know, with

23:38

the better data that are available to

23:41

us today, you know, advance our thinking and

23:43

and generate better evidence. So this

23:45

was actually part of a project

23:47

that we collaborated with with

23:49

folks in office of

23:51

medical policy to try to

23:53

understand, you know, essentially, lots

23:55

of people have looked back and said,

23:57

alright, these clinical trials have been done. Could

23:59

we have gotten the same results if we

24:01

had used observational data.

24:03

Right? And and confirmed essentially,

24:05

you know, that when you apply the same inclusion

24:07

and exclusion criteria, you you get

24:10

basically the same findings for the most

24:12

part. Right? This and that's been shown over

24:14

and over John Ionidas did a great

24:16

systematic review of all of the studies that have done

24:18

that in they they they pretty much match up, but

24:20

there's always this interesting risk of

24:22

bias when you're looking backwards as opposed to

24:24

forwards. And so Working

24:26

with the FDA, we actually identified two

24:29

ongoing clinical trials

24:31

that were kind of relevant to

24:33

the agency where we asked,

24:35

well, could we emulate

24:37

that trial with observational data

24:39

sources? And we wondered whether our

24:41

results would look similar.

24:43

And so we did one trial looking at cardiovascular

24:45

safety outcomes for a

24:47

prostate cancer treatment. And then we did

24:49

this trial, which emulated

24:52

what was considered to be kind

24:55

of the landmark grade

24:57

study. This was a study that

24:59

was launched way back in

25:01

twenty thirteen that asked the question,

25:03

okay, you have a patient with

25:05

diabetes. They're already prescribed

25:07

metformin. What do you give

25:09

them as a second line

25:11

agent? and they tested

25:13

four different medications

25:17

representing four different class

25:19

classes. I think tell

25:20

us the classes, Joe, because I feel like

25:22

the drugs vary in the different places, but

25:24

tell us the classes.

25:25

Yeah. So the

25:27

a short acting insulin or sorry.

25:29

A a

25:32

m they

25:35

tested insulin, insulin glargine,

25:37

the synthetic insulin, they tested

25:39

a sulfonylurea, in this case, glumab

25:41

glumab peride. They tested

25:45

GLP-one receptor, liraglutide,

25:47

and they tested

25:49

a DPP-four cidaglyptan. Now

25:53

you guys

25:54

see patients all the time.

25:56

What's missing? I tell you from that.

25:59

No.

25:59

Well, Juan, I'm

26:02

sure you quickly realize they're

26:04

missing the -- The t's. -- the new this

26:07

sGLT2 inhibitors, which are like the

26:09

actual diabetes medication

26:11

that now is often --

26:13

most often used for second line treatment

26:15

because it's -- there's been good evidence that

26:18

demonstrates not only does it work for glucose

26:20

lowering for patients with diabetes, but it prevents

26:22

cardiovascular risk, heart failure risk, and other renal

26:24

outcomes. And so you know,

26:26

this is the madness of clinical

26:28

trial design. Right? Way back, you know,

26:30

over ten years ago, they thought they

26:32

identified the four best sort of second

26:34

line agents and it

26:36

turns out they were wrong. Right? And

26:38

they missed one. So

26:40

what we did is we we those

26:43

results were actually published

26:45

very recently. But before those results were

26:47

published, we – our study

26:49

was published, which looked

26:51

at testing these these

26:53

four these four different medication classes using,

26:56

you know, essentially health insurance

26:59

claims data that were linked

27:01

to electronic health

27:03

work data. So we could use the lab

27:05

values to identify the

27:08

sort of main outcome, which

27:10

is of the time to a hemoglobin A1C

27:12

greater than seven seven

27:14

percent. Oh, no. You want to jame down?

27:18

Right.

27:18

right So you want

27:21

the

27:21

- essentially, you start with

27:23

a patient. It's very complicated the

27:25

way they designed it, but they essentially said

27:27

they looked for failures of treatment. Okay.

27:30

Yeah. It it so we've tried to

27:32

emulate exactly We did wanna make this easy

27:34

for anyone to understand. You wanted

27:37

to tell bus drug

27:39

that was most least

27:41

likely to cause you to fail. Is that

27:43

is that right? Right. because because you

27:45

want it because essentially what they tested

27:47

is which drug or drug class was

27:49

most effective at maintaining a

27:52

controlled hemoglobin -- Mhmm. -- agency level. Okay.

27:54

It's making a good service now. Yeah.

