MRNA and personalized cancer vaccines are showing tremendous potential in a lot of cancers: https://jakeseliger.com/2024/04/12/moderna-mrna-4157-v90-new.... GBM is particularly gnarly; one of the few other treatments in trials I'm aware of is DCVax: https://www.uclahealth.org/news/article/fda-approval-brain-c....
One big problem is the FDA's slowness regarding treatments for otherwise fatal diseases like GBM.
What do you mean by slowness? They can't skip all the safety stuff!
Why is it that so many people need to die in the name of safety?
Because you can't honestly presume to know the outcome of a clinical trial of an untested product.
So run the clinical trial, advertise the product as untested and dangerous-to-lethal in the meantime, and let people make their own choices?
Smoking is already advertised as dangerous-to-lethal and look how effective it is in preventing people from smoking.
In huge oversimplification some crazy or fraudulent people will claim it cures blindness or cold sores, some other people will believe them and will have to deal with the real danger-to-lethal consequences, with the rest of society paying for their medical care afterwards.
Pretty effective.
In Australia throwing a few diseased lungs on the packs and increasing public awareness has seen usage drop from 35% of the population in 1980 to 11% today.
Not all the drop is purely related to advertising, price increases and restricting sale to out of sight locked access in shops have also helped.
https://www.tobaccoinaustralia.org.au/chapter-1-prevalence/1...
From another perspective it took massive change in generations and over 40 years of campaigning and it is still a problem for the 11 percent.
Knocking back smoking by two thirds has saved billions for the national health system.
On the books, totally worth it.
Sure, but imagine doing the same effort that likely requires critical mass for actual adaption on small obscure medicines and illnesses.
Are they addictive? Then regulate them as addictive drugs.
Are they not addictive? Then it seems a stretch to compare them to cigarettes.
And cost billions in state pensions. I'm not suggesting that's any sort of counterargument but the costs should possibly be offset against other types of end-of-life care.
Sure it's effective if you're looking at the reduction rate of existing number alone. But reverse the problem and the very big effort of warning about dangerous-to-lethal stuff still doesn't stop 11% of people from doing so. That's quite bad, when you think about going from zero (you can't willy-nilly use untested medicine) to 11% of the society.
I have a new drug. It's called aceite deserpiente.
It's a cure for lyme disease, impotence, ALS, chronic fatigue, cancer and aging. Trials are pending but what are you waiting for, do you want to die for lack of trying? 10k/dose.
Nice name choice for your example; I was thinking of paracetamoxyfrusebendroneomycin myself, yours is better.
See, the thing is, I can just choose not to buy it.
This already happens, it's called 'compassionate use'
https://www.ema.europa.eu/en/human-regulatory-overview/resea...
You've proposed a nonsensical epistemic framework. Knowing isn't binary.
You should have a probability distribution over possibilities, based on your experience with similar drugs, expert hunches and animal trials. You then use that to estimate risks and benefits. Then compare this risk-reward profile with the risks of doing nothing -- in this case, near certain death from brain cancer.
This "can't presume to know" framework is just sophistry. And I think deep down you know that, if you had a death sentence from brain cancer you'd be begging them to let you in the trial even if they "couldn't presume to know".
You’re missing that we have treatments with known risk/benefits vs research treatment X with undefined risk and reward.
It’s extremely challenging if not impossible to obtain informed consent in this situation.
We’ve been through this before where a fancy new treatment with promising early/lab results usurped conventional therapy only to later be found inferior.
Earlier TKIs and NSCLC are a recent example that comes to mind.
It's not undefined, though. That's the point I'm getting at. There is no binary of known and unknown. A tentative picture exists based on animal trials and expert judgment. That tentative picture informs an estimation of the risk to reward profile which is then the basis for an informed decision.
This is decision making under uncertainty. It's bad practice to say that uncertainty always means "don't do it".
Because nobody's counting deaths from "not doing stuff". Everybody counts deaths from actions done (things built, products sold, meds taken) but nobody's counting losses from things (like meds) simply missing.
In effect we regulated doing stuff so much in the name of safety that we ended up in an infinite "analysis paralysis" mode where the you have to absolutely prove zero harm from new products/services while completely ignoring the harm the current status quo does.
See current debates over AI, self-driving cars, and of course, meds.
What do you mean "nobody's counting"? Excess mortality from delayed or denied treatments are measured all the time in medical research. How do you think these drugs get made in the first place? We just had a pandemic where a calculated decision was made that the small risk of myocarditis was massively outweighed by the benefits of mass vaccination. When was the last time you saw a drug ad that didn't list potentially fatal or debilitating side effects? "We need something to solve problem X even if it carries risk Y" is absolutely par for the course.
