No clinical trials on pregnant women -> discrimination?

[deepwatersolo]

I don't have much time the next couple of days, but I stumbled over a thread on Twitter have to leave this here, as it struck me (and frankly irritates me to no end) and I'd appreciate outside perspective.

Science journalist Erin Biba on Twitter makes a good point about women having long been ignored by medical studies.
twitter.com/erinbiba/status/1115337518294228993

'Wanna hear something crazy? It wasn't until 2016 that the National Institute of Health required that medical research include male AND female mice as well as male AND female tissue cells in drug development. Before that female mice and female tissue cells didn't need to be used. The NIH also didn't require that women be included in clinical trials for drugs until 1993.'

But then goes on to say:
'Currently there are NO clinical trials for any drug done on pregnant women. Pregnant women are excluded from ALL clinical trials. If a woman in a clinical trial becomes pregnant she must exit the trial.'

And finishes with :
'If you're wondering why women are so susceptible to snake oil and pseudoscience there's your answer. It's because medicine has ignored their health and they're desperate for any possible treatment.'

I cannot overstate, how galling I find it, to bring the issue of 'no trials on pregnant women' into this and imply they are overlooked. Fetal development is quite sensitive to drugs, and I doubt any well informed woman who is not desperate for money would risk this, considering she will probably be stuck with the consequences this may have on her pregnancy & resulting child.

From my perspective it very much looks like an upper class woman - who would never dream of participating in such a trial when pregnant, because risks are too high - bemoans the fact that less privileged and informed women aren't persuaded to play guinea pig for her.

(Also, are women actually so disproportionall susceptible to snake oil? That comment also rubbed me the wrong way. )

Am I getting this wrong? Am I reading too much into this?

Its illegal to experiment on a human fetus in utero. The fetus cannot give consent.

Drugs can be tested on chick embryos to see if they are mutagenic or teratogenic.

that at a bare minimum, women becoming pregnant on the trial should stay in the trial - because the alternative is worse.

It’s not, because the individual result for that one pregnancy is unknown and potentially catastrophic. It would be sacrificing an individual for dubious data. As powershower rightly says, the number of pregnant women in the trial is insufficient to give the power to find any real signal anyway, so it’s all risk and no benefit.

Teratogenic effects are explored mainly in animal studies. These aren’t perfect but they’re the best we have. If, after a history of safe exposure in animals and no adverse effects in accidental ecposures, the drug seems to be ok, it will cautiously be used, mainly off label.
If you look at the pregnancy categories very few drugs are the safest, simply because we can’t guarantee no effects. We can only say we think it’s safe.

It’s not ideal but there’s no way to ethically test such drugs.

When it comes to testing drugs on children many of the same things apply. Paediatric trials need to have the risk/benefit calculation heavily towards benefit, which is why there are fewer lifestyle type drugs and more trials for things like chemotherapy combinations. The ethics hoops you have go through on kids trials are (rightly) extensive.

Also if you becaome pregnant, even if the drug was 100% safe, you’d expect to see changes in many lab / physical values simply because of the pregnancy. That could skew the dataset.

I think it’s really problematic that we avoid clinical trials on pregnant women for so much stuff. Pregnant women still take drugs and without trials we don’t know what impact they have. We have the same problem with children - trials are not common and because of that we don’t have the same understanding of drugs potential for good or harm.

I disagree with pregnant women simply staying in trials when they inadvertently (from the trial perspective) become pregnant. There needs to be more consideration and risk assessment than that. But the argument that there are many reasons drug effects could differ in pregnant women is pretty much the argument used to keep women out of clinical trials previously. If drug effects can differ that’s a reason to study them, not ignore them.

@BoomBoomsCousin There has to be demonstrable benefit or it won't make it through ethics. Nor should it. It's erroneous to say we don't do clinical trials on pregnant women. We do, we just don't do investigative drug trials. We do capture post-approval data. The new MDR compels companies to capture post-market data now. And that's how it should be. When drugs are new and we don't have an established safety profile in healthy subjects it would be ridiculously unethical to include pregnant women or any other vulnerable group.