27:56

Yeah. But it's all everything is complicated

27:58

and and all you know, everything that we did

28:00

was also complicated. I'll try to just keep

28:02

it simple by focusing it on

28:04

two points. the first of which

28:06

was we could not

28:08

actually test the insulin glargine

28:10

arm because when you're doing this

28:12

using observational data sources, your

28:14

data reflect real world practice. And

28:16

as it turns out, no one

28:18

was prescribing insulin engardene as a second

28:20

line agent. Everyone basically got

28:23

some other, you

28:25

know, oral therapy, you know,

28:27

one of these other therapies So we just

28:29

didn't even have enough patients even with

28:31

a massive data set

28:33

to emulate that arm of the

28:36

trial. The

28:36

second thing is, in

28:38

the real world, people don't have their

28:40

A1C measured every three months like

28:42

they do in a trial. So that was

28:45

super complicated to operationalize in

28:47

terms of like, how many A1C

28:49

measures did you have to have in order for

28:51

us to look at you? And is that biasing

28:53

the sample? and all sorts of stuff like that.

28:55

But essentially, we what

28:57

we found was that liraglutide was more

29:00

effective at maintaining glycemic

29:02

control than both glimepyride or sotaglyptin.

29:04

And now we're actually in

29:06

the process of comparing our results to

29:08

the actual trial results, which just came

29:11

out. And we're actually

29:13

gonna extend our emulation to include

29:15

the SGLT2 inhibitors because if we

29:17

feel like, you know, what we did match

29:20

the actual grade study, then we can feel pretty confident in what we

29:22

find with the SGLT2 inhibitors. And

29:24

we hope that this evidence is going to be

29:26

useful. But at the end of the day,

29:28

This is these types of exercises I think

29:31

are kind of what's going to help

29:33

FDA and other regulators in

29:35

terms of like how it use

29:37

these types of data, these types

29:39

of evidence to complement, you know, what we

29:41

get from the clinical trials.

29:43

Do you

29:43

think you can ever use them if you don't

29:46

have clinical trials? because it feels a

29:48

bit like almost you

29:50

need quite

29:52

a good idea of what

29:54

you're gonna do in the trial to

29:57

design this

29:59

the It

30:00

is very complicated because

30:03

how, for instance, do you

30:05

emulate a placebo arm

30:07

right, people who have the disease but don't

30:09

get treated. Like, there's there is

30:12

bias happening there among the, you know, in

30:14

terms of using that as a

30:16

population, as control arm. That's

30:18

very hard to do. If you're comparing

30:20

two active treatments, it's a little

30:22

bit easier because you can do kind of a new incident

30:25

user study with big data

30:27

sets. Right? But it's

30:28

very difficult to just say,

30:31

these these types of data analysis

30:33

are gonna replace a clinical trial. It's

30:35

very hard to emulate

30:38

that opportunity to randomize a

30:40

person and truly get

30:42

a more unbiased the the most

30:44

unbiased estimate of the treatment

30:46

effect. So I am very reluctant

30:48

to think that we'll get there. But

30:50

if you have, you know, datasets

30:52

from nine different countries representing

30:54

nine different populations and

30:57

you examine it and

30:59

pretty consistently find that drug

31:01

a were better than drug b, I think pretty close to the

31:03

truth. We may not have the exact estimate of the

31:05

fact that we get from a clinical trial. So you would

31:07

see kind of the dream that you have the

31:08

trials and then

31:10

these big data things. They can confirm

31:13

things. They can maybe look

31:15

at

31:15

some subgroups.

31:18

Some populations who are representative?

31:20

Yeah. Divested population. So all the

31:22

people all the people. Exactly.

31:25

Uh-huh. I see how you're working here. And

31:27

of course, safety. Right? because clinical

31:29

trials are generally too

31:31

small to get real signals of safety if

31:33

they exist. So -- So how do you

31:35

think? -- the FDA decided what

31:37

they they favor? Oh, as if

31:39

they would say it bold and outright and be

31:42

very clear in their intentions, that's

31:44

not how federal agencies is worth And

31:47

what does what professor

31:49

Ross, what are you pro prescribing in

31:51

your colleague, Alan? Oh, I

31:53

generally You know, I

31:55

I think that the SGLT2 inhibitors,

31:58

not because of the work that we're done, but

31:59

because of the basis of the clinical trial evidence

32:02

tends to have the most rigorous

32:04

evidence behind it in terms of the

32:06

benefit to patients. So I think

32:09

Those are the ones I would prescribe as second

32:11

line. I don't know one, if you agree.

32:13

But to me, there's there's more

32:15

trial evidence that supports their

32:17

Juan, he's bringing you in hand. Do you agree? Yeah.

