Thread by @BettinaRyll

An advocacy colleague of mine just complained about having had to sit through a talk short of an hour on how to talk patients into participating in clinical trials *without* a single reference to what clinical trials have to deliver for patients, so here some explaining 🧵

relevant for any patient considering participating in a clinical trial and equally, any patient advocate asked to provide 'a patient perspective' on clinical trials

in cancer, considering ignoring if it's a trial where the risk to yourself and your life is negligeable or you don't dare contradicting your oncologist anyway (though consider changing oncologist in that case)

With extremely rare exceptions- actually can't think of any example after a decade in this now- any clinical trial design can be explained by 'the cheapest way to get my drug approved (Pharma) aka a paper published (academia)'

There might be slight tweaks to it- more expensive trial to get to market sooner (remember the quality-speed-price triangle?)- but also that in the end boils down to: money 💰💰💰

Once one has understood that clinical trial design is not about scientific-progress-the-patient-at-the-heart-of-all-we-do-innovation-blablah - things get actually pretty easy

A clinical trial design is that design that gives you the cheapest trial that anyone can run that will a) make you look as good as possible b) pass the ethics and b) can be recruited.

a) no one runs trials to fail (though sometimes, one wonders). They are horrendously expensive, share holders don't like failed trials and negative results are painfully hard to publish and not career-building. So this is a game you play to win.

So there are some time-tested strategies for that. Like- compare your new thing to the worst possible option you just get away with- luckily, b) ethics committees don't seem to be too sharp on science all together-

Before you hate me know, thank you for sharing a scientifically sound rationale why umpty ethics have approved BRAFi+MEKi vs BRAFi mono again and again, the #Melanoma community is still wondering- #MelSM

Inclusiong/ exclusion (no one says they have to match mind you, anyone could be getting real information out of clinicaltrials.gov then 🙄) are obviously critical- just exclude anyone who could make results look bad up front

everyone will be so obsessed with p-valued internal validity that that fact will be relegated to a footnote at best. 'Obviously, the findings are limited because of x, but hey, let's run another trial'

And the degree of brainwash is substantial: If you follow any discussion on RWE- Real World Evidence- the common complaint is that the real world does not perform according to the fake reality of RCTs. That's mistaking the tool for reality....

So for patient advocates in trial design, *external* validity- in how far the trial population reflects the real, not some beautified, olympic patient population is critical for us. That does *not* mean one should not be sensitive to heterogeneity obviously!

b) as for ethics- from what gets approved one is rather worried about the quality of the rejects.... But they do not check for external validity nor scientific rationale. And as long as you can call your comparator 'SOC'- standard of care- you seem to get away with anything

and for those of you who now feel offended, there will be enough of us in #Melanoma who would love to take you up on the exclusion of brain mets- or the fake inclusion '2 stable scans ages apart' 😤- or some Science on the MEK pathway

or some DTIC- never worked in #Melanoma- that people seemed to be able to smuggle in again and again. PD1 vs DTIC? We already had Ipi and it was even the *wrong* class of drugs 🙄. Just to say- don't hold your breath on the scientific knowledge of your EC

and then comes c)- you cannot run clinical trials without patients. So patient recruitment and retention are HUGE. And as they cost money- a lot of- this is basically just an iteration of a previous point, albeit with some more detail.

So recruiting patients into clinical trials and keeping them there are big business- just do a quick search on 'patient recruitment CRO', there are full conferences on the topic btw- and there are some main trends we have seen over the last years

It's important to understand that as a rule, larger trials are more expensive than smaller trials. And that the larger the difference between the things you compare, the fewer patients you need to recruit to prove your point.

And most people like things things simple: a huge difference between new and old? Easy for clinicians and regulators and HTAs just *love* it to calculate cost-effectiveness. Hailed as the BIG NEW THING

The problem with the BIG NEW THING? In the trial, patients will be randomised- that's a lottery of the macabre sort- to something that's no use (don't get a big difference otherwise, right?!).

So as a patient in a desperate situation the *most* important thing to understand is that what's good for everyone else is not necessarily good for *you*. The system is quite happy to throw a few of us under the bus- the statistics look better that way at least.

Of course that's not that talk we get. The talk goes something like this: 'at least they will be getting the SOC' (which we all know isn't enough- why else would we have this trial?!) 'not all trials turn out positive' (but the risk is worth taking if the alternative is death)

Usually, one level removed from the patient- few have the guts to tell a Stage 4 cancer patient they'd be better dying for the greater good of society- it's then utilitarian thinking and 'opportunity cost' - nice in theory but not so nice if you are the sacrifice

So the point to understand for patients and for patient advocates is that the system is rigged against the patient. Everyone else has vested interests and the way that happens is normally not good for the patients on the clinical trial.

However, people aren't stupid. Patients who have no treatment options left very well understand the value of taking risks. If your alternative is death, taking a calculated risk might be worth it- while sticking out something known not to work is not.

However, there are some well-known strategies to get patients into trials and to keep them there, independent of whether or not it is good for the patient on the trial (that much about Helsinki)

You can e.g. incentivise recruitment. Clinicians can e.g. get paid to screen for trials. And get paid more when they recruit a patient into a trial. The clinician who recruits most patients becomes first author on the publication- big trials go into NEJM or Lancet = career rocket

So it's probably safe to assume that a clinician who recommends you for his or her own trial benefits from doing so. But it might not be the best one for you. But then, clinicians without trials at all might not know about them in the first place- also not a good place to be.

