You're right that there are ethical problems with giving sick people placebos, which is why new medicines are tested against the existing treatment wherever possible. The UK's NHS website has an easy-to-read guide to clinical trials.

[deleted]

There was a famous case in the UK a few years ago with a double blind trial that had an extremely serious reaction by the volunteers. Participants and staff went through the panic of not knowing who was going to react next, looking at each other, waiting for the next reaction.

Eight men took part, the drug had looked positive in animal testing but reacted very badly in humans. Here’s one article, you can use it to find more, possibly the documentary is online.

And there is an ethical dilemma, giving potentially healthy people something that might harm them. Risk versus reward, the greater good.

Most trials like this have interim reviews for exactly this reason. They take unfinished data at intervals - say, if it’s a 5-year study, they may look at 1 year in and so on - to see if the unknown treatment has already reached a statistically significant improvement over the standard of care (the usual control). If it has, the trial can be stopped early, and all the controls switched to the new med (or conversely if the test is significantly worse they can be switched back to standard treatment).

That way, you first ensure that everyone in your trial is getting at least the current best treatment, and are able to switch over as fast as possible.

It’s pretty unusual for new treatments to be that significantly better; incremental improvement is the norm (but like compound interest, small improvements every year for 50 years can lead to the dramatic improvement in, say, many cancer treatments that we see).

If you’re wondering why we even bother with clinical trials when we know something is going to be da bomb, we are really good at “knowing” wrong - even scientists deep in the field often have incorrect expectations. It’s probably much more common to stop trials early because the test med is worse than standard of care, than because they’re even better than expected.

[removed]

This is how it's done. That's also what you want to compare it against. It usually doesn't make sense to test a product that you expect to perform worse than what's already on the market.

There are numerous regulatory, clinical, legal, and ethical processes and procedures in place to ensure that the potential risk to someone who agrees to participate is minimized. In fact, there's too much for me to easily summarize, so I'll just mention a few of the protections that exist:

• Pre-clinical Testing: Before a drug can be tested in humans, it must undergo rigorous testing in vitro and in animals to identify any risks that might exist. Then regulatory agencies (e.g., FDA and EMA) review the data and either allow or deny test in humans.
• Clinical Trials: There are 3 phases of trials, beginning with small trials with healthy subjects and eventually larger trials involving numerous patients with the disease in question. At every step, safety and efficacy results are analyzed for potential risks and, if necessary, studies are terminated.
• Communication of Risk: Physician investigators and potential subjects are given detailed information about the drug, including risks and benefits, if any. For physicians, this is in the "Investigator's Brochure" and for subjects it's in the "Informed Consent" form. In both cases, the documents must be read, understood, and signed.
• Safety Monitoring: This is an onging process throughout clinical trials during which information about any and all adverse events is continually collected and evaluated for any signs issues.
• Study Design: This is the area that may address your question more specifically because depending on the disease being studied, trials may differ. For cancer trials specifically, placebos are typically not used unless they are given in addition to the best available therapy that exists. Results are then analyzed to determine if there is an additional benefit to the drug beyond what the current treatment alternatives are, and there is no (or very little) additional risk to the patient. Results are also analyzed during the trial (i.e., an interim analysis) to ensure that patients are experiencing some benefit (or the study is terminated due to lack of efficacy) and not experiencing unacceptable adverse events (or the study is terminated for safety).

There are still more safeguards in place, but I hopefully this provides the gist.

We use casual inference, a type of math that is basically allowing us to establish causal relationships based on actions we could have taken but didn't, and give everyone in the trial the drug. We can then compare what "would have happened" with what actually happened.

[removed]

[removed]

It depends on the severity of the disease and type of medication proposed. As others have said, preclinical testing is required before human studies are allowed by the governing body. I am mostly familiar with how this works in the US under the control of the FDA so I will use them as an example, but similar approaches are taken by the various governing bodies in respective regions/countries (e.g. EMA).

A package is developed for your proposed study to the FDA which will include all information known about the medicine, such as molecular structure, mechanism of action, biological models used for study, how the drug will be manufactured and quality tested, relevant animal studies on safety (and ideally efficacy), etc. There is typically discussion with the FDA before submission and after on what would be satisfactory for review so that everyone gets to the goal quicker. The goal being - testing potentially useful therapies in the most safe and ethical way possible.