32:19

I mean, the the

32:22

SGL to

32:24

inhibitors were they

32:28

they came later in my

32:30

practice in that's

32:32

a few years. And for for the country,

32:34

it's working. It was very

32:37

difficult to to have them as second

32:39

line. and when the national guidance in Argentina

32:41

were being updated. When

32:45

I have years go. Basically, there was

32:47

a big push by the societies to put

32:50

in the second line, but it

32:52

was it was not feasible,

32:54

basically, because of the cost. So

32:57

But, yes, they they do come

32:59

as a revolution like one

33:01

of the people compared to

33:03

to statin. rights and further

33:05

effects that go beyond

33:07

the the change in glucose and

33:10

and

33:10

the possible effects of cardiovascular

33:13

fidelity and and they're very

33:15

promising. Perhaps what one question that I

33:17

had was so you said

33:19

that you back now to

33:21

extrapolate, to follow the same

33:23

analysis and include

33:27

the SGLT two

33:31

inhibitors, would that make so

33:35

but that would that would

33:37

be the extrapolation, right, not without the

33:39

comparing it to trial data?

33:41

Right. We would essentially repeat

33:44

the emulation -- Mhmm. -- including an arm

33:46

for people who took an SGLT2 inhibitor.

33:48

And I just I don't want to be

33:50

remiss the, you know, this work, which

33:52

I'm up part of is being

33:54

led by Rosalina McCoy

33:56

at the Mayo Clinic, an incredible

33:58

endocrinologist and clinical researcher

33:59

along with Yi Hung Dan. So there and

34:02

there's a big team of other people. So I'm just wondering Sorry. We

34:04

won't give you too much credit. Joe, you

34:06

can really borrow from me now anyway. But

34:08

while done

34:11

all those people.

34:18

So to our

34:20

final item, chemical

34:23

academics behaving badly, I'm gonna be I'm

34:25

gonna do something which

34:27

I really do, which is I'm gonna be

34:30

silent and see see

34:32

what Joe and Juan wants to

34:34

say because that this is think

34:36

you guys are gonna ask me some questions.

34:40

So

34:41

though I

34:44

started following this this

34:46

debate on online because I

34:48

saw this editorial of the

34:50

British Journal sports medicine about the

34:53

retraction of many of the

34:55

early trials and was a little

34:56

bit confused at first because I

34:59

started seeing all pop up of subtraction,

35:02

subtraction, mass massively the

35:04

journal. And In ABMJ journal,

35:06

no less. In ABMJ

35:08

journal. And of

35:11

course, I I was

35:13

immediately intrigued. Calvin, could you can you

35:15

tell us a little bit Well,

35:18

I'm not sure how much is the backstory, Matt,

35:20

that is all out of it. keep it

35:24

brief. Yeah. Helen, tell us what you've been doing for the past two

35:26

years. He's not as long as she

35:28

is. So a few

35:30

months back, we did a

35:31

track piece.

35:33

It

35:33

was a comedy piece written by a

35:36

clinical academic called Dr.

35:37

Paul Macquarie. He is

35:39

a sports

35:39

medicine doctor House

35:42

in Australia. And he was also the in chief the Journal

35:44

of Sports Medicine,

35:44

BTSM, which is published by

35:47

The Journal. And

35:48

the

35:49

we retracted that 30s piece

35:51

because he plagiarized some content from the early

35:53

thousands. And soon after we

35:55

retracted that piece, we

35:57

were alerted to

35:59

some

35:59

other potentially

36:01

problematic pieces, which might

36:03

contain plagiarism.

36:04

There was

36:06

an instance of misrepresentation

36:09

of someone else's

36:11

quotation in

36:11

Macquarie's work

36:13

and some

36:15

examples of potentially duplicate publications, self

36:20

plagiarism. And so for

36:21

the last few months, once strand

36:23

of my job has been working with the

36:25

current editor in chief of BGSM,

36:27

and

36:27

he and my colleague

36:29

in

36:29

research integrity PMJ have been looking into the allegation.

36:31

We've now provided an update on our

36:34

investigation and our

36:36

next steps.

36:37

So the news

36:39

is is so the

36:41

news

36:41

is we've retracted nine more

36:43

papers on which Macquarie was

36:45

a soul or single office, and

36:48

he was just writing these pieces alone. They were all commentary style pieces,

36:50

so not academic research

36:52

pieces.

36:55

five

36:56

contained plagiarism,

36:58

so similar to

36:59

the first example. Three were

37:01

duplicates or redundant publications where

37:03

he'd been inappropriately reusing

37:06

chunks of his own work

37:08

without reasonable attribution.