Not just safety, but also effectiveness. FDA checks whether the trial(s) to prove the drugs effectiveness were run correctly (eg. the randomization, the control group, etc.), if the statistical analysis was done right, if the endpoints are appropriate (response to treatment is not always objective) etc. etc.
The FDA (and EMA in Europe) are the only thing that protects desperate patients from fraudsters, charlatans and pharma-companies just looking for a return on their investment.
Ideally this is what would happen. In practice there have been very public failures in being overly cautious and aggressive.
While Aduhelm reduces Aβ it has no clinically significant effect. Still, the FDA approved it. Mercifully it'll be discontinued in November.
The covid vaccine represented a huge policy failure by the FDA. While people in nursing homes died in droves we got small clinical trials. When you've got 90 year olds in a congregate setting facing a 50% chance of death, maybe it's time to stop pretending thalidomide may be lurking around every corner. The pediatric trials were just as bad. Due to their sizing it was statistically impossible to detect rare adverse effects. Yet, vaccination was delayed for children while these fruitless trials ran.
In my own experience I had a low cost, high throughput covid testing protocol ready to go in early April 2020. It took the FDA until August 2020 to provide templates and another month to grant emergency use authorization. We could've drastically ramped up testing when it was needed most of the FDA has treated an emergency like an emergency.
Is it your opinion that trials for the Covid vaccine should have been skipped to vaccinate people earlier, or that proper trials should have actually been done to know the efficacy and safety before testing it on the public?
Either would've been preferable to what was done. Waiting on a provably fruitless trial in the midst of pandemic is regulatory homicide.
Throughout 2020, more than 9% of all people in nursing homes died of covid. Depending on age case fatality rates were upwards of 50%. The vaccine should've been offered to these people on a compassionate use basis. Even at the time it was obvious that actual harm posed by the virus vastly outweighed any hypothetical risk of adverse vaccine reaction. Drastically expanding the vaccinated population through compassionate use would have rapidly provided efficacy and safety data.
That's just about most difficult population to determine primary cause of death for. Most people in nursing homes have multiple comorbidities and a long list of medications. Its easy enough to know when someone died with Covid, its much more difficult (if not impossible) to know after the fact whether that's what caused their death or if the infection began after an existing condition worsened and weakened their immune system further.
That wouldn't have helped get efficacy or safety data for the general public though. Vaccinating that population could absolutely have helped determine efficacy for that population and I agree it feels like a reasonable action given the potential risks for that population, but the data wouldn't be useful for the general public that are younger and/or in better health prior to infection.
Nursing home quality, COVID-19 deaths, and excess mortality https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8776351/
At the peak, excess nursing home mortality was nearly 6000 per week. Quibbling about "died with covid" versus "died of covid" isn't a useful exercise. Dead is dead and the excess mortality came from somewhere.
It isn't quibbling when the specific topic is whether or not to treat a population with an untested vaccine (assuming the trials were skipped for at risk populations as proposed above).
In a general sense, I totally agree the "with" versus "of" debate isn't useful. But when considering giving an at risk population an untested vaccine, how is that not important? Any intervention could have downsides, and more importantly an preventative intervention for a secondary infection may not be worth the risk depending on the risk profiles.
One tricky question that would have to be answered is whether the excess deaths were related to changes in nursing home treatment and general conditions. Nursing homes were effectively locked down in many areas, reducing human contact and potentially negatively impacting care. Vaccines would have no impact there, and if the untested vaccine has negative side effects we would have only made things worse.
Vaccine risks tend to be very quickly detectable. The phase three trial timing was driven by needing enough infections and there weren't enough.
People in nursing homes died from untreated illness. They were completely locked down, and isolated from friends and family. They weren't allowed to be transported to actual hospitals. Anyone with simple bacterial pneumonia was left to die.
In the UK, nursing homes were discovered to be sedating patients and not administering water and nutrition. I wouldn't be surprised to learn the same happened in the US.
If something would've gone wrong with rushing the vaccine like that it would've given the anti-vax people a massive boost and the vaccine refusal rates would've skyrocketed.
The refusal rates were already too high with anti-vax people making up lies/distorting data. If they actually had real data things would've been much worse.
Something did go wrong; of the 3 vaccines the FDA approved, 1 of them had to be recalled due to causing fatal blood clots.
