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.