37:11

And in one

37:12

case, there was this instance where he

37:15

misquoted the view of another clinician

37:17

from nineteen fifty. And this

37:18

was a US doctor called

37:21

Thondike. He was seeing patients, he had

37:23

sports injuries at a university

37:25

and and the full driver's recording

37:27

and

37:28

making recommendations based

37:30

on his

37:31

experience observation. This

37:32

is

37:33

quite an old paper but it

37:35

included some cases of concussion. And Thond dupe

37:38

made a recommendation that after

37:39

a certain number, the

37:41

barriers to concussions,

37:42

there's a concussion somebody,

37:44

basically, should have played contact sports again.

37:46

That was the insinuation

37:48

of the of the piece.

37:50

But the way that Macquarie had quoted it was

37:54

inaccurate but it also altered the

37:55

mirror because

37:58

Macquarie quoted Thondike is saying

37:59

that people in these

38:02

circumstances shouldn't play sports until

38:04

the next season.

38:06

And that and

38:07

that wasn't quite

38:09

right. So that

38:10

and That dealt

38:11

with allegations, but we also needed

38:13

to take stock of

38:15

where we are to

38:17

communicate our findings,

38:20

to others,

38:20

and

38:22

and our concerns

38:22

because our trust is broken

38:25

in in this esoteric chief.

38:27

And we

38:27

needed to think about how we handle the

38:30

rest

38:30

of Macquarie's work published in our

38:32

journals

38:32

and by others to to

38:34

play their part in that.

38:36

And so on that basis, we decided to place expression

38:38

of concern upon any content,

38:40

which is written

38:41

by Macquarie

38:44

Ware he is a single or sole author. So his commentary

38:46

style pieces, but

38:47

he's also published a lot of other content,

38:50

particularly in

38:52

BGSM.

38:53

where he's published

38:56

research papers and also this

38:58

consensus statement for

39:00

concussion sport. which is very key to that

39:02

community

39:02

of doctors and and management

39:04

of that particular condition. and

39:08

we're going to ask his institution to look into the standing of

39:11

his research. And for

39:12

the makers of their consensus statement to

39:15

look into whether they consider

39:18

that there's anything

39:18

to be concerned about

39:19

in that regard. We we scream through

39:21

just for plagiarism in the

39:23

in the latest

39:26

twenty sixteen. version and

39:28

didn't find anything there. But

39:30

I still think there's a considerable way

39:32

to go

39:33

on this journey.

39:36

So assuming the best, for

39:39

example, and it's just editorial my

39:41

my Because you are kind,

39:43

haunted present. Wow. Yeah.

39:46

and and that no no harm to patients or will

39:48

come out of it. And to

39:51

what degree do you think

39:54

it is something that we're just seeing one end

39:56

of the spectrum and of

39:57

something that might be happening more

39:59

more globally. Because

39:59

I imagine

40:02

there might be a lot

40:04

of academics listening to this podcast who are quote quoting

40:08

and paraphrasing all the

40:10

time. No. No. No. No.

40:12

No. No. No. It won't

40:14

be very very paranoid because we

40:16

have this. III thought

40:18

in authentic CADE system

40:20

and and Scholar one and the art system

40:22

that sort of catches like

40:24

this gross

40:26

plagiarism. But

40:28

if so, I I once had a

40:30

paper that came and said thirty percent

40:32

overlap and he started seeing all this

40:34

color coded system of the plagiarism system. And

40:37

it was very confusing, like,

40:39

plain jenga. And and but

40:42

beyond that, I

40:44

I couldn't quite III understood that

40:46

the authors were trying to do the

40:49

best of paraphrasing, but they were

40:52

doing very badly. But it's And also, Helen,

40:54

I'm just curious before you answer that is,

40:56

like like how much of this was

41:00

self plagiarism where the,

41:01

you know, essentially, the author's writing the same thing kind of over

41:03

and over as opposed to plagiarizing somebody

41:05

else's writing, which I think is Yeah.

41:07

Mostly Even plagiarism of

41:10

other people's

41:10

content, which I think we can we can all accept

41:14

is is worse

41:15

than reusing the

41:18

AI content.

41:20

And I think, you know, there there are efforts going

41:22

on to help researchers, you

41:24

know, well intentioned people with that paranoia

41:27

of am I

41:29

and my par you know, do I

41:31

need to paraphrase this a bit more so I'm

41:33

not plagiarizing myself? And I

41:36

think this is ah publishers

41:38

are have to

41:38

be pragmatic about these things. If you're so

41:40

so

41:41

the things that we might start

41:43

to look at is

41:45

you know, if you're

41:46

reporting work from

41:48

a research study and the methods

41:50

of that research study

41:53

are the same as methods that are used in a different paper,

41:55

there isn't a need to rephrase

41:58

that for

42:00

the

42:00

sake. trying to

42:01

evade the plagiarism detection

42:04

software. You just need to reference the

42:06

methods and say they're the same, and it's

42:08

absolutely okay to reproduce those.