I've come to the personal conclusion that the oncologist I would trust most would be the one who sent me to a trial to their arch-enemy 😎 (but considering all you have to know to know that....sigh)

So, as clinicians might or might not be somewhat unreliable in their recommendations (personal interest, might not send you to their concurrence, usually not aware about trials abroad), online platforms are trying to fill that gap....

basically, online dating for clinical trials. Also there, the business model is the issue- platforms tend to get paid for recruiting patients into trials. As a patient, the point is not to find *a* trial. It's about finding *the* trial that improves your chances to survive

All over all, patients are probably better off by joining the science nerds in their community- who neither make money nor careers from being there- and to educate themselves to wisely chose the clinical trial that is best for themselves....

Then, there is obviously the most favourite way to trap cancer patients in clinical trials: BLINDING. The amount of pseudoscience that has been produced on blinding in cancer trials is just WOW- I haven't seen any evidence of psychological factors affecting PFS let alone OS.

If you want to go digging- the 'evidence' that is quoted to justify blinding in cancer clinical trials on end points like PFS or OS are studies in pain or conditions like depressions where it is *known* that psychological factors play a role

the argumentation is classic pseudoscientific- this is a good book on the topic btw- amazon.com/Pseudoscience-… - and is basically an invalid deduction of a valid observation.

Then, wrt to trial recruitment, there is also the option to prey on patient communities. We've had some interesting experiences over the years....'could you send me your address book of #Melanoma patients' 🙄🙄🙄

And last but not least, there is the moral hammer. Pure desperation aside- there is a reason why clinical trials are run in countries without access to effective treatments for that condition, folks

Over time, we've come across several narratives, trying to sway patients to join clinical trials. It started with- THE HERO. Just to say- it was highly sensitive culture-wise.

And it went like this-

Then, we had the 'altruism wave'- first you get stage 4 cancer and then you become the mega-altruist while everyone else is making money, something the #EHDS is repeating right now. Not successful....

altruism is something that is granted, not something that can be demanded. Cancer patients are among the most lucid and generous people I've ever meet- but they don't tolerate lightly being taken advantage of.

And now the latest version 'patient-participation in science aka scientific co-creation' for 'just join any clinical trial'. We do *not* improve Science but uncritically joining any clinical trial that is coming our way

to cite Einstein 'insanity is doing more of the same and expecting different results'. The truth is: clinical trials that do not recruit get amended. Trial design is nothing but man-made- it is open to change

We owe our colleagues from the @EATGx HIV/ AIDS community the existence of surrogate endpoints and the fact that we can test 2 unapproved drugs in combination- trials are nothing but societally-agreed scientific constructs

There were times when patients were entered into clinical trials without being told. It seems so outlandish today that I didn't quite believe the gentleman sitting next to me on a plane in 2011- I didn't even ask for his contact details (wouldn't make THAT mistake today)

I had just been to the annual @ASCO meeting, trying to find options for my husband who was progressing on targeted therapy in #Melanoma. And it took me years to do the calculations (my husband died in between, so I had other worries)

Someone who was maybe 60 in 2011 and was on a study as medical student- that would have been 40 years earlier. The story felt like the middle ages- but it was only the 70ies then....

I'm born in 1976. So around the time I was born, patients in Europe were entered into clinical trials *without their knowledge*. A lot has changed then- but it's wise to remember that there are still some stuck in the ol' way of things...

And last but not least, the usual guilt trip 'but without this, there will be no new drugs'. Frankly, that is nothing but BS. If you look at how we did clinical trials 50 yrs ago and today - they are worlds apart. It's just an argument by those who don't want to change

The simple truth is: trials that do not recruit get changed. It explains why there is so much fluff talking patients into joining trials without asking the really important questions- forget that informed consent

Informed consents are there to make sure that a trial participant cannot sue the trial sponsor. They protect those running the trial, not those participating in the trial. That's why they are legalise but not scientific

In informed consent will go to great length telling you about ALL that could go wrong (so you can't say you didn't know)- and then you sign. It will however not tell you *anything* about prior scientific evidence (that might make you not join the trial, go figure)

An informed consent to a Phase 3 clinical trial will present it as if the reason to run this trial kind of fell out of the skies. If you want to find out what is actually known about the stuff they are testing- the informed consent is the wrong place to look

So 'informed consent' is a total misnomer- it's just intended to mislead people into believing they have been 'informed'. Indemnification would be way more appropriate actually- because for the information, you have to look elsewhere

Patients have to understand that you do not start a Phase 3 clinical trial out of thin air: there was a successful earlier Phase 2 or Ph1/2b study. Those will be published and presented at at public congresses

*however* that information will be withheld from patients in the so-called 'informed' consent. Any Ph3 starts with 'we got doubts' (never mind we just presented big at ASCO or ESMO) - so informed consents are NOT there to actually inform patients about what's going on.

Something that was actually valid information- and scientifically substantiated, not some biased fluff- would be 'we know x about the new substance, published in x and presented in y. And we know z about the comparator, published in z and presented in b'

at which point no sane patient would join an equipoise-violating trial so go figure why we have 'informed' consents without information....

And to make this *crystal-clear*: I am absolutely in favour of Science. But what we need is Science that is razor-sharp and Science that matters. Science is there to serve people, not to knowingly induce suffering.

'They would have gotten that anyway' is one of the lamest arguments for control arms in clinical trials I've ever come across- that's all that innovation-sciencey-innovation community can do in the face of suffering?!!

And- #COVID has shown beyond doubt that the community is capable to delivering cutting-edge Science at scale. Suddenly, there was no talk about 'this is not how this is done'. #NoExcuse #TheTimeIsNow