For the study design itself, very few studies are actually testing drug vs. placebo. Similarly, very few phase I studies are actually tested against healthy individuals. Everything depends of course on the disease. If it's a very rare disease, you may not be able to recruit enough diseased individuals for the safety portion so you may add some healthy volunteers. All trials will be against standard of care. So a placebo will be used only if there is no other care available.

Take cancer for example. If you have lung cancer, there are already multiple lines of treatment available. A study will thus be designed either to be administered to patients after all previous lines failed, or to directly compete with the last line of treatment. The reasons for one vs the other are complex and variable based on the disease, commercial landscape, mechanism of action of the drug, etc. So a person in the study is someone who has had chemo, has had a checkpoint inhibitor, maybe even radiotherapy and nothing has helped. At this point they can get on the study where they are informed that they have ~50% of getting a new untested drug + standard of care and 50% of getting placebo + standard of care (could be more chemo or maybe nothing else, depending on what's available).

If they consent, then they get on study where no one knows which one you are getting. If you are clever and study design is poor, sometimes you can figure it out based on side-effects but really, you should not be able to know.

As far as safety, there is even more going on. All that preclinical work provides a rough estimate of what dosage is safe/efficacious. Those estimates are based on years of data we have of how different classes of therapies translate between say non-human primates and humans (the most common but not only comparison used). If say some primates started getting adverse reactions at 15mg/kg dose of a biologic, we know that it will roughly translate to say 12mg/kg in humans (numbers made up). So we expect to see adverse effects at 12mg/kg. The study will start administering the drug at 0.1mg/kg however, significantly lower than expected threshold. A few people will get that dosage, and if there are no adverse effect, then the amounts will slowly move up until max dosage in study design or serious adverse effects are noticed. So the first 3 people may receive 0.1mg/kg, next 3 get 0.3mg/kg, next 3 get 1mg/kg and so on. Let's say the expected efficacy window is not until 3mg/kg. It really sucks for the first 18 people (3 dosages x 3 people x2 for drug/placebo), but safety comes first. In many studies, those people would be allowed to re-enroll later to receive therapeutic doses if it's safe. Unfortunately for things like cancer, it's unlikely many of them will have survived until that point based on disease progression (remember that these patients have already undergone all known therapies).

Once safety is figured out, then you look at efficacy. If the efficacy is better than standard of care, then the drug gets approval. If you tested on patients that have previously had 3 lines of therapies and you show that you provide benefit vs 4th line (or if there isn't one) you become the 4th line of therapy. If you think your drug can help people earlier in the progression, then you can design another study to go against 3rd or 2nd or 1st line therapy. Safety is likely less of a concern (that's been established in your earlier trials) so you just do phase II/III studies.

COVID vaccine trials were a bit different from what I described but nothing special. Since they are preventative studies, they were not tested against other therapies, although of course people that got COVID during the trial were treated with best practices. Similarly, everyone was told to continue using all of the precautions (social distancing, masks, hand washing, etc.) regardless of whether they got placebo or vaccine (again, no one knew what they got). Most vaccine trials take a hell of a lot longer because the disease prevalence is low and you need to wait until a statistically significant number of cases is seen in the placebo population, but with COVID that was not an issue as it was endemic.

>At this point, I feel like there's an ethical issue because are we not knowingly taking individuals with a life threatening illness and deliberately giving them a non treatment?

They wouldn’t be given no medical treatment at all. The control group typically gets whatever the standard treatment is for that condition, while the experimental group gets the new treatment (sometimes on top of the treatment that the control group is getting).

The question being asked by a clinical trial is rarely “does this drug work” it’s “is this drug better than the standard of care”. That’s kind of why the the staunchest defenders of Ivermectin for Covid treatment are wasting their time. It doesn’t really matter if technically there is some slight biological impact on the virus. If it isn’t better than current treatments (which are quite a bit better than they were in Spring 2020) than we have no use for it.

Keep in mind that many times these are tried on people who are otherwise terminally ill and going to pass anyway.

If someone came to you and said "this is experimental, we don't know what the side-effects are exactly, but if you are interested in trying it, it might be your last resort", you'd probably take whatever medication they offered you!