42:10

That's that's fine. That's

42:12

transparent and honest and useful, I

42:14

think. And That's

42:15

what sorry. That's what called

42:17

text recycling. Text recycling.

42:18

Yeah. So that so it I

42:20

suppose it's sort of like a euphemism, but it is

42:22

but it is I think I think it's

42:24

important to conceptualize it as

42:27

a totally different thing. And

42:29

it's also okay

42:30

to write about the

42:32

same research in different

42:33

ways. You know, you could publish your research

42:36

paper. Joe was

42:36

talking about his research today. He

42:38

might

42:39

then want to write an

42:41

opinion piece or he might want to write an

42:43

editorial for a diabetes journal and

42:45

to talk about that study

42:47

and he might repeat some of the results. And again, there's

42:49

no need to be constantly paraphrasing

42:52

all of that information. You just need to

42:55

make it clear and be clear that

42:57

you're not publishing redundant materials.

42:59

So if Joe were to take his research paper

43:01

and so then try and publish it somewhere else,

43:03

that would clearly be inappropriate. That would

43:05

be And just for

43:06

the record, I would never do that. I

43:09

would never do that. I

43:12

didn't want I'm coming off the major

43:14

declaration. No. But there is this practice and

43:16

we see it with trials. I was

43:18

just looking at this when

43:22

when when Ross was summarizing the diabetes

43:24

prevention trial,

43:26

there were, like,

43:27

over forty publications in,

43:30

like, a very short period of the And this is, of

43:32

course, many of them might

43:34

be super relevant, but there's

43:38

a very gray

43:38

concept that is this salami slicing where you have a study

43:41

and you make a lot of papers out

43:43

of it and which

43:45

is set up to the

43:47

point of redundancy. Right? And some

43:49

of these decisions aren't

43:51

easy. And I think this relates to,

43:53

I mean, the art sort of the

43:55

answer to your question, although I've kind of forgotten where your first question started by,

43:57

which is that in general, this

43:59

work is

44:02

is

44:02

quite complex. You have

44:04

to to weigh up a

44:06

a

44:06

lot of information. There's a lot of

44:08

judgment involved. Sometimes it's very

44:12

obvious. things have been cut and pasted. But

44:14

as you say, looking at different publications and thinking, okay, what are the

44:16

new outcomes here or what new audience

44:20

you're trying to reach, you have to you have to weigh those things

44:22

up and come to a decision just like you would

44:24

with any with any sort of

44:28

primary content. So would you

44:28

say just to wrap up, would

44:31

you say that copy and

44:33

pastes someone else's comment

44:36

or publishing your article several times is a

44:38

no no, but perhaps text

44:40

recycling for the methods that

44:44

far. They're always the same crowd. I think we should do a future

44:46

episode on plagiarism and

44:49

fraud. No. Fraud

44:51

is like that another category. I

44:52

feel like this episode has not a

44:55

very practical information for sort

44:57

of continuing professional development. CPD,

44:59

as we call it, over

45:01

here in the UK. And I think while though it's something that you'd

45:03

have to go and reflect upon

45:06

now. It's hard to have a

45:07

good all think about. How many c

45:09

me c m credits you. The listeners

45:11

get it. Well, it depends on how that we

45:13

talk to. Well, not

45:17

sure it should depend on that. It shouldn't depend on the

45:19

quality of the conversation. But Joe tells

45:21

us there's somewhere else he has to be enough. So

45:23

we we we've gotta wrap it up

45:25

for this week. bring the show to

45:27

a friend. So I would like to thank you both, Juan and Joe for

45:29

joining

45:29

us. I'd like to thank

45:31

you for listening. you

45:34

can subscribe wherever you

45:35

listen to a podcast, you can rate us

45:38

especially if you like to rate us

45:40

very highly.

45:42

we really enjoyed looking into Nicole's query

45:44

this month. And if

45:45

you have a query that you'd like us

45:47

to look

45:48

into, or you'd like

45:50

to give further query to me so I can

45:52

give mine and do some homework to do,

45:54

then that would be wonderful.

45:56

So until next month, it's goodbye for me. Goodbye

45:59

for me.

45:59

Goodbye for me.

46:02

Take care.

46:02

the cow that