Who pays for the studies? Even in dogs the datasheet for most licensed drugs says "The safety of this drug has not been established in pregnant or lactating bitches". Much cheaper for a drug company to just slap that arse-covering sentence on the datasheet and forgo the relatively tiny extra revenue from the drug's use in pregnant animals than to pay for separate studies.
And that's a much easier scenario than humans ie no ethical issues with foetal consent and a much, much , much smaller risk of a PR and legal finances disaster if a drug is not as safe on pregnancy as they thought.

usually the pharmaceutical companies pay.
trials are expensive!

however, they are usually done by independent companies and participating hospitals and are very strictly controlled

It wasn't until 2016 that the National Institute of Health required that medical research include male AND female mice as well as male AND female tissue cells in drug development. Before that female mice and female tissue cells didn't need to be used

She's being disingenous bringing this into it too. Or rather cherry picking. There are lots of situations when all female animals are used. Generally all female pig populations are used for many trials.
The reason for doing it is to exclude differences in outcomes due to sex.
And yes, testing on pregnant women is testing on unborn foetuses - highly unethical.

@Blewbird - there has to be demonstrable benefit for any trial to get approved doesn't there?

I thought post-approval data was used in a different way to clinical trial data? Is it sufficient to enable a drug to move from being off label to being recommended?

post approval data can be used to extend a marketing authorisation.
if studies are well managed and the data generated is extensive and well structured.

That sounds promising green. May be trials aren't so important then. Do drug companies get enough post-approval data from pregnant women to be able to do that for them? And are they required to try if they have the data?

no companies cannot be forced to apply for registrations for paediatric use or use in pregnant women.
but if the need is there, the data is good then it's probably of commercial interest.
trials before authorisation are very very important and will keep being required.

I don’t think the law would allow for multiple unborn babies to be put at risk in this manner? It’s surely not ethical for a parent to consent on the babies behalf?

Children don’t generally participate in drug trials, the exception being when they have a disease or condition that isn’t responding to conventional drugs. Even then they are closely monitored by both the testing team doctors and their own consultants and the potential benefits have to be significant.

It’s not comparable to the standard pre-licensed drug trials where adults are compensated for their time and risk. Lots of my (male!) mates used to do this for cash back in the 90s.

Betty if it's unethical for a pregnant woman to consent to a trial because she is carrying a fetus, that implies it's unethical for her to take any off label drug.

@BoomBoomsCousin the ethics are completely different for an investigative drug for which we have extremely limited safety day and an approved drug being used by a doctor to benefit that specific patient. Doctors can and do use drugs off-label all the time. Clinical trials for investigative drugs are largely funded by drug companies hoping to win approval for financial gain. To expose an unborn child to an untested drug for whom there would be no benefit but huge risk is completely different than a doctor weighing up the risks/benefits for a specific mother/baby.

Blewbird I don't mean to argue for pregnant women to be included at that stage, I get that waiting until after the drug has been approved for others makes sense. But that doesn't alter the fact we don't seem to do the investigative work for pregnant women (or children) after it's been shown to be acceptable for others. And that seems quite unreasonable.

No, it doesn’t.

If the pregnant woman has a condition that warrants being medicated using an off label drug, a benefit/risk situation exists, and if the woman were to become seriously ill, the baby’s life would be at risk, along with the mother’s.

Clinical trials on healthy pregnant subjects are of no benefit to the baby. That’s the unethical bit.

If you're wondering why women are so susceptible to snake oil and pseudoscience there's your answer. It's because medicine has ignored their health and they're desperate for any possible treatment.'

Here’s my take on this: it’s twofold.

Firstly, there are a set of diseases/conditions that are more prevalent in women but are under researched and poorly diagnosed. Many of these conditions have quite vague symptoms. Endometriosis is a good example. Far too many women are going to their doctors with symptoms and being told to go home and have two paracetamol and a lie down.
I have experienced this myself, being fobbed off for something that actually turned out to be serious, and I’m a scientific/clinical professional who speaks the lingo. So women are poorly served that way and may turn to alternatives.

Secondly, women often somatise and internalise their emotional problems. Chronic depression for example - it’s seen as purely mental but almost everyone with chronic severe depression has physical aches and pains as well and these are real, but are often dismissed as well

What are the ethical and practical considerations for trials on women who are unable to get pregnant? Is this something pharma companies actively do? I'm thinking of both young women and post-menopausal women.

In what sense? Including them in regular trials or trial for actual infertility interventions?