[removed]

There are some interesting points of view related to the bodies of power that produce, regulate, and price potentially life-saving medications. "Challenge Testing" is discussed at length, along with phase-4 trials.

https://www.youtube.com/watch?v=awIRM3-9JNc

The clip is a bit long; you can watch it at 1.5X speed or skip the bits that are not of interest.

[removed]

Hi, I am a clinical trials results analyst.

All clinical trials do not require a placebo control. Many trials are looking at "how something changes from baseline", in which case we already have baseline data. Additionally many interventions are "how is this in addition to standard of care", so it's not like people are getting no intervention.

This is a common misconception that every single clinical trial must be double blind placebo controlled. We have robust historical data on things.

[removed]

Also why consent and making them aware they may be taking a placebo is important as well

[removed]

[removed]

[removed]

[removed]

I would recommend this episode of Radiolab: https://radiolab.org/episodes/great_vaccinator

About Maurice Hilleman who created over 40 vaccines. If I remember correctly, they talk about trials for the polio vaccine and how hard it was knowing that some of the children that were in the study who got the placebo would die, when if they had gotten the vaccine they would have lived. Roll of the dice.

It's not a comprehensive examination of the ethics, but interesting hearing their first-hand experience grappling with it.

For truly placebo controlled trials where standard of care is either absent or provided to both the test and control group, some studies will use a "crossover" design where participants who received placebo in the first phase of the trial will be offered the active drug in a second phase of the study. So all participants get the drug but the longitudinal data collection is the real test of efficacy (looking for inflections).

Please do be aware that Ivermectin has been reproducibly shown to have no effect against COVID 19 when put to well designed clinical trials.

• Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19 A Randomized Clinical Trial. JAMA 2022
• Effect of Early Treatment with Ivermectin among Patients with Covid-19 NEJM 2022

In addition to some of the other great comments here, it's helpful to adjust your prior beliefs about new treatments we are testing. Even with promising pre-trial data, many will not work in humans, most that do have only slight benefits, and only rarely do we see large benefits. And almost all have some potential side effects. So whatever the control is (placebo or standard of care), it's often not the "worse" arm.

[removed]

[removed]

[removed]

I believe one of the measures that Donald Trump implemented at the federal level when he was president was the Right to Try. Under this rule, terminally ill patients have the right to access experimental therapies (drugs, technologies, etc.) which have not yet been approved by the FDA. I think this was a huge victory for dying people because at the rate at which medicine is advancing, I'm sure a good many of these as yet unapproved therapies will turn out to be effective.

Ehhh, Right To Try has some very valid criticisms. It is largely a political move to reduce the oversight of the FDA. We already have the Expanded Access Programs, and Right to Try removes oversight and liability of treatment, which is dangerous when patients are desperate. There’s also no requirement to report about outcomes from Right To Try, so if you get unfavorable results you can just hide them away and only present the good ones - changing how it looks.

Expanded Access is required by law to be approved or denied in under 30 days, and approves 90% of applications, and requests changes on the rest. It is rarely fully denied.

Right to Try is the first step in trying to remove federal oversight from medicine. It removes any right of patient or family to sue should malpractice occur (a right you retain in Expanded Access).As I said before there’s no reporting requirements. It has no agency running the program, so no one to go to for complaints. Expanded Access requires experimental treatment to be provided at cost, Right to Try technically has the same rule, but with no reporting requirements and it specifically having no government agency to enforce its laws can easily price gouge desperate people for something unknown to work without worrying they’ll get caught.

I’ve got multiple chronic illnesses. It’s unlikely I’ll make it to retirement. Laws like Right to Try scare me because I could very well wind up desperate for experimental treatment, and taking steps to remove oversight puts me in danger. There are already politicians clamoring that if Right to Try works, we should officially remove FDA from oversight of experimental treatment and do away with Expanded Access.

How (if at all) would you make that (double) blind though? For "normal" double blind with placebo, this is as "easy" as making a placebo that resembles the real treatment. But with existing methods this sounds like it could often be obvious which one you're getting, no?