How do we define an acceptable refusal rate? The vaccines were largely untested and given under emergency use authorization. Shouldn't it be reasonable for people to choose for themselves whether to take part in the vaccine campaign or not, especially when we can't provide solid data to support safety or efficacy?
At the end of the day, in my opinion, there is no magic number for vaccine acceptance that is a metric to define beforehand. Refusal rates are a backward looking metric only and simply reflect the willingness to participate and trust in the general public.
How about telling the public the truth? Say something like, "This particular vaccine has not been tested up to normal FDA standards. It may not be as safe as other vaccines. But we are convinced that it will do more good than harm, given the danger of Covid for the unvaccinated."
You could let the public make an actual decision based on actual information, rather than telling them little, projecting false certainty, and then trying to force them to do what you think is the best course. I mean, look, not everyone can be treated like adults. But I think the majority of people can. Tell them the truth, and let them decide.
The FDA approved it via accelerated approval. The intent being "allow access to promising medicine while additional data is collected".
"The FDA (and EMA in Europe) are the only thing that protects desperate patients from fraudsters, charlatans and pharma-companies just looking for a return on their investment."
EMA has some people that were recruited from Big Pharma.
Remember the pandemic? The FDA had safety and effectiveness data by end of August for the vaccine and were unprepared to do an analysis in less than a few months. Nor did they consider drafting the party boys of the Ozarks to get the efficiency data faster. As a result the winter of 2020-2021 saw thousands of preventable deaths.
There's also the part where distribution was done in a way that deliberately killed people so that racial equality goals could be met. Perhaps the worst example of this kind of thinking were teachers in SF getting vaccinated but school not starting again.
True for _all_ 'safety stuff.' However, safety requirements for late-stage patients with very few other options ought to differ from safety requirements for mass adoption.
They already do.
Do they not already?
I mean, if you have an aggressively terminal disease with no known cure, I think the risk-reward calculus is somewhat different from the average drug
The issue, as comes up incessantly in all manner of situations, is the way we regulate drugs as a whole. A lack of safety testing should mean a higher standard of informed consent should be used, not that it should be illegal for someone to get ahold of it
I see lots of benefit to regulatory agencies controlling what claims can be made about medications and holding people selling them to account for quality control failures. Agencies preventing consenting adults from making their own risk-reward calculations does badly on both principle and outcomes
While I agree that my calculation on safety would be different for a terminal illness for which no cure exists, we still need to be careful. The very nature of this situation creates desperate people who are willing to ignore a simple warning label in favour of hope.
Any system / regulator still needs to force companies to prove their treatment has the claimed effect, and block any that simply don't. On safety, I think there's more wiggle room, however. Treatment here can be based on likely ill effects vs the known effects of the illness of the patient.
Nah, I actually think the effectiveness standard is far worse than the safety standard due to what a "block" means and how "effectiveness" is tested.
An RCT, the gold standard by which medicines are often tested, can easily show a negligible effect size because of the vast confound space of individual differences. A medicine that works perfectly for many of a study's participants will be considered "ineffective" routinely
And hey, in cases like that I think the regulators should absolutely have the power to say "selling this without explaining these caveats is criminal fraud", but not that people can't try the drug anyway if informed of the risks and low likelihood of success as determined by the agency's analysis
In an effort to standardize process and appease large incumbent industry players (often, as here, by erecting enormous entry barriers in front of lucrative markets), we frequently create metrics that are too blunt and remedies that favor governments flexing disproportionate power over the lives and choices of individuals
Yes, the system works, and we have very little poison being sold as medicine.
The issue is that with some illnesses/stages, we do not have a good treatment, and a lot of people would like the calculus to be different. We do have compassionate drug rules, but they're a pain for many people.
I'm not in that situation, and not sure how I'd react; but I can see how, having an incurable illness, with tons of suffering or a few months left to live, I might want to try everything. Hydroxychloroquine, Chinese acupuncture, herbal remedies, and experimental treatments.
You seem to imply that the only possible source of slowness if safety, which might not be the case (I've no idea).
One can be fast and safe, it's just that requires spending a lot of money.
It's analogous to cache prefetching and branch prediction in CPUs, except the cost of bad predictions is measured in millions of dollars rather than tens of CPU cycles, and also that the predictions are much harder.
Not that it should matter, but they are also VERY expensive. There is a new standard for NCPDP (how pharmacies and payers send transactions for payment) coming out in the next few years called F6. One of the big changes over the current standard is drugs that cost more than $1M can be processed in a single transaction. https://www.cms.gov/files/document/fact-sheet-11-2022.pdf