An example of what I did for a project was that we know patients with AF need to be anticoagulated and the best thing at the time was warfarin so you compare warfarin to dabigatron instead of comparing dabigatron to nothing. Your control changes to the best current treatment

I work in the pharma industry and despite not dealing directly with trials, I need to analyze them sometimes. Usually, you start testin these new medicines as part of a combination with stablished approved drugs OR in patients that didnt respond well to conventional drugs. And most likely, these new medicines usually are approved as part of a combination or in types of cancer / advanced cancers where "there is not much hope". With time and with the increasing knowledge, these drugs can later be approved as monotherapy.

[removed]

Right-to-try is a niche law championed by the Goldwater Institute, a libertarian think tank. Contrary to what Goldwater suggests, right-to-try only covers a small number of niche therapies, namely: last-line personalised medicines (based on analysis of an individual's genetics) for terminally ill patients.

It doesn't have much bearing on medicine though, because the overwhelming majority of such drugs already fall under FDA's compassionate use regulations, and patients access these drug under those existing guidelines.

There have been a few niche cases where right-to-try allowed someone to buy an experimental drug that they would not have otherwise been allowed to buy under compassionate use guidelines. But I want to emphasize that the numbers are tiny.

Like anything in politics, most of the Goldwater Institute's arguments for right-to-try are pure propaganda, although I do think there is an interesting philosophical debate to be had on right-to-try. Nonetheless, the reality is this law has no virtually effect on the landscape of medical science.

There's a medical documentary on YouTube, called Drug Trial Goes Terribly Wrong: Emergency at the Hospital on a channel called Real Stories.

It's about a drug trial in the UK for a possible treatment of leukemia, which had positive results in monkeys. The reactions to the drug were severe swelling (newspaper called one guy the Elephant Man), multiple organ failure, high fevers, and several fingers/toes were amputated. Lasting effect is possible fertility issues. There was a police investigation to ensure that the drug wasn't tampered with, patients weren't intentionally poisoned, correct dosages, etc.

Many studies are not blind as that would simply be impossible, unethical, or both. But with most things like cancer you don't really have to worry about things like placebo effects as you have objective measures like tumor growth.

[removed]

My biggest ethical concern is that there is an extreme focus on medication for acute and chronic treatment, but you rarely hear anything on actual cures

Yes, it's very hard to find a cure for things, this I concede, but a cure is a worse business proposition over medication for chronic symptom suppression.

[removed]

No, the incidence you mentioned was not a double-blind study. It was a Phase I clinical study. The first test of a drug in humans. This test is done to test the safety, the side effects, the best dose and the best formulation method for the drug. All probands in a clinical phase I study are healthy individuals without the disease in question and all of them receive the drug (after intense studies in animals).

A good example for those crossover design are the Covid vaccines. A friend of mine took place in the test of the vaccine. She was on the control group and was offered the vaccine after the end of the trial.

[removed]

[removed]

If the standard of care (SoC) and trial drug have different administration routes, then sometimes there can be two placebos involved to mimic either the SoC or the trial drug. E.g. Cohort A will receive SoC pill and a placebo injection, Cohort B will receive a placebo pill and trial drug injection.

Yes, exactly this. I have aggressive MS and have been looking into clinical trials, and this is how one of them was set up.

[removed]

I think its been fairly well explained already, but I'm happy to share from a first (well second) hand view. We have two sons with Duchenne Muscular Dystrophy, and our oldest is on a drug trail. Our youngest was too "healthy" to qualify.

Its not one of the gene editing trials, but an anti-inflammatory that shows some promise. He's been on the trial for nearly 3 years now, the first year was double blind. We didn't know if he was getting a placebo or the study medication, and we still don't know, and won't until at least one year after the last boy gets through that first year. This keeps everyone in the trial completely blind for the first year. However, as noted, in this trial (and most of the other DMD trials I've followed), put everyone on the drug after a certain amount of time, assuming the drug is showing its effective and tolerable.

There are a lot of ethical questions around drug trials, but the controls in place try to address those and balance treating people with the condition and determining if the drug is truly effective. Both are priorities, but you can't ignore either one.

The only way it could be studied is by use of placebo and a double blind study. You have to collect data that is unbiased. For participating in such a study at participants understand the possibility that they may receive a placebo. It may not be pretty but it's the best way we have to develop new treatments for other people down the road.

[removed]

[removed]

[removed]

Don't test against a placebo. Test against the currently most effective treatment to see if the new thing is better.